Section 11
Section Editor: /BSJOEFS
1 Singh
146. Management of Hypertension in
Chronic Kidney Disease
Mritunjay Kumar Singh
147. Prevention of Progression of CKD—What Is New?
Krishnaswamy Sampathkumar
148. Lupus Nephritis—Current Understanding
and Management
Krishan Lal Gupta, Joyita Bharati
149. Diagnosis and Management of
Nephrotic Syndrome
Deepti Sharma, Sandeep S, Gopikrishnan R
Section-11.indb 945
Nephrology
150. Dietary Salt and Hypertension
PP Varma
151. Newer Avenues in Management of CKD Anemia
Manish Rathi, Rudreshwar Prabakaran
152. SGLT2 Inhibitors—Mechanisms of
Cardiorenal Protection
Ashwini Balasaheb Gadde, Vijay Kher
153. Optimizing Renal Care in Elderly
Narinder Pal Singh, Rahul Mishra, Shaurya Kaul
154. Understanding the Role of Vitamin D
in Diabetic Nephropathy
Srinath KM, Spoorthy Rajj, , Manjunath S Shetty
28-01-2021 12:25:18
Section-11.indb 946 28-01-2021 12:25:18
 CHAPTER

146 Management of Hypertension in

Chronic Kidney Disease
Mritunjay Kumar Singh

Abstract 
The relationship between hypertension and chronic kidney disease is phenomenal hypertension (HTN) which is considered
as most important modifiable risk factor for chronic kidney disease (CKD). Personalized and individualized HTN therapy
using standardized office BP and home BP monitoring hold great promise. Angiotensin converting enzyme inhibitor (ACEI)
or angiotensin receptor blocker (ARB), Calcium channel blocker (CCB), appropriate diuretic therapy, dietary salt restriction,
and ensuring proper adherence to therapy make up the foundation for the treatment of HTN in CKD.

Introduction peripheral resistance which is due to autoregulatory

Studies from India and abroad have provided concordant
data on high prevalence of chronic kidney disease (CKD)
worldwide. Up to 1 in 10 people world wide has CKD. It is
a silent killer like other metabolic diseases and engages
major human and economical resources. Association
of CKD and hypertension (HTN) is bidirectional. There
is a cause and effect relationship between them. HTN
is considered as most important modifiable risk factor
for CKD. Managing HTN effectively not only retards the
progression of CKD, but also reduces the cardiovascular
risk significantly.
Pathophysiology of HTN in CKD1-3
Pathophysiology of HTN in CKD is multifactorial. It
contains components of neural and hormonal pathways.
The important mechanisms include:
„„ Impaired sodium excretion—Guyton and his team
have shown that HTN can be generated in partially
nephrectomized dog (renal mass reduced to 30%) with
salt loading.4 The elevated blood pressure (BP) in this
setting is induced by increased cardiac output (volume
expansion) initially, and later on sustained by increased
peripheral vascular bed vasoconstriction in response
to increase peripheral perfusion due to extracellular
volume expansion. So sodium retention can induce
HTN in two ways—at first by volume dependent
mechanism (extracellular fluid expansion) and later
on mainly through volume independent mechanism
like increased peripheral vascular resistance.
„„ Increased rennin angiotensin aldosterone activity
(RAAS)—Hypersecretion of rennin in a sclerosed
kidney leads to increased angiotensin II and RAAS
activity leading to increased systemic vascular
resistance, sodium retention, and high BP.
„„ Increased activity of systemic nervous system (SNS)—
The kidney is richly innervated sensory organ. Several
studies from animal and human subjects establish the
kidney-brain axis theory. Sensory inputs from kidney
transmitted to central nervous system in turn lead to
increased activity of SNS leading to vasoconstriction,
rennin secretion, sodium retention, and HTN.
„„ Endothelin dysfunction—CKD is a chronic low-grade
inflammatory state and so endothelial dysfunctions are
commonly observed in CKD. Endothelial dysfunction
leads to impaired nitrous oxide production and

Section-11.indb 947 28-01-2021 12:25:18

 948 SECTION 11 Nephrology

increased endothelin level leading to increased non-diabetics CKD, thus leads to progressive renal
peripheral vasoconstriction and HTN. damage with even moderate elevation of BP.
„„ Vascular stiffness—The distensibility of resistance
arteries is affected by certain functional and Measurement of BP in CKD3,7-9
m o r p h o l o g i ca l c ha ng e s. It i n c l u d e s i nt i ma e
The proper BP measurement is the first step toward the
hyperplasia, medial calcification, smooth muscle
effective BP management in CKD. BP measurement
cell hyperplasia, and endothelial dysfunction. These
can vary depending on the setting (e.g., casual office,
changes are largely contributed by disturbed calcium-
standardized office, or home) and type of device used (e.g.,
phosphorus balance, secondary hyperparathyroidism
aneroid or Oscillometric). Standardized office BP (SOBP) is
and other neurohumoral components discussed
5–10 mm Hg lower than casual office BP. Most of the recent
above. Vascular stiffness leads to increased systolic BP
trials on optimum BP goals have used SOBP as a method
and wide pulse pressure, which is a strong predictor of
of measurement. For standardized office BP measurement
cardiovascular mortality in CKD.
certain preparations are required—(e.g., 5 minutes of
„„ The erythropoietin induced HTN and obstructive sleep
quite rest/no nicotine, caffeine, and exercise 30 minutes
apnea (OSA) are important causes of HTN in CKD,
prior to measurement/well validated and periodically
especially in dialysis population. The erythropoietin or
calibrated device/correct cuff size/middle of the cuff
erythropoietin-stimulating agents used for treatment
should be placed at the level of right atrium/average of
of anemia in CKD can induce HTN or require change
more than two readings obtained on two occasions) as laid
in antihypertensive regimen in approximately 30%
down by 2017 ACC/AHA high BP guidelines.
of the cases. Besides rapid and over correction of
The out of office BP measurement (ambulatory BP and
anemia, HTN in this subset is thought to be caused
home BP monitoring) is required to diagnose white coat
by vasoconstrictor effect of erythropoietin, which
HTN (defined as elevated office BP with controlled out
is independent of hemoglobin.5 OSA is common in
of office BP, prevalence in CKD ranges from 2% to 41%)
advanced CKD population. Chronic intermittent
and masked HTN (defined as controlled office BP and
nocturnal hypoxemia provoke sympathetic nervous
elevated out of office BP, prevalence in CKD ranges from
system activity, RAAS activity, and increases nocturnal
6% to 51%). Additionally 24 hour ambulatory BP gives clue
BP.
about the nocturnal BP. Physiological nocturnal dipping
„„ Medications like over-the-counter nonsteroidal anti-
is absent in 14–75% of the CKD population. Thus in CKD
inflammatory drugs, herbal supplements, steroids,
out of office BP accurately define the clinical problem and
and decongestants can provoke HTN in the CKD
predicts more accurately about the cardiovascular and
population.
renal outcomes than office BP.
„„ The worsening of HTN has been reported in CKD
KDOQI (kidney disease outcome quality initiative)
patients with the use of potent anti-tuberculosis drug
US commentary on the 2017 ACC/AHA HTN guideline
rifampicin. Rifampicin is a potent enzyme inducer and
commented that home BP monitoring can accurately
decreases the level of commonly used antihypertensive
predict target organ damage and better placed than
drugs—amlodipine, metoprolol, and prazosin. So it is
ambulatory BP monitoring and office BP monitoring.
advisable to monitor HTN in CKD patients, once they
HBPM can also help to overcome the therapeutic inertia.
have been put on rifampicin.6
In our limited resource setting we should prefer
„„ The HTN is the most common complication of CKD
standardized office BP, because it requires nothing but
as well as major factor responsible for progression of
our little patience (pre-measurement preparation as
CKD. Renal autoregulatory mechanism protects renal
mentioned above).
vasculatures from elevated BP. Maintenance of afferent
arteriole tone in response to elevated systemic pressure
and increased sodium chloride delivery to macula Target BP in CKD2,3,10-14
densa are part of this autoregulatory mechanism. The management of HTN in CKD is a dynamic process,
However, it is impaired in patients with diabetes and as estimated glomerular filtration rate, comorbidities

Section-11.indb 948 28-01-2021 12:25:18

 Management of Hypertension in Chronic Kidney Disease
and risk changes with time. Due to presence of vascular
stiffness and wide pulse pressure in CKD, achieving a
BP target rapidly may lead to postural hypotension. So
a cautious and gradual approach is required to reach a
desired BP target.
From 1994 till 2010, there were four landmark trials
compared the standard versus intensive BP control in
patients with CKD. These were:
„„ MDRD (modification of diet in renal disease), year
1994
„„ AASK (Africans American study of kidney disease and
hypertension), year 2002
„„ REIN-2 (Ramipril efficacy in nephropathy-2), year 2005
„„ ACCORD (Action to control cardiovascular risk in
diabetes), year 2010
Results of all these trials favored standard BP control
rather than intensive control in most of the CKD patients,
exceptions are patients with proteinuria more than 1 g/
day, which were benefited from intensive control of BP. On
the basis of these trials, KDIGO (kidney disease initiative
global outcome) 2012 suggested a lower BP for significant
proteinuria.
„„ Albuminuria (<30 mg/24 hr): ≤140/90 (1B)
„„ Albuminuria (>30 mg/24 hr): ≤130/80 (2D)
Till year 2015, it was thought that controlling BP to
less than 140/90 mm Hg is likely to be beneficial in CKD
population. But with the advent of SPRINT (systolic BP
intervention trial) study in 2015, intensive control of
systolic BP (<120 mm Hg) has gained momentum. SPRINT
has included data from 9,361 adults age 50 or older with
systolic BP of 130 mm Hg or higher and at least one
additional cardiovascular disease risk factor. Around 28%
of participants had CKD without significant proteinuria.
The highlights of SPRINT study are:
„„ intensive reduction in SBP reduces cardiovascular
events
„„ intensive reduction in SBP has mortality benefit in
CKD population
„„ the subgroup analysis of older patients with CKD in
SPRINT has also favorable outcome
„„ with adoption of SBP <120 mm Hg in all CKD
population, separate BP target for proteinuria is not
required
However, it should be noted that more than 50% of
participants in intensive arm of SPRINT had not achieved
SBP target after 1 year. So targeting and achieving a lower
Section-11.indb 949
CHAPTER 146 949
SBP is a big challenge. Additionally the benefit of lower
BP is less certain in diabetic CKD and advanced CKD
population. The 2017 American College of Cardiology
(ACC) has adopted the result of SPRINT and suggested
more intensive BP control in CKD population. In light of
SPRINT and other newer studies KDIGO controversies
conference 2017 has also suggested for revision in BP
diagnosis threshold and BP treatment target.
In our setting, we should target lower BP:
„„ If SOBP/HBPM is the method used for measurement
of BP
„„ If patient is tolerating the target BP well without
postural hypotension or other adverse effect
„„ If patient is having non-diabetic CKD
Secondary HTN in CKD3
Secondary causes of HTN are potentially treatable and
should be searched in following conditions:
„„ If the onset of elevated BP occurred before puberty and
preceded the development of CKD.
„„ Severe or malignant HTN that is out of proportion to
the degree of CKD is present.
„„ Acute worsening of BP control occurs in a previously
hypertensive patient with good BP control, or resistant
HTN is present.
„„ Persistent hypokalemia off diuretic treatment (primary
aldosteronism).
„„ Development of tremor and palpitation (pheochromo­
cytoma).
„„ Flash pulmonary edema (renal artery stenosis).
Non-pharmacological Therapy1-3
Early institution of non-pharmacological therapy in the
form of dietary modification and life style modification is
the first step to the treatment of HTN in CKD.
„„ Dietary salt restriction (sodium intake <1.5 g/day)—
Reduce BP and proteinuria; potentiate the action of
ACEI/ARB.
„„ DASH (Dietary approach to stop HTN) Diet—Diet
rich in fruits and vegetables, low in saturated and
unsaturated fat can lead to modest reduction in BP.
But it is not appropriate to use DASH Diet in advanced
CKD because of the potential for hyperkalemia.
„„ Modest physical activity of 150 minutes duration/
week is useful for CKD population. It can be modified
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 950 SECTION 11 Nephrology
depending on the cardiorespiratory fitness status and
physical limitation of the individual.
„„ Other life style interventions include weight loss in
obese people, limiting alcohol intake, and avoidance
of over the counter medications such as non-steroidal
anti-inflammatory drugs.
Choosing Antihypertensive
Drugs in CKD2,3,8,15
Most of the CKD patients require multiple
antihypertensives for adequate control of HTN. Certain
classes of antihypertensives are preferred because of their
renoprotective, cardioprotective, and diuretics actions
apart from antihypertensive effects. Before choosing
antihypertensive agents in CKD we should look for
comorbidities, risk benefit ratio of individual drug, volume
status, and age of the patient.
„„ Angiotensin converting enzyme inhibitors (ACEIs)/
angiotensin receptor blockers (ARBs)—
—— ACEI/ARB are the agent of choice to treat HTN in
diabetic CKD with severely increased proteinuria
(>300 mg/day). But the superiority of ACEI/ARB
over other agents (calcium channel blockers,
diuretics) is questionable in non-proteinuric CKD.
However, as majority of CKD patients require
multiple agents to achieve adequate control of
HTN, it is reasonable to include ACEI/ARB as add
on therapy in non-proteinuric CKD patients.
—— Th e c o m m o n s i d e e f f e c t o f AC E I / A R B i s
hyperkalemia particularly in advanced CKD hence
limiting their use despite their proven benefit.
Novel potassium binding agents (patiromer and
sodium zirconium cyclosilicate) in combination
w ith ACEI/ARB could change the way of
pharmacotherapy in HTN in CKD. But further
research is required before their routine clinical
use.
—— Another potential problem with the use of ACEI/
ARB is acute kidney injury. Recent guidelines
suggest that up to 30% increase in serum creatinine
in first few weeks and later on stabilization is an
acceptable physiological change which confers
long-term renoprotection.
—— Combination therapy (ACEI+ARB) has failed to
show any cardioprotection and renoprotection
in major studies. Additionally this combination
Section-11.indb 950
is associated with increase risk of hyperkalemia,
acute kidney injury, and hypotension.
„„ Calcium channel blockers (CCB)—dihydropyridine
(DHP)-CCB (amlodipine) are frequently prescribed
antihypertensives in CKD because:
—— they are the potent antihypertensive agents,
—— can work synergistically with ACEI/ARB,
—— work well in volume expanded states, and
—— minimal side effect (pedal edema).
„„ Diuretics—
—— Sodium retention and volume overload are
the main concerns of the majority of CKD
patients. Diuretics act by natriuresis (promote
sodium excretion through kidney), thus reduce
extracellular volume and has been shown to
improve left ventricular mass index (LVMI)
and arterial stiffness in CKD patients. Diuretics
also enhance the BP lowering effect of ACEI/
ARB. Thiazide diuretics (hydrochlorothiazides
and chlorthalidone) are less effective at lower
glomerular filtration rate so switching to loop
diuretics (furosemide and torsemide) with frequent
dosing is done in advanced CKD. Some times loop
diuretics can be combined with thiazide diuretics
to treat refractory edema in advanced CKD.
—— Diuretics should be avoided in end stage renal
disease with no residual function and polycystic
kidney disease as they can lead to accelerated cyst
growth and decreased renal function. The major
adverse effects of diuretics are volume depletion
and electrolyte imbalance.
—— Mineralocorticoid receptor antagonists (MRA) are
effective drugs for resistant HTN but may cause
hyperkalemia in patients with low-estimated
glomerular filtration rate, so better to avoid at
estimated glomerular filtration rate below 45 mL/
min/m2.
„„ Beta blockers—
—— Although beta blockers has lost credential in
treatment of primary HTN in general population,
but still they are found to be useful adjunctive
therapy in CKD population because they decrease
sympathetic over activity and are cardioprotective.
A recent trial named HDPAL (HTN in hemodialysis
patients treated with atenolol or lisinopril) has
concluded that atenolol arm has less cardiovascular
28-01-2021 12:25:18
 Management of Hypertension in Chronic Kidney Disease
events and better BP control than lisinopril arm in
hemodialysis patients.
—— Other antihypertensive agents for patients with
CKD include direct vasodilator (minoxidil and
hydralazine), centrally acting alpha adrenergic
agonist (clonidine), alpha blockers (prazosin), and
direct rennin inhibitors (aliskiren).
„„ Resistant and refractory HTN in CKD1,3,16—
—— The prevalence is up to 40% as shown in CRIC
Study. It has got poor prognosis—increases the risk
of death by 30% and the risk of heart failure by 59%.
The selection of complementary medications and
ensuring drug adherence often resolve treatment
resistance. Thiazide and thiazide-like diuretics in
combination with ACE/ARB or MRA can be very
effective in treatment of CKD populations with
apparent drug resistant HTN.
Adherence2,9
Adherence to therapy is poor due to frequent dosing of
pills, pill burden, drug interaction, and adverse effects.
Strategies to improve adherence include:
„„ Patients should be communicated regarding treatment
and its importance.
„„ Use of combination pill and whenever possible long
acting, once a day medication to be used.
2,17,18
Nocturnal Therapy
Non-dipping is detected more frequently in later stages of
CKD and associated with significant CV death. Multiple
clinical trials have shown an improvement in nocturnal
dipping of BP by dosing at least one antihypertensive
medication at bedtime.
Management of HTN in
Patients on Dialysis2,3,19,20
The relationship between BP and CVD in this group is
more complex. There is U-shaped relationship between
24-hour ambulatory SBP and all cause mortality as noted
by Mayer et al. So BP treatment should be individualized
in this group keeping in mind of comorbid conditions.
Besides pharmacotherapy, these are the novel measures
to treat HTN in dialysis patients:
„„ Dry weight reduction (DRIP trial)
„„ Dietary sodium restriction
Section-11.indb 951
CHAPTER 146 951
„„ Dialysate sodium restriction
„„ Adequate time on dialysis
„„ Consideration of frequent dialysis
Managing HTN Following
Kidney Transplantation1-3
HTN is common in post-transplant period. It has been
reported that HTN is prevalent in more than 90% of
calcineurin inhibitors treated kidney transplant recipient.
The higher BP is associated with poor graft survival,
increased CVD risk, and most common cause of death
post-transplant. KDIGO and the ACC/AHA guidelines
currently recommend a BP target <130/80 mm Hg. Some
useful tips to manage HTN following kidney transplants
are:
„„ Weight control
„„ Steroid and CNI dose optimization
„„ During 1st year after transplant, CCB (DHP) is the
preferred antihypertensive agent over ACEI/ARB
„„ In patient with mild graft dysfunction with proteinuria,
ARB are the preferred drug
„„ In case of post-transplant hyperuricemia losartan is
the preferred drug
Future Perspective21-25
In recent years, the underlying mechanism and unmet
therapeutic needs to halt the progression of CKD and CVD
have been better understood. Due to this few promising
therapeutic measures have emerged. They are:
„„ Sodium glucose transport 2 inhibitor (SGLT-2I): Interest
in molecules of this group has intensified following
the result of EMPA-REG OUTCOME (Empagliflozin
Cardiovascular Outcome Event Trial in Type 2 Diabetes
Mellitus Patients) and CREDENCE (Canagliflozin and
Renal Outcomes in Type 2 Diabetes and Nephropathy)
trials, which demonstrated significant slowing of CKD
progression and a reduction in the composite outcome
of death from CVD. Combining ACEI/ARB with SGLT2I
may further reduce intraglomerular pressure by their
synergistic effects.
„„ The DUET (Dual Endothelin Receptor and Angiotensin
Receptor Blocker) trials with sparsentan and irbesartan
have shown promising results in control of HTN and
proteinuria in IgA nephropathy and focal segmental
glomerulosclerosis (FSGS).
28-01-2021 12:25:18
 952 SECTION 11 Nephrology
„„ Renal denervation therapy (RDN): After initial hiccups
this radio frequency energy based therapy for ablation
of the networks of nerves around renal arteries has
shown promising results in newer trials. However, this
strategy is still in experimental stage.
Conclusion
The Prevalence of HTN in CKD is very high, but HTN control rate
is far from optimal. When CKD and HTN coexist, CV morbidity
and mortality is substantially increased. Personalized and
individualized HTN therapy using standardized office BP and
home BP monitoring holds great promise. ACEI or ARB, CCB,
appropriate diuretic therapy, dietary salt restriction, and
ensuring proper adherence to therapy make up the foundation
for the treatment of HTN in CKD.
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Nephrology, 5th edition. Elsevier Saunders; 2014. p. 1320.
2. Pugh D, Gallacher PJ, Dhaun N. Management of hypertension in
chronic kidney disease. Drugs. 2019;79(4):365-79.
3. Ku E, Lee BJ, Wei J, et al. Weir hypertension in CKD: core curriculum
2019. Am J Kidney Dis. 2019;74(1):120-31.
4. Coleman TG, Guyton AC. Hypertension caused by salt loading in
the dog. 3. Onset transients of cardiac output and other circulatory
variables. Circ Res. 1969;25(2):153-60.
5. Krapf R, Hulter HN. Arterial hypertension induced by erythropoietin
and erythropoiesis-stimulating agents (ESA). Clin J Am Soc Nephrol.
2009;4:470-80.
6. Agrawal A, Agarwal SK, Kaleekal T, et al. Rifampicin and anti-
hypertensive drugs in chronic kidney disease: pharmacokinetic
interactions and their clinical impact. Indian J Nephrol.
2016;26(5):322-8.
7. Whelton PK, Gidding S, Carey RM, et al. 2017 ACC/AHA/AAPA/
ABC/ACPM/ AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the
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Pressure in Adults A Report of the American College of Cardiology/
American Heart Association Task Force on Clinical Practice
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8. Cheung AK, Chang TL, Cushman WC, et al. Blood pressure in
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Kdigo Executive Conclusions. 2019;95(5):1027-36.
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10. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein
restriction and blood pressure control on the progression of
chronic renal disease. Modification of Diet in Renal Disease Study
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11. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure
lowering and antihypertensive drug class on progression of
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12. Ruggenenti P, Perna A, Loriga G, et al. Blood-pressure control
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23. Herrington WG, Preiss D, Haynes R, et al. The potential for improving
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EMPA-KIDNEY study. Clin Kidney J. 2018;11(6):749-61.
24. Komers R, Gipson DS, Nelson P, et al. Efficacy and safety of
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 CHAPTER

147 Prevention of Progression of

CKD—What Is New?
Krishnaswamy Sampathkumar

Abstract 
Chronic kidney disease (CKD) afflicts approximately 7–10% of adult population of India. It is a silent killer due to its
far reaching ill effects on the cardiovascular system. The manifestations of CKD are varied and can mimic a variety of
medical and surgical conditions. Early recognition is of paramount importance since preventive strategies are successful
only if applied before irreversible renal fibrosis sets in. This article gives an overview of recent evidences. Dietary protein
restriction should be applied to meat based diets and not for vegetable proteins. Plant-based protein intake has been
shown to be renoprotective due to its alkaline nature and fiber content. RAS blocker therapy, and antihypertensive therapy
are the inseparable duo of prevention. A dose escalating strategy of RAS blockade aiming for proteinuria reduction has
been successfully applied in the Indian context. However, it requires close serum creatinine and potassium monitoring to
prevent harm. Based on well conducted large trials, SGLT2-inhibitors have provided substantial benefits in terms of renal,
cardiac, and all cause mortality. Their use is recommended for both diabetic and non-diabetic renal diseases. Sodium
bicarbonate and statin usage have shown benefits. However, uric acid lowering therapy has failed to provide beneficial
effects in recent trials.

Introduction Contributors to Accelerated

Chronic kidney disease (CKD) is a silent killer, which
afflicts approximately 7–10% of world’s adult population. It
means that India which makes up 17% of world population
carries a large burden of the disease. 1 It is commonly
mistaken for a number of conditions such as nutritional
anemia, nutritional rickets, peptic ulcer disease,
dysfunctional uterine bleeding, etc. In the absence of a
National Registry, the exact prevalence of the disease is
open to conjecture. A population based study showed
incidence of End Stage Renal Disease (ESRD) to be 159
per million population.2 Once a patient reaches ESRD the
treatment is not only prohibitively expensive but survival
rates are worse than advanced malignancy. Thus every
physician should update himself with current practice
guidelines for optimal prevention of progression of CKD.
GFR Loss
The glomerular filtration rate (GFR) falls at a rate of
approximately 0.5 mL/min/year in the normal adult
population. Patients with progressive CKD the loss of
GFR may be as steep as 5–15 mL/min/year. In addition
to non-alterable factors such as age, gender, and genetics
a number of factors which are potentially treatable
contribute to the risk of progression. A recent work
showed genetic polymorphisms involving intracellular
antioxidant systems can accelerate the progression and
mortality dramatically.3 Dietary factors, lack of exercise,
albuminuria, hypertension, hyperglycemia, lipids, morbid
obesity, and metabolic acidosis, mini AKIs, and gut
dysbiosis are some of the modifiable risk factors.

MU-147.indd 953 29-01-2021 15:02:04

 954 SECTION 11 Nephrology
Lifestyle Modifications
Diet
Earlier view—Restricting all forms of proteins in the diet
retards the progression of CKD.
Current view—Plant based proteins are renal friendly
and should be promoted.
In a community-based study of adults without
CKD, higher adherence to a healthy plant-based diet
or a provegetarian diet was associated with lower CKD
risk. 4 Higher consumption of healthy plant foods
(fruits, vegetables, whole grains, nuts, legumes, coffee,
tea) was associated with a lower risk and slower eGFR
decline in GFR. Dietary red meat contains cardiotoxic
metabolites from lecithin and carnitine such as
trimethylamines. Plant-based proteins are recommended
for a variety of reasons such as higher fiber content, lesser
diet acid load, less phosphorus and uric acid generation,
enhanced vitamin K (reduction of coronary calcium
scores), and promotion of healthy gut microbiome.
Dals, lentils, and Soya beans can be substituted for
dietary animal proteins such as meat and dairy products.
Daily intake of locally available fruits and vegetables
are recommended in CKD Stages 3–4. Compensatory
potassium excretion from the colon increases when dietary
fiber intake is liberalized. Vegetable diet also inhibits the
enzyme 11-beta-hydroxysteroid dehydrogenase type 2
in the distal convoluted tubule cells which increase the
cortisol induced K excretion in addition to aldosterone
effect.
Physical Exercise
Physical deconditioning sets in during progressive
CKD, which results in muscle energy dysmetabolism.
A reduction in mitochondrial activity develops even in
earlier stages of CKD, which is progressive. Oxidative
stress, inflammation, erythropoietin, vitamin D, and
testosterone deficiencies are possible reasons. The
symptoms include easy fatigability and proximal muscle
weakness. Later, muscle atrophy sets in. As in general
population, the cardiovascular benefits of exercise cannot
be ignored in CKD patients. Regular moderate intensity
exercises involving all the major core groups of muscles
are recommended. Both endurance and weight bearing
exercises are indicated in Stage 3 CKD.
MU-147.indd 954
Albuminuria
Earlier view—Albuminuria is a marker of severity of renal
disease.
Current view—It is both a marker and maker of
progression of renal disease.
Albuminuria is both a marker and maker of glomerular
injury. A direct quantitative relationship exists between
the higher proteinuric CKD and faster progression. Filtered
albumin is taken up by the proximal convoluted tubule
cells where it is toxic and inflammatory. Tubulointerstitial
fibrosis sets in faster when the rates of proteinuria are
higher. RAS blockers have shown to reduce proteinuria
and prevent progression of renal disease. Highest tolerable
doses of angiotensin receptor blockers (ARBs) and
angiotensin converting enzyme (ACE) inhibitors are
recommended to provide optimal renoprotection. Higher
doses are accompanied by hyperkalemia. An important
advance has been the clinical entry of New K binding agents
like zirconium and patiromer, which permit continued
and safe use of RAS blockade in the face of hyperkalemia.
In the OPAL-HK study involving CKD patients with
hyperkalemia, treatment with patiromer reduced the
serum potassium levels and enabled significantly more
patients to continue RAS blockers without interruption
than placebo.5 The drug was well tolerated.
Hypertension
Earlier target—BP reduction below 130/80.
Current view—More intensive BP reduction below
120–125/<80 in proteinuric CKD.
Long-term follow-up of 15 years in MDRD and AASK
trials highlighted that intensive BP control reduced both
overall mortality and progression to ESRD. The recently
released SPRINT trial data showed that in CKD subgroup
the all cause mortality was lower in the intensive arm. 6
However, the incidence of ESRD or a 50% decline in GFR
was not altered in the intensive arm. However, a note of
caution is that diastolic BP reduction below 70 mm Hg is not
recommended in older adults with atheromatous central
arteries, which can lead onto coronary insufficiency.
ARBs and ACE inhibitors are the preferred first-line
agents. Maximally tolerated doses of these drugs should
be given. As an example losartan is started on 50 mg OD
and titrated up depending on proteinuria reduction and
BP reduction to 50 mg BID. Supra pharmacological doses
29-01-2021 15:02:04
 Prevention of Progression of CKD—What Is New?
can be prescribed with a close, watch on serum K and BP.
The dose required to optimize GFR reduction was 150±88
mg/day in an Indian Study. 7 Though combinations of
ACEi and ARBs are prohibited by most of the guidelines,
individualization of therapy can result in better outcomes.
Since multiple drugs are required in CKD, calcium
channel blockers, diuretics (Thiazides in Stage 3 and loop
diuretics in Stage 4), are added in a stepwise fashion.
Dietary sodium restriction to below 2–3 gm/day is
an important adjunct to improve BP control. Due to
concerns about hyperkalemia, there is reluctance to
start spironolactone therapy in those with resistant
hypertension. Recently published AMBER study showed
that when patiromer is added to spironolactone more
patients could continue the latter drug without developing
hyperkalemia.8
Canrenone and Finerenone are novel non-steroidal
aldosterone receptor antagonists with low risk of
hyperkalemia. Current prospective trials are testing their
efficacy and safety in CKD patients.
Glucose Control
Earlier view—Insulin therapy for Stage 3 CKD onward.
Re c e nt v i e w —S G LT 2 i n h i b i t o r s a re s t ro ng l y
recommended to prevent progression of CKD and reduce
cardiovascular morbidity and mortality.
CREDENCE trial on canagliflozin versus placebo
on CKD patients has shown remarkable renal and
cardiovascular benefits for patients with diabetic
nephropathy.9 All the patients had an estimated GFR of
30 to less than 90 mL/minute and albuminuria and were
treated with renin-angiotensin system blockade. The
primary outcome was a composite of end-stage kidney
disease, or a doubling of the serum creatinine level, or
death from renal or cardiovascular causes. Over a 2.6-year
period, the relative risk of the primary outcome was 30%
lower in the canagliflozin group than in the placebo group
(hazard ratio, 0.70). The relative risk of the renal-specific
composite of end-stage kidney disease, a doubling of the
creatinine level, or death from renal causes was lower by
34% (hazard ratio, 0.66) and the relative risk of end-stage
kidney disease was lower by 32% (hazard ratio, 0.68).
Cardiovascular events were also significantly less in the
treatment arm. Risk of amputations or fractures were
not significantly elevated in the treatment arm. Sodium
reabsorption is inhibited in the proximal convoluted
MU-147.indd 955
CHAPTER 147 955
tubule cells following SGLT2 inhibitor therapy. This
results in more sodium ions reaching the DCT and
thereby producing afferent arteriolar vasoconstriction.
This ultimately results in renal preservation since
intraglomerular pressure is lessened.
GLP1 analogs (liraglutide) have also shown both
renal and cardiovascular benefits in trials. In the LEADER
trial involving liraglutide new onset of persistent
macroalbuminuria, occurred in significantly fewer
participants in the liraglutide group than in the placebo
group (hazard ratio, 0.74).10 The reduction in GFR in the
placebo arm was −5 mL/min/year, which reduced to −0.3
mL/min/year in the treatment group.
In contrast, DPP4 inhibitors have not shown reno- or
cardioprotective benefits in trials. But they are still useful
agents since the incidence of hypoglycemia is less, which
enhances the acceptability of the drug in CKD population.
The recommended target HbA1C level for the
prevention of progression of CKD is between 6.5–7%.
However, in those with higher comorbidities who are
prone for complications of hypoglycemia, one can opt for
a compromised target of 7.5–8%.
Acidosis Correction
R e c e n t v i e w —S o d i u m b i c a r b o n a t e t h e r a p y i s
nephroprotective.
The serum bicarbonate levels are ideally maintained
above 22 meq/L in patients with CKD. Acidosis correction
improves bone health and retards progression of renal
disease. The latter is due to reduced ammonia generation,
which is linked to inflammation by stimulation of
alternate complement pathway. A condition called
normobicarbonatemic acidosis develops in CKD, which
is characterized by reduced urinary excretion of citrate.11
This can be addressed by providing fruits and vegetables,
which are a rich source of citrate.
Sodium bicarbonate is commonly given by oral route
in tablet or capsule forms. Adult dose is between 1.5–2.5
gm/day depending on the degree of acidosis. Each gram
contains 12 mEq of base. The potential side effects include
gastic distension and metabolic alkalosis. Aggravation of
hypertension is uncommon. It decreases the absorption
of ranitidine and increases the propensity of quinolones
for crystalluria. It is contraindicated in hypocalcemia and
hypokalemia.
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 956 SECTION 11 Nephrology
Management of Hyperlipidemia
Earlier view—Statin therapy is beneficial at the earlier
stages of CKD. No new data have emerged recently.
Observational studies among apparently healthy
individuals or in patients with preexisting cardiovascular
disease (CVD) have shown a roughly linear relationship
between risk of cardiovascular-related death and serum
total and low-density lipoprotein (LDL) cholesterol.
Among patients with CKD, however, this relationship is
much less obvious. The cardiovascular abnormalities
in Stage 4–5 CKD are progressive medial vessel wall
calcification, left ventricular hypertrophy (LVH) and
diastolic dysfunction. These are poorly responsive to statin
therapy. There are no new evidences in the last decade in
this field in the aftermath of SHARP trial, which showed a
significant, 17% reduction in major atherosclerosis events
and a 15% reduction in major cardiovascular events in
the entire cohort of 9,000 patients. The earlier the statin
therapy is initiated, the better were the cardiovascular
protection benefits.
Prevention of AKI
Earlier view—Recovered AKI patients regain normal renal
function.
Current view—Up to 30% of patients with comorbidities
who develop AKI may progress to CKD.
In CKD patients multiple episodes of AKI are the cause
of accelerated decline in GFR.
The downtrending of GFR slope from above 90 mL/min
to 10 mL/min does not occur in a straight line if plotted
against time. There are periods of flattening interspersed
with periods of acute reduction. These “Mini AKIs” due
to volume depletion, cardiac failure, UTI, hypotension,
and NSAID drug toxicity result in incomplete recovery to
original levels. It is critically important that these events
are aggressively managed.
Intestinal Microbial Flora
Recent view—It is beneficial to alter the dysbiosis, which is
prevalent in CKD patients.
Human gastrointestinal (GI) tract is home to trillions
of bacteria, which undergo both a qualitative and
quantitative alterations in CKD. Products of bacterial
metabolism are linked to inflammation, uremic syndrome,
and cardiovascular disease. Oral ingestion of probiotics
MU-147.indd 956
has been shown to reduce the serum levels of products
of protein metabolism like p-cresol and indoxyl sulfate,
which induce cardiovascular toxicity.
Obesity
Earlier view—Weight loss should be routinely advised in
CKD patients.
Recent view—Mildly overweight category of patients
show best survival.
The association between body mass index (BMI) and
mortality has shown some surprising findings. In a large
observational study from US veterans found that best
survival of Stage 3–4 CKD was seen in those with BMI
between 25 and 35 kg/m 2. In morbidly obese patients,
when bariatric surgery was undertaken, both proteinuria
and GFR reduction are attenuated.12
Uric Acid
Earlier view—Treatment of hyperuricemia is reno­
protective.
Recent view—Hyperuricemia correction does not
result in renal benefits.
Uric acid produces inflammation and proliferation of
afferent arterioles in mouse models of CKD. Extracellular
precipitation in the form of microscopic crystals and
macroscopic urate stones can cause structural damage.
Intracellular mechanisms show its propensity to precipitate
injury relating to its oxidative properties. Humans and
other primates are prone to hyperuricemia because
enzyme uricase was lost in evolutionary mutation. To
lower uric acid levels, xanthine oxidase inhibitors (XOIs)
such as allopurinol and febuxostat are commonly used in
clinical arena.
Does Reduction of Uric Acid
Produce Renal Benefits?
The short answer seems to be no. Based on many
observational studies which reported that higher serum
uric acid levels heightened the risk for new-onset CKD as
well hastened its progression, a commonly held view was
that a level above 7 mg% required intervention for renal
benefits. However, two large, high-quality trials, which
were published recently refuted a causal relationship and
revealed that urate-lowering therapy neither prevents
CKD nor slows down its progression.
29-01-2021 15:02:04
 Prevention of Progression of CKD—What Is New?
PERL trial randomized over 500 adults with type 1
diabetes and early-to-moderate diabetic kidney disease,
with allopurinol versus placebo. At 3 years treatment with
allopurinol had no effect on the change in measured GFR
compared with placebo; worryingly, allopurinol increased
albuminuria, and nonsignificantly increased the rate of
fatal or nonfatal cardiovascular events. In the CKD-FIX
study of over 350 adults with more advanced CKD, the rate
of decline of estimated GFR at 2 years was the same with
allopurinol and placebo.
Anemia correction and correction of calcium
phosphorus dysmetabolism have not been shown to have
any effect on the progression of CKD, and hence they are
not discussed at length. But they have to be addressed
all the same since cardiovascular and skeletal health are
inseparable sufferers from renal dysfunction.
Thus a multipronged strategy implemented with
attention to minutiae will be needed. Though the task
looks daunting, it is achievable if pursued with dedication
as shown by Prof. M. K. Mani at Chennai.
Conclusion
CKD can be termed as An Orphan Disease since awareness
levels are low even amongst the physicians. The four most
effective strategies for its prevention are RAS Blockade, SGLT2
inhibitor therapy, Hypertension control, and Blood Glucose
control. In the years to come personalized medicine looking at
the genetic makeup of the patient may become an added tool
to decide the therapeutic options.
MU-147.indd 957
CHAPTER 147 957
References
1. Varma PP. Prevalence of chronic kidney disease in India—where are
we heading? Indian J Nephrol. 2015;25(3):133-5.
2. Jha V. Current status of end-stage renal disease care in India and
Pakistan. Kidney Int Suppl. 2013;3(2):157-60.
3. Vasudevan V, Ramprasath T, Sampathkumar K, et al. GSTM1-null
allele predicts rapid disease progression in nondialysis patients and
mortality among South Indian ESRD patients. Mol Cell Biochem.
2020;469(1-2):21-8.
4. Kim H, Caulfield LE, Garcia-Larsen V, et al. Article plant-based diets
and Incident CKD and kidney function. Clin J Am Soc Nephrol.
2019;14(5):682-91.
5. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with
kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl
J Med. 2015;372(3):211-21.
6. Wright JT, Williamson JD, Whelton PK, et al. A randomized trial of
intensive versus standard blood-pressure control. N Engl J Med.
2015;373(22):2103-16.
7. Limesh M, Annigeri RA, Mani MK, et al. Retarding the progression
of chronic kidney disease with renin angiotensin system blockade.
Indian J Nephrol. 2012;22(2):108-15.
8. Agarwal R, Rossignol P, Romero A, et al. Patiromer versus placebo to
enable spironolactone use in patients with resistant hypertension
and chronic kidney disease (AMBER): a phase 2, randomised, double-
blind, placebo-controlled trial. Lancet. 2019;394(10208):1540-50.
9. Perkovic V, Jardin MJ, Neal B, et al. Canagliflozin and renal outcomes
in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:
2295-306.
10. Kalra S. Follow the LEADER—Liraglutide Effect and Action in
Diabetes: Evaluation of Cardiovascular Outcome Results Trial.
Diabetes Ther. 2016;7(4):601-9.
11. Maalouf NM, Moe OW, Gianella FG, et al. Spot urinary citrate-to-
creatinine ratio is a marker for acid-base status in chronic kidney
disease. Challenge parameter defense mechanisms excretion
results acid. Kidney Int. 2020.
12. Jun LL, Kamyar KZ, Jennie Z, et al. Association of body mass
index with outcomes in patients with CKD. J Am Soc Nephrol.
2014;25(9):2088-96.
29-01-2021 15:02:04
 CHAPTER
Lupus Nephritis—
148 Current Understanding
and Management
Krishan Lal Gupta, Joyita Bharati

Abstract 
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, and lupus nephritis (LN) is associated with
increased morbidity and mortality. Kidney biopsy is essential and the “gold standard” for diagnosing LN. Extra-glomerular
involvement is seen in up to two-thirds of patients with LN and is associated with poor outcomes. The revised 2018
International Society of Nephrology/Renal Pathology Society classification for LN has changed parameters for activity index
and redefined few pathological parameters. Repeat kidney biopsy is done for resistant disease or during flare, usually when
atypical features are present. Protocol biopsy is a promising tool to monitor patients with LN and decide maintenance
therapy. Newer therapies like multi-targeted therapy and biological agents such as obinutuzumab have shown promise in
treating LN.

Introduction Pathology of Lupus Nephritis

Lupus nephritis (LN) is seen in 25–50% of patients at the
outset of systemic lupus erythematosus (SLE) and about
60% of the patients are affected during the disease course,
which varies with race and ethnicity.1-3 The probability
of a new renal flare is 20–30% per patient-year of follow-
up.4 Patients with LN, particularly those with proliferative
histology, are at 2.28 times higher risk of mortality as
compared to those without LN and up to one-third of
them progress to end stage renal disease (ESRD) within
15 years. 5,6 The prevalence of SLE and the chances of
developing LN vary considerably between different
regions of the world, with higher rates in Africans and
Hispanics.7 Most often, LN occurs early (within 5 years)
in the disease course of SLE.8 SLE is more prevalent in
women than men across all age groups and populations;
the female-to-male ratio is highest at reproductive age,
ranging between 8:1 and 15:1, and is lowest in prepubertal
children at about 4:3.9-11
LN is initiated by deposition of circulating immune
complexes and by binding of autoantibodies to antigens in
the glomerulus and vessel walls. This interaction activates
complement mediated cytotoxicity, macrophage, and
natural killer cell-induced cell cytotoxicity along with
Fc receptor-based T-cell mediated cell damage. Anti-
phospholipid antibodies can result in thrombotic lesions
in the glomerulus and in the vessels. In 20–30% of patients
with LN, anti-neutrophil cytoplasmic antibody can
be positive and may contribute to the development of
vasculitic lesions.12
Value of Renal Biopsy
Treatment of LN is guided by the histological patterns
described in the classification system 2003 International
society of Nephrology/Renal Pathology Society (ISN/RPS)
classification. Clinical severity does not always correlate
with histological severity and is shown in Table 1.

MU-148.indd 958 29-01-2021 15:01:50

 Lupus Nephritis—Current Understanding and Management CHAPTER 148 959

TABLE 1 Clinicopathological correlation in lupus nephritis

Lupus nephritis class Proteinuria Active urine Increased serum Active lupus Hypertension
(ISN/RPS) sediment creatinine serology

Class I –* – – +/– –

Class II +/– * – – +/– –

Class III ++ (NS: 30%) + +/– +/– +/–

Class IV +++ (NS: 50%) ++ +/– ++/– ++/–

Class V +++ (NS: 60%) – +/– +/–– +/–

Class VI ++ +/– + +/–– +

(+) represents frequent occurrence of symptom/sign, (–) represents infrequent occurrence of symptom/sign, NS: Nephrotic syndrome; * NS is
seen in class I/II LN in presence of podocytopathy

Therefore, renal biopsy remains indispensable and the Extraglomerular Involvement

“gold standard” to correctly classify LN. The Kidney Disease
Initiative Global Outcomes (KDIGO),13 American College
of Rheumatology (ACR),14 and European League Against
Rheumatism/European Renal Association-European
Dialysis and Transplantation Association (EULAR/ERA-
EDTA)15 guidelines recommend that a renal biopsy should
be performed to confirm and classify LN in cases of SLE
with clinical manifestation of proteinuria (>500 mg/day),
urinary red blood cells (>5 per high power field) or cellular
casts (any), or unexplained renal dysfunction.
Classification of LN: The classification of LN (based on
histology) has been in place for over five decades with the
latest modification in 2018.
2003: ISN/RPS16 proposed a new classification system
that would provide better clinical correlation, uniformity
in reporting and reproducibility. The classification
schema is based on glomerular pathology, which
includes assessment by light microscopy (LM) and
immunofluorescence (IF). Class IV LN is the commonest
pattern seen worldwide. In a study from our center, of total
232 patients, Class II was seen in 21, Class III in 36, Class IV
in 130, and Class V in 30 patients.17
2018: Changes in the 2018 ISN/RPS18 revision were: the
distinction between class IV-S and IV-G was not evidence
based and hence, has been removed; the threshold for
defining crescent is lowered and various types of crescents
are defined in addition; activity and chronicity scores are
modified and are required to be mentioned instead of A
(activity) or C (chronicity).
Tubular atrophy and interstitial fibrosis (IFTA) are one of
the strongest predictors of renal failure. Various studies
reported vascular involvement in LN to indicate increased
risk for progression to renal failure. In a study from our
center,9 of total 197 patients, thrombotic microangiopathy
(TMA) was found in 25.4% with 10% having concomitant
APS. Patients of LN with TMA had significantly higher
rates of oliguria (p=0.035), advanced renal injury, that
is, serum creatinine more than 3 mg/dL (p=0.002),
fibrocellular and fibrous crescents (p=0.01), and tubular
atrophy (0.001) compared to non-TMA patients. They also
had higher rates of treatment failure (p=0.02) compared
to the group without TMA.9 Another study (unpublished
data) from our center included 241 patients with LN with
60% having tubulointerstitial involvement, 32.3% having
vascular involvement. Those with tubulointerstitial and
vascular involvement had lower rates of remission.
Role of Repeat Biopsy
Repeat biopsy is done during renal flare for refractory
LN or as a protocol after induction and/or maintenance
therapy for LN. Repeat biopsy is useful as histological
transformations are common and may affect treatment
decisions. It has also been shown to be predictive of
long-term outcomes. Protocol re-biopsies can guide
therapeutic decision as 20–50% of patients in clinical
complete response after therapy were shown to have
histological activity on the biopsy.19 Furthermore, protocol
biopsy after prolonged clinical remission can help in
deciding safe withdrawal of maintenance therapy, as

MU-148.indd 959 29-01-2021 15:01:50

 960 SECTION 11 Nephrology
was shown recently in a prospective study on clinically
quiescent LN patients. 20 Recently, the EULAR 2019 21
guideline has recommended repeat biopsy in those with
incomplete renal response defined as 24-hour proteinuria
more than 0.8–1 g/day with stable/improved renal
function despite at least 1 year of immunosuppressive
treatment. In a study from our center, which included
62 patients who underwent repeat biopsy for clinical
indications, we found histological transformations in
61.3% of the patients.22 Class switch from proliferative to
non-proliferative occurred in 13.7% and 18.2% of patients
with non-proliferative histology switched to proliferative
classes. On repeat biopsy, endocapillary proliferation and
fibrinoid necrosis decreased whereas glomerulosclerosis
and IFTA increased (P<0.001). Presence of IFTA more than
30% and TMA on the second biopsy correlated with worse
long-term outcome.22
Management of Lupus Nephritis
Treatment of LN involves use of aggressive immuno­
suppressive therapy in the induction phase to achieve
rapid control of inflammation in the kidneys followed by
less intense immunosuppression to maintain remission.
The initial phase for induction is for a duration of 3–6
months followed by a maintenance phase of 3–5 years
usually.
Induction Agents
Corticosteroids: Steroids form the backbone of induction
therapy of active LN. However, there is an increasing
concern about the side-effects with high and prolonged
doses of steroids. Many newer trials have investigated this
by trying to compare regimens, which include introduction
of lesser toxic novel agents to allow reduction of steroid
dose versus the standard induction therapy. Based on
these concerns and the existing literature, the 2019
EULAR-ERA/EDTA guideline23 for LN has recommended
the use of methylprednisolone pulse (at doses between
500–2,500 mg) followed by oral prednisolone of 0.3–0.5
mg/kg/day and a rapid taper to reach less than 7.5 mg/day
by 3–6 months.
Cyclophosphamide: Intravenous cyclophosphamide
(CYC) along with corticosteroids became the standard
of care for treatment of LN based on randomized control
trials conducted by the National institute of health (NIH).
MU-148.indd 960
The NIH regimen includes monthly intravenous pulses of
CYC at a dose of 500–1,000 mg/m2 for 6 months followed
by maintenance with quarterly infusions at same dose for
the next 2 years.24 Using this protocol, remission could be
achieved in 61% of patients at the end of induction phase
and there were no relapses in the 2-year follow-up period.
A similar study at our center revealed overall response rate
of 70% (Complete + Partial remission) and 30% failure rate
(Failure 20% + Death 10%).25 Major side effects associated
with CYC such as leukopenia, infections, gonadotoxicity,
hemorrhagic cystitis, and risk of malignancies in long-
term are associated with cumulative dose received. Fixed
low-dose intravenous CYC, that is, six doses of 500 mg
every 2 weekly followed by azathioprine (2 mg/kg) as
maintenance agent was compared with NIH regimen in
the European Lupus Nephritis Trial (ELNT).26 This trial,
which included predominantly Caucasians and excluded
severe renal involvement, showed no difference in long-
term outcomes like patient survival, renal survival, or
doubling of serum creatinine in the two arms. Another
trial27 done at our center comparing CYC given as ELNT
protocol with mycophenolate mofetil (MMF) for induction
in patients with LN showed similar renal outcomes in both
the arms. A total of 100 patients were equally randomized
to receive either CYC or MMF. At 24 weeks, 37 patients in
each group achieved the primary end point. The complete
remission rate was 50% in CYC and 54% in MMF group.
Mycophenolate mofetil: MMF was first used in induction
phase in a pilot study conducted in Chinese patients
with class IV LN and was shown to be non-inferior to
oral CYC.28 Subsequently, a multiethnic study comparing
MMF with intravenous CYC, by Ginzler et al.29 showed
non-inferiority of MMF as compared to CYC. One of the
largest multicentric randomized control trials by Appel et
al.,30 Aspreva Lupus Management Study (ALMS) involving
370 patients comparing intravenous monthly CYC with
MMF showed similar clinical response rates (53% vs. 56%,
respectively) at the end of 6 months in both the arms.
MMF had better response rates compared to CYC in Blacks
and Hispanics (60% vs. 39%).
Although guidelines for management of LN including
ACR, EULAR/ERA-EDTA, and KDIGO recommend CYC or
MMF as agents for induction in LN, high dose CYC (NIH
regimen) is routinely reserved for severe renal disease
(Sr Creatinine >3 mg/dL), crescentic glomerulonephritis,
TMA, and in the presence of concomitant extraglomerular
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 Lupus Nephritis—Current Understanding and Management CHAPTER 148 961

lesions like central nervous system (CNS) lupus or diffuse 0.6 mg/kg/day of prednisolone), called multitargeted
alveolar hemorrhage. therapy (MTT), as induction therapy was compared with
intravenous monthly CYC (0.75 g/m2) in 368 Chinese
Calcineurin inhibitors (CNIs): CNIs act by inhibiting T-cell
patients with active LN. MTT was superior to CYC, with
activation and, in turn, decreasing B-cell activation and
complete remission rates being 46% versus 26% at the
antibody production. Furthermore, it stabilizes the actin
end of 6 months. However, rates of serious infections were
cytoskeleton in podocytes, thus contributing to reduction
higher in the MTT group.35
in the degree of proteinuria. However, long-term uses of
CNIs are associated with nephrotoxicity and there is a
higher chance of relapse once the drug is withdrawn. Maintenance Therapy
After the induction phase, maintenance immuno­
Cyclosporine: Cyclofa-Lune study31 involved 40 patients
suppressive agent is necessary to reduce the risk of
of proliferative LN who were randomized to Cyclosporine
flares and further renal damage. NIH trials showed that
A and intravenous CYC. Clinical outcomes at the end of
maintenance with quarterly pulses of intravenous CYC
induction phase and maintenance phase were similar
for a period of 2 years had lesser episodes of relapses
between two groups; response rates were 52% versus 43%
in comparison to no maintenance. 24 Contreras et al. 36
in CYC and Cyclosporine arms, respectively at the end
showed that maintenance with MMF or azathioprine was
of induction, and they were 38% versus 58% for overall
better than quarterly pulses of CYC in terms of efficacy and
response at the end of maintenance phase. The extended
side effects.
follow-up (median: 7.7 years) of these patients showed
similar rates of renal survival, patient survival, and MAINTAIN trial:37 It included 105 predominantly white
proteinuria in the two arms.32 patients induced with intravenous CYC by ELNT regimen
and were followed up for 5 years. There was no statistical
Tacrolimus: Comparison of tacrolimus with MMF for
difference between rates of renal flare between MMF
induction in active LN patients showed similar rates of
(19%) and azathioprine (25%) maintenance, respectively.
complete remission at the end of 6 months.33 In those
with pure membranous LN, tacrolimus resulted in higher ALMS maintenance trial:38 It included 227 patients who
response rates of 100% as compared to 75% in MMF group. achieved remission with MMF induction and were
However, the rates of relapses by the end of 5 years were randomized to MMF and azathioprine maintenance. At
higher in those who received tacrolimus (62%) than those 36 months, composite outcome which included renal
who received MMF (42%).34 flare, ESRD, doubling of serum creatinine, death, or use of
rescue therapy was significantly lesser in the MMF group
Voclosporin: Voclosporin is a structural analogue (trans-
than the azathioprine group (16.4% vs. 32.4%). The ALMS
isomer) of cyclosporine which is fourfold more potent
maintenance trial, which included multiethnic patients,
than cyclosporine and is associated with lesser off-target
larger number of patients, and had compared composite
side effects such as cosmetic effects and nephrotoxicity. In
outcomes, favors use of MMF as maintenance agent
addition, it does not require drug level monitoring owing
over azathioprine. The ACR14 and KDIGO13 guidelines
to stable pharmacokinetics. In a recently completed phase
recommend use of either MMF or azathioprine as
2 trial on patients with LN, voclosporin, added to MMF
maintenance agent; however, 2019 EULAR/ERA-EDTA23
and low-dose steroid achieved complete renal remission
guideline recommends MMF maintenance specifically
in 32.6% patients with 23.7 mg twice a day dosage regimen
for patients induced with MMF. Duration of maintenance
as compared to 19.3% in placebo group. 34 The phase
immunosuppression is recommended to be at least 3
III AURA-LV trial evaluating the efficacy and safety of
years in patients who achieve complete remission at
voclosporin in patients with active LN is ongoing, with
the end of induction therapy.23 In those with high risk of
interim analysis showing promising results.
deterioration of renal function such as failure to achieve
Multitargeted therapy: Combination of tacrolimus complete remission after induction therapy, frequent
(4 mg/day) with MMF (1 g/day) and steroids (intravenous renal flares, and high disease activity index, prolonged
methylprednisolone 500 mg for 3 days followed by immunosuppression is given usually.

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 962 SECTION 11 Nephrology
Newer Therapies
Biological Agents
Despite the use of conventional immunosuppressive
agents, response rates of LN are only 60–70% at the end of
induction therapy. High rates of relapses after achieving
remission and reduction of drug toxicity have been unmet
needs in the management of LN. Hence, there is need for
newer drugs which are safer and more effective. Biological
agents with specific targets in the immune system have
been used as alternative options for conventional drugs for
achieving higher rates of remission, managing refractory
disease and as steroid sparing agents.
Rituximab: This is a chimeric monoclonal antibody against
CD20 on the B-cell surface. Several nonrandomized
studies have shown efficacy of rituximab in managing
patients with LN. LUNAR (Lupus nephritis assessment
with Rituximab) trial39 was a placebo-controlled phase
3 RCT. Those in rituximab arm received 1,000 mg of
rituximab 2 weeks apart at the start and it was repeated
after 6 months. All the patients received three pulses of
intravenous methylprednisolone followed by oral steroids
along with MMF at a dose of 2–3 g/day. Renal response
at the end of 52 weeks was not different between both
the arms (57% vs. 46% in rituximab vs. placebo arms).
However, rituximab was shown to be effective in refractory
LN. 40 Rituximab has also been proven to be effective
as a steroid sparing agent in a pilot trial of 50 patients
of active LN who were given two doses of 1 gm/dose
rituximab 2 weeks apart along with MMF and single dose
of intravenous methyl prednisolone (500 mg). About 86%
of patients achieved response (52% complete response
and 34% partial response) at the end of 52 weeks.41 Based
on the encouraging results, an open label, multicentric
RCT (RITUXILUP) was being carried out using rituximab
for steroid sparing effect. Rituximab or any B-cell depleting
agent causes B-cell activating factor/B lymphocyte
stimulating agent (BAFF/BLyS) to increase, which in
turn can lead to early repopulation of remnant B-cells.
So, combination of agents to block both would have the
maximum effect. To test this hypothesis, CALIBRATE
(ClinicalTrials.gov Identifier: NCT02260934) trial was
conducted where in patients with resistant active LN were
treated with CYC and rituximab followed by belimumab.
An interim analysis42 of data from CALIBRATE shows:
MU-148.indd 962
„„ Anti-BAFF following anti-CD20 for LN did not improve
clinical outcome at week 24;
„„ Anti-BAFF delayed blood B-cell reconstitution
following B-cell depletion; and
„„ Anti-BAFF following anti-CD20 was not associated
with hypogammaglobulinemia or an increase in
serious infections. Further analyses at 48 weeks and
beyond are awaited.
Belimumab: This humanized monoclonal antibody
binds to BAFF leading to decreased activation of B-cells.
Belimumab is the only biological agent approved for
treatment of active SLE. The BLISS-LN (Efficacy and safety
of Belimumab in patients with Active Lupus Nephritis)
study was recently announced to have favorable findings;
although, the results are yet to be published (https://
www.clinicaltrialsarena.com/news/gsk-benlysta-sle-
phaseiii-data/). It met its primary endpoint demonstrating
that a statistically significant greater number of patients
achieved Primary Efficacy Renal Response over 2 years
when treated with belimumab plus standard therapy
compared to placebo plus standard therapy in adults
with active LN (43% vs. 32%, odds ratio (95% CI) 1.55
(1.04, 2.32), p=0.0311). Based on the positive post hoc
analyses from trials in non LN patients and the benefits of
belimumab in observational studies involving LN, it has
been suggested to be used as add-on in treating extrarenal
flares/disease activity in LN patients by the 2019 EULAR/
ERA-EDTA guideline. 23 It can also be used as steroid
sparing agent.
Obinutuzumab: NOBILITY trial 43 —In patients with
proliferative LN, Obinutuzumab (intravenous) in addition
to MMF (2–2.5 g/day) and steroids (0.5 mg/kg/day of
prednisone followed by taper) versus placebo in addition
to MMF and steroids at same doses as intervention arm—
overall renal response was higher than placebo arm at
52 weeks. Obinutuzumab was as safe when compared
to placebo. From this trial, it becomes apparent that
more effective B-cell depletion results in better clinical
outcome, unlike the LUNAR trial. More stringent CD19
B-cell depletion could be achieved with Obinutuzumab
as compared to Rituximab as Obinutuzumab is a type
II monoclonal antibody known to enhance antibody
dependent cytotoxicity of B-cells and therefore, better and
deeper response.
29-01-2021 15:01:51
 Lupus Nephritis—Current Understanding and Management
Other biological agents that were tested or being tested
in clinical trials for Lupus Nephritis are—
Trials which failed or were terminated:
„„ Abatacept (CTLA4-Ig)—(ACCESS trial)—failed to meet
the endpoint
„„ Bortezomib (plasma cell proteasome inhibitor)—trial
terminated
„„ Rituximab (anti-CD20)—failed to meet endpoint
„„ Ocrelizumab (anti-CD20)—failed to meet endpoint
„„ Sirukumab (anti-IL6)—failed to meet endpoint
„„ Tabalumab (anti-BLyS)—failed to meet endpoint
Trials which showed encouraging results or are ongoing:
„„ Laquinimod—encouraging phase 2 trial results
„„ Obinutuzumab: humanized anti-CD20 antibody:
NOBILITY—phase 2 clinical trial—encouraging
results—show better overall renal response than
placebo arm
„„ Belimumab—anti-BLyS/BAFF antibody: BLISS-LN—
phase 3 clinical trial-met the primary endpoint
„„ Rituximab and cyclophosphamide followed by
belimumab: CALIBRATE—phase 2 clinical trial
„„ Anifrolumab—anti-IFN alpha-R antibody: phase 3
clinical trial—TULIP-LN1-ongoing
„„ Voclosporin—calcineurin inhibitor: AURA-LV-phase
2 trial—met its primary endpoint; AURORA phase
3 clinical trial (https://www.clinicaltrialsarena.
com/news/aurora-trial-lupus-kidney-disease-drug-
therapy/): met the primary endpoint
Conclusion
LN is characterized by flares and about 30–40% of patients do
not respond to conventional induction therapy. Protocol repeat
biopsy is a promising tool to monitor LN. Less toxic and more
effective agents are the unmet needs in the management of LN.
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27. Rathi M, Goyal A, Jaryal A, et al. Comparison of low-dose
intravenous cyclophosphamide with oral mycophenolate mofetil
in the treatment of lupus nephritis: Kidney Int. 2016;89(1):235-42.
28. Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil
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30. Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil
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32. Závada J, Sinikka Pesicková S, Rysavá R, et al. Extended follow-up of
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33. Mok CC, Yong KY, Yim CW, et al. Tacrolimus versus mycophenolate
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34. Rovin BH, Solomons N, Pendergraft WF 3rd, et al. A randomized,
controlled double-blind study comparing the efficacy and safety of
dose-ranging voclosporin with placebo in achieving remission in
patients with active lupus nephritis. Kidney Int. 2019;95(1):219-31.
35. Bao H, Liu ZH, Xie HL, et al. Successful treatment of class V+IV
lupus nephritis with multitarget therapy. J Am Soc Nephrol.
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36. Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for
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37. Houssiau FA, D’Cruz D, Sangle S, et al. Azathioprine versus
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38. Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus
azathioprine as maintenance therapy for lupus nephritis. N Engl J
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39. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in
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40. Weidenbusch M, Römmele C, Schröttle A, et al. Beyond the LUNAR
trial. Efficacy of rituximab in refractory lupus nephritis. Nephrol Dial
Transplant. 2013;28(1):106-11.
41. Condon MB, Ashby D, Pepper RJ, et al. Prospective observational
single-centre cohort study to evaluate the effectiveness of treating
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oral steroids. Ann Rheum Dis. 2013;72(8):1280-6.
42. Aranow C, Dall’Era M, Byron M, et al. FRI0305 Phase 2 trial of
induction therapy with anti-cd20 (RITUXIMAB) followed by
maintenance therapy with anti-baff (BELIMUMAB) in patients with
active lupus nephritis. Ann Rheum Dis. 2018;77:690.
43. Furie R, Aroca G, Alvarez A, et al. A Phase II Randomized, Double-
Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety
of Obinutuzumab or Placebo in Combination with Mycophenolate
Mofetil in Patients with Active Class III or IV. Lupus Nephritis
[abstract no. 939]. Arthritis Rheumatol. 2019;71(10).
29-01-2021 15:01:51
 CHAPTER

149 Diagnosis and Management of

Nephrotic Syndrome
Deepti Sharma, Sandeep S, Gopikrishnan R

Abstract 
Nephrotic syndrome is an important presentation of glomerular disease featured by heavy proteinuria, hypoalbuminemia,
and edema. The etiology of nephrotic syndrome is more complex and heterogenous in adults compared to children. The
renal function is often normal but can progress to chronic renal failure which depends on the duration and amount of
proteinuria. Acute renal failure is rare and mostly caused by a precipitating event. Early recognition is possible through
urine protein estimation, but a renal biopsy is often recommended. Current treatment recommendations are mostly based
on randomized control trials (RCTs) in children, and there are only small RCTs and a few case series studies in adults.
Diuretics are required in large doses due to the low-serum albumin levels. Immunosuppressive treatment is often used with
little evidence. Prophylactic treatment to prevent infection or thrombosis is not recommended routinely unless indicated.

Introduction may modulate the passage of macromolecules across

Nephrotic syndrome is a glomerular disease, defined
as a pentad of proteinuria more than 3.5 g/day,
hypoalbuminemia less than 3.5 g/dL, edema, hyper­
cholesterolemia, and lipiduria.1 Patients present with
edema, typically periorbital or at dependant sites or as a
complication of nephrotic state such as thromboembolism.
Etiology
Ne p h ro t i c s y n d ro m e may b e d u e t o a p r i ma r y
glomerulopathy, secondary to systemic diseases or as a
result of genetic mutations. The primary disorders are
minimal change disease, focal segmental glomerulo­
sclerosis, and membranous nephropathy (MN). Secondary
causes are elaborated in Table 1.
Pathophysiology and Clinical Manifestation
Proteinuria
Protein loss is due to glomerular proteinuria. Electrical
potential differences generated by transglomerular flow
the glomerular capillary wall.2 The podocyte appears
to be the major target of injury in idiopathic nephrotic
syndrome. Adult-onset primary MN and focal segmental
glomerulosclerosis (FSGS) may be due to autoantibodies
to podocyte or circulating factor that affect the podocyte.
Hypoalbuminemia
Most of albumin loss is due to urinary excretion leading
to reduction in total protein and serum albumin with
increased α2-globulin and reduced γ-globulin fraction.
Hepatic albumin synthesis is increased in response to the
albumin loss mediated by an increase in gene expression
and the release of an unidentified circulating factor.3
Edema
Two major mechanisms have been thought to be
responsible for the development of edema. One is
“underfill hypothesis” where secondary sodium retention
due to low plasma oncotic pressure causes shifting of
fluid into the interstitium leading to underfilling of the

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 966 SECTION 11 Nephrology

TABLE 1 Secondary causes of nephrotic syndrome

MCD FSGS MN Others

Drugs Virus associated Autoimmune diseases zz Diabetes
zz NSAID zz HIV-1 zz Class V lupus nephritis zz Plasma cell disorder
zz Interferon-a zz Parvovirus B19 zz Rheumatoid arthritis zz Paraprotein deposit disease

zz Lithium zz Simian virus 40 (SV40) CMV zz Sarcoidosis zz AA amyloidosis

zz Gold Drug induced zz Sjogren zz Pre-eclampsia

Allergy zz Heroin Infections

zz Pollens zz Interferon zz Hepatitis B

zz House dust zz Lithium zz Hepatitis C

zz Insect stings zz Pamidronate zz HIV

zz Immunizations zz Sirolimus zz Syphilis

zz Poison oak zz Anabolic steroids zz Malaria

Malignancy zz Tyrosine kinase inhibitors zz Schistosomiasis

zz Hodgkin disease Hyperfiltration injury Malignancy

zz Mycosis fungoides zz Renal agenesis zz Solid tumors (colon, stomach, lung, prostate)

zz CLL

vasculature and activation of the renin–angiotensin–
aldosterone system (RAAS) causing further sodium
and water retention. Second mechanism is “Overfill
hypothesis” where primary sodium retention occurs due
abnormalities in tubular function like increased activity
of the Na-K-ATPase pump, epithelial sodium channel
(ENaC),4 and relative resistance to ANP and urodilatin due
to increased phosphodiesterase activity.
Enhanced hepatic synthesis of lipoproteins containing
apolipoprotein B and cholesterol and diminished
catabolism caused by inhibition of lipoprotein lipase
due to elevated levels of sialylated angiopoietin like-4
(especially triglycerides) is thought to be the mechanism
behind this. Lipoprotein glomerulopathy is a rare form of
glomerular disease that is associated with dyslipidemia
and lipoprotein deposits in the glomeruli.

Hypercoagulability AKI and CKD in Nephrotic Syndrome

Patients with the nephrotic syndrome have an increased
incidence of arterial and venous thrombosis, particularly
deep vein thrombosis (DVT) and renal vein thrombosis.
Thrombotic state occurs mainly due to urinary loss of
antithrombin III, plasminogen, protein C and S. Increased
platelet activation, thrombocytosis, hyperfibrinogenemia,
and inhibition of plasminogen activation also contributes.
Renal vein is a common site of thrombosis in nephrotic
syndrome, possibly due to stimulation of thrombin
production in the glomerular efferent vessels as a result of
glomerular injury.
Hyperlipidemia
Hyperlipidemia is triggered by the reduction in plasma
oncotic pressure. The severity of the hyperlipidemia
is inversely related to the fall in oncotic pressure and
resolves with the remission of nephrotic syndrome.
Acute kidney injury (AKI) is less common in nephrotic
syndrome. Most cases of nephrotic syndrome have a risk
of progression to chronic kidney disease (CKD) except
minimal change disease (MCD). Greatest risk factor is the
degree of proteinuria (>5 g/day). Table 2 shows various
causes for AKI in nephrotic syndrome.
Diagnosis
Urine Analysis
„„ Twenty-four hour urine protein estimation: More than
3.5 g/day is considered nephrotic-range proteinuria.
„„ Protein-to-creatinine ratio: It is only an alternative
to the 24-hour urine protein estimation. The total
protein-to-creatinine ratio (mg/mmol) on early
morning sample of urine is calculated. This ratio
correlates closely with daily protein excretion in

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 Diagnosis and Management of Nephrotic Syndrome CHAPTER 149 967

TABLE 2 Various causes for AKI in nephrotic syndrome TABLE 3 Serologic studies (marker and diagnosis)

zz AIN secondary to drugs (including diuretics) Serological marker Diagnosis

zz ATN due to volume depletion or sepsis Anti-PLA2R Primary MN (70–80%)
zz Hemodynamic response to NSAIDS, ACEI, ARBs Anti-THSD7A Primary MN (5%)
zz Nephrosarca ANA, anti-dsDNA, anti-Ro/La Lupus nephritis (MN), Sjögren (MN)
zz Pre-renal failure due to volume depletion HBSAg, Anti-HCV, HIV, Secondary MN
zz Renal vein thrombosis VDRL/FTA-Ab

zz Transformation of underlying glomerular disease PSA Ca prostates (MN)

CEA Ca colon (MN)
HIV antibody FSGS >> MN
g/1.73 m 2 of body surface area. A value more than Low C3.C4 levels MPGN Type 1
300 mg/mmol is considered nephrotic range. But this Plasma-free light chains Multiple myeloma (MN)
method has limitations and 24-hour urine protein
RA factor, Anti-CCP MN
estimation is more preferred.
RBS, HbA1c Diabetic nephropathy

Serologic Studies
A number of serologic studies often are obtained in the Histological Patterns
evaluation of patients with the nephrotic syndrome
See Table 4.
depending upon clinical setting (Table 3).

Renal Biopsy Management

In adult nephrotic syndrome, biopsy is indicated when
the etiology of persistent nephrotic-range proteinuria is in
doubt in order to determine management decisions.
Indication for biopsy:
„„ Adult with nephrotic syndrome
Management of nephrotic syndrome consists of general
supportive measures, disease-specific therapy for the
underlying cause in secondary nephrotic syndrome,
and immunosuppression in case of primary nephrotic
syndrome.

„„ Children with:

—— age <1 year or >12 years

General Supportive Treatment
—— Gross hematuria It includes measures to reduce proteinuria, edema,
—— Marked hypertension control blood pressure, and to address other metabolic
—— Renal failure without severe hypovolemia consequences of nephrotic syndrome.
—— Low C3 level

Imaging
„„ Ultrasound: It must be done routinely before planning
renal biopsy to rule out small kidneys or kidneys with
severe cortical thinning, as they indicate chronic
irreversible disease. These findings can limit renal
biopsy and aggressive immunosuppressive therapy.
„„ 2D Echocardiography: When infective endocarditis is
suspected.
„„ Renal Doppler: Indicated in patients with flank pain,
hematuria, and rapid worsening of renal function to
rule out renal vein thrombosis.
Treating Edema
All patients with nephrotic edema are initially treated with
diuretics and dietary sodium and water restriction. It is
recommended to restrict salt intake to less than 3 g per/
day and water intake less than 1.5 liter/day.5 Most patients
respond well to loop diuretics. They are highly protein-
bound but this bonding is reduced with hypoalbuminemia
resulting in a slower rate of delivery to the kidneys. Loop
of Henle may be relatively resistant to loop diuretics. Gut
edema also limits the oral absorption of diuretics. Thus,
the effective diuretic dose is usually higher in patients
with nephrotic syndrome. Intravenous infusion can also

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 968 SECTION 11 Nephrology

TABLE 4 Histopathological patterns

MCD FGGS MN
LM Normal Sclerosis in parts (segmental) of Homogenus thickening of capillary wall (H&E)
some (focal) glomeruli
Spikes in GBM (Silver stain)
EM Diffuse foot process Diffuse foot process effacement Sub-epithelial deposit on surface of GBM
effacement
Wrinkling and retraction of GBM Foot process effacement
Hyaline accumulation
IF No deposits IgM, C3, C1q (Classical) Diffuse global finely granular deposits of IgG along outer
surface of all capillary walls
Pathology Circulating Podocyte injury Immune complex and complement mediated podocyte injury
permeability factor (Secondary MN)
Abnormal regulation Nephron loss Autoantibody mediated podocyte injury
of T-cell

be tried as it increases the diuretic efficacy. Furosemide
40 mg orally twice a day or bumetanide 1 mg twice daily
is a reasonable starting dose and may be increased up
to a dose of 600 mg/day according to need. Patients who
do not respond adequately to loop diuretic require the
addition of a thiazide diuretic. Alternatively, amiloride 6
or acetazolamide7 can be combined with loop diuretics
in patients with refractory edema. Prior administration of
albumin increases the efficacy of diuretics.8
Proteinuria
Progressive loss of renal function can be reduced if
proteinuria can be reduced below 0.5 g/day. It can
be controlled by either blocking efferent arteriole
vasoconstriction or decreasing the preglomerular pressure
(antihypertensives). Angiotensin converting enzyme
inhibitors (ACEIs) and angiotensin-receptor blockers
(ARBs) are the agents of choice. They reduce proteinuria
independent of blood pressure and can be safely used in
normotensive patients. If proteinuria persists in spite of
ACEI/ARB, aldosterone antagonists can be added. They
can raise the serum creatinine by 30–40% as glomerular
filtration rate (GFR) is reduced, but should not be stopped
unless serum creatinine levels are continuously increasing.
Hypoproteinemia
Adequate dietary protein intake of 0.8–1 g/kg/day with
high carbohydrate to maximize the use of that protein
is recommended. In heavy proteinuria, add the amount
of urinary protein loss to dietary protein intake. As a last
resort, nephrectomy and renal artery embolization can be
done if protein loss cannot be managed medically.
Hypertension
Hypertension in nephrotic syndrome requires strict
control to delay the progression of renal disease and
prevent cardiovascular complications. Initially life style
modification can be adopted. High dose diuretics and
dietary salt restriction are necessary. The KDIGO guideline
recommends a target BP <130/80 mm Hg,9 but recent
SPRINT trial suggests a target of 120/80 mm Hg. ACEIs and
ARBs are the first choice. DHP-CCBs are not preferred as
they increase GFR causing worsening of proteinuria and
also add to peripheral edema.
Hyperlipidemia
Control of hyperlipidemia is important in preventing
cardiovascular complications. Dietary modification alone
has only a moderate effect on hyperlipidemia. Statin alone
is preferred in patients more than 50 years of age with
early stage CKD and in late stages, addition of ezetimibe is
recommended. In young adults, consider statin if having
significant comorbidity.
Prophylaxis for Thrombosis
The decision to prescribe prophylactic anticoagulation
must be balanced against the risk of bleeding. If the

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 Diagnosis and Management of Nephrotic Syndrome CHAPTER 149 969

bleeding risk is unclear, ATRIA Risk score or HAS-BLED
risk can be used to take a decision. Prophylactic low-dose
heparin is indicated in cases with high risk for thrombosis,
like in pregnancy or an immobilized patient, with a
serum albumin less than 2.5 g/dL. If albumin is less than
2 g/dL, full anticoagulation with low-molecular-weight
heparin (LMWH) or warfarin should be considered. 10
Patients with MN are at high risk for thrombosis, and if the
albumin level is very low and even if the risk of bleeding
is intermediate, they may benefit from anticoagulation.
Warfarin is preferred over LMWH because of low levels of
antithrombin III impeding efficacy.
Management and Prevention of Infection
R i s k o f i n f e c t i o n i s e x a c e r b a t e d b y n e p h ro t i c
immunodeficiency caused by T-cell transformation
dysfunction and urinary loss of immunoglobulins
including IgG and alternate pathway complement factors.
Patients may develop recurrent respiratory and urinary
tract infections, peritonitis, and sepsis; particularly with
encapsulated bacteria. Antibiotic with pneumococcal
coverage is the mainstay in infections and prophlylactic
pneumococcal vaccination is recommended. In case of
repeated infection, IgG level should be estimated and if
low IVIgG should be given to maintain a level above 600
mg/dL.11
Steroid Dependent (Table 5),
Frequently Relapsing and Resistant MCD
These patients should be started on second-line therapy.
This includes:
„„ Cyclophosphamide: 2–2.5 mg/kg/day orally for 12
weeks is given. Due to risk of infertility, banking of
sperm and ova is to be considered before starting
therapy.
„„ Calcineurin inhibitors:
—— Cyclosporine: 4–6 mg/kg/day for at least 12
months is given. Nephrologists prefer calcineurin
inhibitors over cyclophosphamide in young adults
to prevent infertility.
—— Tacrolimus: A dose of 2–4 mg twice daily, adjusted
to maintain a target level of 5–10 ng/mL is given. It
may be considered as a first line or second line in
patient with contraindication for or intolerance to
high dose corticosteroid.12
„„ MMF: 750–1,000 mg twice daily for 6 months may be
used in cyclosporine dependant cases but did not
appear as effective as cyclosporine in studies.
„„ Rituximab: It is a B-Lymphocyte depleting agent (anti-
CD20) and is used when disease is unresponsive to all
Terminologies regarding treatment outcomes of
TABLE 5
nephrotic syndrome

Treating MCD Complete Reduction of proteinuria to ≤0.20 g/day and serum

remission albumin >3.5 g/dL
Initial Treatment Partial Reduction of proteinuria to between 0.21 g/day and
remission 3.4 g/day ± decrease in proteinuria of ≥50% from
Low dose oral prednisolone (1 mg/kg/day up to maximum baseline
80 mg/day) should be started according to KDIGO No remission Failure to reduce urine protein excretion by 50%
guideline and recommends it to be continued up to 6 from baseline or persistent excretion uPCR >2000
months. Initial dose should be maintained for a minimum mg/g (>200 mg/mmol)
of 4 weeks if full remission achieved or 16 weeks if Steroid Persistence of proteinuria despite prednisolone
full remission not achieved. Once remission has been resistance therapy, 1 mg/kg/day for 16 weeks
achieved, dose should be tapered at least within 4 weeks Relapse Proteinuria ≥3.5 g/day occurring after complete
of response. Induction with methylprednisolone pulse remission obtained for >1 month
therapy may lead to rapid response and fewer relapses. Infrequent One relapse within 6 month of initial response, or
relapse one to three relapses in any 12-month period
If the patient has not achieved remission even after
12–16 weeks of treatment, consider repeating biopsy, Frequent Two or more relapses within 6 month of initial
relapse response, or four or more relapses in any 12-month
as it can be FSGS which might have been missed due to period
limited number of nephrons in earlier specimen. If MCD Steroid Two consecutive relapses during corticosteroid
presents with non-nephrotic range proteinuria, it can dependence therapy, or within 14 days of completing
be managed with ACEIs/ARBs and there is no need for corticosteroid therapy
starting steroids. Reference: Comprehensive Clinical nephrology - 6th edition

MU-149.indd 969 29-01-2021 15:01:47

 970 SECTION 11 Nephrology
other treatments, but RCT have not been performed.
Non RCT studies have shown benefit and reduction
in relapse in corticosteroid dependant and frequent
relapse cases. 13 A dose of 375 mg/m 2 weekly for 4
weeks.
FSGS
It is very difficult to distinguish between primary and
secondary FSGS and most of the times they are treated
as primary FSGS. All patients will benefit from good
supportive treatment and immunosuppression.
Initial Treatment
It consist of 6 months of continuous corticosteroid (1 mg/
kg/day), later tapered over 4–8 weeks.
Steroid Resistant Cases
„„ Cyclosporine: Low dose of 3–6 mg/kg/day is given for
2–6 months. Recent studies show that combination
of cyclosporine and corticosteroids has a higher
remission rate.14
„„ Tacrolimus: Used in cases resistant or intolerant to
cyclosporine.
„„ MMF and Dexamethasone: As per KDIGO guidelines,
they can be given in corticosteroid resistant cases that
are intolerant to calcineurin inhibitors.
„„ Rituximab: Used when all other treatments fail and
this drug has shown promising results in steroid-
dependent cases.
„„ Abatacept (CTL A-4-Ig): An inhibitor of T-cell
costimulator y molecule B7-1(CD-80) showed
remission in some patients and further studies are in
progress.15
Secondary FSGS
Patients with primary FSGS typically present with an acute
onset nephrotic syndrome, whereas slowly increasing
asymptomatic proteinuria and renal insufficiency over
a period of time without profound hypoalbuminemia
or edema are characteristic of secondary FSGS. Unlike
primary FSGS, these patients are less responsive to
immunosuppression and the mainstay of the treatment
is to correct the primary cause and provide supportive
treatment.
MU-149.indd 970
Membranous Nephropathy
It is very difficult to treat MN due to its chronic nature, the
tendency for spontaneous remission and relapse and the
variability in clinical severity. Specific immunosuppressive
therapy should not be considered unless the patient
has a persistent nephrotic-range proteinuria (>4 g/day)
and it has not declined more than 50% from baseline,
over a minimum period of 6 months, despite maximum
antihypertensive and antiproteinuric therapy.16 Treatment
of secondary MN focuses on cessation of the offending
drug or effective treatment of the underlying disease.
Immunosuppression
„„ Corticosteroids: RCTs showed no significant long-term
benefit on proteinuria or rate of disease progression.
Therefore, use of oral corticosteroids as a single agent
is not recommended.
„„ Cytotoxic agents with corticosteroids (PONTICELLI
REGIMEN): Benefitted in patients at moderate risk
for progression. It starts with methylprednisolone
pulses 1 g IV for 3 days at the beginning of months
1, 3, and 5 followed by oral methylprednisolone 0.4
mg/kg/day for 27 days, and each cycle followed by
1 month of cytotoxic agent (cyclophosphamide or
chlorambucil).17 Cyclophosphamide-based regimen is
preferred because of a better safety profile.
„„ Calcineurin inhibitors : Given in patients with
corticosteroid-resistant MN but has a higher relapse
rate.
—— Cyclosporine: It is used along with low-dose
corticosteroids. It may reduce proteinuria not only
through its immunosuppressive effects but also by
direct effects on the podocyte.
—— Tacrolimus: It can be used as monotherapy, but
relapse rate was found to be high.
„„ MMF: Along with steroids, it showed good initial
response, but relapse rate was high.18
„„ Rituximab: Used in steroid resistant cases. Decline in
anti-PLA2R antibody and proteinuria was achieved,
subsequently resulting in a partial or complete
remission.
Plasma Exchange
It may be useful in resistant MN, severe nephrotic
syndrome, and high anti-PLA2R antibody titer cases. A
29-01-2021 15:01:47
 Diagnosis and Management of Nephrotic Syndrome
study in such type of patients, treated with a “rescue”
regimen consisting of four plasma exchanges, 20 g of
intravenous (IV) immunoglobulin, and 375 mg/m2 of
rituximab showed shorter remission time compared to
previous regimens.19
Adrenocorticotropic Hormone (ACTH)
ACTH acts via melanocortin 1 receptor expressed on
podocytes. Synthetic form of ACTH, 1–2 mg weekly
intramuscularly for 1 year showed prolonged remission in
the majority of patients with MN.20
Conclusion
Nephrotic syndrome includes a wide spectrum of primary
glomerular disorders and secondar y diseases. Early
recognition through urine protein estimation and bringing
out the histological variant through renal biopsy aids in
planning treatment properly in order to prevent progression
into renal failure. At present, reducing proteinuria and
immunosuppression remains the mainstay in most of the
cases and larger RCTs are lacking. Many new treatment targets
have been identified, which needs further studies. A proper
recommendation for management of nephrotic syndrome
needs to be postulated.
References
1. Or th SR, Ritz E. The nephrotic syndrome. N Engl J Med.
1998;338(17):1202-11.
2. Hausmann R, Kuppe C, Egger H, et al. Electrical forces determine
glomerular permeability. J Am Soc Nephrol. 2010;21(12):2053-8.
3. Sun X, Martin V, Weiss RH, et al. Selective transcriptional
augmentation of hepatic gene expression in the rat with Heymann
nephritis. Am J Physiol. 1993;264(3 Pt 2):F441-7.
4. Svenningsen P, Bistrup C, Friis UG, et al. Plasmin in nephrotic
urine activates the epithelial sodium channel. J Am Soc Nephrol.
2009;20(2):299-310.
5. Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. BMJ.
2008;336(7654):1185-9.
MU-149.indd 971
CHAPTER 149 971
6. Hoorn EJ, Ellison DH. Diuretic resistance. Am J Kidney Dis.
2017;69(1):136-42.
7. Fallahzadeh MA, Dormanesh B, Fallahzadeh MK, et al. Acetazolamide
and hydrochlorothiazide followed by furosemide versus furosemide
and hydrochlorothiazide followed by furosemide for the treatment
of adults with nephrotic edema: a randomized trial. Am J Kidney
Dis. 2017;69(3):420-27.
8. Fliser D, Zurbrüggen I, Mutschler E, et al. Coadministration of
albumin and furosemide in patients with the nephrotic syndrome.
Kidney Int. 1999;55(2):629-34.
9. Kidney Disease: Improving Global Outcomes. Clinical practice
guideline for the evaluation and management of chronic kidney
disease. Kidney Int. 2013;3(Suppl 1):1-150.
10. Lee T, Biddle AK, Lionaki S, et al. Personalized prophylactic
anticoagulation decision analysis in patients with membranous
nephropathy. Kidney Int. 2014;85(6):1412-20.
11. Ogi M, Yokoyama H, Tomosugi N, et al. Risk factors for infection
and immunoglobulin replacement therapy in adult nephrotic
syndrome. Am J Kidney Dis. 1994;24(3):427-36.
12. Li X, Liu Z, Wang L, et al. Tacrolimus monotherapy after intravenous
methylprednisolone in adults with minimal change nephrotic
syndrome. J Am Soc Nephrol. 2017;28(4):1286-95.
13. Ruggenenti P, Ruggiero B, Cravedi P, et al. Rituximab in
steroiddependent or frequently relapsing idiopathic nephrotic
syndrome. J Am Soc Nephrol. 2014;25(4):850-63.
14. Laurin LP, Gasim AM, Poulton CJ, et al. treatment with glucocorticoids
or calcineurin inhibitors in primary FSGS. Clin J Am Soc Nephrol.
2016;11(3):386-94.
15. Hogan J, Bomback AS, Mehta K, et al. Treatment of idiopathic focal
segmental glomerulosclerosis with adrenocorticotropic hormone
gel. Clin J Am Soc Nephrol. 2013;8(12):2072-81.
16. Johnson R, Feehally J, Floege J, et al. Comprehensive Clinical
Nephrology, 6th edition. Philadelphia: Elsevier; 2019.
17. Ponticelli C, Zucchelli P, Passerini P, et al. A 10-year follow-up of a
randomized study with methylprednisolone and chlorambucil in
membranous nephropathy. Kidney Int. 1995;48(5):1600-4.
18. Dussol B, Morange S, Burtey S, et al. Mycophenolate mofetil
monotherapy in membranous nephropathy: a 1-year randomized
controlled trial. Am J Kidney Dis. 2008;52(4):699-705.
19. Müller-Deile J, Schiffer L, Hiss M, et al. A new rescue regimen
with plasma exchange and rituximab in high-risk membranous
glomerulonephritis. Eur J Clin Invest. 2015;45(12):1260-9.
20. van de Logt AE, Beerenhout CH, Brink HS, et al. Synthetic
AC TH in high risk patients with idiopathic membranous
nephropathy: a prospective, open label cohort study. PLoS ONE.
2015;10(11):0142033.
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 CHAPTER

150 Dietary Salt and Hypertension

PP Varma

Abstract 
Epidemiological data suggests that dietary salt is a modifiable risk factor for hypertension; especially in those with salt
consumption in the highest tertile. WHO recommends 5 gm of salt intake per day but we in India are consuming 9–12 gm
of salt per day. Besides hypertension, salt is also incriminated for CV mortality, stroke, and obesity. Hence, there is need
to restrict salt consumption to check the menace of hypertension. Here we bring the update on association of salt and
hypertension.

Introduction (NaCl) crystals are white in color and readily dissolve in

Today over 30% of world’s adult population has
hypertension (HT). Over 60% of the cerebrovascular
diseases and about half of ischemic heart diseases are
attributable to HT. Dietary salt is one of the modifiable
culprits in causation of HT. Present commentary is about
data on dietary salt and its association with HT.
Historical Perspective
During paleolithic times, hunter gathering man was
dependent on raw meat and his dietary salt intake was
less than 1 gm a day. Around 5,000 years back, Chinese
learnt that food can be preserved with the help of salt
and Egyptian used this knowledge for preservation of
mummies. Civilizations started developing along the salt
routes, which was considered a precious entity. In Libya,
salt was exchanged for equivalent amount of gold. French
salt tax “gabellee” probably incited French revolution. In
India, Britishers did not allow Indians to make their own
salt and wanted them to buy expensive salt brought from
England. This was the genesis of famous Dandi March,
an important event in the freedom struggle of India. Salt
water. The molar mass is 58.5 g/mol.
With agricultural revolution our food habits changed,
and from 100% animal food, now plant based food formed
50% of our diet; however, salt intake remained less than
a gram per day. Earliest comment relating to dietary salt
and HT came from Chinese doctor, Huang Ti Nei Ching
Su Wen, who wrote in The Yellow Emperor’s Classic of
Internal Medicine—“therefore, if large amounts of salt are
taken, the pulse will stiffen or harden.” However, over the
years with civilization and changing food habits our dietary
salt intake has increased and this is being correlated with
increasing prevalence of HT. Today average Indian salt
intake is 9–12 gm/day against WHO recommendation
of 5 gm.4 In this article we shall review the available data
showing correlation between salt intake and HT.
Consumption and Its Source
A study reported by George Institute from India found
that average Indian is taking 10.98 gm of salt per day.
Salt consumption is higher in south Indians than north
Indians. If one looks at the source of consumed salt, there

MU-150.indd 972 29-01-2021 15:01:42


are three sources: our natural food (cereals, vegetables,
fruits, non-vegetables) contains less than a gm of salt
and makes 10% of daily intake. Another 2–3 gm (20–30%)
is added as cooking salt in our food and vegetables.
However, 70% of our consumed salt comes from processed
food—snacks, bread and bread products, pizza, French
fries, pasta, pickles, sauces, etc. It may be interesting to
know that each large slice of bread has 500 mg of salt in it.
Twenty-four hour urinary sodium estimation is the best
marker of salt consumption.
Data on Salt Studies and Hypertension
„„ Epidemiologically: It is known that areas with low salt
consumption have lower incidence of HT. Solomon
islanders consume less than 2 gm of salt per day and
have an HT prevalence of 1%. Among Yanomamo
Indians from Brazilian amazon, 84% have urinary
sodium excretion of 1 mmol/24 hours. Their mean BP
is 96/60.0 mm Hg (78/37–128/86 mm Hg) and there
is no change in BP with age. In tribes with salt intake
of 3 gm/day, prevalence of HT is 3%. Interestingly in
Newfoundland average salt intake is of 6.7–7.3 gm
and HT prevalence is 15%. Its coastal area where salt
consumption is of 8.4–8.8 gm/day, HT prevalence is
27%. This data suggests that with increasing salt intake
prevalence of BP increases.
„„ The effect of life style change and migration is
exemplified by Yi community living in southwestern
China. Those still living in mountainous environment
and eating sodium-poor diet had yearly rise of systolic
and diastolic BP by 0.13 and 0.23 mm Hg, respectively.
In contrast, Yi community who had migrated in urban
areas and consumed sodium-rich diet had a yearly
rise of 0.33 mm Hg for both systolic and diastolic BP,
stressing the importance of life-style change on BP.
„„ Fi r s t g o o d a n i m a l s t u d y a b o u t s a l t a n d i t s
correlation with HT came from chimpanzees that
are phylogenetically similar to humans. Normally
chimpanzees eat diet rich in fruits/vegetables with
dietary salt content of 0.5 gm/day. Study was done on
26 chimpanzees.1 To their normal diet ~15 gm of salt
was added. BP started rising and after 84 weeks BP rose
by 33/10 mm Hg. Again chimpanzees were reverted
back to their original diet, without added salt. BP
reverted back to normal 6 months later. Study shows
the effect of salt on BP in chimpanzees.
MU-150.indd 973
Dietary Salt and Hypertension CHAPTER 150 973
„„ The first double-blind controlled study of moderate
salt restriction on human was from MacGregor et al.3
They recruited 19 patients with mild to moderate HT
(average supine BP of 156/98 mm Hg). Patients were
advised not to take sodium laden food. After 2 weeks
of dietary salt restriction, patients entered an 8-week
double-blind randomized crossover study. One group
was given “Slow Sodium Ciba” (Ciba-10 mmol of
sodium per tablet) and other group received “Slow
Sodium Placebo.” In fourth week, the mean supine BP
was 7.1 mm Hg (6.1%) lower in slow sodium placebo
group (p<0.001). Urinary sodium excretion in the
fourth week of slow sodium ciba was 162±9 mmol/24
hours and that in the fourth week of slow sodium
placebo was 86±9 mmol/24 hours (p<0.001). They
suggested that moderate sodium restriction should
become part of the management of essential HT and
one should avoid sodium-laden foods.
„„ First large international study on salt and HT was
“Intersalt study.” 2 The study was conducted in 52
centers from 22 countries; each with sample size
of 200 with a total of 10,079 participants. Four of
these 52 centers, were tribal belts with very low
salt consumption. Data from 48 centers showed an
insignificant trend but pooled data from 52 centers
showed that higher salt consumption was associated
with age-related rise in BP. This study prompted lot
of debate whether to reduce salt consumption or not.
A revisit of study inferred that 100 mmol of extra salt
intake (70 mmol vs. 170 mmol) was associated with
higher BP by 5–7/2–4 mm, stressing the need to reduce
salt intake.
„„ A community trial was done to study the effect of salt on
HT in Portugal. Two communities with 800 persons each
were selected. Both had salt intake of 21 gm/day and HT
prevalence of 30%. In one of the two communities with
extensive health education, salt intake could be reduced
to 12 gm/day. By the end of second year BP dropped
in intervention community by 13/6 mm Hg. BP drop
was across all age groups and in both normotensives
and hypertensives alike. Those with greatest fall in salt
excretion had the largest fall in BP.
„„ Trials of hypertension prevention (TOHP I & II): TOHP
I was conducted over 18 months’ duration and TOHP
II for over 36 months. Lower salt intake (lower by 44
mmol and 33 mmol/day) in intervention group was
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 974 SECTION 11 Nephrology
associated with 25% lower CV events. So, besides
lowering BP, lower salt intake is associated with lower
CV events also. 6 A metanalysis of 13 studies, with
177 025 participants (FU 3.5–19 years) showed that
higher salt intake was associated with greater risk of
stroke (RR1.23) and cardiovascular disease (RR 1.14).
A Finnish study on impact of salt and CV events,
comprising of 1,173 men and 1,263 women found that
increased sodium intake by 100 mmol/day increased
the hazard ratio for coronary artery disease, CV
disease, and all-cause mortality by 50% (HR of 1.51).
„„ INTERMAP study: A recent study (Hypertension
2018;71:631-37)9 included 4,680 persons from China,
Japan, UK, and the USA. This study addressed the
effect of dietary salt intake on BP and its possible
modulation with other dietary factors. Study found
that group with two SD higher sodium excretion was
associated with rise in BP by 3.5/1.7 mm Hg (p<0.001)
and most other 26 micro- or macronutrients in diet
had only a modest countervailing effects on Na-BP
relationship. The study again emphasized the need for
salt restriction as other micro- or macronutrients did
not make much difference.
„„ Prospective urban rural epidemiology (PURE) study
(Mente et al., 2018)10 was conducted in 18 countries
on a population of 1,68,000, in the age group of 35–70
years. The 664 communities from low, middle, and
high income countries were selected. A 24-hour
sodium excretion was divided into three tertiles:
low—4.04, middle—4.70, and high tertile—5.75 gm.
The study found that mean systolic BP increased by
2.86 mm Hg per 1 gm increase in salt intake. Sodium
intake was also associated with cardiovascular disease
and strokes. This association was however significant
only in those falling in highest tertile of salt intake
(p<0.0001). Study suggested that those in highest
tertile of salt consumption had significant detrimental
effect.
„„ Dietary approaches to stop hypertension (DASH): In this
study 412 normotensive and hypertensive participants
were assigned to eat either typical American diet
(control diet) or DASH diet. DASH diet is rich in fruits,
vegetables, and has low-fat dairy products. Aim of the
study was to test if DASH diet reduced BP and if salt
reduction in patients on DASH diet had an additional
advantage. Study population was divided in three
groups:
MU-150.indd 974
—— high salt intake—150,
—— intermediate salt intake—100, and
—— low salt intake—50 mmol/day.
In control group, reduction of sodium intake from the
“high to the intermediate level” over 30 days, resulted in
reduction of systolic BP by 2.1 mm Hg (p<0.001) and in
the “from intermediate to the low level” by 4.6 mm Hg
(p<0.001). In DASH group salt reduction resulted in drop
of BP by 1.3 mm Hg (p=0.03) and 1.7 mm Hg (p<0.01)
“from high to intermediate” and “intermediate to low
salt” group respectively. Benefit of salt reduction was
observed in both sexes, all races and in normotensives
also. The study inferred that participants in DASH diet
had a significantly lower systolic BP at each sodium level.
If one compares control diet group with high salt intake
and DASH diet group with low salt intake, there is a BP
difference of 7.1 mm Hg in normotensives and 11.5 mm Hg
in hypertensives.
Few important points emerge from these studies:
„„ Epidemiological data clearly shows low prevalence of
HT in areas with low salt intake.
„„ Animal and human trials show drop in BP with
reducing salt intake and increase in BP with increased
salt intake.
„„ Cardiovascular mortality also increases with increase
in salt intake.
An important inference is that prevalence of HT and
risk of CV mortality is prominent and significant in group
with highest tertile of salt intake.
„„ Salt intake and obesity: It has been observed that
excessive salt intake is associated with obesity. As small
as 1 gm of extra salt consumption per day by children
and adolescents has been found to be associated
with consumption of 27 gm of sugar-sweetened soft
drink. There has been controversy, if obesity is due
to consumption of extra sugar or processed food
or due to extra salt. However, increasing evidence
suggests that there is direct link between salt intake
and obesity independent of total energy intake. Even
after adjusting variables like ethnic group, social status,
energy intake, educational status, smoking, alcohol
consumption, etc., 1 gram a day of extra salt increases
the risk of obesity by 28% (p=0.0002) in children and
26% (p<0.0001) in adults.
„„ Is very low salt intake detrimental: In the “Framingham
Offspring study”—a 16-year follow-up data, of 2,632
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 Dietary Salt and Hypertension CHAPTER 150 975

men and women between 30–64 years, showed that

very low intake of salt (<2.5 gm) is associated with
increased BP. This is in line with many workers who feel
that there is J-shaped curve between salt consumption
and hypertension (Fig. 1).

Salt Sensitive Hypertension

An important and debatable issue is that should salt
restriction advise be universal or only for those having
inappropriately high consumption/salt sensitive
population. Luft et al studied 14 subjects (7 white and 7
black) and gave them increasing doses of salt, 10-1500
meq/day. He found mean rise in blood pressure in both
groups but rise in blood pressure was higher in blacks
(Fig. 2); showing the racial difference. Salt sensitivity can
be studied by giving high and then low salt—1 week of 200
mmol and another week of 30 mmol of salt and then seeing
the BP response. A 24-hour urinary sodium is collected on
last day of the week to see compliance. However, long 29
days compliance for this test is an issue, so an abbreviated
version (7 day test) has been suggested. Rise and drop Fig. 1: Graph shows J-shaped relationship between salt and
in BP by 5–10% is taken as positive test.7 Castiglioni et hypertension

Fig. 2: Percentage change in mean arterial pressure in normotensive subjects receiving incremental increases in sodium. Blood pressure at the
end of 7 days of low (10 mmol/d) salt intake was taken as baseline. All subjects demonstrated an increase in blood pressure with salt loading

MU-150.indd 975 29-01-2021 15:01:43

 976 SECTION 11 Nephrology
al.8 suggested that ambulatory BP monitoring (ABPM)
is a better option and more practical. It is assumed that
patients who are salt sensitive retain salt and water with
resultant loss of circadian nocturnal dip of BP and higher
mean heart rate. No salt restriction is required in this test.
Based on these two parameters Indices have been devised
and patients have been divided into mild, moderate, or
highly salt sensitive. Most workers believe that 25% of
general population and 50% of hypertensive population is
salt sensitive. Salt sensitivity is largely genetic.
Conclusion
In India, average salt intake is between 9–12 gm/day, against
recommended 5 gm by WHO. Most of the epidemiological
animal and human data show that high sodium intake in both
normotensive and hypertensive individuals is associated with
age related HT. Excessive salt intake is also associated with
increased cardiovascular mortality and obesity. Reduction of
salt intake reduces BP and CV mortality. Some limited data also
suggests that very low salt intake (<3 gm) may be detrimental.
It is recommended to consume salt in moderation (approx.
5 gm per day). Maximum benefit of salt restriction occurs in
population consuming high/very high amount of salt.
References
1. Denton D, Weisinger R, Mundy NI, Wickings EJ, Dixson A, Moisson
P, Pingard AM, Shade R, Carey D, Ardaillou R, Paillard F, Chapman
J, Thillet J, Michel JB. The effect of increased salt intake on blood
pressure in chimpanzees. Nat Med. 1995; 1: 1009–1016.
MU-150.indd 976
2. Intersalt Cooperative Research Group. Intersalt: an international
study of electrolyte excretion and blood pressure: results for 24
hour urinary sodium and potassium excretion. BMJ. 1988;297(6644):
319-28.
3. MacGregor GA, Markandu ND, Sagnella GA, et al. Double-blind
study of three sodium intakes and long-term effects of sodium
restriction in essential hypertension. Lancet. 1989;2(8674):1244-7.
4. World Health Organization. Guideline: sodium intake for adults
and children. Available from https://www.who.int/publications/i/
item/9789241504836
5. Weinberger MH. Salt sensitivity of blood pressure in humans.
Hypertension. 1996;27(3 Pt 2):481-90.
6. Strazzullo P, D Elia L, Kandala NB, et al. Salt intake, stroke, and
cardiovascular disease: meta-analysis of prospective studies. BMJ.
2009;339:b4567.
7. Galletti F, Ferrara I, Stinga F, et al. Evaluation of a rapid protocol
for the assessment of salt sensitivity against the blood pressure
response to dietary sodium chloride restriction. Am J Hypertens.
1997;10(4):462-6.
8. Castiglioni P, Parati G, Brambilla L, et al. Detecting sodium-sensitivity
in hypertensive patients: information from 24-hour ambulatory
blood pressure monitoring. Hypertension. 2011;57(2):180-5.
9. Stamler J, Chan Q, Daviglus ML, et al. Relation of dietary sodium to
blood pressure and its possible modulation by other dietary factors
The INTERMAP Study. Hypertension. 2018;71(4):631-7.
10. Mente A, O’Donnell M, Rangarajan S, et al. Urinary sodium
excretion, blood pressure, cardiovascular disease, and mortality:
a community-level prospective epidemiological cohort study.
Lancet. 2018;392(10146):496-506.
11. Luft FC, Rankin LI, Bloch R, Weyman AE, Willis LR, Murray RH,
Grim CE, Weinberger MH. Cardiovascular and humoral responses
to extremes of sodium intake in normal black and white men.
Circulation. 1979; 60:697-706.
29-01-2021 15:01:43
 CHAPTER

151 Newer Avenues in Management

of CKD Anemia
Manish Rathi, Rudreshwar Prabakaran

Abstract 
Anemia remains one of the challenging aspects in the management of chronic kidney disease (CKD) till date. Oral/
intravenous iron and erythropoietin stimulating agents (ESAs) remain the key modalities in the management of anemia in
CKD. Traditional forms of oral iron therapy are limited by poor oral tolerance and insufficient absorption from the gut in
dialysis population. Newer forms of oral iron such as sucrosomial iron and ferric citrate offer advantages such as alternate
mechanism of absorption from the gut, relatively better oral tolerance, and additional properties such as phosphorous
binding. Newer forms of intravenous iron preparations have the advantage of higher stability, lesser risk of infusion
reactions, and bolus dosing. ESAs are being used for the treatment of anemia in dialysis patients since the 1980s. Although
they are effective, higher doses, and higher hemoglobin targets are associated with significant risk of adverse cardiovascular
events such as myocardial infarction and stroke. Studies have shown that though anemia predisposes to a poor quality of
life and high cardiovascular risk in CKD, correction of anemia does not reduce the cardiovascular risk in these patients.
This could be because of the limited options of therapeutic agents available at present and higher doses of both intravenous
iron and ESAs have been shown to predispose to higher cardiovascular risk. Thus, there is a need for agents which can not
only correct anemia but also not contribute to the pre-existing cardiovascular risk in CKD patients. Hypoxia inducible factor
(HIF) stabilizers are one of the newer agents being studied at present in various trials. Studies have shown that these agents
can not only reduce the dosages of intravenous iron and ESAs needed to maintain hemoglobin levels in dialysis patients but
can also reduce cardiovascular risk. They also have beneficial effect on iron profile such as reduction of hepcidin levels,
thus enabling better iron absorption. Thus, research for newer modalities of anemia management in CKD aims to address
not only the hemoglobin levels but also improving the quality of life and longevity of CKD patients.

Introduction dialysis dependent patients.2 Intravenous iron although

Anemia in Chronic Kidney Disease (CKD) predisposes to
low quality of life, increased mortality, and cardiovascular
disease risk. 1 The incidence of iron deficiency anemia
increases with the progression of CKD. Cornerstone of
anemia management in CKD so far has been iron therapy
and use of erythropoietin stimulating agents (ESAs).
Traditional oral iron therapy is limited by poor tolerability,
gastrointestinal adverse event, and poor absorption in
rapidly restores iron stores is limited by infusion reactions,
infections, oxidative stress, iron overload, and increased
cardiovascular risk.3 ESAs, though they reduce the need
for blood transfusions, are associated with increased
cardiovascular risk when hemoglobin levels exceed
13 g/dL.4 Thus, at present, search is ongoing for agents
which not only increase hemoglobin levels, but also reduces
the risk of adverse cardiovascular events seen with the
present agents.

MU-151.indd 977 29-01-2021 15:01:38

 978 SECTION 11 Nephrology
Erythropoietin-stimulating Agents
Traditionally used ESAs include epoetin alfa (half-live, t1/2
6.8–19.4 hours, 50–100 u/kg/week dosing), darbepoetin
alfa (t1/2 25.3–48.8 hours, 0.45 µg/kg per week to every
2–4 weeks dosing), and methoxypolyethylene glycol-
epoetin beta (t1/2 130 hours, 0.6 µg/kg every 2–4 weeks).
Longer half-live are achieved through subcutaneous
route for epoetin and darbepoetin preparations. Dose
escalations beyond double the initial weight based
dose are discouraged by KDIGO due to risk of adverse
cardiovascular events as observed from the TREAT
study. Recently the MIRCERA PASS trial,5 a multicentre
randomized non-inferiority trial, randomized 2818 CKD
patients to methoxypolyethylene glycol-epoetin beta
(MIRCERA) and reference erythropoiesis stimulating
agents. The primary outcome of the study was composite
of time to occurrence of death, non-fatal myocardial
infarction, or nonfatal stroke. This occurred in 45.4% in
the MIRCERA group and 45.7% in the reference group.
Higher dose of ESAs was associated with higher risk of
primary outcome.
Iron Deficiency Anemia in
Chronic Kidney Disease
Iron deficiency is one of the important causes of anemia
in CKD. The NHANES (National Health and Nutrition
Examination Survey) 1988 to 2004 data of non-dialysis
dependent CKD showed that low iron stores defined as
TSAT less than 20% or serum ferritin less than 100 ng/
mL were present in 57.8–58.8% of men and 69.9–72.8%
of women. 6 Causes of iron deficiency in CKD include
gastrointestinal bleeding, retention of blood in dialyzers
and blood lines, repeated sampling, surgical procedures
such as arteriovenous fistula creation, drugs such as
proton pump inhibitors and phosphate binders and
reduced absorption.7
Transferrin saturation (TSAT) and serum ferritin are
widely used as indicators of iron status in CKD population.
KDOQI 2006 guidelines recommend maintaining serum
ferritin more than 200 ng/mL with TSAT more than 20%
in dialysis dependent CKD population and serum ferritin
more than 100 ng/mL and TSAT more than 20% in non-
dialysis dependent CKD population.8 ERBP (European
renal best practice)9 and NICE guidelines10 recommend
iron therapy when serum ferritin is less than 100 ng/
mL and TSAT less than 20%. KDIGO 2012 guidelines
MU-151.indd 978
recommend iron therapy if TSAT less than or equal to 30%
and serum ferritin is less than or equal to 500 ng/mL.7
However, TSAT is not an ideal marker of iron status.
Levels can increase in the setting of inflammation and
decrease in the setting of malnutrition predisposing to
low and high TSAT respectively if the circulating iron
levels are constant. Transferrin levels also exhibit diurnal
variation.11 Serum ferritin being an acute phase reactant
can be increased in later stages of CKD because of
systemic inflammation and by itself may not reflect true
iron status at high levels.12 As a result of these variations
NICE guidelines in 201510 recommend not to use TSAT
or ferritin levels alone to assess iron deficiency status in
CKD. The guidelines recommend the use of percentage of
hypochromic red cells (<6%) and reticulocyte hemoglobin
content (CHr, <29 pg), if possible, in the place of TSAT and
ferritin levels.
Newer Forms of Oral Iron Therapy
KDIGO 2012 guidelines recommend that 1–3 months trial
of oral iron therapy can be considered in non-dialysis
dependent CKD population with anemia and TSAT less
than or equal to 30% and serum ferritin less than or equal
to 500 ng/mL.7 Elemental iron (200 mg) per day is the
recommended daily dosage for these patients. In a normal
individual 1–2 mg of dietary iron is absorbed per day and
with oral iron supplementation. The maximum absorption
of iron per day during oral iron supplementation is around
25–30 mg/day.13 This is impaired in patients with uremia14
due to rising hepcidin levels,15 hence oral iron therapy is
not very effective in dialysis dependent CKD population.
Oral iron supplementation comes in ferric and ferrous
forms. The bioavailability of ferrous form is 10–15%
whereas that of ferric forms of iron is three to four times
lower due to reduced solubility of ferric iron in the alkaline
media of the gut.16 Several forms of oral iron are available
with wide variations in their extent of absorption and
adverse effects (Table 1).
The most common forms of side effects with oral iron
therapy are gastrointestinal like nausea, heartburn, pain,
constipation, and diarrhea. This is seen in 30–70% of the
cases. Among all the oral iron formulations, this risk is
highest with ferrous fumarate.10
Ferric Citrate
Ferric citrate is ferric iron preparation, which was
approved as a phosphate binder by US FDA in 2014 for
29-01-2021 15:01:38
 Newer Avenues in Management of CKD Anemia CHAPTER 151 979

TABLE 1 Different forms of available oral iron preparations17

acetate). The trial showed ferric citrate significantly raised
hemoglobin levels, TSAT, and serum ferritin and had a
Agent Elemental iron Salt content comparable phosphate binding ability when compared
per tablet per tablet with active control. Those in ferric citrate arm received
Ferric sulfate 65 mg 325 mg less intravenous iron and dose of erythropoietin also
Ferrous fumarate 106 mg 325 mg significantly reduced with similar adverse events between
Ferrous gluconate 37.5 mg 325 mg the two groups. 22 Median daily dose was 1680 mg of
Ferric citrate 210 mg 1g elemental iron per day. Similar results were shown in 2019
Ferric citrate hydrate 45 mg 250 mg by the ASTRIO study which compared ferric citrate with
Liposomal iron 30 mg 30 mg
non-iron based phosphate binders in 93 hemodialysis
dependent patients.23

dialysis dependent CKD patients. The formation of ferric Ferric Maltol

citrate coordination inhibits the precipitation of ferric iron
and enables better absorption. Formation of oligomeric
complexes in acidic pH enables phosphate binding
and monomeric complex formation in alkaline pH of
duodenum enables ferric iron absorption.17 Ferric citrate
is always administered with meals.
Non-Dialysis Dependent CKD (ND-CKD)
Population
Phase 3 multicenter double-blind randomized placebo-
controlled trial with primary end point as change in
serum phosphate showed significant reduction of serum
phosphate and FGF23 level and significant increase in
serum iron, ferritin, and TSAT compared to placebo. 18
Placebo controlled phase 2 (n=149) 19 and phase 3
(n=233)20 trials with primary end point as mean change
in TSAT/phosphorous and more than or equal to 1 g/
dL hemoglobin rise showed positive results for patients
in ferric citrate arm with similar rate of adverse events
between the two groups. Mean drug doses used in the two
studies were 5.4 g and 5.7 g/day. Pooled analysis of both
the trials showed that the percentage of adverse events
were not different from that seen with older conventional
forms of oral iron with gastrointestinal events being the
commonest.21 To our knowledge trials with head to head
comparison with other oral forms of iron do not exist.
Ferric citrate was approved for the treatment of iron
deficiency anemia in ND-CKD patients in 2017.
Dialysis Dependent-CKD (DD-CKD)
Population
In a randomized trial of 441 patients, ferric citrate was
compared with active control (sevelamer and calcium
Ferric maltol is novel preparation consisting of ferric iron
complexed with maltol (3-hydroxy-2-methyl-4-pyrone).
Its hydrophilic and lipophilic properties enable higher
bioavailability and better absorption of ferric iron. Since
it is not a salt-based formulation, iron is directly absorbed
from the complex, and the adverse effects due to free iron
seen in salt-based formulations are reduced. Although
this compound was described as early as 1980s, it was
approved by US FDA for the treatment of iron deficiency
anemia in CKD in 2019.
AEGIS-CKD study24 is a placebo controlled double blind
randomized trial conducted in non-dialysis dependent
CKD patients, which showed that the compound was well
tolerated and produced a significant rise in hemoglobin at
week 16. The dose used was 30 mg twice daily.
Sucrosomial Iron
Sucrosomial iron consists of a ferric pyrophosphate
core surrounded by a phospholipid bilayer consisting of
lecithin and sucrester matrix. Ingredients such as starch
and tricalcium phosphate further the coat the structure
forming the sucrosome. The phospholipids allow the iron
to be absorbed in a vesicular form through transcellular
and paracellular routes. The absorption is mediated by ‘M’
cells of the Peyer patches.25 Thus, bioavailability of iron is
high with less free iron mediated gastrointestinal adverse
effects. Cell culture studies using the Caco-2 cell lines
showed threefold higher absorption rates for sucrosomial
iron when compared to ferrous sulfate.26 Animal studies
with iron deficient mice have shown that increase in
hepcidin that is seen with other oral iron formulations
is not seen with sucrosomial iron. 27 An open label
randomized control of 99 ND-CKD patients28 compared
sucrosomial iron (30 mg/day for 3 months) and IV ferrous

MU-151.indd 979 29-01-2021 15:01:38

 980 SECTION 11 Nephrology

gluconate (1 g) in a 2:1 ratio. The study found that at the
end of 1 month, greater number of patients in the IV iron
group had increase in hemoglobin, but this difference
was absent at the end of 3 months. On discontinuation,
hemoglobin levels were stable in IV iron group whereas
it fell to baseline in sucrosomial iron group. Adverse
events such as hypotension, headache, and infusion
reaction were more common in IV iron group. Only 5%
of patients experienced gastrointestinal side effects in the
sucrosomial group. Thus, although sucrosomial iron is
a safer formulation and high bioavailability, iron stores
repletion may be slower when compared to conventional
iron formulations.
Dialysate Iron (Ferric Pyrophosphate Citrate)
This water-soluble preparation consists of ferric iron
tightly complexed to citrate and pyrophosphate to reduce
the amount of free iron released into the circulation.29
This form of iron is administered via the bicarbonate
component of the dialysate. On entering the circulation,
the iron component is directly transferred thus raising
TSAT levels. The advantage of this preparation is that it
reduces risk of iron overload. For an individual patient
5 mL (5.44 mg/mL) is added to 9.46 liters of bicarbonate
concentrate, which gives a concentration 110 µg/L of
iron in the dialysate. The drug is administered in each
HD session with TSAT and ferritin levels being done
every 3 months. Doses are held if TSAT more than 50%
or serum ferritin more than 1000 ng/mL. PRIME, 30 a
phase 2 prospective randomized double blind trial with
primary end point as change in ESA dose showed that
dialysate iron significantly reduced the need for IV iron
and increase in ESA dose. Phase 3 CRUISE 1 and 2 studies31
showed that dialysate iron significantly raised hemoglobin
when compared to placebo. The study had three stages:
Stage 1—run in period, Stage 2—randomization without
change in ESA dose (no IV iron), and Stage 3—open
label. Hypotension, headache, and muscle spasms were
commonly reported side effects.
Intravenous Iron
Intravenous iron preparations contain an iron hydroxide
core surrounded by a carbohydrate shell.10 The stability
of this determines how much iron is released into the
circulation at a time. In older preparations such as iron
sucrose, adverse effects like infusion reactions and
oxidative stress frequent due to low stability of the core
and higher release of free iron. Newer preparations
(Table 2) have a more stable core and thus relatively fewer
adverse effects.10 Table 2 shows the different intravenous
iron preparations used over the years.
KDIGO guidelines 2012 suggests that a trial of
intravenous iron may be considered in adult CKD patients
with anemia and TSAT less than or equal to 30% and
serum ferritin less than or equal to 500 ng/mL, who are
not on ESAs or in those who are on ESA and increase in
hemoglobin or reduction in ESA dose is desired. 6 The
guidelines were based on short-term studies with small
number of patients and there were very few trials which
looked at the safety of giving IV iron in patients with TSAT
more than 30% and ferritin more than 500 ng/mL. In 2007,
DRIVE 33 study randomized 134 hemodialysis patients

TABLE 2 Properties of different intravenous iron preparations32

Iron gluconate Iron sucrose Low molecular Iron Iron Ferumoxytol

weight dextran isomaltoside carboxymaltose
Carbohydrate shell Gluconate Sucrose Dextran Isomaltoside Carboxymaltose Polyglucose sorbitol
polysaccharide carboxymethylether
Stability of complex Low Medium High High High High
Labile iron release High High Medium Low Low Low
Plasma half-life (hrs) 1 6 5–20 20 7–12 15
Maximum single 125 mg 200 mg 20 mg/kg 20 mg/kg 1000 mg 510 mg
dose
Minimum infusion 30–60 60 60 15 15 15
time (min)

MU-151.indd 980 29-01-2021 15:01:38

MU-151.indd 981
TABLE 3 HIF alpha stabilizers and their related trials
Drug Dosage used in Trials
studies
Roxadustat 20–250 mg zz Phase 341 (n=154) multicentre,
double blind trial comparing
roxadustat with placebo in
non-dialysis dependent CKD
42
zz Phase 3 (n=305) study
comparing roxadustat
and epoetin alfa in dialysis
dependent CKD
43
Molidustat 25–200 mg zz Phase 2b trial (16 weeks)
DIALOGUE 1: 25, zz DIALOGUE 1(n=121):
50, or 75 mg once randomized double-blind
daily/25 or 50 mg control trial comparing
twice daily molidustat and placebo for
DIALOGUE 2: 25, 50, patients not in dialysis
or 75 mg once daily zz DIALOGUE 2(n=124): open
(plus additional 15, label molidustat in previously post-baseline visit
100, or 150 mg) darbepoetin treated patients
DIALOGUE 3: 25, 50, versus continuing darbepoetin
75, or 150 mg once for patients not on dialysis
daily (plus additional zz DIALOGUE 3 (n=199): open
15, 100, and 200 mg label molidustat in previously
once daily) epoetin alfa or beta treated
patients versus continuing
epoetin for patients on dialysis
zz DIALOGUE EXTENSION
STUDIES:
44
—— DIALOGUE 4 (<36
months): all patients from
DIALOGUE 1 and 2 who
achieved their mean Hb
targets were made to
continue their respective
treatment for 36 months
44
—— DIALOGUE 5: patients
from DAILOGUE 4 who
achieved mean Hb targets
were continued on their
treatments for 36 months
29-01-2021 15:01:39
Primary end point Results Other observations
Mean change in 1.9±1.2 g/dL raise in zz Significant reduction in hepcidin
hemoglobin over week hemoglobin in roxadustat and cholesterol levels in roxadustat
7 through 9. group (p<0.001) group. Hyperkalemia and metabolic
Mean change in Greater mean change in acidosis seen more in roxadustat
hemoglobin level from hemoglobin in roxadustat group
baseline during weeks group zz Significant reduction in mean
23–27 hepcidin and cholesterol levels in
roxadustat group. Hyperkalemia and
upper respiratory tract infection seen
more in roxadustat group. Greater
rise in Hemoglobin in those with
higher CRP
Change in hemoglobin DIALOGUE 1: Significant Estimated difference in mean change in
level between baseline number of patients hemoglobin between molidustat and
and the mean value achieved the estimated darbepoetin was 0.6 g/dL
from the last 4 weeks of mean hemoglobin in the Lower starting doses were associated
the treatment period molidustat group with a fall below target range in
Change in hemoglobin DIALOGUE 2: Mean hemoglobin in the first week. Small
from baseline to each hemoglobin was increase in hemoglobin was seen with
maintained in the target starting dose of 150 mg/day
range for each dose in Side effects: Adverse effects were
molidustat group comparable between both the groups
DIALOGUE 3: Mean and were mild to moderate in intensity
hemoglobin levels were in all three trials. Numerically more
maintained for 75 mg– number of patients had hypertension
150 mg daily as a starting and nasopharyngitis in molidustat
dose group
Mean hemoglobin Mean hemoglobin levels were
concentration during maintained from baseline and
study were 11.10±0.508 throughout the study period in both the
g/dL in molidustat group groups. Similar percentage of adverse
and 10.98±0.571 g/dL in events in both the group (85.6% vs.
darbepoetin group 85.7%). 21% discontinued drug in
Mean hemoglobin molidustat arm when compared to 10%
concentration during in darbepoetin arm
study were 10.37±0.56 g/ Mean hemoglobin levels were
dL in molidustat group maintained from baseline and
Newer Avenues in Management of CKD Anemia
and 10.52±0.47 g/dL in throughout the study period in both the
epoetin group groups. Similar percentage of adverse
events in both the groups (91.25%
vs. 92.2%). More number of patients
experienced severe adverse events in
molidustat arm (51% vs. 37%). More
number of patients discontinued in
CHAPTER 151
molidustat arm (23% vs. 7%)
Contd...
981
 982

MU-151.indd 982
Contd...
SECTION 11

Drug Dosage used in Trials Primary end point Results Other observations
studies
Vadadustat 450–600 mg 1) Phase 2b study (non-dialysis Percentage of patients 54.9% patients in More number of patients had serious
300 mg OD, 450 dependent CKD, n=210)45 who in the last 2 weeksvadadustat arm achieved adverse events in the vadadustat arm
mg OD and 450 mg 2) Open label phase 2 trial achieved Hb ≥11 g/ primary endpoint compared to placebo (23.9% vs. 15.3%).
thrice weekly (n=94)46 comparing vadadustat dL or an increase in compared to 10.3% in Three deaths occurred in vadadustat
Nephrology

and epoetin alfa Hb ≥1.2 g/dL over the placebo arm

predose average No statistically significant Nausea, diarrhea, and vomiting were the
Mean change in hemoglobin from common adverse effects noted in the
in hemoglobin pre-baseline average was vadadustat group. No serious adverse
concentration observed for all three event was noted in the same
doses
Daprodustat 10, 25, 50, and 100 1) Multicenter, single blind, Increase and response Both non dialysis and Treatment was discontinued in 33% in
mg placebo-controlled study (n=70, rates in achieving target dialysis dependent the ND-CKD group and 22% in DD-CKD
0.5, 2, and 5 mg NDD-CKD and 37, DD-CKD)47 hemoglobin, plasma population showed a group due to high rate of hemoglobin
2) Phase 2a placebo-controlled Erythropoietin level and dose dependent increase rise (≥1 g/dL in any 2 week period)
study (n=73, NDD-CKD and n=83, reticulocyte count in hemoglobin, plasma or high absolute Hb value (≥13 g/
DD-CKD)48 Change in hemoglobin EPO concentrations dL). Hepcidin level decreased and
over 4 weeks of and reticulocyte count TIBC and unsaturated iron binding
treatment compared to placebo capacity increased significantly in the
NDD-CKD group: Dose daprodustat group
dependent increase in Hemoglobin rise occurred with
hemoglobin concurrent rise in endogenous
DD-CKD group: 5 mg once erythropoietin levels in daprodustat
daily dose maintained group. The drug was well tolerated
mean hemoglobin
levels after switch from
erythropoietin
Enarodustat 2 ,4, and 6 mg 1) Phase 2 study placebo Rate of rise in ESA naïve group: Dose Ferritin and hepcidin levels decreased
controlled randomized trial in hemoglobin per week dependent increase TIBC increased in enarodustat group
nondialysis dependent CKD in ESA naïve group and in hemoglobin in
(n=94, ESA naïve group and proportion of patients enarodustat group
n=103, who previously received who maintained Previously ESA treated
ESA)49 change in hemoglobin group: 70% of subjects
in previously ESA in enarodustat arm
treated group maintained their
hemoglobin levels over
24 weeks

29-01-2021 15:01:39
 Newer Avenues in Management of CKD Anemia
with ferritin 500–1200 ng/mL and TSAT less than or equal
to 25% to intravenous ferric gluconate and no iron. The
study found that hemoglobin increased significantly in the
IV iron group with similar side effects between both the
groups. FIND-CKD study in 2014 found that hemoglobin
rise was significant in ND-CKD patients randomized to
high ferritin targets (400–600 µg/L) when compared to
lower targets. REVOKE34 trial in 2015 which randomized
patients to oral ferrous sulfate and IV iron sucrose found
similar results but with increased serious adverse events
in the Intravenous group. PIVOTAL, 35 an open label
multicenter trial in 2019 randomized 2141 patients on
maintenance hemodialysis less than 1 year to IV iron
sucrose in a proactive fashion (400 mg monthly, unless
TSAT ≥40% or ferritin ≥700 µg/L) or reactive fashion (400
mg if ferritin ≤200µg/L or TSAT <20%). The primary end
point was composite of nonfatal MI, stroke, death, and
hospitalization for heart failure. The study found that
hemoglobin rise was rapid, blood transfusion, and ESA
dosage was reduced in the proactive group. Adverse effects
were similar between the groups and the most common
adverse event was infection. Thus, higher ferritin targets
than that proposed by 2012 KDIGO guidelines, may reduce
the need for blood transfusion and higher ESA exposure.
HIF Stabilizers
Hypoxia inducible factors (HIFs) are transcription
factors made of α (1α, 2α, and 3α) and β subunits. 36
HIF 1α is widely expressed across all normal tissues
whereas HIF 2α expression is restricted to endothelium,
selected cells in the kidney, gut, lung, liver, and carotid
body. During normoxia, the enzyme prolyl hydroxylase
(PHD1, PHD2, and PHD3) hydroxylate prolyl residues
in the alpha subunit of HIF. Hydroxylation leads to
recognition by von Hippel Lindau (VHL) ubiquitin E3
ligase and subsequent proteosomal degradation of HIF.
During hypoxic conditions, the PHDs are inactive and
this leads to dimerization of α and β subunits of HIF and
target gene expression. HIF 2α regulates erythropoiesis.
HIF 2 binds to hypoxia response elements of genes
encoding proteins such as duodenal cytochrome B and
ferroportin and enables iron absorption. 37 HIF 2α also
suppresses hepcidin levels which are elevated in chronic
inflammatory states such as ESRD.38 HIF alpha stabilizers
which are currently under study are mentioned in Table 3.
Most of the trials related to HIF stabilizers are phase 2 in
MU-151.indd 983
CHAPTER 151 983
nature (Table 3). Phase 3 studies are ongoing. So far, phase
2 studies have shown that these drugs are well tolerated
in both dialysis dependent and dialysis independent
CKD population. Apart from correction of anemia, other
effects such as reduction in cholesterol levels have been
documented in studies.38 Preliminary data from phase 3
trials (DOLOMITES study, NCT02021318) of Roxadustat
has shown that it reduces major adverse cardiac events by
30%. Despite their beneficial effects shown in the studies,
other proposed harmful effects such as promotion of
tumor growth39 by increasing VEGF levels are yet to be
studied. Long-term studies with large numbers of patients
are required to enable safe introduction of these drugs into
clinical practice.
Other Upcoming Therapeutic Strategies
Lexaptepid pegol is a pegylated L-oligo-ribonucleotide,
which inactivated hepcidin. Phase 1 studies 40 of the
compound have shown good safety profile and dose
dependent reduction of hepcidin levels in healthy
volunteers and in hemodialysis patients. Activins are
dimmers, which belong to transforming growth factor beta
(TGF-β) family which influence erythropoiesis. Sotatercept
is a fusion protein of Fc domain of human IgG1 and activin
receptor IIa. Phase 2 studies in hemodialysis patients
have shown acceptable safety profiles, stable hemoglobin
levels, and lower rates of rescue with ESAs.
Conclusion
Newer modalities of management of anemia in CKD patients
are aimed at development of agents, which can reduce the
need for blood transfusion, need for escalation of dose of ESAs
and maintain stable hemoglobin levels for prolonged periods
of time without increasing the risk for adverse cardiovascular
events associated with the current available agents.
References
1. Iimori S, Naito S, Noda Y, et al. Anaemia management and mortality
risk in newly visiting patients with chronic kidney disease in Japan:
The CKD-ROUTE study. Nephrology (Carlton). 2015;20(9):601-8.
2. Hörl WH. Iron therapy for renal anemia: how much needed, how
much harmful? Pediatr Nephrol. 2007;22(4):480-9.
3. Macdougall IC, Bircher AJ, Eckardt KU, et al. Iron management
in chronic kidney disease: conclusions from a “Kidney Disease:
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4. Pfeffer MA, Burdmann EA, Chen CY, et al. TREAT Investigators: a trial
of darbepoetin alfa in type 2 diabetes and chronic kidney disease.
N Engl J Med. 2009;361(21):2019-32.
5. Locatelli F, Hannedouche T, Fishbane S, et al. Cardiovascular safety
and all-cause mortality of methoxy polyethylene glycol-epoetin
beta and other erythropoiesis-stimulating agents in anemia of
CKD: a randomized noninferiority trial. Clin J Am Soc Nephrol.
2019;14(12):1701-10.
6. Fishbane S, Pollack S, Feldman HI, et al. Iron indices in chronic
kidney disease in the National Health and Nutritional Examination
Survey 1988-2004. Clin J Am Soc Nephrol. 2009;4(1):57-61.
7. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work
Group. KDIGO clinical practice guideline for anemia in chronic
kidney disease. Kidney Int Suppl. 2012;2(4):279-335.
8. KDOQI; National Kidney Foundation. KDOQI clinical practice
guidelines and clinical practice recommendations for anemia in
chronic kidney disease. Am J Kidney Dis. 2006;47(5.3):11-145.
9. Locatelli F, Covic A, Eckardt K, et al. Anaemia management in
patients with chronic kidney disease: a position statement by the
Anaemia Working Group of European Renal Best Practice (ERBP).
Nephrol Dial Transplant. 2009;24(2):348-54.
10. Ratcliffe LE, Thomas W, Glen J, et al. Diagnosis and management
of iron deficiency in CKD: a summary of the NICE guideline
recommendations and their rationale. Am J Kidney Dis.
2016;67(4):548-58.
11. Wish JB. Assessing iron status: beyond serum ferritin and transferrin
saturation. Clin J Am Soc Nephrol. 2006;1(1):4-8.
12. Kalantar-Zadeh K, Kalantar-Zadeh K, Lee GH, et al. The fascinating
but deceptive ferritin: to measure it or not to measure it in chronic
kidney disease? Clin J Am Soc Nephrol. 2006;1(1):9-18.
13. Girelli D, Ugolini S, Busti F, et al. Modern iron replacement
therapy: clinical and pathophysiological insights. Int J Hematol.
2018;107(1):16-30.
14. Nakazawa R, Kaneko M, Hoshi H, et al. Iron absorption in patients
with chronic uremia on maintenance hemodialysis and in healthy
volunteers measured with a simple oral iron load test. Nephron.
1996;73(3):403-6.
15. Ganz T, Nemeth E. Iron balance and the role of hepcidin in chronic
kidney disease. Semin Nephrol. 2016;36(2):87-93.
16. Muñoz M, Gómez-Ramírez S, Bhandari S, et al. The safety of
available treatment options for iron-deficiency anemia. Ex Op Drug
Saf. 2018;17(2):149-59.
17. Pergola PE, Fishbane S, Ganz T, et al. Novel oral iron therapies for
iron deficiency anemia in chronic kidney disease. Adv Chronic
Kidney Dis. 2019;26(4):272-91.
18. Yokoyama K, Hirakata H, Akiba T, et al. Ferric citrate hydrate for the
treatment of hyperphosphatemia in nondialysis-dependent CKD.
Clin J Am Soc Nephrol. 2014;9(3):543-52.
19. Block GA, Fishbane S, Rodriguez M, et al. A 12-week, double-blind,
placebo-controlled trial of ferric citrate for the treatment of iron
deficiency anemia and reduction of serum phosphate in patients
with CKD stages 3–5. Am J Kidney Dis. 2015;65(5):728-36.
20. Fishbane S, Block GA, Loram L, et al. Effects of ferric citrate in
patients with nondialysis-dependent CKD and iron deficiency
anemia. J Am Soc Nephrol. 2017;28(6):1851-8.
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21. Chertow GM, Block GA, Neylan JF, et al. Safety and efficacy of ferric
citrate in patients with nondialysis-dependent chronic kidney
disease. PLoS One. 2017;12(11):0188712.
22. Umanath K, Jalal DI, Greco BA, et al. Ferric citrate reduces
intravenous iron and erythropoiesis-stimulating agent use in ESRD.
J Am Soc Nephrol. 2015;26(10):2578-87.
23. Yokoyama K, Fukagawa M, Akiba T, et al. Randomised clinical trial
of ferric citrate hydrate on anaemia management in haemodialysis
patients with hyperphosphataemia: ASTRIO study. Sci Rep.
2019;9:8877.
24. Kopyt NP. AEGIS-CKD Study Group. Efficacy and safety of oral ferric
maltol (FM) in treating iron-deficiency anemia (IDA) in patients with
CKD: randomized controlled trial [FR-OR120]. J Am Soc Nephrol.
2018;29:70-1.
25. Gómez-Ramírez S, Brilli E, Tarantino G, et al. Sucrosomial® Iron:
a new generation iron for improving oral supplementation.
Pharmaceuticals (Basel). 2018;11(4):97.
26. Tarantino G, Brilli E, Zambito Y, et al. Sucrosomial® Iron: a new highly
bioavailable oral iron supplement. Blood. 2015;126(23):45-61.
27. Asperti M, Gryzik M, Brilli E, et al. Sucrosomial® Iron supplementation
in mice: effects on blood parameters, hepcidin, and inflammation.
Nutrients. 2018;10(10):1349.
28. Pisani A, Riccio E, Sabbatini M, et al. Effect of oral liposomal iron
versus intravenous iron for treatment of iron deficiency anaemia
in CKD patients: a randomized trial. Nephrol Dial Transplant.
2015;30(4):645-52.
29. Fishbane S, Shah HH. Ferric pyrophosphate citrate as an iron
replacement agent for patients receiving hemodialysis. Hemodial
Int. 2017;21(1):104-9.
30. Gupta A, Lin V, Guss C, et al. Ferric pyrophosphate citrate
administered via dialysate reduces erythropoiesis-stimulating
agent use and maintains hemoglobin in hemodialysis patients.
Kidney Int. 2015;88(5):1187-94.
31. Fishbane SN, Singh AK, Cournoyer SH, et al. Ferric pyrophosphate
citrate ( Triferic™) administration via the dialysate maintains
hemoglobin and iron balance in chronic hemodialysis patients.
Nephrol Dial Transplant. 2015;30(12):2019-26.
32. Auerbach M, Macdougall I. The available intravenous iron
formulations: history, efficacy, and toxicology. Hemodial Int.
2017;21(1):83-92.
33. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly
efficacious in anemic hemodialysis patients with high serum
ferritin and low transferrin saturation: results of the Dialysis Patients’
Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc
Nephrol. 2007;18(3):975-84.
34. Agarwal R, Kusek JW, Pappas MK, et al. A randomized trial of
intravenous and oral iron in chronic kidney disease. Kidney Int.
2015;88(4):905-14.
35. Macdougall IC, White C, Anker SD, et al. Intravenous iron in
patients undergoing maintenance hemodialysis. N Eng J Med.
2019;380(5):447-58.
36. Schödel J, Ratcliffe PJ. Mechanisms of hypoxia signalling:
new implications for nephrology. Nature Rev Nephrol. 2019;
15(10):641-59.
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37. Taylor M, Qu A, Anderson ER, et al. Hypoxia-inducible factor-2alpha
mediates the adaptive increase of intestinal ferroportin during iron
deficiency in mice. Gastroenterol. 2011;140(7):2044-55.
38. Liu Q, Davidoff O, Niss K, et al. Hypoxia-inducible factor regulates
hepcidin via erythropoietin-induced erythropoiesis. J Clin Invest.
2012;122(12):4635-44.
39. Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev
Cancer. 2013;13(12):871-82.
40. Renders L, Budde K, Rosenberger C, et al. First-in-human Phase I
studies of PRS-080#22, a hepcidin antagonist, in healthy volunteers
and patients with chronic kidney disease undergoing hemodialysis.
PLoS One. 2019;14(3):0212023.
41. Chen N, Hao C, Peng X, et al. Roxadustat for anemia in patients
with kidney disease not receiving dialysis. N Engl J Med.
2019;381(11):1001-10.
42. Chen N, Hao C, Liu BC, et al. Roxadustat treatment for anemia
in patients undergoing long-term dialysis. N Engl J Med.
2019;381(11):1011-22.
43. Macdougall IC, Akizawa T, Berns JS, et al. Effects of molidustat in
the treatment of anemia in CKD. Clin J Am Soc Nephrol. 2019;14(1):
28-39.
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44. Akizawa T, Macdougall IC, Berns JS, et al. Long-term efficacy
and safety of molidustat for anemia in chronic kidney disease:
DIALOGUE Extension Studies. Am J Nephrol. 2019;49(4):271-80.
45. Pergola PE, Spinowitz BS, Hartman CS, et al. Vadadustat, a novel oral
HIF stabilizer, provides effective anemia treatment in nondialysis-
dependent chronic kidney disease. Kidney Int. 2016;90(5):1115-22.
46. Haase VH, Chertow GM, Block GA, et al. Effects of vadadustat on
hemoglobin concentrations in patients receiving hemodialysis
previously treated with erythropoiesis-stimulating agents. Nephrol
Dial Transplant. 2019;34(1):90-9.
47. Brigandi RA, Johnson B, Oei C, et al. A Novel Hypoxia-Inducible
Factor-Prolyl Hydroxylase Inhibitor (GSK1278863) for anemia
in CKD: a 28-Day, Phase 2A Randomized Trial. Am J Kidney Dis.
2016;67(6):861-71.
48. Holdstock L, Meadowcroft AM, Maier R, et al. Four-Week Studies
of Oral Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor
GSK1278863 for treatment of anemia. J Am Soc Nephrol.
2016;27(4):1234-44.
49. Akizawa T, Nangaku M, Yamaguchi T, et al. A placebo-controlled,
randomized trial of enarodustat in patients with chronic kidney
disease followed by long-term trial. Am J Nephrol. 2019;49(2):165-74.
29-01-2021 15:01:39
 CHAPTER

152 SGLT2 Inhibitors—Mechanisms

of Cardiorenal Protection
Ashwini Balasaheb Gadde, Vijay Kher

Abstract 
Sodium Glucose co-transporter-2 (SGLT2) inhibitors are a class antihyperglycemic agents, which act by selectively
inhibiting SGLT2 present in the proximal tubules in the kidney causing glucosuria and to some extent natriuresis. Though
originally invented as one of the oral hypoglycemic agent (OHA), many randomized controlled trials have confirmed
their role far beyond this, in cardiovascular (CV) and renoprotection. This is in sharp contrast to other OHAs which were
associated with either mild CV benefits or rather harm. The benefit possibly extends to nondiabetic population as well.
Though SGLT2 inhibitors act mainly by causing glucosuria, natriuresis, and by inhibiting tubuloglomerular feedback
(TGF), these effects are insufficient to explain the impressive CV and renal outcomes. In this review we aim to explain the
possible mechanisms of cardiorenal protection of SGLT2 inhibitors.

Introduction a paradigm shift in the management of CV and renal

Sodium Glucose co-transporter-2 (SGLT2) inhibitors
(-gliflozins) are a class antihyperglycemic agents, which
act by selectively inhibiting SGLT2 present in the proximal
tubules in the kidney, leading to increased glucosuria and
thereby decreasing blood glucose levels. Though initially
approved in 2013 as one of the oral antihyperglycemic
agents for type 2 diabetes, the outcomes in EMPA-REG
OUTCOME trial opened a window to its role far beyond
glycemic control.1 This study established a remarkable
and unexpected cardiovascular (CV) and renal benefits
of empagliflozin in patients with type 2 diabetes with
clinical cardiovascular disease (CVD). Later many studies
supported and strengthened their role in wide class of
patients, including those without established CVD proving
their beneficial effects in diabetes mellitus as primary as
well as secondary prevention for CV & renal endpoints.2-7
Table 1 summarizes the CV and renal outcomes in major
trials. These trials have established SGLT2 inhibitors as
complications of type 2 diabetic patients2-5 and may be in
nondiabetic CKD patients as well.6
Basic Mechanism of Action of
SGLT2 Inhibitors9
Approximately 90% filtered glucose reabsorption is
mediated by SGLT2 channels located on S1 segment of
proximal convoluted tubules (PCT). These channels are also
responsible for 5–14% of Sodium reabsorption depending
upon the glycemic status. Thus, the physiological effects
of SGLT2 inhibitors are a consequence of both glucosuria
and natriuresis.
Before going in detail, let’s concentrate on the glucose
absorption in diabetes mellitus and effects of SGLT2
inhibitors on tubuloglomerular feedback (TGF)—an
important mechanism for glomerular hemodynamic
alteration of in type 2 diabetes and diabetic nephropathy
(Fig. 1).

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 SGLT2 Inhibitors—Mechanisms of Cardiorenal Protection CHAPTER 152 987

TABLE 1 Cardiovascular and renal outcomes of SGLT2 inhibitors in trials

Trial Population Cardiac end point Renal end points

Hazard ratio (confidence interval) Hazard ratio (confidence interval)
EMPA-REG OUTCOME1 T2D+CVD 3-point MACE* Doubling of serum creatinine with eGFR<45,
N=7020 eGFR>/30 0.86 (0.74–0.99) initiation of RRT or kidney-related death
0.54 (0.40–0.75)
CANVAS program2 T2D+CVD (if>/30 yrs) or 3-point MACE* Progression of albuminuria 0.73 (0.67–0.79)
n=10,142 >2 CV risk factors if >/50 yrs 0.86 (0.75–0.97) 40% reduction in eGFR, RRT, or renal-related
death 0.60 (0.47–0.77)
DECLARE -TIMI584 T2D+CVD/>2 CV risk factors 3-point MACE* >40% decrease in eGFR to <60, ESRD or
N=17,160 0.93 (0.0.84–1.03) non-significant. renal-related death
Composite of CV death or HHF 0.83 0.53 (0.43–0.66)
(0.73–0.95)
CREDENCE 3 T2D+ eGFRof 30 to <90, Composites of CV death or HHF 0.69 Relative risk of the primary outcome
N=4401 albuminuria and on stable (0.57–0.83) composite of ESRD, doubling of the serum
dose of ACEi/ARBs for >/4 3-point MACE 0.80 (0.67–0.95) creatinine level from baseline or death from
weeks 3 HHF 0.61(0.47–0.80) renal or cardiovascular disease.
Was 30% lower (hazard ratio, 0.70
(0.59–0.82)*
DAPA-HF5 Heart failure and an ejection The primary composite outcome of A composite of worsening renal function
N=4744 fraction of 40% or less worsening heart failure or CV death 0.71 (0.44–1.16) §
(irrespective of the diabetes 0.74 (0.65–0.85)
status)
DAPA-CKD6 Adults with CKD with an The composite of CV death or HHF Primary composite endpoint 
N=4304 eGFR ≥25 but ≤75 mL/ 0.71 (0.55 to 0.92). zz Time to ≥50% eGFR decline from baseline

min/1.73 m2 and a UACR (confirmed by ≥28-day serum creatinine)

≥200 mg/g but ≤5000 mg/g zz Time to ESRD defined as eGFR <15 mL/

on stable dose of ACEi/ARBs min/1.73 m2, need for chronic dialysis

for >/4 weeks (both confirmed after ≥28 days) and renal
transplantation
zz Time to renal or cardiovascular death

0.61 (0.51 to 0.72)

*Primary outcome, §Not significant
3-point MACE, major adverse cardiac events (composite of nonfatal stroke, nonfatal MI, cardiovascular death); ACEi/ARB, angiotensin converting
enzyme inhibitors/aldosteron receptor blockers; CKD, chronic kidney disease; CVD-cardiovascular disease; ESRD, end stage renal disease; HHF,
hospitalization for heart failure; RRT, renal replacement therapy; T2D, type two diabetes; UACR, urine albumin creatinine ratio

In hyperglycemic state, filtered glucose load
is increased. To handle that load, there is increased
expression of SGLT2 on PCT. Along with glucose, sodium
reabsorption also increases. This increased work of Na and
glucose reabsorption leads to increased cortical oxygen
consumption and also tubular hypertrophy, resulting
in renal cortical ischemia, which promotes interstitial
fibrosis.8 As more glucose and sodium are absorbed in
PCT, less sodium will be delivered to distal convoluted
tubules (DCT), which is sensed by macula densa. This
causes increase in single nephron glomerular filtration
rate (SNGFR) via TGF. Due to the decreased sodium in
DCT (TGF), there is afferent arteriolar dilatation and
efferent arteriolar vasoconstriction due to increase in renin
secretion and increased renin–angiotensin–aldosterone
system (RAAS) activation.8 High SNGFR further increases
the work of reabsorption continuing this vicious cycle.
Hyperfiltration and increase in intraglomerular pressure
also causes proteinuria which is nephrotoxic and
contributes to progression of diabetic nephropathy.
SGLT2 inhibitors interfere with these essential
pathophysiological effects in a diabetic kidney (Fig. 2).
By inhibiting SGLT2 channels, hyper-reabsorption of Na
and glucose reabsorption is inhibited thus decreasing
the tubular work load and oxygen consumption avoiding
cortical ischemia. Because of the inhibited Na and

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 988 SECTION 11 Nephrology

Fig. 1: Glucose absorption in diabetes mellitus and effects of SGLT2 on tubuloglomerular

feedback and in evolution of diabetic nephropathy
JGA, juxtaglomerular apparatus; SNGFR, single nephron glomerular filtration rate; MD, macula densa

Fig. 2: Effect of SGLT2 inhibitors on pathophysiological mechanisms on diabetic nephropathy

glucose reabsorption in PCT, more is delivered the
DCT. This causes afferent arteriolar constriction and
decreases SNGFR via TGF mechanism. Also because of
increased load of sodium and potassium in DCT, tubular
backpressure in the Bowman’s capsule increases, leading
to decrease in SNGFR. These effects together lead to
decrease in intraglomerular hypertension, glomerular
blood flow leading to decrease in proteinuria.
These effects to some extent do explain the renal
benefits of SGLT2 inhibitors but may be inadequate to
explain the mechanism for CV benefits. Although the
glucose lowering efficacy of SGLT2 inhibitors declines at

MU-152.indd 988 29-01-2021 15:01:36

 SGLT2 Inhibitors—Mechanisms of Cardiorenal Protection
the lower eGFR range, the CV benefits are persistent across
wide spectrum kidney disease (eGFRs of 30–60 mL min−1
[1.73 m]−2, 60–90 mL min−1 [1.73 m]−2 and >90 mL min−1
[1.73 m]−2).10 Also, beneficial effects of SGLT2 inhibitors
extend to nondiabetic population as well (Table 1).6 This
implies that many “extrarenal” effects might play a role.
Metabolic Effects Secondary to Glucosuria
Reduction in HbA1c
Placebo substracted HbA1c difference in EMPA-REG was
mild (0.4%) but it showed impressive 38% reduction in
CV death, 35% reduction in heart failure, and 46% risk
reduction was seen in composite renal outcome. This is
in sharp contrast with other oral hypoglycemic agents
(OHAs), which were associated with either mild CV
benefits or sometimes even harm. 11-13 So, mechanisms
other than this need to looked into.
It is important to note that SGLT2 inhibitors do
not cause hypoglycemia. This is due to intact counter-
regulatory mechanisms including upregulation of hepatic
gluconeogenesis. Also, SGLT1 downstream prevents
glucose excretion during SGLT2 inhibition when the
filtered glucose falls below the transport capacity of
SGLT1.7
Weight Loss
SGLT2 inhibitors reduce body weight and fat mass,
especially epicardial fat which is important for leptin (a
proinflammatory adipokine) secretion. In a 52-week study
comparing canagliflozin with glimepiride, canagliflozin
reduced serum leptin levels by 25% and increased the
levels of the anti-inflammatory adipokine adiponectin
by 17%. 14 The antinatriuretic, anti-inflammatory and
antifibrotic effects of SGLT2 inhibitors (discussed further)
antagonise the deleterious effects of leptin on heart and
kidneys.14
Decrease in Uric Acid15
Though benefit of this effect on CV protection is unclear.
Hemodynamic Effects Secondary
to Natriuresis
Blood Pressure Reduction
Along with SGLT2 inhibition, direct inhibition of the
cardiac sodium-hydrogen exchanger (NHE)1 by SGLT2
MU-152.indd 989
CHAPTER 152 989
inhibitors is another pathway hypothesized in natriuresis
and reduction in BP.
In EMPA-REG trial, SGLT2 inhibitors reduced systolic/
diastolic BP by around 5/2 mm Hg.1 A recent meta-analysis
of 43 randomized controlled trials with 22,528 patients
assessed the seated clinic blood pressure effects of SGLT2
inhibitors in patients with type 2 diabetes mellitus. The
reduction in blood pressure was over and above the
already receiving antihypertensive therapy.16
Diuretic Effect
SGLT2 inhibitors decrease preload by both natriuresis and
osmotic diuresis secondary to glucosuria. But those are
different from other conventional loop/thiazide diuretics.
They do not cause reflex sympathetic activity thus
causing no compensatory tachycardia.17 It is postulated
that as opposed to diuretics, SGLT2 inhibitors promote
a greater decrease in interstitial fluid relative to blood
volume.18 This may have significant benefits in reducing
neurohormonal activation via their effects on RAAS. Also,
thiazide/loop diuretics are known to cause hyperuricemia
and sometimes hyperglycemia, but these parameters are
positively affected by SGLT2 inhibitors.
Decrease in Intraglomerular Hypertension
As explained earlier, natriuresis also causes increased
delivery of sodium to macula dense which will lead to
afferent arteriolar constriction via TGF mechanism.
This decreases the intraglomerular hypertension and
hyperfilteration occurring in early diabetic nephropathy.
This will also decrease proteinuria but at the cost of initial
dip in eGFR (around 4–6 mL/min) in initial 3–4 weeks,1
which is reversible either after stopping medication or
sometimes even after continuous prolonged treatment.
This suggests that it’s related to a functional change rather
than structural changes, similar to angiotensin-converting
enzyme inhibitor (ACEi)/angiotensin receptor blockers
(ARBs).
Currently, ACEi/ARBs are the standard treatment for
this purpose, which dilates efferent arteriole. In EMPA-
REG as well as other studies related to SGLT2i, most of
the patient population (almost 80%) was already on ACEi/
ARBs. Benefits of SGLT2i are additive to current optimal
therapy. RAAS blockers are active through neurohormonal
pathways of hyperfiltration whereas SGLT2 inhibitors
work via tubular pathway.
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 990 SECTION 11 Nephrology
Though above mentioned hemodynamic and
metabolic effects have positive impact on CV outcome,
in practice, this impact is unexpectedly strong. Previously
it was thought that these CV benefits are because of the
effect on atherosclerosis, but benefits are seen as early as 3
months from the start of treatment. It is very unlikely that
atherosclerosis-related effect will show impact so early. So,
more possible mechanisms have been proposed and are
getting tested.
Cardiac Fuel Energetics
So to explain these remarkable cardiac and renal benefits,
Ferrannini et al. came up with a “Thrifty substrate”
hypothesis.19 Glycosuria lowers insulin levels and raises
fasting and post-meal glucagon concentrations. This
causes restriction of glucose utilization and increase in lipid
mobilization. Increased delivery of free fatty acids (FFAs) to
the liver stimulates ketogenesis. In conditions of prolonged
hyperketonemia, b-hydroxybutyrate is freely taken up by
the heart and oxidized in preference to fatty acids. The
benefit of preferential fuel selection was demonstrated in
a study of 3-hydroxybutyrate versus placebo in humans
with chronic HF in which ketone infusion increased stroke
volume, cardiac output, and LVEF in a dose responsive
fashion.20 This fuel selection improves work efficiency with
respect to oxygen consumption especially, in failing heart
and also in kidneys.21 But recently this theory has been
challenged. Animal studies to prove this change in cardiac
energetics have been inconclusive. Also, the stressed
heart already preferentially utilizes ketone bodies, and the
diabetic kidney is a ketogenic organ21,22 so what difference
does SGLT2 inhibitors do? It needs to be delineated and
explored further.
Cellular Reprogramming to
“Dormancy State”
Another theory seems to be that instead of postulating
a drug-induced enhancement of fuel supply, Avogaro
et al. suggest that SGLT2 inhibitors induce a “dormancy
state” that mimics starvation.23 When cells are stressed
by starvation or by hypoxia or reactive oxygen species,
injured organelles, and misfolded proteins, they
activate a transcriptional program to adapt to this low-
nutrient conditions. Sirtuin 1 (SIRT1) and adenosine
monophosphate–activated protein kinase (AMPK) are the
MU-152.indd 990
key enzymes in this respect. SIRT1 decreases oxidative
stress by enhancing antioxidant activity, AMPK reduces
the formation of reactive oxygen species, In addition, both
enzymes inhibit energy storage (glycogen synthesis and
lipogenesis) while promoting energy utilization (fatty acid
oxidation leading to ketonemia). Coordinated activation
of two signaling stimulates autophagy which is a lysosome
mediated pathway that removes potentially dangerous
constituents and recycles cellular components. Since type
2 diabetes is perceived by cells as a state of nutrient excess,
it is accompanied by suppression of SIRT1 and AMPK.
SGLT2 acts as a sensor of energy overabundance in this
situation. SGTL2 inhibitors block this sensing mechanism
and inhibits suppression of this SIRT1/AMPK pathway.
Hemoconcentration/Erythropoietin
Activation
SGLT2 inhibitors may not only deceive cells into believing
that they are fasting but also that they are hypoxic, which
activate hypoxia-inducible factor-2α (HIF-2α) via this
SIRT1/AMPK pathway. Also, decreased reabsorption in
early PCT causes compensatory increased transport work
in late PCT and medullary thick ascending loop. This leads
to relative medullary hypoxia and stimulation of HIF 1&2
which cause increase in erythropoietin secretion. Elevated
hematocrit is also a surrogate marker of reduced plasma
volume as well as of recovery of tubulointerstitial function
associated with SGLT2 inhibitor therapy. In mediation
analysis of EMPA-REG, changes in hematocrit contributed
51.8% of the effect of empagliflozin versus placebo on
the risk of CV death, maximum of all the effect of SGLT2
inhibitors.24
Direct Effect on LV Mass
Along with decreasing preload and afterload, it is possible
that SGLT2 inhibitors have direct beneficial impact
of cardiac remodeling. The EMPA-Heart trial which
included patients with T2D and coronary artery disease
demonstrated a reduction in LV mass indexed to body
surface area in patients treated with empagliflozin. This
was thought to be in part due to a reduction in wall stress.25
Effect on NLRP3 Inflammasome
Activation of the NLR family, pyrin domain-containing 3
(NLRP3) inflammasome in the innate immune cells and
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 SGLT2 Inhibitors—Mechanisms of Cardiorenal Protection
subsequent interleukin (IL)-1β release has been proposed
as one of the pathogenic mechanisms in diabetes,
atherosclerosis, and heart failure. SGLT2 inhibitors
have been shown to inhibit this effect with respect to
sulfonylureas.26
Effect on Arterial Stiffness
A post-hoc analysis of trials and study comparing
dapagliflozin with hydrochlorothiazide demonstrated that
empagliflozin was associated with not only decreased BP,
but showed positive effects on markers of arterial stiffness
and vascular resistance, that is, aortic pulse wave velocity,
brachial flow mediated dilation, and shear rates.27,28
In addition to these mechanism, many others are
being considered and getting investigated in animal/
human-inhibition of sodium-hydrogen exchanger 1 on
cardiac myocytes,29 increase in Circulating Pro-Vascular
Progenitor Cells.30
Conclusion
To conclude, though the exact mechanism of cardiorenal
protection is still unclear, one thing is clear that we need
to expand the horizon of SGLT2 inhibitors from a “glucose
lowering agent” to “organ protective” agent. Studies are
underway trying to find its use in nondiabetic population
(DAPA CKD, EMPA-KIDNEY, TRANSLATE). Results of DAPA-HF
trial have shown positive results in nondiabetic heart failure
patients.5 There were initial safety concerns with respect to
acute kidney injury, diabetic ketoacidosis, amputations, urinary
and genital tract infections, bladder cancer, and bone fractures.
However, recent trials have downplayed these risks, and
benefits are found to outweigh risks.
References
1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular
outcomes, and mortality in type 2 diabetes. N Engl J Med.
2015;373(22):2117-28.
2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and
cardiovascular and renal events in type 2 diabetes. N Engl J Med.
2017;377:644-57.
3. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal
outcomes in type 2 diabetes and nephropathy. N Engl J Med.
2019;380(24):2295-306.
4. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular
outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-57.
5. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in
patients with heart failure and reduced ejection fraction. N Engl J
Med. 2019;381(21):1995-2008.
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6. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al; Dapagliflozin in
Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):
1436-46.
7. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of
cardiovascular benefit: a state-of-the-art review. Diabetologia.
2018;61(10):2108-17.
8. Peti-Peterdi J, Harris RC. Macula densa sensing and signaling
mechanisms of renin release. J Am Soc Nephrol. 2010;21(7):1093-6.
9. Nespoux J, Vallon V. SGLT2 inhibition and kidney protection. Clin Sci
(Lond). 2018;132(12):1329-39.
10. Wanner C, Lachin JM, Inzucchi SE, et al. Empagliflozin and clinical
outcomes in patients with type 2 diabetes mellitus, established
cardiovascular disease, and chronic kidney disease. Circulation.
2018;137(2):119-29.
11. Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical
trials of glucose-lowering agents in patients with diabetes. Eur J
Heart Fail. 2017;19(1):43-53.
12. Son JW, Kim S. Dipeptidyl peptidase 4 inhibitors and the risk of
cardiovascular disease in patients with type 2 diabetes: a tale of
three studies. Diabetes Metab J. 2015;39(5):373-83.
13. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and
cardiovascular outcomes in type 2 diabetes. N Engl J Med.
2016;375(4):311-22.
14. Garvey WT, Van Gaal L, Leiter LA, et al. Effects of canagliflozin versus
glimepiride on adipokines and inflammatory biomarkers in type 2
diabetes. Metabolism. 2018;85:32-7.
15. Zhao Y, Xu L, Tian D, et al. Effects of sodium-glucose co-transporter
2 (SGLT2) inhibitors on serum uric acid level: a meta-analysis of
randomized controlled trials. Diabet Obes Metab. 2018;20(2):
458-62.
16. Mazidi M, Rezaie P, Gao HK, et al. Effect of sodium-glucose
cotransport-2 inhibitors on blood pressure in people with type
2 diabetes mellitus: a systematic review and meta-analysis of 43
randomized control trials with 22,528 patients. J Am Heart Assoc.
2017;6(6):e004007.
17. Herat LY, Magno AL, Rudnicka C, et al. SGLT2 inhibitor–induced
sympathoinhibition. J Am Coll Cardiol Basic Trans Science.
2020;5(2):169-79.
18. Hallow KM, Helmlinger G, Greasley PJ, et al. Why do SGLT2
inhibitors reduce heart failure hospitalization? A differential volume
regulation hypothesis. Diabetes Obes Metab. 2018;20(3):479-87.
19. Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG
OUTCOME Trial: a “Thrifty Substrate” hypothesis. Diabetes Care.
2016;39(7):1108-14.
20. Nielsen R, Moller N, Gormsen LC, et al. Cardiovascular effects of
treatment with the ketone body 3-hydroxybutyrate in chronic
heart failure patients. Circulation. 2019;139(18):2129-41.
21. Aubert G, Martin OJ, Horton JL, et al. The failing heart relies on
ketone bodies as a fuel. Circulation. 2016;133(8):698-705.
22. Zhang D, Yang H, Kong X, et al. Proteomics analysis reveals diabetic
kidney as a ketogenic organ in type 2 diabetes. Am J Physiol
Endocrinol Metab. 2011;300(2):E287-95.
23. Avogaro A, Fadini GP, Del Prato S. Reinterpreting cardiorenal
protection of renal sodium–glucose cotransporter 2 inhibitors via
cellular life history programming. Diabetes Care. 2019;43(3):501-7.
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24. Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin
reduce cardiovascular mortality? Insights from a mediation analysis
of the EMPA-REG OUTCOME trial. Diabetes Care. 2018;41(2):356-63.
25. Verma S, Mazer CD, Yan AT, et al. EMPA-heart cardiolink-6 trial:
a randomized trial evaluating the effect of empagliflozin on
left ventricular structure, function and biomarkers in people
with type 2 diabetes and coronary artery disease. Circulation.
2019;140(21):1693-702.
26. Kim SR, Lee S, Kim SH, et al. SGLT2 inhibition modulates NLRP3
inflammasome activity via ketones and insulin in diabetes with
cardiovascular disease. Nat Commun. 2020;11(1):2127.
27. Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin
on blood pressure and markers of aterial stiffness and vascular
MU-152.indd 992
resistance in patients with type 2 diabetes. Diabetes Obes Metab.
2015;17(12):1180-93.
28. Solini A, Giannini L, SeghieriM, et al. Dapagliflozin acutely improves
endothelial dysfunction, reduces aortic stiffness and renal resistive
index in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol.
2017;16(1):1-9.
29. Uthman L, Baartscheer A, Bleijlevens B, et al. Class effects of SGLT2
inhibitors in mouse cardiomyocytes and hearts: inhibition of
Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation.
Diabetologia. 2018;61(3):722-6.
30. Hess DA, Terenzi DC, Trac JZ, et al. SGLT2 Inhibition with
empagliflozin increases circulating provascular progenitor cells in
people with type 2 diabetes mellitus. Cell Metab. 2019;30(4):609-13.
29-01-2021 15:01:36
 CHAPTER

153 Optimizing Renal

Care in Elderly
Narinder Pal Singh, Rahul Mishra, Shaurya Kaul

Abstract 
The global burden of chronic kidney disease (CKD) is increasing particularly among elderly. Aging itself increases
vulnerability for poor renal health. High cost of management and poor outcomes of CKD necessitate optimization of renal
care to be started early in the course of the disease. Collaborative involvement of patient, caregiver, primary care provider
and multidisciplinary clinics is required to achieve optimal conservative care and renal replacement modality. Dietary
changes, lifestyle modification, managing the pill-burden, appropriate nutrient supplementation, and vaccination to take
care of risks and complications of CKD are key steps as per latest evidences available. For those progressing to end-stage
renal disease (ESRD), an approach, taking into consideration of patient’s perspectives and functional and cognitive status,
to decide appropriateness of renal replacement therapy (RRT) or end-of-life care is a very essential particularly for elderly
patients. There is need of progressive work for optimizing various facets of renal care in elderly patients particularly in
economically constrained regions where most of the CKD patients fail to receive appropriate care.

Introduction arteriosclerosis, glomerulosclerosis, interstitial fibrosis,

The global burden of kidney disease, which has been
rising consistently, poses a major challenge to the primary
care physician. Recent GBD reported that out of 697.5
million worldwide CKD patients, India harbored 115.1
million. 1 As per latest census in India (2011), around
104 million people were 60 years or above and by 2021
this number is predicted to reach 133.32 million. So,
the likely CKD burden among elderly is expected to
rise proportionately. Indian CKD registry2 reported that
diabetic nephropathy was most common cause (31%) for
CKD and mean age of CKD patient was 50 years. Prevalence
of CKD and its risk factors like diabetes, hypertension,
obesity, and cardiovascular disease increases with
age. Age-related changes in kidney include structural
changes like macrostructure changes (decrease in cortical
volume, increase in surface roughness, and size of simple
renal cysts), microstructure changes (nephrosclerosis-
tubular atrophy), and functional decline in total-kidney
GFR due to decrease in total nephron count. 3 Optimal
care of CKD risk factors can delay or even prevent this
progression of healthy aging of kidneys into CKD. Elderly
population needs special attention to their physical and
functional deficits including multiple co-morbidities
(hypertension, diabetes), cognitive impairment, frailty
and progressive sensory impairment. Owing to high
cost and poor outcomes of CKD management, there is a
definitive need for optimization of care in elderly CKD
patients on individual basis. Optimal care goals include
best outcomes at individual, population and society
levels for betterment of survival and quality of life. The
management of advanced CKD in the elderly can be
challenging in regards to prediction of disease progression
to ESRD, selection of RRT modality, and choice of optimal
vascular access (VA) for hemodialysis (HD). There is a

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 994 SECTION 11 Nephrology
need for collaborative efforts between patient, caregiver,
primary care provider, and interaction of multidisciplinary
clinics. Current review will focus on optimizing renal
care including conservative medical management and
selection of RRT modalities such as HD, peritoneal dialysis
(PD) and kidney transplant (KT) for elderly to maximize
functional status and minimize treatment-associated
morbidity.
Pre-RRT Phase: Elderly Focused
Conservative Care
In India, a country with 1.3 billion people and around
two thousand nephrologists, practices that promote
renal health and prevent renal disease progression
are important. Optimal care for elderly involves mix of
pharmacological and non-pharmacological interventions.
Diet may be important in deciding course of CKD before
dialysis. Moderate intake of protein, especially dietary
strategies that increase plant protein, low sodium,
dietary fiber, vitamin D, and reduction in obesity may
limit worsening of CKD. 4 Renoprotective effects of
maintaining muscle health, especially among elderly
who have high prevalence of sarcopenia, are documented
and they must be stressed upon in routine care.5 Life
style changes can be recommended based on specific
comorbidity of CKD patients, for example, increasing the
aerobic exercise capacity in those with cardiovascular
disease, high dietary fiber and moderate intensity exercise
for patients with chronic lung disease or rheumatoid
arthritis and weight reduction for diabetic patients. 6
CKD patients are likely to encounter polypharmacy
risks, potential drug-drug interactions (pDDI) and
inappropriate prescriptions. Incorporating procedures
and pharmacists to determine pDDI into the kidney
care model could help dealing these challenges. 7,8
Non-adherence is a possible outcome of multiple pill
burden among CKD patients. Whenever possible during
clinical management, tapering thereafter deprescription
strategies should be planned. Recommendations have
been made on approach to deprescribe PPIs, statins and
oral hypoglycemic agents in CKD patients to reduce pill
burden.9 Practices involving identification and avoidance
of agents like nephrotoxic antimicrobials, radio-contrast
exposure, combining ACEI and ARBs, NSAIDs and
diuretics that might precipitate AKI should be promoted.10
MU-153.indd 994
Providing recommended vaccinations—hepatitis B,
pneumococcal, influenza, and other routine vaccines
are essential for optimum care of CKD patients.11 Focus
should be laid upon patient’s values and perspectives
about the disease, as deficiency about health literacy is
widespread in CKD population.12,13 Information should
be provided using simple terms and techniques like
“teach back” to ensure attention and understanding.14
Routine screening for anxiety, depression, and cognitive
impairment may be important because CKD is associated
with increased risk for dementia in elderly and poor
functional status (including poor overall cognition,
language, and memory). Various mediators accounted for
cognitive derangement like anemia, increased oxidative
stress, inflammatory markers, and changes in lipid and
homocysteine metabolism are found in CKD patients.15
Identifying functional changes is important in order to
optimize the management outcome, as studies have
shown association of cognitive impairment with negative
outcome and increased risk of 1-year mortality among
elderly severe CKD patients who were in-hospital.16-18 The
conservative pharmacological management is sometimes
the only choice in elderly patients who are declining or not
fit for RRT (Flowchart 1).
Risks and Complications of CKD
CKD, due to any cause, can progress through I to V stages.
Complications and their management begin usually by
stage III onward, and by stage IV aim is to prepare the
patient for dialysis with suitable measures like VA to be
needed during stage V. Appropriate timely management
is required, particularly in elderly patients who may have
multiple modifiable risk factors that could prevent or delay
this progression.
Diabetes Mellitus
Diabetes mellitus is the most common cause of CKD and
this holds true for both the developed and the developing
world. Diabetic glomerulopathy might be contributing
to over half of the ESRD cases. Bringing down of blood
glucose levels (to preserve average HbA1c 7%) reflects
as delay in urinary albumin excretion, GFR decline, and
requirement for dialysis. The use of ACEI/ARBs can
further prevent kidney damage in normotensive diabetics
with proteinuria.19 In the elderly, frail, and CKD patients,
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Flowchart 1: Options for renal care in elderly
the consequences of hypoglycemia are very serious
including injury, myocardial infarction, stroke, and death.
Therefore, a tailored approach for target HbA1c levels
should be followed for elderly CKD patients to avoid risk of
hypoglycemia.20 Metformin is usually the first antidiabetic
to begin with. For reducing risk of lactic acidosis, a rare
event, FDA recommends avoiding its use if creatinine in
men >1.5 mg/dL and women >1.4 mg/dL. Sulfonylureas
undergo renal clearance; therefore, risk of hypoglycemia
is more in advanced CKD patients and their use should be
avoided if GFR <30 mL/min/1.73 m2. Among meglitinides,
repaglinide is safe to use in CKD. Thiazolidinediones are
hepatically metabolized so can be used in CKD with caveat
that fluid retention and increased risk of fracture rates in
women especially with underlying renal osteodystrophy
could be concerning. Insulin is safe for all CKD patients
and long acting single dose can be used when oral
agents fail to obtain target sugar levels. However, more
complicated regimens with multiple insulin dosing may
increase chances of error and hypoglycemia, especially
among elderly with cognitive impairment. Among GLP1
agonists, no dose adjustments are needed for dulaglutide
or albiglutide in CKD while exenatide and liraglutide
should be avoided with eGFR <30 mL/min/1.73 m2 due
to poor renal clearance. DPP4 inhibitors (sitagliptin,
saxagliptin, linagliptin, vildagliptin) are well tolerated
and have some renal clearance and require dosage
adjustment. 21 Cardioprotective and renoprotective
effect of SGLT2 inhibitors (Empagliflozin, Canagliflozin,
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Optimizing Renal Care in Elderly CHAPTER 153 995
Dapagliflozin) have been demonstrated in diabetic kidney
disease.22
Hypertension
With regards to CKD, hypertension is related as both the
cause and effect. Hypertension is a major risk factor that
increases the risk of progression of kidney disease and
increase the risk of cardiovascular complications. The
KDIGO (2012) guidelines have described the general
management strategies for controlling blood pressure in
non-dialysis-dependent CKD patients. A combination
of lifestyle changes and pharmacological management
are the key approach to achieve target BP goal in CKD
patient. Gradually lowering of blood pressure should
be recommended. Blood pressure readings based
upon ambulatory and self-measurements better reflect
hypertension compared to office blood pressure readings
and allow individualizing of antihypertensive treatment.
Blood pressure targets need to be individualized and
medical management should be based on the age,
presence of illness and end-organ damage (cardiovascular
and retinopathy), progression of renal disease, and
tolerance to treatment. Vascular stiffness necessitates
periodic monitoring for postural hypotension as it causes
higher systolic blood pressure whereas the diastolic blood
pressure could still decline. Slowing of the progression of
kidney disease and reduction in CVD risk are the goals
of antihypertensive therapy and target BP, as suggested
by KDIGO guidelines for non-dialysis patients, 140/90
mm Hg in nondiabetics/diabetics without proteinuria
and 130/80 mm Hg in patients with proteinuria, is a
key strategy to prevent further renal function decline.
Initial fixed dose RAAS inhibitor (ACEI/ARBs) based
combination therapy (coadministration of CCB, diuretic,
α-blocker, or β-blocker) is more effective and efficient
than sequential monotherapy for achieving target blood
pressure and reduces risk of adverse events by allowing
use of lower doses of each drug.
Anemia
In the elderly especially frail elderly with CKD,
anemia is related to poor function and quality of life,
increased frequency and duration of hospital stays
and mortality. 23 Normocytic normochromic anemia a
common complication seen in CKD patients. A thorough
assessment of other causes of anemia starting with
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complete blood count, peripheral smear, iron studies,
B12 and folate levels should be performed before labeling
anemia of CKD. As per KDOQI 2012 guidelines, target
hemoglobin between 10–11.5 gm/dL is desired in all
CKD patients. Consider ESA in pre-dialysis and dialysis
patients with Hb below 10 g/dL and between 9–10 g/dL,
respectively.24 KDOQI Anemia Work Group recommends
sufficient iron supplementation to maintain serum ferritin
concentration >200 ng/mL in HD patients and >100 ng/
mL in non-dialysis or on peritoneal dialysis CKD patients
for optimal erythropoiesis.24
Vitamin and Electrolyte Abnormality
Vitamins and minerals supplementation is critical
for elderly care. For CKD patients who are already
deficient (S.vit. D <20 ng/mL) or insufficient (S.vit.
D = 20–29 ng/mL) in vitamin D, adequate vitamin
D is absolute requirement for preventing secondary
hyperparathyroidism (SHPT) and its complications.
Supplementation with ergocalciferol or cholecalciferol
should be done as per individual needs. However, once
SHPT develops, vitamin D receptor agonists and/or
calcimimetics are required. Ensuring normal reference
levels of electrolytes like calcium and phosphorous is
essential for prevention of bone disorders among CKD
patients. Dyselectrolytemias including hypo- and hyper-
natremia and hyperkalemia are well associated with aging
kidneys.25 Caution with use of potassium sparing drugs
among CKD patients is required to avoid serious adverse
events. Metabolic acidosis in CKD patients is often due
to impaired ammonia excretion and its management, for
example using sodium bicarbonate, improves nutritional
parameters as well as CKD progression.26
Renal Replacement Therapy
CKD patients are prone to progress to ESRD. Options of RRT
include HD, which can be provided in-center or at home,
PD, and KT. Economic constraint limits RRT availability
to majority of ESRD patients in India. Elderly patient on
HD are physically frail with multiple comorbidities and
functional dependencies. Initiation of dialysis in elderly
should use multidisciplinary approach taking into account
various factors including life expectancy, pros and cons
of each dialysis modality, quality of life, and patient and
caregiver preferences. Possibility of survival benefit for
MU-153.indd 996
elderly patients on dialysis as compared to those with no
RRT patients cannot be ruled out; however, they tend to
spend lot of time around health-care facility and may not
get life satisfaction.27 Assessing HD accessibility for each
elderly patient opting for RRT is necessary as caregivers
and patients feel overwhelmed and burdensome about
frequent multiple visits (at least thrice weekly) to
a faraway located dialysis center. The approach of
incremental dialysis in elderly may assist them in adjusting
to dialysis and sustaining residual kidney function.28
Suggested incremental dialysis approach involves 1–2
dialysis session weekly, each around 1.5–2.5 hours
duration until worsening of renal function necessitates
further modification. Home dialysis can be suitable for
those able to perform it by themselves or with a family
member support. However, it may not be preferred choice
for elderly with multiple comorbidity, frailty, and lack of
support. Exploration of ideal RRT has led to understanding
that diverse modalities are used by patients during the
entire course of CKD. A term coined as “Integrated Care”
has been popularized.29,30 Originally, it suggested starting
with PD and then changing to in-center HD (CHD). The
centers pursuing this approach had reported survival
benefits and cost optimization.31,32 PD needs assistance
and can be preferred as home based dialysis modality in
presence of an assistant. However, PD may not be suitable
for elderly having poor functional status and declining
vision. PD is relatively contraindicated among those with
severe pulmonary disease, irreducible hernias, active
inflammatory bowel disease, significant scar from previous
abdominal surgery, colostomy, ileostomy, or gastric
tubes.33 Decision about choice of dialysis modality should
also match patient’s values with treatment characteristics
in order to maximize achievable quality of life in elderly.
Vascular Access
An effective VA is very essential for carrying out HD and
comprises of arteriovenous fistula (AVF), arteriovenous
graft (AVG), and central venous catheter (CVC). For long,
as first choice, AVF has been created in the non-dominant
hand. Procedure began at a distal site to safeguard
proximal blood vessels for future use, thus radiocephalic
fistulas became initial choice.34 This site also reported to
have higher failure rate because of thrombosis and inability
to mature, requiring more surgeries and use of tunneled
catheter for dialysis. Moreover, preserving a venous
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location in a frail elderly may not be prudent due to fixed
life anticipation, so, the most appropriate AVF, utilizing
the most excellent vessels should be created first. 35,36
Complications such as stenosis, thrombosis, and distal
hypoperfusion ischemic syndrome (DHIS) are concerning
and add to heavy cost and morbidity with access. Therefore,
varying views arise stating creation of upper arm AVFs in
elderly as standard care or preferring AVGs and CVCs as
more suitable options depending on individual patient.
De Silva et al. found similar survival for elderly aged >80
years using either AVFs or AVGs, though, that could be
attributed to lesser number of patients receiving AVG
(25.4%) as compared to AVF (43.2%) that were chosen
for tunneled dialysis.37 Risk of death is more than risk of
progression to ESRD in most elderly CKD, especially if age
>85 years, so benefits of an invasive procedure should be
weighed against associated complication and additional
cost arising out of any potential unnecessary procedure.27
O’Hare et al. demonstrated that only about 25% and 33%
of patients started dialysis within 6 month and 1 year,
respectively, after access creation in 85–100 year old
patients with eGFR <15 mL/min/1.73 m2.38 Therefore, life
expectancy and rate of deterioration of disease should
form basis for timing and type of access creation in
elderly. For example, a tunneled catheter usually not
the most appropriate access choice, could be considered
for those with a life very limited life expectancy (e.g., <6
months). CVCs are preferred in IJV and femoral vein since
subclavian vein has high risk of thrombosis. Infections, as
the complication, amount to about 30–60% of HD CVCs
removal and also, hospitalization rates are higher with
CVCs than AVF.39 Active surveillance and monitoring of
AVF is recommended. Physical examination of VA is very
useful tool to assess inconvenience during cannulation or
clot aspiration, bleeding at cannulation sites post dialysis
or failure to attain target blood flows while dialysis. If
any such sign present, further evaluation with direct
flow rate [using Doppler US and magnetic resonance
angiography (MRA)], or indirect flow rate measurement
modality [UD ( Transonic), timed ultrafiltration
methods, ionic dialysance, differential conductivity, and
glucose infusion] should be considered. 40 A low-cost
method using hemoglobin dilution test was described by
Tiranathanagul et al. which can be used in the resource
limited areas where ultrasound dilution test (UDT) is
costly and unavailable.41
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Optimizing Renal Care in Elderly CHAPTER 153 997
Kidney Transplant—An Option in Elderly?
Although, age itself is not a contraindication to KT, but
poor accessibility and associated comorbidities could
make elderly ineligible for getting a transplant organ.
There is lower 5-year survival probability among KT
recipients aged >65 years compared to aged 35–49 years
(61% vs. 75% respectively).42 Though Kaul et al. reported,
in a retrospective study of ESRD patients, that after
adjusting for albumin and BMI, KT group had better
short-term and long-term survival as compared to PD
group.43 So, despite increased age, in the absence of other
significant factor limiting the life expectancy, KT could
be beneficial for elderly. 44 Factors that reduce KT rate
in elderly may be strict selection criteria, health-care
providers’ apprehensions and decreased willingness
among older patients for kidney transplantation.45 Thus,
instead of kidney transplantation, most of the elderly with
ESRD undergo dialysis.
Social Support and End-of-Life Care
Like most non-communicable diseases, the treatment for
CKD is non-curative, thus patient has to learn living with
it. This creates functional restrain thereby limiting social
involvement and a feeling of being isolated. Increased
requirement of assistance for executive functions,
dependency for care including dialysis, adjusting to
new pattern of daily routine and cognitive changes of
ageing may cause a lot of stress, resulting in a feeling of
helplessness. Social support including emotional and
instrumental is essential for overcoming. Instrumental
support helps patient carrying out all routine and financial
activities while emotional support enables person to
feel loved and cared.46 Ultimately, terminal patient-care
needs interdisciplinary management. End-of-life care
discussion involving patient and family members, taking
care of their preferences to reach a consensus regarding
accepting any intervention or simply withdrawing dialysis
for palliative care and reviewing goals of advance care
should be considered. Kirchhoff et al. observed that after
intervening with patient-centered advance care planning,
a significant percentage of ESRD patients withdrew dialysis
as compared to those without intervention.47 Informed
choice about all available options, including their pros and
cons, can augment decision-making especially for patients
on HD among whom 9–13% succumb within 1 year.48
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 998 SECTION 11 Nephrology
Conclusion
Optimization of renal care in a developing country, where
health-care infrastructure is already struggling, is challenging.
Regardless, perpetual efforts for active care, prevention from
and preparation for deteriorating CKD stages and befitting RRT
are needed. Optimal care of elderly patients with CKD may be
rewarding by decelerating fall in renal functioning, better care
of complications, and enabling a rational choice of RRT with
well-timed carried out VA.
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16. Di Rosa M, D’Alia S, Guarasci F, et al. Cognitive impairment, chronic
kidney disease, and 1-year mortality in older patients discharged
from acute care hospital. J Clin Med. 2020;9(7):2202.
17. Shirazian S, Grant CD, Aina O, et al. Depression in chronic kidney
disease and end-stage renal disease: similarities and differences
in diagnosis, epidemiology, and management. Kidney Int Rep.
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18. Etgen T, Chonchol M, Förstl H, et al. Chronic kidney disease and
cognitive impairment: a systematic review and meta-analysis. Am J
Nephrol. 2012;35(5):474-82.
19. National Kidney Foundation. KDOQI Clinical Practice Guideline for
Diabetes and CKD: 2012 Update. Am J Kidney Dis Off J Natl Kidney
Found. 2012;60(5):850-86.
20. Hahr AJ, Molitch ME. Management of diabetes mellitus in patients
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21. Bittle PA. The use of dipeptidyl peptidase-4 inhibitors in patients
with type 2 diabetes & chronic kidney disease. Nurse Pract.
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22. Górriz JL, Navarro-González JF, Ortiz A, et al. Sodium-glucose
cotransporter 2 inhibition: towards an indication to treat diabetic
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23. Musio F. Kidney disease and anemia in elderly patients. Clin Geriatr
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24. Drüeke TB, Parfrey PS. Summary of the KDIGO guideline on anemia
and comment: reading between the (guide)line(s). Kidney Int.
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25. Schlanger LE, Bailey JL, Sands JM. Electrolytes in the aging. Adv
Chronic Kidney Dis. 2010;17(4):308-19.
26. de Brito-Ashurst I, Varagunam M, Raftery MJ, et al. Bicarbonate
supplementation slows progression of CKD and improves
nutritional status. J Am Soc Nephrol JASN. 2009;20(9):2075-84.
27. Berger JR, Jaikaransingh V, Hedayati SS. End-stage kidney disease in
the elderly: approach to dialysis initiation, choosing modality, and
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33. Ahmed FA, Catic AG. Decision-making in geriatric patients with
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 CHAPTER
Understanding the Role
154 of Vitamin D in Diabetic
Nephropathy
Srinath KM, Spoorthy Raj, Manjunath S Shetty

Abstract 
Diabetes mellitus includes a group of metabolic disorders which share the common phenotype of hyperglycemia. Diabetes
mellitus is the leading cause of end stage renal disease. With the prevalence of diabetes mellitus increasing enormously in
present times, the burden of end stage renal disease caused by diabetes mellitus assumes significance.
Three major pathways are implicated in the development of DKD (Diabetic Kidney Disease) initiated by hyperglycemia.
They are Activation of Protein Kinase C and polyol pathways, formation of advanced glycation end products, and
glomerular hyperfiltration leading to glomerular hypertension.
Vitamin D is known to prevent beta cell apoptosis, increase insulin synthesis and enhance peripheral insulin
sensitivity. Also, it is known to suppress RAS (Renin Angiotensin Aldosterone System), prevent podocyte loss and structural
derangement of slit diaphragm, suppress inflammation and prevent glomerulosclerosis.
Hence, addition of Vitamin D supplements to ACE inhibitors/ARBs is proposed as a novel mechanism to prevent and
halt the progression of Diabetic Kidney disease.

Introduction Over 20% of the newly diagnosed T2DM have

concurrent DKD and a further 20–40% develop diabetic
Diabetes mellitus (DM) poses a major global public health
nephropathy mostly within 10 years of diagnosis.4
problem with ever increasing incidence and prevalence in
Several genetic and environmental factors lead to
recent years.
pathogenesis of DN.
At present, diabetes is the most common cause of end
Hyperglycemic state of diabetes leads to various
stage renal disease (ESRD).
hemodynamic, biochemical, metabolic changes in
Increasing burden of diabetic kidney disease (DKD) is
kidneys including inflammation and oxidative stress.5
secondary to widespread prevalence of diabetes.
Considering the burden imposed by diabetes and
According to International Diabetic Federation, the
DKD, extensive research is done in search of therapeutic
number of diabetics is expected to exceed 435 million by
agent, which can reduce or stop the progression of
2030, with more than 90% having type 2 diabetes.1
diabetic kidney disease. One such novel therapeutic agent
The increased risk of all cause and cardiovascular
for diabetic nephropathy is vitamin D and its analogues.
mortality in patients with diabetes is due to the presence
of DKD.2
Approximately, 25–40% of type 1 DM patients and Risk Factors Associated with DKD
5–40% of patients with type 2 diabetes develop this Multiple factors are responsible for the development of
microvascular complication.3 diabetic nephropathy and its progression.

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 Understanding the Role of Vitamin D in Diabetic Nephropathy
These factors can be categorized as susceptibility
factors—which predispose patients to the risk of developing
DKD and are considered as non-modifiable factors. Acute
kidney injury (AKI), dietary factors, hyperglycemia, and
hypertension which initiate kidney damage and worsen
the DKD are considered as modifiable factors.6
Hence, the risk factors for DKD are summarized as:
„„ Susceptibility factors: Old age, male sex, African-
American race, and significant family history
„„ Initiation factors: Hyperglycemia and AKI
„„ Progression factors: Hypertension, obesity, dietary
factors, and smoking7
Among the various risk factors hyperglycemia and
hypertension are the most predominant risk factors.
Natural History of DKD8
The progressive model of the natural history of DKD has
been shown in Figure 1.
Fig. 1: The progressive model of the natural history of diabetic kidney disease. Duration of diabetes, in years, is presented on the horizontal
axis. Timeline is well characterized for type 1 diabetes mellitus; for type 2 diabetes mellitus, timeline may depart from the illustration due to
the variable timing of the onset of hyperglycemia
MU-154.indd 1001
CHAPTER 154 1001
Pathogenesis of Diabetic Nephropathy
Hyperglycemia is the necessary factor in the initiation
of renal injury. Abnormal intracellular metabolism,
involving three major pathways that are associated with
the development of diabetic nephropathy shown in
Flowchart 1.9
„„ Activation of protein kinase C and polyol pathways
„„ Advanced glycation end-products formation
„„ Glomerular hyperfiltration leading to intra-glomerular
hypertension
It is also implicated that there is an excessive
production of mitochondrial reactive oxygen species.
Interactions between metabolic changes induced by
hyperglycemia with hemodynamic factors, including
vasoactive hormones such as angiotensin II, play a critical
role in inducing renal injury. These mechanisms result
in cell injury and activate inflammatory cascade which
further perpetuates cell injury and results in vicious
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 1002 SECTION 11 Nephrology

Flowchart 1: Pathophysiology of diabetic nephropathy

Source: Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clinical science. 2013 Feb 1;124(3):139-52.

cycle of cell injury—inflammation—further cell injury—
fibrosis.9
The molecules responsible for inflammation in
diabetic nephropathy include:
„„ Transcription factors, NF-κB
„„ Proinflammatory cytokines & signaling molecules—
IL-6, IL-18, IL-1, TNF, JAK2, & STAT 1&3
„„ Chemokines CCL2 (MCP-1) and CCR2, CXCL12
(stromal-cell-derived factor-1), CX3CL1
„„ Fractalkine and CX3CR1
„„ Adhesion molecules: Intercellular adhesion molecule
1 (ICAM1), Vascular cell adhesion protein 1 (VCAM1),
E-selectin (SELE); Toll like receptors—(TLR2, TLR4)
„„ Adipokines: Adiponectin, Leptin; Nuclear receptors—
VDR, NR1H4 (FXR) PPARα PPARγ, PPARδ
„„ TGF-β1 (transforming growth factor-β1) is a well
determined molecule for the accumulation of ECM
glycoproteins and subsequent glomerulosclerosis10
Pathology of Diabetic Nephropathy
Diabetic nephropathy was first described as glomerulo­
pathy, mainly affecting mesangial cells; however, with
further research it is found that glomerular epithelial cell
abnormalities like podocyte dysfunction (angiotensin
II mediated reduced expression of Nephrin), apoptosis,
ultimately resulting in depletion of podocytes is central to
development of proteinuria which is a hallmark feature of
diabetic nephropathy. Also identified are the important
changes in other sites like tubules, interstitium, medulla,
and papilla. Renal function and prognosis correlate better

MU-154.indd 1002 29-01-2021 15:01:27

 Understanding the Role of Vitamin D in Diabetic Nephropathy
with structural lesions in tubules and cortical interstitium
than with classic glomerular changes.11
The steps resulting in diabetic nephropathy are:12
„„ Hypertrophy of glomerulus and hyperfiltration
„„ Glomerular and tubulo-interstitial inflammation
„„ Decrease in number of cells by apoptosis and
accumulation of ECM.
Vitamin D
Fat soluble vitamin D exists in two major forms, namely
ergocalciferol (D2) and cholecalciferol (D3).
The main source of vitamin D for human body is
endogenously biosynthesized in the skin. Vitamin D
absorbed from diet and synthesized endogenously is
biologically inert. Vitamin D in liver is converted into
25-hydroxyvitamin D (25(OH) D3) by liver enzyme
25-hydroxylase, which can be measured clinically. 25(OH)
D3 is further hydroxylated to 1, 25(OH)2 D3 by kidney-
derived 1-alpha-hydroxylase which is an active form of
Vitamin D.
The activated form of vitamin D (1,25(OH)2D3) further
binds with vitamin D receptors (VDRs) and activates
various transcription factors. It is now found that, VDRs
and 1-alpha-hydroxylase is expressed in tissues like
islets of pancreas, hepatocytes, vascular smooth muscle
cells, macrophages, mesangial cells, and podocytes.
Vitamin D acts in autocrine manner and exerts multiple
non-calcemic effects through VDRs. This includes
vascular, immunomodulatory, anti-inflammatory effects,
suppression of RAS, and control of glucose homeostasis.13
Role of Vitamin D in Insulin Synthesis and
Regulating Insulin Sensitivity
Hyperglycemia results in endoplasmic reticulum stress,
inflammation (lipotoxicity) and loss of insulin sensitivity.
Thus, hyperglycemia plays a key role in causation of
resistance to insulin and β-cell failure.14-16 Diet induced
hypovitaminosis D in animal mice models revealed this
hypovitaminosis D is a result of impaired glucose tolerance,
decreased islet function related gene transcription, and
increased RAS expression.17
The postulated molecular mechanism behind
regulation of insulin homeostasis by Vitamin D includes:
„„ Promoter regions of insulin receptor genes have VDR
response elements (VDREs).18
MU-154.indd 1003
CHAPTER 154 1003
Fig. 2: Role of vitamin D in hepatic glucose homeostasis
„„ Calcitriol in liver is known to induce calcium flux
and activate calcium/calmodulin dependent protein
kinase (CaMkkB), which further activates 5’ AMP
(Adenosine monophosphate) activated protein
kinase (AMPK). This results in down regulation of
Phosphoenol pyruvate carboxy kinase (PEPCK) and
Glucose 6 phosphatase (G6Pase) and thus reduce
hepatic glucose output. AMPKa activation can also
downregulate sterol regulatory element binding
protein 1 (SREBP1c),FAS and Acetyl co-A carboxylase
(ACC) which further reduces the hepatic triglyceride
content shown in Figure 2.
„„ Increased intracellular ionized calcium and subsequent
downstream signaling mediated by vitamin D is known
to enhance glucose and arginine mediated insulin
release from β-cells of pancreas.19
„„ Suppress the transcription of renin, angiotensin
receptors and serve to inhibit local RAS mediated beta
cell injury.
„„ Hyperglycemia and increased free fatty acids result
in endoplasmic reticulum stress and reduced activity
of Akt pathway, which ultimately results in β-cell
apoptosis.
  Vitamin D helps in beta cell survival and also
increases compensatory beta cell growth in insulin
resistant states by enhancing activity of Akt pathway.20
„„ Vitamin D also reduces accumulation of hepatic
triglyceride and glucose output through Ca2+/CaMKK/
AMPK signaling activation.
„„ Vitamin D also inhibits VDR mediated PPAR activity
thus inhibits adipogenesis.21
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 1004 SECTION 11 Nephrology
Vitamin D Role in Inflammation
Activation of NF-kB pathway results in increased
transcription and production of proinflammatory
cytokines like TNF-α, IL-1, and IL-6. This proinflammatory
milieu leads to leukocyte infiltration of pancreas resulting
in reduced β-cell mass, reduced insulin synthesis, islet
amyloid deposition, altered downstream insulin signaling
through IRS/AKT/PI3K resulting in insulin resistance and
also affects the maintenance of energy and blood sugar
balance in hypothalamus.22
VDD promotes inflammation through NF-kB
pathway as evidenced by animal model, whereas vitamin
D supplementation has shown beneficial effects in
preventing the same.22
Vitamin D Role in Diabetic Nephropathy
Diabetic nephropathy is associated with increased
incidence of vitamin D deficiency. Probable explanation
for the same includes reduced sunlight exposure (e.g., in
elderly, sick, dark-skinned people, people wearing veil,
losses of vitamin D-binding protein in proteinuric states).
Vitamin D is known to ameliorate the harmful effects
of hyperglycemia on kidney by following mechanism:23
„„ Vitamin D inhibits RAS by downregulating renin,
angiotensinogen and angiotensin II receptor
expression.
„„ Enhances the expression of nephrin and prevents
structural derangement of slit diaphragm.
„„ Inhibits activation of ERKs, p38-MAPK, Wnt-b catenin
pathway, and down regulates proapoptotic signals
Bad, Bak, and upregulate anti-apoptotic signal Bcl2
and prevent podocyte apoptosis and podocyte loss.
„„ Inhibits the expression of Smad 3 protein or by the
physical interaction of VDR with Smad 3 protein
downregulates the intracellular level of Smad 3 and
thus, reduce the expression of TGF-β, and prevent
glomerulosclerosis.
„„ Inhibits the expression of fibronectin and extracellular
matrix proteins from mesangial cells and protect
against glomerulosclerosis.
„„ Inhibits the expression of MCP-1 (Monoc yte
Chemotactic Protein 1) which results in decreased
leukocyte recruitment to kidneys and reduces the renal
inflammation.
MU-154.indd 1004
Evidence from Clinical Studies
Clinical trial evidence indicates that combined
treatment with losartan and paricalcitol completely
prevented albuminuria as well as markedly reduced
glomerulosclerosis while restoring glomerular filtration
barrier structure. 2 The vitamin D receptor activator
(paricalcitol) in albuminuria lowering (VITAL) study
showed that addition of two micrograms of paricalcitol
to RAS inhibitors safely lowers albuminuria in patients
with diabetic nephropathy and can be a novel approach
to reduce residual renal risk in patients with diabetic
nephropathy who are already on treatment with optimal
doses of RAS inhibitors.24
Conclusion
Diabetic nephropathy is a common renal complication of DM
and a major cause of ESRD. RAS is the predominant mediator of
progressive injury to renal system in DN. Hence, RAS inhibitors
are being used as the mainstay of treatment for DN; however,
RAS inhibition leads to compensatory rise in the renin due to
the disruption of renin feedback inhibition. Vitamin D plays a
renal protective role in DM by suppressing rennin expression
by negative regulation of RAS. Combination therapy with RAS
inhibitors and active vitamin D and its analogue markedly
ameliorates renal injury.
However, Vitamin D is currently only recommended in
treatment of patients with moderate CKD associated with
secondary hyperparathyroidism and vitamin D insufficiency.
Hence, further study is required to answer many questions and
thereby uncover the potential renoprotective role of vitamin D
and its analogues in treatment of patients with CKD.
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