CHRONIC KIDNEY DISEASE
 Encompasses a spectrum of different pathophysiologic
processes associated with abnormal kidney function and a
progressive decline in glomerular filtration rate
 Previously, CKD had bed staged solely by the GFR;
however, the risk of worsening of kidney function is closely
linked to the amount of albuminuria
DEFINITION OF CKD (KDOQI/KDIGO)
 Chronic Kidney Disease:
o Presence of kidney damage OR
o Decreased kidney function for
o AT LEAST THREE TO FOUR MONTHS, irrespective
of the cause
 Criteria for chronic kidney disease
Criteria Remarks
Duration >3 Duration is necessary to distinguish chronic
months, based from AKI
on - Clinical evaluation can often suggest
documentation duration
or inference
Glomerular GFR is the best overall index of kidney function
filtration rate in health and disease
(GFR) <60 - Normal GFR in young adults –
mL/min/1.73 125mL/min/1.73m2
m2 - GFR <15 mL/min/1.73m2 – kidney
failure
Kidney 1) Pathologic abnormalities - cause is based
damage, as on underlying illness and pathology
defined by - Glomerular diseases (diabetes,
structural autoimmune diseases, systemic
abnormalities infections, drugs, neoplasia)
other than - Vascular diseases (atherosclerosis,
decreased GFR hypertension, ischemia, vasculitis,
thrombotic microangiopathy)
- Tubulointerstitial diseases (urinary
tract infections, stones, obstruction,
drug toxcity)
- Cystic diseases (polycystic kidney
disease)
2) History of kidney transplantation
- Chronic allograft nephropathy
(nonspecific findings of tubular
atrophy, interstitial fibrosis, vascular
and glomerular sclerosis)
- Rejection
- Drug toxicity (calcineurin inhibitors)
- BK virus nephropathy
- Recurrent disease (glomerular
disease, oxalosis, Fabry disease)
3) Albuminuria marker of kidney damage
(increased glomerular permeability, urine
albumin-to-creatinine ratio >30mg/g)
- Normal ACR in young adults: <10
mg/g
- Mildly increased ACR: 10-29
- Moderately increased ACR: 30-300
- Severely increased ACR: >300
- Urine ACR >2200 mg/g is
accompanied by signs and symptoms
of nephrotic syndrome (low serum
albumin, edema, and high serum
cholesterol)
4) Urinary sediment abnormalities
- RBC casts: proliferative
glomerulonephritis
- WBC casts: pyelonephritis or
interstitial nephritis
- Oval fat bodies/fatty casts: diseases
with proteinuria
- Granular cast and renal tubular
epithelial cells: parenchyma disease
5) Imaging abnormalities (UTZ, CT and MRI
with or without contrast, isotope scans,
angiography)
- Polycystic kidneys
- Hydronephrosis due to obstruction
- Cortical scarring due to infarcts,
pyelonephritis or vesiculoureteral
reflux
- Renal masses or enlarged kidneys
due to infiltrative diseases
- Renal artery stenosis
- Small and echogenic kidneys
ETIOPATHOGENESIS
 2 broad sets of mechanisms of damage
1) Initiating mechanisms specific to the underlying
etiology (genetically determined abnormalities in
kidney development or integrity, immune complex
deposition and inflammation in certain types of
glomerulonephritis, or toxin exposure in certain
diseases of the renal tubules and interstitium)
2) Set of progressive mechanisms involving
hyperfiltration and hypertrophy of the remaining
viable nephrons, irrespective of underlying etiology
- The responses to reduction in nephron number
are mediated by vasoactive hormones,
cytokines, and growth factors
- Eventually these short term adaptations of
hypertrophy and hyperfiltration become
maladaptive as the increased pressure and flow
within the nephron  distortion of glomerular
architecture, abnormal podocyte function and
disruption of filtration barrier  sclerosis and
dropout of remaining nephrons
- Increased intrarenal activity of the renin-
angiotensin system appears to contribute both
to the initial adaptive hyperfiltration and to the
subsequent maladaptive hypertrophy and
sclerosis.
 LEADING ETIOLOGIES: diabetic nephropathy,
glomerulonephritis, hypertension-associated CKD (vascular
and ischemic kidney disease)
 RISK FACTORS
o small for gestation birth weight
o childhood obesity
o hypertension
o diabetes mellitus
o autoimmune disease
o previous episode of acute kidney injury
o presence of proteinuria, abnormal urinary
sediment or structural abnormalities of the
urinary tract
o rare inherited forms: follows a Mendelian
inheritance pattern, often as part of a systemic
syndrome
 autosomal polycystic kidney disease
  
STAGING
 To stage CKD, it is necessary to estimate the GFR rather
than relying on serum creatinine
 Stages of CKD are stratified by both eGFR (left side) and
degree of albuminuria (right side) – KDIGO 2012
ETIOLOGY
 Stages 1 and 2 CKD: usually not associated with symptoms
arising from the decrement in GFR
 Stages 3 and 4: clinical and laboratory complications of
CKD become more prominent
o Virtually all organs are affected
o Most evident complications:
 anemia, easy fatigability, decreased
appetite with progressive
malnutrition
 abnormalities in calcium, phosphorus,
mineral regulating hormones
(calcitriol, PTH, fibroblast growth
factor 23
 abnormalities in sodium, potassium,
water and acid-base homeostasis
o Many patients, especially the elderly, will have
eGFR values compatible with stage 2 or 3 CKD
 If patient progresses to CKD V, toxins accumulate such that
patients usually experience a marked disturbance in their
ADLs, well-being, nutritional status and electrolyte
homeostasis  uremic syndrome
 The equations for estimating GFR are valid only if the
patient is in steady state – serum creatinine is neither
rising nor falling over days
PATHOPHYSIOLOGY AND BIOCHEMISTRY OF UREMIA
Measurement of albuminuria is also helpful for
monitoring nephron injury and the response to therapy in
many forms of CKD, especially chronic glomerular diseases.
o 24 hour urine: standard for measurement of
albuminuria
o Protein-to-creatinine ratio in a spot first
morning urine: more practical and correlates
well, but not perfectly, with 24h urine collections
o Microalbuminuria: excretion of amounts of
albumin too small to detect by urinary dipstick of
conventional measures of urine protein.
 Good screening test for early detection
of renal disease and may be a marker
for the presence of microvascular
disease
 Leading categories of etiologies of CKD
o Diabetic nephropathy
o Glomerulonephritis
o Hypertension-associated CKD (includes vascular
and ischemic kidney disease and primary
glomerular disease with associated
hypertension)
o Autosomal dominant polycystic kidney disease
o Other cystic and tubulointerstitial nephropathy
 Most frequent cause: diabetic nephropathy, most often
secondary to T2DM
 Patients with newly diagnosed CKD often also present with
hypertension; when no overt evidence for a primary
glomerular or tubulointerstitial kidney disease process is
present, CKD is often attributed to hypertension
 It is now appreciated that such individuals can be
considered in two categories.
o First: patients with a silent primary
glomerulopathy, such as focal segmental
glomerulosclerosis, without the overt nephrotic
or nephritic manifestations of glomerular disease
o Second: patients in whom progressive
nephrosclerosis and hypertension is the renal
correlate of a systemic vascular disease, often
also involving large- and small-vessel cardiac and
cerebral pathology. This latter combination is
especially common in the elderly, in whom
chronic renal ischemia as a cause of CKD maybe
underdiagnosed.
 Pathophysiology of uremic syndrome
1) Consequence of accumulation of toxins that normally
undergo renal excretion, including products of
metabolism
2) Consequence of the loss of other kidney functions
(metabolic and endocrine), such as fluid and
electrolyte homeostasis and hormone regulation
3) Progressive systemic inflammation and its vascular
and nutritional consequences
 Hundreds of toxins that accumulate in renal failure have
been implicated in the UREMIC SYNDROME
o Water-soluble, hydrophobic, protein bound,
charged and uncharged compounds
o Nitrogenous excretory products – guanido
compounds, urates, and hippurates, products of
 nucleic acid metabolism, polyamines,
myoinositol, phenols, benzoates, indoles
 Uremic syndrome and the disease state associated with
advanced renal impairment involve more than renal
excretory failure.
o The metabolic and endocrine functions that are
normally performed by the kidneys is also
impaired or suppressed 
 Anemia
 Malnutrition
 Abnormal metabolism of carbohydrates,
fats, proteins
 Plasma levels of many hormones (PTH,
FGF-23 insulin, glucagon, steroid hormones
including vitamin D and sex hormones and
prolactin) are changed due to reduced
excretion, decreased degradation, r
abnormal regulation.
o CKD is also associated with worsening systemic
inflammation.
 Elevated levels of CRP are detected along
with other acute-phase reactants
 Decreased negative acute-phase reactants
(albumin, fetuin) – decline with progressive
reduction in GFR.
 The inflammation associated with CKD is
important in the malnutrition-
inflammation-atherosclerosis/calcification
syndrome, which contributes in turn to the
acceleration of vascular disease and
comorbidity associated with advanced
kidney disease.
o in the distal nephron
 -
CLINICAL MANIFESTATIONS
- History: DM, HTN, abnormal UA, preeclampsia or early
pregnancy loss, drug history (NSAIDs, COX-2 inhibitors,
antibiotics, chemo, antiretrovirals, PPIs, phosphate
containing bowel cathartics, lithium
- PE: check BP and target organ damage from hypertension;
fundoscopy and precordial examination (left ventricular
heave, S4) should be carried out
- Findings of asterixis or a pericardial friction rub not
attributable to other causes usually signifies the presence of
the uremic syndrome
- In evaluating the uremic syndrome: ask about appetite,
weight loss, nausea, hiccups, peripheral edema, muscle
cramps, pruritus, and restless legs.
Systemic findings Remarks
Fluid, electrolyte, acid-base disorders
Sodium and water - Total body content of Na and H2O
homeostasis are modestly increased 
hypertension and peripheral
edema
- Kidney disease  disrupt intake
and out balance (ie dietary intake
of sodium exceeds its urinary
excretion)  sodium retention
and attendant extracellular fluid
volume expansion 
hypertension  accelerate the
nephron injury
- Patients with ECFV expansion
(peripheral edema, sometimes
hypertension poorly responsive to
therapy) should be counseled
regarding salt restriction.
- Hyponatremia uncommon; when
present, responds to water
restriction
- Thiazide diuretics have limited
utility in stages 3-5 CKD, loop
diretics (furosemide, bumetanide,
torsemide) may be needed
- Impaired renal conservation of
sodium and water
Management
- Dietary salt restriction and loop
diuretics, +/- metolazone – to
maintain euvolemia
- But overzealous salt restriction or
diuretic use can lead to ECFV
depletion and precipitate a further
decline in GFR.
- Patients with salt-losing
nephropathy may require a sodium
rich diet or salt supplementation.
- Water restriction is indicated only if
there is problem with
hyponatremia
- Intractable ECFV expansion, despite
dietary salt restriction and diuretic
therapy – indication to start renal
replacement therapy
Potassium - Urinary potassium excretion –
homeostasis predominantly mediated by
aldosterone-dependent secretion
Hyperkalemia may be due to a
decline in urinary K excretion  K
retention
- Hyperkalemia is precipitated by
increased dietary K intake, protein
catabolism, hemolysis,
hemorrhage, transfusion of RBC,
metabolic acidosis, medications
(RAAS inhibitors, spironolactone,
NSAIDs)
- Hypokalemia is uncommon
(reduced dietary intake, excessive
diuretics, GI loss); the use of
potassium supplements and
potassium-sparing diuretics may be
risky in patients with impaired
renal function  should be
constantly reevaluated as GFR
declines
Management
- Hyperkalemia – dietary restriction
of potassium, use of kaliuretic
diuretics, and avoidance of both
potassium supplements and
potassium retaining medications
(ACE-I or ARBs).
- Potassium-binding resins (calcium
resonium, sodium polystyrene)
can promote potassium loss
through the GI tract
- Intractable hyperkalemia –
indication for dialysis
Metabolic acidosis - Common disturbance in advanced
CKD
- They can acidify the urine, but they
produce less ammonia  cannot
excrete the normal quantity of
protons in combination with this
urinary buffer.
- Hyperkalemia further depresses
ammonia production
- Hyperkalemia and hypechloremic
metabolic acidosis is often present,
even at earlier stages of CKD (1-3),
in patients with diabetic
nephropathy or in those with
predominant tubulointerstitial
disease or obstructive uropathy 
non-anion gap metabolic acidosis
- Due to impaired amniogenesis 
impaired excretion of protons
- NAGMA in early stages  HAGMA
in later stages
- With worsening renal function, the
total urinary net daily acid
excretion is usually limited to 30-40
mmol, and the anions retained
organic acids  anion-gap
metabolic acidosis
- Even modest degree of metabolic
acidosis may be associated with
the development of protein
catabolism.
Management
- In most patients, the metabolic
acidosis is mild and can usually be
corrected with oral sodium
bicarbonate supplementation.
- Alkali supplementation may
attenuate the catabolic state and
possibly slow CKD progression and
accordingly is recommended when
the serum bicarbonate
concentration falls below 20-23
mmol/L
Disorders of Calcium and Phosphate Metabolism
Bone manifestations - Pathophysiology of secondary
hyperparathyroidism  high
turnover bone disease
1) Declining GFR  reduced
excretion of phosphate 
phosphate retention
2) Retained phosphate 
increased synthesis of FGF-23
by osteocytes and PTH and
stimulates growth of
parathyroid gland mass
3) Decreased levels of ionized
calcium, resulting from
suppression of calcitriol
production and by the failing
kidney, as well as phosphate
retention, also stimulate PTH
production
4) Low calcitriol levels
contribute to
hyperparathyroidism, both by
leading to hypocalcemia and
also by a direct effect on PTH
gene transcription
These changes start to occur when
the GFR falls below 60 mL/min (st.
3)
- High bone turnover with increased
PTH levels: osteitis fibrosa cystica
(classic lesion of secondary
hyperparathyroidism) – bone
histology shows abnormal osteoid
bone and bone marrow fibrosis,
and in advanced stages, the
formation of bone cysts,
sometimes with hemorrhagic
elements appear brown  brown
tumor
- Clinical manifestations of severe
hyperparathyroidism: bone pain,
fragility, brown tumors,
compression syndromes,
erythropoietin resistance in part
related to the bone marrow
fibrosis.
- PTH itself is considered a uremic
toxin, and high levels are
associated with muscle weakness,
fibrosis of cardiac muscle and
nonspecific constitutional
symptoms
- Low bone turnover with
low/normal PTH: adynamic bone
disease (reduced bone volume and
mineralization and may result from
excessive suppression of PTH
production, chronic inflammation
or both. Suppression of PTH can
result from the use of Vitamin D
preparations or from excessive
calcium exposure in the form of
calcium-containing phosphate
binders or high-calcium dialysis
solutions) and osteomalacia
- Complications of adynamic bone
disease (1) increased incidence of
fracture and bone pain (2)
association with increased vascular
and cardiac calcification (3)
occasionally the calcium will
precipitate in the soft tissues into
large concretions termed “tumoral
calcinosis”
- FGF-23: phosphatonin produced by
osteocytes which promotes
phosphate excretion; earliest to
increase during the course of CKD,
even before PTH, calcium and
phosphorous levels rise, and
vitamin D levels fall;
- High levels of FGF-23 are also an
independent risk factor for LVH
and mortality in CKD, dialysis, and
renal transplant patients.
- Elevated levels of FGF-23 may
indicate the need for therapeutic
 intervention (phosphate
restriction) even when the serum
phosphate levels are within the
normal range.
Management
- Optimal management of
secondary hyperparathyroidism
and osteitis fibrosa is prevention.
Once the parathyroid gland mass
is very large, it is difficult to
control the disease.
- Advise low-phosphate diet as well
as the appropriate use of
phosphate-binding agents (taken
with meals and compex the
dietary phosphate to limit its GI
absorption).
- Phosphate binders: calcium
acetate and calcium carbonate;
Major side effect of calcium-
phosphate binders is calcium
accumulation and hypercalcemia,
esp in patients with low-turnover
bone disease.
- Sevelamer and lanthanum non-
calcium containing polymers that
also function as phosphate
binders; they do not predispose
CKD patients to hypercalcemia
and may attenuate calcium
deposition in the vascular bed
- Calcitriol exerts a direct
suppressive effect on PTH
secretion and also indirectly
suppresses PTH secretion by
raising the concentration of
ionized calcium. Side effect:
hypercalcemia and/or
hyperphosphatemia through
increased GI absorption of these
minerals. Certain analogues
(paricalcitol) suppress PTH
secretion with less attendant
hypercalcemia
- Target PTH level: 150 and 300
pg/mL, recognizing that very low
PTH levels are associated with
adynamic bone disease and
possible consequences of fracture
and ectopic calcification.
Calcium, Phosphorus - Strongly association between
and Cardiovascular hyperphosphatemia and increased
System CV mortality in patients with CKD 5
- Hyperphosphatemia and
hypercalcemia associated with
increased vascular calcification
- CKD patients have calcification in
their arterial media in contrast to
the usual atherosclerosis which
involves arterial intima layer
Calciphylaxis - Almost exclusive to advanced CKD
(calcemic-uremic - Livedo reticularis: patches of
arteriolopathy) ischemic necrosis especially on
legs, thighs, abdomen and breasts
(warfarin treatment is a risk for its
development – one of the effects
of warfarin therapy is to decrease
the vitamin K-dependent
regeneration of matrix GLA
protein); pathologically: evidence
of vascular occlusion in association
with extensive vascular and soft
tissue calcification.
Cardiovascular Abnormalities: CVD is the leading cause of
morbidity and mortality in patients at every stage of CKD)
Ischemic Vascular - CKD is a major risk factor for
disease ischemic CVD
- Risks:
 Presence of traditional RF in
CKD pxs (hypertension,
hypervolemia, dyslipidemia,
sympathetic overactivity,
hyperchromocysteinemia
 CKD-related nontraditional
RF: anemia,
hyperphosphatemia,
increased FGF-23, sleep
apnea, and generalized
inflammation
- The inflammatory state associated
with a reduction in kidney
function is reflected in increased
circulating acute-phase reactants
(CRP and inflammatory cytokines)
and fall in the “negative acute-
phase reactants” (serum albumin
and fetuin)
- Cardiac troponins frequently
elevated in CKD patients without
evidence of acute ischemia; serial
measurements may be needed,
and if the level is unchanged, it is
possible that there is no acute
myocardial ischemia; Interestingly,
consistently elevated levels are an
independent prognostic factor for
averse cardiovascular events in this
population
Heart failure - Abnormal cardiac function from
ischemia, left ventricular
hypertrophy and frank
cardiomyopathy in combination
with the salt and water retention
that can be seen with CKD  heart
failure or even pulmonary edema
- Heart failure can be a consequence
of diastolic or systolic dysfunction
or both.
- “low pressure” pulmonary edema
in advanced CKD manifest as
shortness of breath and “bat
wing” distribution of alveolar
edema fluid on the chest x-ray
(increased alveolar capillary
permeability due to uremia)
responds to dialysis
- Other CKD-related risk factors,
including anemia and sleep apnea,
may contribute to the risk of heart
failure
Hypertension and - Hypertension develops early in
Left Ventricular CKD; usually early during the
Hypertrophy course of CKD – associated with
adverse outcomes (LVH and mor
rapid loss of renal function)
- LVH and dilated cardiomyopathy
are the strongest risk factors for
death and morbidity in CKD
patients
- Anemia and the placement of an
arteriovenous fistula for HD can
generate a high cardiac output
state and consequent heart failure.
- Absence of hypertension (worse
prognosis) may signify a salt-
wasting form of CKD, effect of
antiHPN therapy, volume depletion
or poor LV function;
- The use of exogenous
erythropoiesis-stimulating agents
can increase blood pressure and
the requirement for
antihypertensive drugs.
Management
- The overarching goal of
hypertension therapy in CKD is to
prevent the extrarenal
complications of high BP
(cardiovascular disease and stroke)
- In CKD patients with diabetes or
proteinuria >1 g per 24 h, BP
should be reduced to 130/80
mmHg. (*JNC 140/80)
- Salt restriction should be the first
line of therapy.
- When volume management alone is
not sufficient, the choice of
antihypertensive agent is similar to
that in the general population.
- ACE-I and ARBs appear to slow the
rate of decline of kidney function in
a manner that extends beyond
reduction of systemic arterial
pressure and that involves
correction of the intraglomerular
hyperfiltration and hypertension
involved in progression of CKD.
- BUT, sometimes ACE-I and ARBS can
actually precipitate an episode of
AKI, especially when used in
combination in patients with
ischemic renovascular disease.
- Use of ACE-I and ARBs may also be
complicated by the development of
hyperkalemia.
- Lifestyle changes (exercise, diet)
should be advocated.
Hyperlipidemia in patients with CKD
should be managed according to
national guidelines.
- If dietary measures are not
sufficient, preferred lipid-lowering
medications (statins) should be
used.
Pericardial disease - Chest pain with respiratory
accentuation accompanied by
friction rub  PERICARDITIS
- Classic ECG of pericarditis – PR
interval depression and diffuse ST-
segment elevation
- Pericarditis can be accompanied by
pericardial effusion that is seen on
echocardiography and can rarely
lead to tamponade.
- Pericarditis observed in advanced
uremia (more often seen in
underdialzyed, non-adherent
patients)
Management
- Uremic pericarditis is an absolute
indication for the urgent initiation
of dialysis or intensification of the
dialysis prescription in those already
receiving dialysis.
- Because of the propensity to
hemorrhage in pericardial fluid,
hemodialysis should be performed
without heparin.
- Pericardial drainage should be
considered in patients with
recurrent pericardial effusion,
especially with echocardiographic
signs of impending tamponade.
- Nonuremic causes of pericarditis
and effusion: viral, malignant,
tuberculous and autoimmune
etiologies, after MI and as
complication of treatment with
minoxidil
Hematologic abnormalities
Anemia - Normocytic, normochromic
anemia observed as early as CKD 3
and universal in CKD 4
- Primary cause: insufficient
production of erythropoietin by
the diseased kidneys
- Anemia  adverse
pathophysiologic consequences
(decreased issue oxygen delivery
and utilization, increased cardiac
output, ventricular dilation and
ventricular hypertrophy)
- Clinical manifestations: fatigue,
diminished exercise tolerance,
angina, heart failure, decreased
cognition and mental acuity,
impaired host defense against
infection, growth restriction (in
kids)
- Anemia and resistance to
exogenous erythropoietic-
stimulating agents are associated
with poor prognosis
- Causes include: relative EPO
deficiency, diminished RBC
survival, bleeding diathesis, iron
deficiency,
hyperparathyroidism/narrow
fibrosis, chronic inflammation,
folate or vitamin b12 deficiency,
 hemoglobinopathy
- Other causes: comorbid conditions
such as hypo/hyperthyroidism,
pregnancy, HIV, autoimmune
disease, immunosuppressive drugs
Management
- Human exogenous erythropoietic
agents
- Adequate bone marrow iron stores
should be available before
treatment with ESA is initiated.
- Iron supplementation is usually
essential to ensure an optimal
response to ESA in patients with
CKD because the demand for iron
by the bone marrow frequently
exceeds the amount of iron that is
immediately available for
erythropoiesis (measured by
percent transferrin saturation) as
well as the amount in iron stores
(measured by serum ferritin)
- For CKD patients not yet on dialysis
or treated with peritoneal dialysis,
oral iron supplementation should be
attempted or IV iron infusion if with
GI intolerance
- Keep in mind though that iron
therapy can increase the
susceptibility to bacterial infections.
- Other major substrates and
cofactors of red cell production
must be ensured (vitamin B12 and
folate)
- Anemia resistant to recommended
doses of ESA in the face of
adequate stores may be due to
some combination of the following:
acute or chronic inflammation,
infrequent dialysis, severe
hyperparathyroidism, chronic blood
loss or hemolysis, chronic infection
or malignancy.
- Blood transfusions increase the riks
of hepatitis, iron overload and
transplant sensitization – they
should be avoided unless the
anemia fails to respond to ESA and
the patient is symptomatic.
- Target hemoglobin concentration
of 100-115 g/L
Abnormal - Later stages of CKD - Prolonged
hemostasis bleeding time, decreased activity
or platelet factor III, abnormal
platelet aggregation and adhesion
and impaired prothrombin
consumption
- Clinical manifestation: increased
tendency to bleeding and bruising,
prolonged bleeding from surgical
incisions, menorrhagia and GI
bleeding.
- Greater susceptibility to
thromboembolism especially if
with nephrotic range proteinuria
 hypoalbuminemia and renal
loss of anticoagulant factors 
thrombophilic state
Management
- Abnormal bleeding time and
coagulopathy in patients with renal
failure may be reversed temporarily
with desmopressin (DDAVP),
cryoprecipitate, IV conjugated
estrogens, blood transfusions, and
ESA therapy
Other Systemic Manifestations
CNS, Peripheral and - Retained nitrogenous metabolites
Autonomic and middle molecules
Neuropathy - Early signs seen at CKD 3; usually
clinically evident at CKD 4
- Early: mild disturbances in
memory, concentration and sleep
- Late: hiccups, cramps, twitching
restless leg syndrome
- Advanced untreated CKD:
asterixis, myoclonus, seizures,
coma
- Peripheral neuropathy usually
becomes clinically evident after
patient reaches stage 4 CKD.
- Sensory nerves are involved more
than motor, lower extremities
more than upper, and distal parts
of the extremities more than
proximal.
- Restless leg syndrome – ill’defined
sensations of sometimes
debilitating discomfort in the legs
and feet relieved by frequent leg
movement.
- If dialysis is not instituted soon
after onset of sensory
abnormalities, motor involvement
follows, including muscle
weakness.
- Evidence of peripheral neuropathy
without another cause (DM) is an
indication for starting renal
replacement therapy.
- Many of the complications
described will resolve with dialysis
Gastrointestinal - Uremic Fetor: urine-like breath
manifestations odor derives from the breakdown
of urea to ammonia in saliva and is
often associated with
- dysgeusia (unpleasant metallic
taste)
- Gastritis, peptic disease or mucosal
ulcerations at any level of the GI
tract  abdominal pain, nausea,
vomiting and GI bleeding
- Protein restriction may be useful to
decrease nausea and vomiting
however, it may put the patient at
risk for malnutrition
- Anorexia due to retention of
uremic toxins
 Protein Energy - Consequence of low protein and
Malnutrition caloric intake, metabolic acidosis,
inflammatory cytokines
- Resistance to anabolic effects of
insulin and growth factors
- Assessment for PEM starts at Stage
3 damage
Endocrine/Metaboli - Abnormal glucose metabolism:
c Disturbances slowed response to glucose
loading, FBS normal or slightly
elevated, and diminished renal
degradation of insulin (kidney
contributes t insulin removal from
the circulation  plasma levels of
insulin are slightly to moderately
elevated); patients on insulin
therapy may need progressive
reduction in dose as their renal
function worsens; many
hypoglycemic agents (gliptins)
require dose reduction in renal
failure and some such as
metformin are contraindicated
when GFR is less than half of
normal (GFR 30)
- In women: Low estrogen,
menstrual abnormalities, inability
to carry pregnancies to term; when
GFR has declined to ~40mL/min,
pregnancy is associated wth a high
rate of spontaneous abortion
- In men: Reduced plasma
testosterone, oligospermia, Sexual
dysfunction, sexual maturation
may be delayed or impaired in
adolescent children with CKD
- Many of these abnormalities
improve or reverse with intensive
dialysis or with successful renal
transplantation
Dermatologic - Skin changes: pruritis,
manifestations hyperpigmentation (deposition of
retained pigmented metabolites,
or urochromes)
- Many of the cutaneous
abnormalities improve with
dialysis, pruritus is often tenacious.
- Nephrogenic dermopathy:
progressive subcutaneous
induration especially on the arms
and legs associated with exposure
to gadolinium; unique to CKD
patients
- Current recommendation: patients
with CKD 3 should minimize
exposure to gadolinium; and those
with CKD 4 should avoid the use of
gadolinium agentsunless it is
medically necessary.
DIAGNOSIS
Acute Kidney Disease versus Chronic Kidney Disease
Index AKD CKD
Functional AKI GFR <60mL/min/1.73m2
Criteria GFR <60mL/min/1.73 for > 3 months
m2 for <3months
Decrease in GFR by
>35% or increased in
SCr by >50% for
<3months
Kidney Present <3 months Present >3 months
Kidney Normal or large Small (except in DM,
size HIV, PCKD, amyloidosis)
Size discrepancy may be
present
Loss of renal cortex
(cortical thinning <1cm)
DIAGNOSTICS
Diagnostic Comments/expected findings
Basic - CBC: to check for anemia, infection,
laboratory thrombocytopenia
tests - BUN, crea: to estimate GFR
- Electrolytes: to determine abnormalities
from deranged renal function
(hyponatremia, Hyperkalemia,
hypocalcemia, hyperphosphatemia,
hypermagnesemia)
Measuremen - 24 urine collection: standard for
t of measurement of albuminuria
albuminuria - Protein-to-creatinine ratio: spot first
morning urine – more practical and
correlates well with 24 urine collection
Urinary - Microscopic hematuria with abnormal RBC
sediment morphology (anisocytosis): GBM disorders
abnormalities - RBC casts: proliferative glomerulonephritis
- WBC casts: pyelonephritis, interstitial
nephritis
- Oval fat bodies/ fatty casts: disease with
proteinuria
- Granular casts and renal tubular epithelial
casts – non-specific for parenchymal
disease
Renal - Most useful imaging study
ultrasound - Verifies presence of 2 kidneys, determines
symmetry, estimates size and rules out
masses/obstruction
- Discrepancy >1cm in kidney length suggest
either: unilateral developmental
abnormality, renovascular disease causing
hypoperfusion to smaller kidney
- Finding of bilaterally small kidneys support
CKD (except for early DM, amyloidosis,
HIV, PCKD)
- DM nephropathy (kidney size is increased
at the onset of DM nephropathy before CKD
supervenes)
- Polcystic kidney disease that has reached
some degree of renal failure will almost
always present with enlarged kidneys with
multiple cysts
Renal biopsy - Not advised for bilaterally small kidneys
because
1) It is technically difficult and has a
greater likelihood of causing bleeding
and other adverse consequences
2) There is usually so much scarring that
the underlying disease may not be
apparent
 3) The window of opportunity to render for initiating dialysis
disease-specific therapy has passed Electrolyte Hyponatremia Responds to water
- Other contraindications: uncontrolled abnormalities restriction
hypertension, active UTI, bleeding diathesis Hyperkalemia Dietary restriction
and severe obesity of K and avoidance
- Ultrasound-guided percutaneous biopsy is of K supplements
he favored approach; bleeding time should Kaliuretic diuretics:
be measured and if increased, promote urinary K
desmopressin should be administered excretion
immediately prior to the procedure Potassium binding
resins (calcium
MANAGEMENT resonium, sodium
Interventions and Goals in CKD polystyrene)
Intervention Goals promote K loss
Slow Elevated BP increases proteinuria by increasing through the GI tract
progression its flux across the glomerular capillaries Dialysis for
of CKD ACE-I or ARBs (to reduce intraglomerular intractable
hypertension and proteinuria) may be used to hyperkalemia
target: Hypocalcemia If asymptomatic:
- Urine protein level <0.5 g/day oral calcium
- Slow progression of CKD and GFR decline supplementation
to <1mL/min/year taken in between
ACE-I and ARBs inhibit the angiotensin-induced meals
vasoconstriction of the efferent arterioles of the If symptomatic: may
glomerular microcirculation  reduction in both give IV calcium to
intraglomerular filtration pressure and target serum Ca
proteinuria levels within normal
Target blood pressure using recent hypertension range (2.1-2.5
guidelines mmol/L)
- Harrisons’: 130/80 mmHg in proteinuric Hyperphosphatemi Low phosphate diet
CKD patients a Phosphate binding
Weight loss if Aim for 5% weight loss agents taken with
obese meals to limit GI
Dietary salt <5g/day (equivalent to 90 mEq Na/day absorption of dietary
restriction phosphate
Dietary Avoid high protein intake >1.3 g/kg/day Target phosphate
protein In CKD 4-5 non-dialytic patients: levels within normal
restriction - Caloric intake: 30-35 kcal/kg/day range (0.81 – 1.45
- Low protein diet: protein intake of 0.6- mmol/L)
0.8 g/kg/day Target intact PTH
- Supplemented very low protein diet: levels 2-9x the upper
protein intae 0.3 g/kg/day with keto- normal limit of assay
analogues of amino acid (KAA)
supplementation Metabolic Alkali supplementation (NaHCO3): may slow
Glycemic A1C <7.0% Acidosis down CKD progression (Started when HCO3
control FBS 90-130 mg/dL <20-23 mmol/L)
Smoking Complete cessation Concomitant sodium load in NaHCO3 needs
cessation careful attention to volume status and possible
Lipid Total cholesterol <200mg/dL need for diuretics
lowering LDL cholesterol <100 mg/dL Cardiovascular Hypertension: control BP based on current
therapy abnormalities guidelines
Avoid and Manage AKI risk during intercurrent illness or Ischemic heart disease
prevent AKI during procedures that are likely to increase AKI Uremic pericarditis: absolute indication for
risk urgent initiation or intensification of dialysis
(heparin free)
Management of Uremic Symptoms Anemia Recombinant human EPO: initiated once there
Manifestation Manamgement are adequate bone marrow iron stores
Fluid Salt restriction: if with evidence of volume Iron supplementation: to ensure adequate
Disturbances expansion bone marrow iron stores (avoid when ferritin is
Loop Diuretics: +/- metolazone to maintain >500 ng/mL)
euvolemia (thiazides have limited utility in CKD Vitamin B12 and Folate Supplementation
3-5) Target hemoglobin 100-115 g/L, transferrin
Intractable edema, hypertension and saturation <30%, serum ferritin >500 ng/mL
hyperkalemia in advanced CKD are indications Neuromuscula Most resolve with dialysis and successful renal
 r abnormalities transplantation weight 1x/wk SC IV
Nutritional Protein energy malnutrition: indication to do
abnormalities renal replacement therapy Drugs for Mineral Bone Disorders
Protein restriction may slow renal decline at CLASS REMARKS EXAMPLES
earlier stages (may increase protein intake for Phosphate Calcium-based: more Calcium carbonate
those with r at risk of PEM) binders (taken commonly used but 500mg/tab
Dermatologic Local moisturizers, mild topical steroids, UV with meals) dose is restricted contains 200 mg of
abnormalities radiation (<20000 mg/day) to elemental Ca, given
Minimization of exposure to gadolinium in prevent 1 tab TID with
CKD3 and avoidance in CKD 4-5 hypercalcemia meals
Non-calcium based: Calcium acetate
Commonly Used Drugs in Management of CKD patients less calcium 667 mg/cap
Renin- ACE-I and ARBs are the first line exposure to patients contains 169 mg of
Angiotensin antihypertensive elemental Ca, given
System Optimal renoprotective doses: with each meal
Blockers - Losartan 100mg daily Sevelamer 800
- Candesartan 16 mg daily mg/tab, 1 tab TID
- Irbesartan 900 mg daily with meals
- Valsartan 320-640 mg daily Lanthanum
- Lisinopril 40 mg daily carbonate:
Caution: may cause reversible hyperkalemia effective binder but
and AKI especially in advanced CKD and no long term
renovascular hypertension studies
Diuretics Useful in CKD because there is decrease in Aluminum
filtered load of salt and fluid when there is hydroxide: now
reduced GFR avoided due to
Loop diuretics: preferred in dissipating edema potential for
and in treating hypertension, acidosis and aluminum toxicity
hyperkalemia Calcimimetics Used in CKD 5 (on Cinacalcet 30 mg
Avoid exceeding ceiling doses of loop diuretics dialysis) with OD (downregulates
to prevent AKI, ototoxicity and electrolyte hyperparathyroidis PTH levels)
imbalances m
GFR Ceiling dose Used in combination
Furosemide Bumetanide with calcitriol or
GFR 20-50 80-160 mg 6 mg IV or vitamin D analogs
mL/min IV PO Calcitriol and Not routinely used Calcitril 0.25 mg
160 mg PO Vitamin D Reserved for CKD OD-BID while
GFR <20 200 mg IV 10 mg IV or Analogues stage 4-5 with carefully
mL/min 200 mg PO PO severe monitoring for
hyperparathyroidis hypercalcemia and
m hyperphosphatemia

Bicarbonate Therapy
- Start oral bicarbonate supplementation when serum
Drugs for Anemia bicarbonate levels fall <22 mmol/L
CLASS REMARKS EXAMPLES - Dose of oral sodium bicarbonate: 0.5 to 1 mEq/kg/day (target
Oral Iron To provide ~200 Ferrous sulfate 325 HCO3 level within normal range)
Supplement mg/day of mg/tab (elemental o Oral sodium bicarbonate 650 mg contains 7.7 mEqs of
elemental iron in iron 65 mg/tab) bicarbonate
nondialytic CKD TID - can slow down progression of CKD
patients
Intravenous iron Can be used in both Iron sucrose 1000 Ketoanalogues of Amino Acids Supplement
nondialytic and mg IV in 10 doses - mixture of essential amino acids and nitrogen-free
dialytic CKD (100mg/dose) is ketoanalogues
patients equivalent to iron - given as supplement to a very low protein diet (0.3 g/kg/day)
Better tolerated content in one bag - shown to delay onset of uremia and initiation of dialysis
compared to oral of packed RBC - Dose: Ketoanalogue 600mg/tab, given as 1 tablet per 5-10kg of
iron (but more body weight
expansive) - Carefully monitor serum Ca levels as KAA preparations contain
Erythropoiesis Preferred initial Erythropoietin different Ca salts
Stimulating Agents form of therapy alpha/beta 20-50
Used when Hgb IU/kg body weight Renal Replacement Therapy
<100 g/L despite 3x/wk SC/IV - Can be in the form of kidney transplant, hemodialysis or
correction of iron Darbopoietin-alpha peritoneal dialysis
deficiency 0.45 ug/kg body
- KT offers best potential for complete rehabilitation as HD/PD
replaces only small fraction of the kidney’s filtration and none
of the other renal functions such as endocrine and anti-
inflammatory effects
- Dialysis relies on the principle of solute diffusion across a
semipermeable membrane, where movement of metabolic
waste products takes place down a concentration gradient
from the circulation into the dialysate
Absolute indications Relative Indications
- Pericarditis or pleuritis - Anorexia and vomiting
(urgent indication) - Impaired nutritional
- Progressive uremic status
encephalopathy or - Increased sleepiness
neuropathy, with signs - Decreased energy level,
such as confusion, attentiveness and
asterixis, myoclonus, cognitive tasking
wrist or foot drop, or in
severe cases, seizures
(urgent indication)
- A clinically significant
bleeding diathesis
attributable to uremia
(urgent indication)
- Persistent metabolic
disturbances that are
refractory to medical
therapy, these include
hyperkalemia, metabolic
acidosis, hypercalcemia,
hypocalcemia, and
hyperphosphatemia
- Fluid overload refractory
to diuretics
- Hypertension poorly
responsive to
antihypertensive
medications
- Persistent nausea and
vomiting
- Evidence of malnutrition