SLOWING PROGRESSION AND PREVENTING

COMPLICATIONS OF CHRONIC KIDNEY DISEASE

Luca De Nicola, Chiara Ruotolo and Roberto Minutolo

Nephrology and Dialysis Unit, Department of Advanced Medical and Surgical Sciences, University L. Vanvitelli, Naples, Italy

Corresponding author: Luca De Nicola; email: luca.denicola@unicampania.it

Content Summary

The therapeutic approach to CKD is undergoing a ‘seismic revolution’ due to the development of novel
strategies that are effective in preventing the progression of kidney disease and the onset of dependent
complications. A preliminary and essential step is to identify the patients at risk of progressive CKD who
need closer monitoring and intensive treatment, ideally in the nephrology setting, i.e. the reference of care
for these patients. Overlooking this step precludes optimal implementation of nephroprotective therapy.
This chapter will address the strategies to identify progressive CKD and the non-pharmacological and
pharmacological therapy aimed at slowing down the progression of CKD and its complications.

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 1

 Slowing progression and preventing
complications of chronic kidney disease
Novel strategies to prevent the progression of kidney disease and onset of dependent complications are now available for patients with chronic kidney
disease (CKD). This chapter will firstly address the strategies to identify progressive CKD and then the non-pharmacological and pharmacological therapy
aimed at slowing down the progression of CKD and its complications.

Main issues:
• Identification of progressive CKD Who Which What
• Treatment of progressive CKD should be test to to do with
Optimal blood pressure control screened? screen? CKD patients?
Lowering proteinuria
• Treatment of main CKD complications
Cardiovascular events
Anemia
• Hypertension • eGFR Ask nephrologist if: Treat to goals:
Hyperkalemia • Diabetes • ACR • Hereditary kidney disease • Euvolemia
Metabolic acidosis • CV disease • Urine exam • eGFR <30 mL/min/1.73 m2 • Normal BMI
Mineral bone disease • Obesity • Acute kidney injury • BP around 130/80 mmHg
Nutritional impairment • eGFR loss ≥5 mL/min/year • ACR ≤30 mg/g or 50%
• ACR >300 mg/g • Hb 10.5–12.0 g/dL
• Glomerular hematuria • TSAT ≥20%
• Anemia of unknown cause • Ferritin ≥200 ng/mL
In the spotlight
• Cognitive impairment in CKD The 3W-approach to identify • Resistant hypertension • HbA1c 7.0–8.0% in diabetes
• High sK, high sP or PTH • Normal pNA, sK and sP
• RAAS inhibitors: good for heart and kidney, but and treat progressive CKD • PTH 70–300 pg/dL (stage 3–5)
how to manage hyperkalemia? • HCO3 >22 mmol/L

Nephrologists of the third millennium are facing a major mind-shift in the care of CKD, moving focus from dialysis De Nicola, L., et al.
to the remission of progressive CKD. This objective is today reachable thanks to innovative agents; however, the ERA Neph-Manual
first essential step still remains timely identification of high-risk patients to enable multifactorial treatment. 2023

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 2

Case Report
In October 2020, a 71-year-old Caucasian woman was referred by her general practitioner to our outpatient
renal clinic because of a finding on routine examination of an increased serum creatinine level (1.3 mg/dl)
versus her last available creatinine value of 0.95 mg/dl from 6 months before. She has a clinical history of
long-standing hypertension (from 1999) and diabetes mellitus diagnosed in 2000 complicated by proliferative
diabetic retinopathy. An acute myocardial infarction (MI) occurred in 2007 that was treated with percutaneous
transluminal coronary angioplasty (PTCA) and stenting. She quit smoking (15–20 cigarettes/day for years) after
the MI.

At the clinic visit the patient appeared in good general condition; she had a body weight of 87 kg and her body
mass index (BMI) was 30.8 kg/m2. Office blood pressure (BP) was out-of-target (160/90 mmHg with a heart
rate of 78 bpm). On physical examination, we found an absence of peripheral oedema, with normal respiratory
sounds and heart sounds. On abdominal ultrasound, the kidneys had a regular shape, with a mild reduction of
cortical thickness and kidney size (longitudinal diameter 97 mm right kidney, 100 mm left kidney).

A recent cardiology visit showed on electrocardiogram only aspecific abnormalities of left ventricular
repolarization. Echocardiography showed left ventricular hypertrophy with anterior wall and septal hypokinesia,
an ejection fraction (EF) 45%, dilated left atrium, altered diastolic function, mitral annulus valve calcifications and
poor collapse of the inferior vena cava with inspiration. The cardiologist recommended the use of a beta blocker
at increasing dosage because of a slight decline in the EF from a previous visit (51%).

The laboratory tests performed by her general practitioner showed chronic kidney disease (CKD) stage G3bA3,
hyperglycaemia, mild albuminuria on urinalysis without haematuria and normal urinary sediment. At referral,
we requested a 24-h urine collection to estimate daily albuminuria, sodium and protein intake and home blood
pressure (HBP) monitoring (measurements in the morning and in the evening in the 7 days before the next visit) to
confirm the degree of hypertension (Table 1).

Therapy at the referral visit (prescribed by general practitioner) included olmesartan 20 mg at 8:00 A.M.,
furosemide 25 mg at 1:00 P.M., clopidogrel 75 mg after lunch, atorvastatin 20 mg at 8:00 P.M., metformin 500
mg/day, rapid insulin 4 + 12 + 8 UI and basal insulin 18 UI at bedtime.

We did not perform a kidney biopsy and we diagnosed diabetic nephropathy on a clinical basis. Indeed, the
presence of long-standing type 2 diabetes mellitus (20 years), proliferative diabetic retinopathy, albuminuria
without haematuria and normal urinary sediment are all in agreement with diabetic nephropathy [1, 2]. In
addition, it was likely that a biopsy sample could only provide limited information due to the reduced cortical
thickness at ultrasound and the advanced CKD (high likelihood of detecting sclerotic glomeruli and a higher risk
of bleeding).

Considering the results of the diagnostic tests at the first visit and the uncontrolled HBP (158/82 mmHg), we
prescribed a low sodium diet, increased the dose of furosemide to 50 mg/day and confirmed the prescription of
the cardiologist (bisoprolol 1.25 mg in the morning titrated up to 5 mg/day in the following weeks).
At the follow-up visit performed after 3 months, we found the HBP was persistently high (150/78 mmHg). To
gain information on BP at night, we prescribed ambulatory blood pressure (ABP) monitoring, which showed
sustained hypertension and an altered circadian profile (reverse dipper). Daytime BP, in fact, was 136/80 mmHg
and night-time BP was 150/75 mmHg. Therefore, we added amlodipine 10 mg at 10:00 P.M. Albuminuria
decreased by 20% and sodium intake slightly decreased to 170 mEq/day (Table 2).

After 8 weeks, the patient returned to our clinic because her HBP had decreased but was above the target (mean
HBP in the previous week was 142/82 mmHg). We added spironolactone 50 mg in the afternoon to reduce
albuminuria and enhance natriuresis.

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 3

 Parameter Value
Serum creatinine (eGFR, MDRD equation) 1.30 mg/dl (eGFR 44 ml/min/1.73 m2)
Azotaemia 52 mg/dl
Plasma sodium 140 mEq/l
Serum potassium 4.1 mEq/l
Glycemia (glycated haemoglobin) 151 mg/dl (7.8%)
Albumin 4.1 g/dl
Haemoglobin 12.0 g/dl
Ferritin 165 ng/ml
Transferrin saturation 24%
Calcium 10.0 mg/dl
Phosphorus 4.5 mg/dl
Intact parathyroid hormone 67 pg/ml
Urinalysis Albuminuria +++, no haematuria, normal microscopy
Proteinuria 1850 mg/day
Albuminuria 1370 mg/day
Urinary sodium (salt intake) 214 mEq/day (13 g/day)
Urinary potassium 42 mEq/day
Urinary urea nitrogen (protein intake) 26 g/day (1.1 g/kg body weight/day)

Table 1: Examination findings.

eGFR: estimated glomerular filtration rate; MDRD: Modification of Diet in Renal Disease.

Baseline 2 weeks 4 weeks 8 weeks

Parameter
(August 2021) (September 2021) (October 2021) (November 2021)
Serum creatinine 1.55 1.70 1.80 1.88
eGFR (ml/min/1.73 m2) 35 32 30 28
Serum potassium (mEq/l) 4.9 5.2 5.5 6.3
Albuminuria (mg/day) 950 – 680 355
Add-on ramipril Withdrawal of
Changes in therapy - Withdrawal of Ramipril
5 mg/day spironolactone
Add-on oral sodium
bicarbonate and sodium
polystyrene sulfonate
Table 2: Laboratory tests and changes in therapy in the 8 weeks after starting dual RAAS blockade.

At the 6-month visit we detected an increase in parathyroid hormone (PTH) and urinary urea nitrogen. We
therefore prescribed paracalcitol 1 μg/day, not only to lower PTH, but also to reduce albuminuria according
to evidence suggesting antiproteinuric effects driven by suppression of renin–angiotensin–aldosterone system
(RAAS) activity [3–5], and recommended a low protein diet after seeing an increase in azotaemia (0.6–0.8 g/
kg/day and 30 kcal/kg/day)

After 10 months, the patient was in good general condition but she had persistent albuminuria. Considering

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 4

 the stability of renal function and normal potassium levels, we decided to suppress the RAAS further by adding
ramipril 5 mg/day followed by frequent laboratory checks and BP monitoring (Table 2).

Intensive RAAS blockade induced a progressive decline in albuminuria; however, the progressive increase in
serum potassium, persisting despite spironolactone withdrawal, led us to discontinue ramipril and to prescribe
oral sodium bicarbonate 3 g/day due to metabolic acidosis, and sodium polystyrene sulfonate (withdrawn after
few days because of intolerance). Serum potassium normalized after 4 weeks, but a rebound of albuminuria
was detected. At the same time, the large decrease in glomerular filtration rate (GFR) observed with dual RAAS
blockade promptly reversed after withdrawal of ramipril (Figure 1). The need to reduce albuminuria became
mandatory when looking at GFR changes in the first year of follow-up in the clinic: the patient was a fast
progressor, as seen by the rapid GFR decline (we calculated −6.5 mL/min/year without considering the acute
decrease during ramipril).

A B
Δ Albuminuria –36% Δ eGFR –6.5 mL/min/year

1500 45

1200 Start dual 40

RAS blockade Start dual
RAS blockade
eGFR (mL/min/1.73 m2)
Albuminuria (mg/day)

900 35

600 30

300 25 Withdrawal dual

RAS blockade
Withdrawal dual
RAS blockade
0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 0 1 2 3 4 5 6 7 8 9 10 11 12 13
Months Months

Figure 1: (A) Albuminuria and (B) eGFR during the first 13 months in the nephrology clinic.

In December 2021, the Italian Medicines Agency made available the prescription of sodium–glucose co-
transporter 2 inhibitor (SGLT2i) to nephrologists and thus we decided to treat the increased albuminuria by
prescribing dapagliflozin 10 mg/day for its well-known antiproteinuric and nephroprotective effects.
Dapagliflozin improved the clinical picture in the following months: albuminuria decreased by 66%, reaching
a value of 299 mg/day; the HBP target was achieved and maintained even after furosemide withdrawal;
haemoglobin A1c (HbA1c) was better controlled, thus allowing a reduction of the insulin dose; and the serum
potassium level was reduced, allowing restarting of spironolactone (as recommended for her heart failure) (Table
3).

Albuminuria reduction and better BP control were associated with stability of GFR over time. Indeed, in the period
following the start of dapagliflozin, GFR decreased by only 1.4 ml/min/year (Figure 2).

Comment: The combination of antihypertensive therapy, antiproteinuric agents (olmesartan, ramipril,

spironolactone and paricalcitol), hyperkalaemia treatment (nowadays more feasible due to the new and better-
tolerated potassium binders, Patiromer and Sodium Zirconium Cyclosilicate) and low protein diet allowed limiting
the progression of CKD and stabilization of her clinical condition as well. Therefore, this case report, while
confirming concerns on dual RAS blockade, supports multifactorial therapy aimed at minimizing albuminuria as
the main strategy to limit CKD progression.

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 5

 December January February March June September
Parameter
2021 2022 2022 2022 2022 2022
HbA1c (%) 7.6 – – 7.1 6.5 7.0
Office BP (mmHg) 144/72 140/70 142/76 140/70 142/74 140/80
Home BP (mmHg) 124/76 – – 118/66 120/68 124/72
Body weight (kg) 88.0 87.4 87.4 86.8 86.6 86.4
Urinary sodium (mEq/day) 110 156 138 120 114 115
Serum creatinine (mg/dl) 1.51 1.60 1.67 1.56 1.57 1.60
eGFR (ml/min/1.73 m2) 37 34 33 35 35 34
Albuminuria (mg/day) 870 620 505 520 312 299
Haemoglobin (g/dl) 11.6 – 12.1 – 12.2 11.4
Serum potassium (mEq/l) 4.9 4.6 4.8 4.5 4.6 4.7
Add-on Add-on
Withdrawal of Reduction of
Changes of therapy dapaglifozin spironolactone
furosemide insulin dose
10 mg/day 50 mg/day
Table 3: Changes in clinical and laboratory parameters and therapy after starting dapagliflozin.

Δ Albuminuria Δ eGFR post-DAPA

A B
Δ Albuminuria –36% post-DAPA –66% Δ eGFR –6.5 mL/min/year –1.4 mL/min/year

1500 45

1200 Start dual 40 Start dual

RAS blockade RAS blockade
eGFR (mL/min/1.73 m2)
Albuminuria (mg/day)

900 35

600 30

300 25 Withdrawal dual

RAS blockade
Withdrawal dual
RAS blockade
0 0
0 2 4 6 8 10 12 14 16 18 20 22 0 2 4 6 8 10 12 14 16 18 20 22
Months Months

Figure 2: Changes in (A) albuminuria and (B) eGFR before and after dapagliflozin.

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 6

Identification of Patients at Risk of Progressive CKD

CKD is a public health priority that affects about 10% of the general population worldwide and 30–40% of
high-risk populations, globally amounting to >850 million individuals, 95% of them living with non-dialytic stages
of disease [6, 7]. According to the Global Burden Disease (GBD) study, progressive CKD has a major effect by
acting not only as a direct cause of mortality and morbidity, including cognitive impairment (see ‘In the spotlight:
Cognitive impairment in CKD’ in Supplementary Material), but also as major risk factor for cardiovascular events
[8]. The GBD study highlighted that between 1990 and 2017, CKD-related mortality increased 41%, with cardi-
ovascular deaths attributable to CKD representing 8% of deaths due to cardiovascular disease in 2017. Prema-
ture mortality is only part of the problem because survivors can progress to kidney failure, a condition leading to
excess mortality, disability and worsening of quality of life, as well as substantial social and financial costs. In this
regard, the last annual report of the European Renal Association showed a relentless increase in the incidence of
dialysis-treated patients over the last 20 years [9].

Although the burden of CKD is great in terms of numbers and outcomes, disease awareness remains low among
non-nephrologist physicians and, consequently, among patients who should be advised about their kidney dis-
ease by general practitioners or other physicians. In fact, awareness averages 20–30% among affected peo-
ple, with an even lower frequency in the early phases (CKD stages 1–3), where again, on-time intervention can
improve the prognosis [10–13].

The remarkable but underestimated CKD burden has led the Kidney Disease: Improving Global Outcomes (KDI-
GO) expert panel to include in the general framework for optimal management of progressive CKD a proactive
plan of CKD screening and risk stratification that should be considered as relevant as therapy [13]. This should be
the object of straightforward communication with primary care physicians and specialists. To this aim, we propose
a ‘3W’ approach to identify patients with CKD who should undergo a multifaceted treat-to-goal therapy either in
the nephrology outpatient (fast progressors) or general practitioner (slow progressors) clinic (Figure 3).

Who Which What

should be test to to do with
screened? screen? CKD patients?

• Hypertension • eGFR Ask nephrologist if: Treat to goals:

• Diabetes • ACR • Hereditary kidney disease
• CV disease • Urine exam • eGFR <30 mL/min/1.73 m2
• Obesity • Acute kidney injury
• eGFR loss ≥5 mL/min/year
• ACR >300 mg/g
• Glomerular hematuria
• Anemia of unknown cause
• Resistant hypertension
• High sK, high sP or PTH
• Euvolemia
• Normal BMI
• BP around 130/80 mmHg
• ACR ≤30 mg/g or 50%
• Hb 10.5–12.0 g/dL
• TSAT ≥20%
• Ferritin ≥200 ng/mL
• HbA1c 7.0–8.0% in diabetes
• Normal pNA, sK and sP
• PTH 70–300 pg/dL (stage 3–5)
• HCO3 >22 mmol/L

Figure 3: The ‘3W’ approach to limit the burden of CKD.

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 7

On the other hand, the pivotal KDIGO guidelines of 2012 had already emphasized the ‘therapeutic role’ of cor-
rect referral by adding two recommendations into the ‘heat map’ of CKD (Figure 4) [14].

Figure 4: Referral decision making and frequency of monitoring by eGFR and albuminuria levels.
(Note: referral policies may differ by country.)

If you want to know more...

See ‘Why the risk of progression to kidney failure may be underestimated?’ in Supplementary Material.

It is well known that higher albuminuria and/or lower eGFR are major and independent predictors of worse
kidney and cardiovascular outcomes [6, 7, 13]. In 2016, Tangri et al. [15] developed and validated in 31 CKD
cohorts from 30 countries including >700,000 individuals, a risk prediction tool, the Kidney Failure Risk Equation
(KFRE; available at https://kidneyfailurerisk.com/). The tool includes age, sex, eGFR and urine albumin:creati-
nine ratio (UACR) to predict kidney failure at 2 and 5 years in patients with CKD stages 3a–5. The KFRE calcula-
tor is now widely available on the internet and is recommended by various guidelines and should be a stimulus to
all physicians for estimating albuminuria in all patients with CKD.

The importance of concurrent estimation of GFR and albuminuria to identify progressive CKD was further sup-
ported by a multicohort prospective study in almost 4000 patients with CKD stages 3–5 referred to nephrology
clinics [16]. The study demonstrated that filtration-adjusted 24-h proteinuria [FUprot = (24-h proteinuria/eGFR) ×
100] significantly improves, as compared with absolute 24-h proteinuria and KFRE, the reclassification of patients
for renal risk, especially in more advanced and complicated disease. These two easy-to-calculate tools may help
in daily practice in nephrology clinics, allowing a higher level of care in terms of frequency of visits and intensity
of treatment, timely planning of dialysis and identification of high-risk patients, while time-consuming visits and
overzealous and potentially risky treatments can be avoided in low-risk patients.

As for the risk of kidney failure, cardiovascular risk stratification in the general population has improved during
the last decade by adding renal measures. The use of cystatin C alone or in combination with creatinine has been
found to strengthen the association between eGFR and the risks of all-cause and cardiovascular death, espe-
cially for eGFR values <85 ml/min/1.73 m2, i.e. levels well above the threshold of 60 ml/min/1.73 m2 for the
detection of CKD by creatinine-based eGFR [17]. The underlying mechanism is that serum creatinine levels are
lower than expected for the level of true GFR in those patients who are in poor health (low muscle mass). More
recently, the CKD Patch calculator (http://ckdpcrisk.org/ckdpatchpce/), which adds eGFR and albuminuria to

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 8

traditional risk factors, has been demonstrated to significantly enhance equations for cardiovascular risk predic-
tion recommended in major US and European guidelines [18]. Similarly, integrating the CHA2DS2VASC score,
originally used for stroke risk prediction, with information on renal function, arterial stiffness and cardiac mor-
phology by echocardiography is effective in improving the performance of the score for cardiovascular outcome
prediction in CKD [19].

Treatment of Patients with Progressive CKD

Once patients at risk of progression to kidney failure are identified, the therapeutic approach should be goal
oriented according to current KDIGO guidelines (Figure 4) [13, 14, 20]. Treatment should primarily focus on
hypertension and proteinuria, which have been identified as the two major modifiable (and interrelated) deter-
minants of progressive decline of kidney function in CKD. More recently developed agents such as SGLT2is and
non-steroidal mineralocorticoid receptor antagonists (MRAs) do not have a clear mechanism related to BP and
proteinuria; however, they have provided strong evidence for reducing renal and cardiovascular risk and thus
should be considered in the therapy of patients with CKD [21, 22].

Optimal BP Control in CKD: What measure? What treatment?

BP control is a cornerstone of therapeutic strategies for CKD patients, with the aim of slowing CKD progression
and reducing cardiovascular risk. The targets for systolic BP (SBP) and diastolic BP (DBP) levels recommended for
CKD patients by contemporary major international guidelines are reported in Table 4.

Guideline SBP target DBP target

ACC/AHA 2017 <130 mmHg <80 mmHg
ESC/ESH 2018 130–139 mmHg <80 mmHg
Canadian Cardiovascular Society 2018
•No diabetes <140 mmHg <90 mmHg
•Diabetes <130 mmHg <80 mmHg
•ACC/AHA 2019 <130 mmHg <80 mmHg
•ISH 2020 <130 <80
NICE 2021
•No diabetes 120–139 mmHg <90 mmHg
•Diabetes and/or albuminuria 120–129 mmHg <80 mmHg
KDIGO 2021 <120 mmHg –

Table 4: BP targets for CKD patients.

ACC/AHA: American College of Cardiology/American Heart Association; ESC/ESH: European Society of Hypertension/European
Society of Cardiology; ISH: International Society of Hypertension.

If you want to know more...

See ‘How was the relation between blood pressure (BP) level and GFR decrease established?’
in Supplementary Material.

However, the BP targets can be properly applied only if BP is measured by a standardized technique.

If you want to know more...

See ‘How to measure adequately blood pressure (BP) burden?’ in Supplementary Material.

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 9

The KDIGO guidelines recommend that adults with high BP and CKD should be treated to a target SBP of <120
mmHg, when tolerated [20]. However, this recommendation does not consider DBP values and is mainly based
on a secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) in patients with an eGFR <60
ml/min/1.73 m2 [23]. Furthermore, the benefits of targeting SBP to <120 mmHg must be carefully balanced
against the risks induced by intensive lowering of SBP, such as hypovolaemia, hyperkalaemia and lower DBP,
which may impair coronary artery flow [24].

A non-trivial argument against the KDIGO recommended target is also its generalizability in renal clinics. Indeed,
SPRINT excluded individuals <50 years of age and those with diabetes mellitus, proteinuria ≥1 g/day, polycystic
kidney disease, glomerulonephritis treated or likely to be treated with immunosuppressive therapy and an eGFR
<20 ml/min/1.73 m2. When applying the same selection criteria of SPRINT to the real-world CKD population,
SPRINT appears to be generalizable to only 20% of CKD patients referred to nephrologists [25]. In contrast with
the KDIGO guidelines, the other international guidelines for CKD suggest aiming for an SBP <130 mmHg and
DBP <80 mmHg in the majority of cases [26–31] (Table 4).

What Measure?
Almost all guidelines highlight the importance of integrating office BP measurements with out-of-office BP monitor-
ing. This can be obtained by HBP or 24-h ABP monitoring, with the latter being the only method for assessment of
nocturnal BP. Recommendations on when and how to use HBP and ABP measures are reported.

If you want to know more...

See ‘How to measure adequately blood pressure (BP) burden?’ in Supplementary Material.

ABP and HBP are stronger predictors of end-stage kidney disease (ESKD) and death as compared with office BP
(measured in the clinic), with achievement of night-time BP control being more important in predicting renal events
compared with daytime targets [32–35].

Out-of-office BP monitoring allows the identification of white coat hypertension (WCH; uncontrolled BP in the
office and normal out-of-office BP). Conversely, an office BP at goal in the presence of out-of-office BP not at
target denotes masked hypertension, which is further classified as masked uncontrolled hypertension (MUCH)
when patients are receiving antihypertensive therapy. Concordance of the two measurements classifies patients
as normotensive (both measures at goal) or sustained hypertensive (both above the goal) (Table 5).

24-h ABP
<120/80 mmHg ≥120/80 mmHg
<130/80 mmHg Normotension Masked hypertensiona
Office BP
≥130/80 mmHg WCH Sustained hypertension

Table 5: Classification of hypertensive status of CKD patients by office and ABP values (mmHg).
a
If the patient is treated with BP drugs, it is defined as MUCH.

The International Database of Ambulatory BP in Renal Patients (I-DARE) has shown that the worldwide prevalenc-
es of WCH and MUCH average 20% and 16%, respectively, in non-dialysis CKD [36]. Recognition of MUCH
and WCH are relevant for deciding on a therapeutic approach [37,38]. Similarly, the prognosis of cardiorenal
outcome greatly differs in patients with WCH versus MUCH, with the latter having a higher risk similar to sus-
tained hypertension, while the cardiovascular and renal prognosis of patients with WCH does not differ from that
of patients with normotension [38].

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 10

In physiologic conditions, nocturnal BP declines by at least 10% as compared with daytime measurements;
patients with a smaller decrease in nocturnal BP or with higher BP values during the night are classified as
non-dippers and reverse dippers, respectively. Non-dipping status is common among non-dialysis CKD patients
(61–80%) [32, 33, 35, 38] and associates with adverse outcome independent from ABP control [39]. A practical
way to integrate the different BP measures in clinical practice is depicted in Figure 5.

Office blood pressure >130/80 mmHg

HBP <125/75 mmHg HBP >125/75 and <135/85 mmHg HBP >135/85 mmHg

Perform ABP monitoring

ABP at goal ABP above goal

Daytime <135/85 mmHg and Daytime ≥135/85 mmHg or
night time <120/70 mmHg night time ≥120/70 mmHg

Intensify antihypertensive therapy

Check the results with

HBP or ABP monitoring

Maintain the same HBP or ABP HBP or Non dipping

antihypertensive therapy at goal ABP above goal at ABP

Repeat HBP before each visit Change/intensify antihypertensive therapy

Repeat ABP every 1–2 years Consider chronotherapy for non dippers

Figure 5: Integrated use of HBP and ABP monitoring in clinical practice.

What Treatment?
Hypertension control in non-dialysis CKD appears to be hard to achieve in daily practice, even if patients are
followed in a tertiary nephrology care setting [40, 41]. A major contributing factor is the underestimation of
extracellular volume (ECV) expansion, the major determinant of CKD-related hypertension [40]. Indeed, in renal
clinics, adherence to a low sodium diet is low (23–28%) and diuretic therapy is prescribed in only 40–50% of
patients [40, 42, 43]. Poor BP control is not limited to office measurements but extends to ABP. The I-DARE study
has shown that 45% of patients had ABP at goal [36]. Furthermore, in patients with CKD under nephrology care,
24-h ABP is controlled in 57% patients and the night-time goal is achieved less frequently (35%) compared with
the daytime goal (51%) [39, 43].

In contrast, interventions aimed at limiting ECV expansion are efficacious at improving the hypertensive status in
CKD. Of note, ECV expansion also largely contributes to the development of resistant hypertension (RH), defined
as uncontrolled BP despite three antihypertensive drugs at full dose, including a diuretic. RH occurs in ≈25–30%
of non-dialysis CKD patients [44, 45] and heralds a remarkable 3-fold higher risk of progressing to kidney failure
versus normotension as well as a 2-fold higher risk of facing a cardiovascular event. These are risk excesses even
higher than those associated with non-resistant sustained hypertension. A proper diagnosis of RH requires exclu-
sion of so-called pseudo-resistance, in which adherence of patients to therapy and/or inaccurate BP assessment
may lead to the wrong classification of RH.

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 11

Overall, these data call for greater attention to ECV control in CKD, with advice for reducing sodium intake being
the first approach that must complement prescription of RAAS inhibitors and is similarly important. Patients should
be informed about foods to prefer/avoid as hidden dietary sources of salt. Adherence to a low sodium diet is
a progressive process requiring a few months to complete, as individuals with CKD may frequently experience
impaired salt taste sensitivity, thus requiring higher dietary concentrations of sodium to recognize salty foods [46].
Patients require 4–6 months to attain significant improvements in recognizing the thresholds for salty taste and in
liking low salt foods [47, 48]. Dietary counselling for effectively implementing a low sodium diet is summarized in
Table 6.

1. Avoid adding salt during cooking (in the first period, a pinch of salt can be used on top of cooked food before consuming it)
2. Avoid adding salt to meats and salads
3. Avoid fish preserved in salt
4. Avoid aged cheese (cheddar, parmesan, pecorino cheese, Gouda, Manchego, Gruyère etc)
5. Avoid cured meats (salami, ham, sausages) and canned foods (legumes, fish, tuna)
6. If canned food cannot be avoided, choose those not containing salt and drain and flush canned food with water before cooking
7. Use crackers without salt
8. Avoid processed French fries, peanuts, pretzels and snacks
9. Use bread without salt
10. Use herbs and spices (sage, rosemary, basil, parsley, chili, nutmeg etc.)

Table 6: Dietary counselling for reducing salt intake.

While all contemporary guidelines indicate salt restriction is a mainstay (together with RAAS inhibitors), recom-
mendations on diuretic agents are less clear (Table 7). In patients with more advanced CKD, loop diuretics are
generally preferred to thiazides because the latter are believed to be of limited efficacy in this population. How-
ever, renewed interest in this class of drug has emerged as a result of newly gathered evidence [49] that is mainly
based on the work of Agarwal et al. [50] showing that chlorthalidone (a long-acting thiazide-like diuretic) in
patients with a GFR <30 ml/min/1.73 m2 effectively improved hypertension control by reducing ambulatory SBP
by 10.5 mmHg versus placebo, in conjunction with weight loss of 2.1 kg, with a consequent decrease in UACR
50% greater than in the control arm.

Of great importance is the sequence of intervention. A judicious approach is to avoid vasodilating agents before
adherence to a low salt diet (or at least a significant reduction) is attained and/or efficacious diuretic therapy is
implemented. Indeed, in the presence of untreated volume overload, the initial BP decline induced by pure vaso-
dilators is counteracted over the long term due to a compensatory increase of tubular sodium reabsorption with
consequent worsening of ECV expansion (Figure 6) [40].

Accordingly, dietary salt restriction should be prescribed first in all hypertensive patients with CKD. However,
greater use of diuretic therapy in CKD is definitely required. This is supported by an observation in a large re-
al-world population with CKD stage 3-4 where newer users of either loop or thiazide diuretics had slower CKD
progression versus non-users [51]. After first-line intervention for volume expansion, other drugs can be added.

If you want to know more...

See ‘Treatment of extracellular volume (ECV) expansion in hypertension control’ in Supplementary Material.

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 12

 Guideline Low sodium diet First-line agents Diuretic therapy
Diuretics as additive therapy.
Chlorthalidone preferred on the basis of
NaCl intake: encourage
ACC/AHA 2017 RAAS inhibitor first prolonged half-life and proven trial reduction of
salt reduction
CVD; loop diuretics preferred in moderate–
severe CKD
Loop diuretics when eGFR is <30 ml/min/1.73
RAAS inhibitor combined with
m2 because thiazide/thiazide-like diuretics are
ESC/ESH 2018 NaCl intake: <5.0 g/day calcium channel blocker or
less effective/ineffective when eGFR is reduced
diuretics as initial therapy
to this level
Thiazide/thiazide-like diuretics are
Canadian
recommended as additive antihypertensive
Cardiovascular NaCl intake: 5.0 g/day RAAS inhibitor first
therapy. For patients with volume overload, loop
Society 2018
diuretics are an alternative
NaCl intake: 3.0 g/day
ACC/AHA 2019 and/or decrease of at RAAS inhibitor first No specific indication on diuretics
least 0.5 g/day
NaCl intake: encourage
ISH 2020 RAAS inhibitor first Loop diuretics if eGFR <30 ml/min/1.73 m2
salt reduction
Thiazide-like diuretic to treat hypertension as
NaCl intake: encourage RAAS inhibitor first in second line or in non-albuminuric patients if a
NICE 2021
salt reduction albuminuric patients calcium channel blocker is not tolerated (e.g.
oedema)
Thiazide diuretics lose efficacy in diuresis and BP
lowering as GFR worsens, but chlorthalidone,
RAAS inhibitor first. There are
metolazone and indapamide (thiazide-like
KDIGO 2021 NaCl intake: <5.0 g/day insufficient data on the role of
diuretics) appear effective at a GFR <30 ml/
diuretics as first-line therapy
min/1.73 m2. Loop diuretics are often effective
at a lower GFR
Table 7: Main therapeutic recommendations (in addition to physical exercise, body weight control, reduction of alcohol intake) provided
by major contemporary guidelines on hypertension management in adults with CKD.
ACC/AHA: American College of Cardiology/American Heart Association; ESC/ESH: European Society of Cardiology/European So-
ciety of Hypertension; ISH: International Society of Hypertension; KDIGO: Kidney Disease: Improving Global Outcomes; NaCl: sodium
chloride; NICE: National Institute for Health and Care Excellence.

Vasodilating BP drugs
• DHP CCB
• Alfa blockers
• Clonidine
• Minoxidil

BP reduction

Compensatory activation
of RAAS and SNS

↑Proximal tubular ↑Distal tubular

Na+ reabsorption Na+ reabsorption

ECV expansion

Limitation of
antihypertensive effect

Figure 6: Sodium reabsorption and dependent volume expansion induced by antihypertensive vasodilating drugs. DHP-CCB: dihydro-
pyridine calcium channel blockers; SNS: sympathetic nervous system. Modified from De Nicola et al. [40].

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 13

 If you want to know more...
See ‘Algorithm for treatment of hypertension in non-dialysis CKD patients’ in Supplementary Material.

In CKD patients with RH, spironolactone (12.5–25 mg/day) or eplerenone (25–50 mg/day) are recommended
[52]. However, their use is limited by hyperkalaemia [53]. Agarwal et al. [54] showed that the new potassi-
um binder patiromer mitigates the risk of hyperkalaemia when coupled with spironolactone in stage 3–4 CKD
patients with RH. However, about one-third of patients treated with patiromer still experienced serum potassium
values ≥5.5 mEq/L [54]. In this regard, based on findings from a study of chlorthalidone [50], this agent could
be considered as an alternative in RH patients with more advanced CKD. Beta blockers (preferably with a hepat-
ic elimination route to prevent drug accumulation), alpha blockers and centrally acting alpha agonists (methyldo-
pa or clonidine) can then be added in cases where BP is still high [52]. Direct vasodilators such as hydralazine or
minoxidil should be avoided, as they are associated with more severe fluid retention.

If you want to know more...

See ‘Proposed approach to the patient with suspected RH’ in Supplementary Material.

Lowering Proteinuria Besides and Beyond BP

Abnormal albumin excretion is a major proxy of worse kidney outcome, independent of age, diabetes, hyperten-
sion and eGFR level [55–59]. The recent EMPA-KIDNEY trial emphasized this concept by showing a very slow
rate of eGFR decline (−0.88 ml/min/year) similar to the physiological age-related GFR loss in control patients
with normoalbuminuria (UACR <30 mg/g), and this occurred despite the low eGFR in this subgroup (20–45 ml/
min/1.73 m2) was expected to be associated with fast progression [60].

Albuminuria has now climbed the rank of importance, from being considered merely as a marker of kidney failure
risk, to become a major goal of therapy in most patients. This change comes from recent evidence that the larger
the extent of albuminuria reduction in the first months of antiproteinuric therapy, the lower is the risk of ESKD in the
following years, with an approximate 30% rule, i.e. a 30% reduction of albuminuria heralds a 30% decrease in
ESKD risk [61–64]. The pathophysiological rationale for reducing albuminuria is based on experimental evi-
dence of the causative role of albuminuria in the progressive scarring in CKD [65]. Indeed, lowering albuminuria
to normal, or by at least 30% versus baseline (first day of antiproteinuric treatment), is today considered a main
mediator of most nephroprotective interventions, whether based on hypertension control (see above) or not (Ta-
ble 8).

Non-pharmacological Pharmacological
Angiotensin-converting enzyme inhibitors or angiotensin receptor
Reduction of excess body fat (lifestyle change, bariatric surgery)
blockers
Dietary salt restriction (even if moderate) SGLT2is
Dietary protein restriction (even if moderate) Non-steroid MRAs

Table 8: Main antiproteinuric interventions, besides BP lowering, that slow the progression of CKD

If you want to know more...

...about proteinuria reduction, see Supplementary Material.

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 14

Treatment Of Main CKD Complications
Besides therapy aimed at slowing the progression of CKD, including optimal control of BP and volume status,
additional interventions are required to efficaciously prevent the complications of CKD.

Cardiovascular Events
According to the current guidelines, patients ≥50 years of age with an eGFR <60 ml/min/1.73 m2 not treated
with chronic dialysis or kidney transplant and low-density lipoprotein cholesterol >70 mg/dl should be treated
with statins or a statin/ezetimibe combination [66, 67].

Dapagliflozin should be prescribed according to the DAPA-CKD trial, which showed a 31% reduction in all-
cause mortality and a 29% reduction of the risk of death from cardiovascular causes or hospitalization for heart
failure in CKD patients with or without diabetes and an eGFR of 25–75 ml/min/1.73 m2 and a UACR of 200–
5000 mg/g [68]. While the beneficial effect on all-cause death has been seen only for dapagliflozin, cardio-
vascular protection can be hypothesized for the entire SGLT2i class [21].

An elevated thromboembolic risk characterizes CKD patients and requires anticoagulation to prevent stroke in the
presence of atrial fibrillation, but the high rates of haemorrhage make it challenging. Direct oral anticoagulants
(in particular apixaban, because of its lower renal excretion) should be preferred in mild–moderate CKD, while
data are controversial for the more advanced stages [69, 70].

Anaemia
The (still effective) 2013 European Renal Best Practice guidelines on anaemia management in CKD recommend
treating patients with iron supplements (oral and eventually intravenous in the case of poor response or intoler-
ance) in the presence of iron deficiency (transferrin saturation <20% and/or serum ferritin <100 ng/ml). Erythro-
poiesis-stimulating agents (ESAs) should be prescribed when haemoglobin is <10 g/dl or higher (but <11 g/dl)
in younger patients with very few comorbidities or in patients with ischaemic heart disease with worsening ischae-
mic symptoms, with the goal of reaching and maintain haemoglobin at 11–12 g/dl [71].

Hypoxia-inducible factor stabilizers are a new class of novel anti-anaemic agents. Potential advantages over
ESAs are the oral formulation, stability outside of refrigeration, less requirement of iron supplementation and
greater efficacy in inflamed patients [72]. Updated guidelines including recommendations for this new class of
agents are still awaited.

Hyperkalaemia
Prevention and treatment of hyperkalaemia is a major goal of conservative therapy. Multifactorial, non-pharma-
cological and pharmacological approaches are indicated, especially in patients on RAAS inhibitors or MRAs
(see ‘In the spotlight: RAASis: good for heart and kidney, but how to manage hyperkalaemia?’ in Supplementary
Material).

Metabolic Acidosis
To prevent hyperkalaemia, muscle mass wasting, bone disease, insulin resistance and tubulointerstitial fibrosis that
contributes to CKD progression, we recommend maintaining normal serum bicarbonate levels (22–26 mEq/L)
[73] by promoting a base-producing diet (fruits and vegetables) while minimizing the intake of animal protein
and prescribing supplementation with oral sodium bicarbonate or sodium citrate.

Mineral and Bone Disorder (MBD)

In 2017, the KDIGO 2009 updated guidelines on CKD-MBD emphasized the need to limit hyperphosphatae-
mia and hypercalcaemia and to monitor trends (rather than a single value) in MBD parameters [74], including
lowering elevated phosphate levels toward the normal range by nutritional intervention (reduction of phosphate
sources from meat, vegetables and additives) and by using non-calcium-based phosphate binders in case of

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 15

progressively or persistently elevated serum phosphate. The use of calcitriol and vitamin D analogues should be
limited to patients with CKD stage 4–5 with severe and progressive hyperparathyroidism. Patients with level of
intact PTH that is progressively rising or persistently above the upper normal limit for the assay should be evaluat-
ed for modifiable factors (hyperphosphataemia, hypocalcaemia, high phosphate intake and vitamin D deficien-
cy). Finally, management of patients with osteoporosis and/or a high risk of fracture (World Health Organization
criteria) should be similar to that indicated in the general population, including diagnosis and treatment of vitamin
D deficiency/insufficiency based on 25-hydroxyvitamin D levels.

Proper prevention and treatment of CKD complications, as well as optimal slowing of progression to kidney fail-
ure, must include dietary recommendations as the basic essential approach. A pragmatic approach that consid-
ers recent studies and recommendations issued by guidelines and experts [20, 74–80] is summarized in Table 9.

KDIGO risk category 1 KDIGO risk category 2 KDIGO risk category 3 KDIGO risk category 4
Risk of progression Mild Moderate High Very high
G1A3, G2A3, G3aA2, G3aA3, G3bA2/A3,
CKD stage G1A1, G2A1 G1A2, G2A2, G3aA1
G3bA1 G4Ax, G5Ax
0.6 or 0.3 plus ketoana-
Protein intake 0.8–1.2 0.8–1.0 0.6–0.8 logues depending on the
(g/kg BW/day) Adapt to activity level Adapt to activity level Control nutritional status patient’s adherence and
nutritional status
25–35, based on BMI, 25–35, based on BMI, 25–35, based on BMI, 25–35, based on BMI,
Energy intake
age, sex, physical activi- age, sex, physical activi- age, sex, physical activity, age, sex, physical activi-
(kcal/kg BW/day)
ty, inflammation ty, inflammation inflammation ty, inflammation
<800; minimize added <800; minimize added
<1000; limit inorganic
Phosphorus intake inorganic phosphorus inorganic phosphorus and <800; minimize added
phosphorus in processed
(mg/day) and encourage more encourage more plant- inorganic phosphorus
foods
plant-based foods based foods
Calcium intake
1000–1300 800–1000 800–1000 800–1000
(mg/day)
6.0–8.0; lower if 5.0–6.0; lower if 5.0–6.0; lower if heart
heart failure, nephrotic heart failure, nephrot- failure, nephrotic syn- ≤5.0 (exclude salt-losing
Salt (NaCl) intake
syndrome (exclude ic syndrome (exclude drome (exclude salt-losing with untreated normo-
(g/day)
salt-losing with untreated salt-losing with untreated with untreated normoten- tension)
normotension) normotension) sion)
Adjust intake to maintain Adjust intake to maintain
No restriction in the ab- No restriction in the ab-
Potassium intake serum potassium in the serum potassium in the
sence of hyperkalaemia sence of hyperkalaemia
normal range normal range
No restrictions; avoid No restrictions; avoid No restrictions; avoid No restrictions; avoid
over- and underhydra- over- and underhydration over- and underhydration over- and underhydra-
Water intake
tion (maintain normal (maintain normal plasma (maintain normal plasma tion (maintain normal
plasma sodium levels) sodium levels) sodium levels) plasma sodium levels)
Table 9: Nutritional recommendations in non-dialysis CKD

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 16

Summary and Conclusions

Nephrology is facing a major mind shift in the care of patients with CKD, moving its focus from dialysis to medical
management aimed at attaining remission of progressive kidney disease. This objective can be reached thanks
to the development of innovative nephroprotective agents. However, the process cannot rely on therapy alone,
because the first step—largely unmet so far—is to identify on time and carefully monitor the subgroup of patients
who require intensive treatment because of a high risk of progression to ESKD. Therefore, more straightforward
communication between nephrologists and physicians working in the primary care setting and in specialties other
than nephrology is needed to promote on-time identification of patients with albuminuria and decreasing GFR.

As depicted in Figure 7, once a patient with progressive CKD is identified, non-pharmacological and pharmaco-
logical interventions, rather than strict protocols, should be variably combined and calibrated in each individual
patient by considering compliance to prescriptions and eventual side effects. Similarly, in older patients, thera-
peutic goals may be less stringent than those recommended by guidelines if the GFR decrease during follow-up is
close to 1.0 ml/min/year, i.e. the physiological GFR loss related to aging. Slowing progression of CKD will also
significantly contribute to reducing the burden of the multiple systemic complications that characterize this high-
risk population.

First line
• Reduce excess of body fat, K intake
• Protein intake 0.6–0.8 g/kg/day or less
• Salt intake 6–8 g/day or less
• Chlortalidone or furosemide
• ACEi or ARB* Goals
 UACR <30 mg/g or ↓ ≥30%
 Home BP <130/80 mmHg
 Day BP <135/85 mmHg
 Night BP <120/70 mmHg
Second line
• SGLT2-I
• MRA*
• Other anti-hypertensive drugs

Figure 7: Pragmatic approach to stop progressive CKD.

*Add patiromer or sodium zirconium cyclosilicate in case of serum potassium is ≥5.5 mmol/L despite standard treatment.
ACEi: angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker.

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 17

Test Yourself
Case 1
A general practitioner sends note for nephrology consultation: male patient, normal BMI, age 74 years, hyper-
tension for 20 years under ACEi therapy, office BP 120/65 mmHg, eGFR stable at 47 ml/min/1.73 m2, UACR 3
mg/mmol (27 mg/g), urine microscopy not significant. What is the best approach for the nephrologist?

A. Ask for an immediate referral to the renal clinic for assessment of 24-h urine parameters
B. Recommend for monitoring once a year
C. Add furosemide
D. Add MRA
E. Add very low protein diet

Case 2
A general practitioner sends a note for nephrology consultation: female patient, overweight, age 58 years,
hypertension for 6 years treated with calcium channel blocker, office BP 152/88 mmHg, eGFR 50 ml/min/1.73
m2, UACR 150 mg/mmol (1327 mg/g), urine microscopy not reported. What is the best approach?

A. Ask for immediate referral to the renal clinic to evaluate eligibility for kidney biopsy
B. Recommend for monitoring twice a year
C. Add SGLT2i
D. Add MRA
E. Add angiotensin II receptor blocker

Case 3
A general practitioner sends a note for nephrology consultation: female patient, obese (BMI 36 kg/m2), age 50
years, office BP 120/75 mmHg on beta blocker, eGFR 32 ml/min/1.73 m2, UACR 191 mg/mmol (1690 mg/g),
urine microscopy not significant. What is the best approach?

A. Ask for immediate referral to the renal clinic to evaluate for eligibility for kidney biopsy
B. Recommend for monitoring three times a year
C. Add SGLT2i
D. Add MRA
E. Suggest urgent start of obesity treatment and add ACEi

Case 4
Male patient under nephrology follow-up: normal BMI, age 62 years, hypertension onset 5 years ago when IgA
nephropathy was diagnosed (responsive to steroids for 8 months). Current office BP is 130/70 mmHg on ARB
and furosemide, eGFR 33 ml/min/1.73 m2 (with eGFR loss of 2 ml/min/year in the last 3 years), serum potas-
sium 4.6 mmol/L, UACR 100 mg/mmol (885 mg/g), urine microscopy unchanged in the last 3 years (5–15 red
cells). What is the best approach?

A. Repeat kidney biopsy

B. Add ACEi
C. Add SGLT2i
D. Add very low protein diet and switch from ARB to ACEi
E. Keep same treatment

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 18

Case 5
Female patient under nephrology follow-up: obesity with BMI 33 kg/m2, age 50 years, hypertension in the last 5
years when IgA nephropathy was diagnosed and treated with steroids for 6 months. Current office BP is 160/96
mmHg on ARB, beta blocker, calcium channel blocker and furosemide. Serum potassium 4.7 mmol/L, eGFR 19
ml/min/1.73 m2 with eGFR loss of 2.5 ml/min/year in the last 3 years, UACR 10 mg/mmol (88.5 mg/g), urine
microscopy not significant. What is the best approach?

A. Repeat kidney biopsy

B. Recommend preparation for dialysis
C. Add SGLT2i
D. Verify adherence to low salt diet and ask for home BP monitoring
E. Keep same treatment

Case 6
Male patient under regular nephrology follow-up: normal BMI kg/m2, age 72 years, hypertension in the last 18
years, office BP 130/78 mmHg on ARB and calcium channel blocker, eGFR 19 ml/min.1.73m2 with eGFR loss of
0.9 ml/min/y in the last 3 years, UACR 25 mg/mmol (221 mg/g), urine microscopy not significant. What is the
best approach?

A. Evaluate for kidney biopsy

B. Recommend preparation for dialysis
C. Add SGLT2i
D. Add MRA
E. Keep same treatment

Case 7
Male patient under infrequent nephrology follow-up: overweight, age 60 years, hypertension in the last 7 years
and myocardial infarction 2 years ago (coronary stenting). Office BP currently 130/80 mmHg on ACEi, beta
blocker and chlortalidone. eGFR 23 ml/min.1.73 m2, UACR 12 mg/mmol (106 mg/g), urine microscopy not
significant. What is the best approach?

A. Evaluate for kidney biopsy

B. Recommend preparation for dialysis
C. Add furosemide
D. Check 24-h BP
E. Keep same treatment

Case 8
Male patient under infrequent nephrology follow-up: normal BMI kg/m2, age 72 years, hypertension in the
last 8 years, current office BP 150/70 mmHg on ACEi, calcium channel blocker and alfa agonist. eGFR 27 ml/
min/1.73 m2, UACR 185 mg/mmol (1637 mg/g), urine microscopy not significant. What is the best approach?

A. Evaluate for kidney biopsy

B. Recommend preparation for dialysis
C. Add SGLT2i
D. Verify adherence to low salt diet before adding SGLT2i
E. Keep same treatment

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 19

Answers

Case 1
Answer: B
Explanation: This patient needs only monitoring, because of the absence of adequate control of risk factors.

Case 2
Answer: A
Explanation: Evaluation of possible biopsy is justified by the high albuminuria and non severe eGFR impairment.
Urine microscopy and kidney ultrasound are mandatory.

Case 3
Answer: E
Explanation: Severe obesity associates per se with albuminuria and higher risk of kidney biopsy failure. Biopsy
may be postponed after substantial weight loss if albuminuria persists.

Case 4
Answer: C
Explanation: ACEi as add-on to ARB is not recommended, while SGLT2i or MRA can be a valid alternative as
demonstrated by secondary results of the DAPA-CKD trial.

Case 5
Answer: D
Explanation: Optimal control of BP is the basic intervention to slow down progression of CKD. Low salt diet is
the cornerstone of antihypertensive therapy even in patients under diuretic therapy (braking phenomenon).

Case 6
Answer: E
Explanation: The substantial stability of eGFR coherent with hypertensive, low albuminuric, CKD justifies the
maintenance of current therapy.

Case 7
Answer: D
Explanation: CKD patients frequently have high nocturnal BP that increases the risk of ESKD.

Case 8
Answer: D
Explanation: Due to high albuminuria, the patient may have beneficial effects of SGLT2i on renal outcome;
however, preliminary evaluation of adherence to low salt diet is mandatory to optimize BP control before adding
SGLT2i.

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 20

Meet the Authors

Luca De Nicola received his MD degree in 1987, PhD in 1992 and specialization in
nephrology in 1996. From 1989 to 1991, he was a visiting professor at the Renal Micro-
puncture Lab of the Nephrology Division at University of California, San Diego, where he
did several studies to assess the renal haemodynamic and tubular effects of the balance
between angiotensin II and nitric oxide in physiological and kidney disease conditions. He
has been a consultant nephrologist since 1999, first as assistant professor, then as associ-
ate professor and from 2019 to date as full professor of nephrology at University Vanvitelli
in Naples, Italy, where he currently is director of the nephrology unit and postgraduate
school of nephrology. He is an expert in the conservative management of CKD, including therapy of hyperten-
sion and abnormalities of nutritional status and hydroelectrolyte homeostasis. His research interests are broad but
focus mainly on improving the prognosis of patients with non-dialysis CKD. As of March 2023, he has published
293 full papers, with a Hirsch index of 47 and >7000 citations, in peer-reviewed journals. He also has a special
interest in supervising medical school students and the education of nephrology fellows. He serves on the board
of the Italian Nephrology Society and is referee for several nephrology journals. In recent years he has launched
the first observational study in Italy depicting the state-of-art of conservative therapy in CKD patients under
nephrology care (the TABLE study), led the largest national health examination survey in Italy to estimate the
prevalence of CKD in general population (the CARHES study), designed and conducted the first controlled study
to assess outcome of patients under integrated conservative-low dose peritoneal therapy (the I-COPE study),
and has acted as a country coordinator in Italy for international trials on nephroprotective agents, the main being
SONAR, CREDENCE and ALIGN.

Chiara Ruotolo received her MD degree in 2020. In 2021 she became a resident
physician in nephrology at the University of Campania - Luigi Vanvitelli in Naples, Italy,
taking care of patients with all types of renal disease. She is currently involved in research,
acting as a subinvestigator in the ZENITH-CKD study (Zibotentan and Dapagliflozin for
the Treatment of CKD; NCT04724837), ALIGN study (Atrasentan in Patients With IgA
Nephropathy; NCT04573478) and I-COPE study (Integrated COnservative-PEritoneal
dialysis in CKD). She is a co-author of one paper published in June 2022, Chronic Hyper-
kaliemia in Chronic Kidney Disease: An Old Concern with New Answers. Her research
interest focuses mainly on conservative therapy of non-dialysis CKD, peritoneal dialysis
and haemodialysis.

Roberto Minutolo received his MD degree in 1990, specialization in nephrology in

1994, PhD in 1998 and research contracts in 1999 and 2000. He has been a consultant
nephrologist since 2001, first as assistant professor, then as associate professor of neph-
rology since 2017 at University Vanvitelli in Naples, Italy. Since 2003, Dr Minutolo has
been responsible for the outpatient clinic activities at the nephrology unit of the Univer-
sity of Campania. His clinical and research activity is mainly dedicated to management
of complications in non-dialysis CKD patients and their prognostic impact. He has been
the author of >200 peer-reviewed articles published in main nephrology journals, with a
Hirsch index of 45 and >5700 citations, and he is/has been a member of the editorial
boards for several journals. He serves on the board of the Center for Clinical Studies of the Italian Nephrology
Society and is referee for several nephrology and internal medicine journals. In recent last years he has acted as
a country coordinator in Italy for international trials on nephroprotective agents and on steering committees of
several Italian observational studies.

SLOWING PROGRESSION AND PREVENTING COMPLICATIONS OF CHRONIC KIDNEY DISEASE 21