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Am J Kidney Dis. Author manuscript; available in PMC 2022 June 01.
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Published in final edited form as:

Am J Kidney Dis. 2021 June ; 77(6): 969–983. doi:10.1053/j.ajkd.2020.12.022.

Reducing Kidney Function Decline in Patients With CKD: Core

Curriculum 2021
Teresa K. Chen, MD, MHS1,2, Christopher J. Sperati, MD, MHS1, Sumeska Thavarajah, MD1,
Morgan E. Grams, MD, PhD1,2
1Divisionof Nephrology, Department of Medicine, Johns Hopkins University School of Medicine,
Baltimore, Maryland, USA;
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2Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical
Institutions, Baltimore, Maryland, USA.

Abstract
An estimated 8–16% of the world’s population has chronic kidney disease, defined by low
glomerular filtration rate or albuminuria. Progression of chronic kidney disease is associated with
adverse outcomes, including incident kidney failure with replacement therapy, accelerated
cardiovascular disease, disability, and mortality. Therefore, slowing kidney function decline is
paramount in the management of a patient with chronic kidney disease. Ascertaining the cause of
kidney disease is an important first step and may compel specific therapies. Effective approaches
that apply to the vast majority of patients with chronic kidney disease include the optimization of
blood pressure and blockade of the renin-angiotensin aldosterone system, particularly if
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albuminuria is present. Recent studies suggest that sodium/glucose cotransporter 2 inhibitors are
highly effective treatments in patients with diabetes and/or albuminuria. For patients with type 2
diabetes, glycemic control is important in preventing the development of microvascular
complications, and glucagon-like peptide 1 receptor agonists may help reduce albuminuria levels.
Other strategies include correction of metabolic acidosis, maintaining ideal body weight, following
diets that are low in sodium and animal protein, and avoidance of potential nephrotoxins such as
nonsteroidal anti-inflammatories, proton-pump inhibitors, and iodinated contrast.

Keywords
chronic kidney disease (CKD); blood pressure (BP); albuminuria; diabetes; CKD progression;
renal function; estimated glomerular filtration rate (eGFR); proteinuria; sodium/glucose
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cotransporter 2 inhibitor (SGLT2i); glucagon-like peptide 1 receptor agonist (GLP1-RA);

hypertension management; glycemic control; lifestyle modification; uric acid; review

Address for Correspondence: Teresa K. Chen, MD, MHS; 1830 E. Monument Street, Suite 416; Baltimore, MD 21287.
[email protected].
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relevant financial interests.
 Chen et al. Page 2
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Introduction
Chronic kidney disease (CKD) affects more than 697 million individuals worldwide and is
associated with increased morbidity and mortality. In 2017, 1.2 million deaths and 35.8
million disability-adjusted life-years were attributed to CKD. Among Medicare beneficiaries
in the United States, annual spending for kidney failure with replacement therapy (KFRT)
and earlier stages of CKD exceeded $120 billion. Different causes of kidney disease may
require specific treatments, such as immunosuppressive therapy. However, some strategies to
delay the progression of CKD to KFRT are applicable to most patients. Early detection and
treatment to slow kidney function decline are paramount to improving outcomes in patients
with CKD. Hallmarks of CKD management include control of hypertension and
hyperglycemia, inhibition of the renin-angiotensin-aldosterone (RAAS) system, correction
of metabolic acidosis, lifestyle modification, and avoidance of nephrotoxins. Two new
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classes of medications, sodium/glucose cotransporter 2 (SGLT2) inhibitors and glucagon-

like peptide 1 (GLP-1) receptor agonists, also improve kidney outcomes among individuals
with diabetes and/or albuminuria.

Additional Readings
• GBD Chronic Kidney Disease Collaboration; Global, regional, and national
burden of chronic kidney disease, 1990–2017: a systematic analysis for the
Global Burden of Disease Study 2017. Lancet. 2020;395:709–733.

• Saran R, Robinson B, Abbott KC, et al. US Renal Data System 2019 Annual
Data Report: epidemiology of kidney disease in the United States. Am J Kidney
Dis. 2020;75(1)(suppl 1):S1-S64.
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Blood pressure control

[ISP]Case 1: A 60 year-old man with CKD glomerular filtration rate category 3b (G3b) and
albuminuria category 2 (A2; corresponding to an urinary albumin-creatinine ratio [UACR]
of 30–300 mg/g), hypertension, and stable angina returns for follow-up. His estimated GFR
(eGFR) has declined from 57 to 44 ml/min/1.73 m2 over the past 13 years. His blood
pressure (BP) averages 135/72 mm Hg on a regimen of valsartan 320 mg daily, amlodipine 5
mg daily, and indapamide 1.25 mg daily.

Question 1: Based on the results of SPRINT, which one of the following

statements is most accurate regarding a systolic BP goal of <120 vs. <140
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mmHg?
a. All-cause mortality is reduced

b. CKD progresses more slowly at the lower BP goal

c. Incidence of KFRT is higher at the lower BP goal

d. Incidence of kidney transplantation is lower at the lower BP goal

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Question 2: Which one of the following patients would be most appropriate

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for a lower BP goal to help slow progression of CKD?

a. CKD G3aA1 with UACR 10 mg/g

b. CKD G4A1 with critical bilateral renal artery stenosis

c. CKD G3bA3 with UACR 3,000 mg/g

d. CKD G3bA3 with UACR 1,200 mg/g and history of repeated falls
For the answer to the questions, see the following text.

The AHA/ACC recommend a goal BP <130/80 mmHg for all patients with CKD, whereas
the KDIGO guidelines recommend a target of ≤140/90 mmHg when UACR is <30 mg/d and
≤130/80 mmHg when UACR is ≥30 mg/d (Table 1). The KDIGO recommendations are
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based, in part, on two landmark randomized controlled trials. AASK randomized

participants without diabetes to a mean arterial pressure (MAP) goal of ≤92 versus 102–107
mmHg. Although there was no difference in rate of eGFR decline or a composite clinical
outcome (eGFR decline, KFRT, or death) overall, participants with a baseline urinary
protein-creatinine ratio (UPCR) >0.22 g/g were 27% less likely to develop a doubling of
serum creatinine, KFRT, or death when randomized to intensive versus standard BP control
in the extended cohort phase. The MDRD Study randomized participants to a MAP goal of
92 versus 107 mmHg. Again, there were no differences overall, but participants with
proteinuria ≥3 g/d had lesser GFR decline in the intensive BP control group. These and other
trials of BP control are summarized in Table 2.

More recently, SPRINT randomized adults without diabetes but at increased risk for
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cardiovascular events to a systolic BP <120 versus <140 mmHg. Intensive BP control was
associated with lower risk of myocardial infarction, acute coronary syndrome, stroke, heart
failure, and cardiovascular death (hazard ratio [HR], 0.75 [95% CI, 0.64–0.89]) and all-
cause mortality (HR, 0.73 [95% CI, 0.60–0.90]). Results were consistent among participants
with baseline CKD (n=2,646). Intensive BP control did not prevent adverse kidney outcomes
(≥50% eGFR decline or KFRT). Among participants without baseline CKD (n=6,677),
intensive BP control resulted in 3.5-fold higher risk of ≥30% reduction in eGFR to <60
ml/min/1.73 m2, a finding which may reflect hemodynamic changes rather than true kidney
injury.

For Question 1, (a) reduced all-cause mortality is the correct answer. Lower BP goal did not
slow progression of CKD, and SPRINT was not powered to assess KFRT and kidney
transplantation events. For Question 2, (c) the patient with CKD G3bA3 and UACR 3,000
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mg/g would most likely benefit from a lower BP goal based on subgroup analysis from
clinical trials. Patients with A1 albuminuria, critical bilateral renal artery stenosis, or
repeated falls are less likely to benefit from a lower BP goal or may be at higher risk of
treatment-related complications.

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Additional Readings
Author Manuscript

• Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group.

KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of
Chronic Kidney Disease. Kidney Int Suppl. 2013;3(1):1–150.*ESSENTIAL
READING

• Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/

ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention,
Detection, Evaluation, and Management of High Blood Pressure in Adults: A
Report of the American College of Cardiology/American Heart Association Task
Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):e13-e115.

• Wright JT, Bakris G, Greene T, et al; Effect of Blood Pressure Lowering and
Antihypertensive Drug Class on Progression of Hypertensive Kidney Disease:
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Results from the AASK trial. JAMA. 2002;288(19):2421–2431.

• Klahr S, Levey AS, Beck GJ, et al; The Effects of Dietary Protein Restriction
and Blood-Pressure Control on the Progression of Chronic Renal Disease. N
Engl J Med. 1994;330(13):877–884.*ESSENTIAL READING
• Appel LJ, Wright JT, Greene T, et al; Intensive Blood-Pressure Control in
Hypertensive Chronic Kidney Disease. N Engl J Med 2010;363(10):918–
929.*ESSENTIAL READING

• Ruggenenti P, Perna A, Loriga G, et al; Blood-pressure control for

renoprotection in patients with non-diabetic chronic renal disease (REIN-2):
multicenter, randomized controlled trial. Lancet.2005;365(9463):939–946.

• The SPRINT Research Group. A Randomized Trial of Intensive versus Standard

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Blood-Pressure Control. N Engl J Med. 2015;373(22):2103–2116.*ESSENTIAL

READING

• Cheung AK, Rahman M, Reboussin DM, et al; Effects of Intensive BP Control in

CKD. J Am Soc Nephrol. 2017;28(9):2812–2823.

RAAS inhibition
Case 2: A 46 year-old woman with type 2 diabetes returns for her 2nd appointment. History
is notable for retinopathy and CKD G3aA3 attributed to diabetic kidney disease. She denies
orthostatic symptoms and chest discomfort. Automated office BP is 118/75 mmHg on
atenolol and chlorthalidone. Laboratory testing reveals stable eGFR (at 55 ml/min/1.73 m2)
with UACR 1,200 mg/g.
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Question 3: Which one of the following would be the most appropriate anti-
hypertensive therapy to help slow CKD progression?
a. No change in therapy since BP is controlled to goal

b. Change atenolol to an angiotensin-receptor blocker (ARB)

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c. Change chlorthalidone to an ARB

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d. Add an ARB to the current 2 drug regimen

Case 3: A 56 year-old woman with CKD G3aA3 due to biopsy-proven diabetic kidney
disease has an average out-of-office BP of 144/83 mmHg on a regimen of lisinopril 20 mg
daily, chlorthalidone 50 mg daily, and amlodipine 10 mg daily. UACR is 800 mg/g.

Question 4: Which one of the following interventions would be most

appropriate to reduce the risk of CKD progression?
a. Add an ARB to current regimen

b. Change lisinopril to a mineralocorticoid receptor antagonist (MRA)

c. Increase lisinopril dose

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d. Change chlorthalidone to indapamide

For the answers to the questions, see the following text.

The cornerstone of albuminuria management is RAAS inhibition. The KDIGO guidelines

recommend that all adults with CKD, hypertension, and UACR >300 mg/g be treated with
an angiotensin-converting-enzyme inhibitor (ACEI) or ARB. Among those with diabetes
and UACR > 30 mg/g, ACEI or ARB use should be considered. RAAS inhibition in patients
with CKD and hypertension is also supported by all major hypertension guidelines (Table 1).
Multiple trials have demonstrated that ACEI or ARB therapy delays CKD progression
among individuals with albuminuria (Table 3). The REIN trial, which randomized patients
with CKD to ramipril versus placebo, showed that mean GFR decline was significantly
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slower in the ramipril group among participants with proteinuria ≥3 g/d. In the RENAAL
study, patients with type 2 diabetes and CKD randomized to losartan had a 16% lower risk
of developing a doubling of serum creatinine, KFRT, or death compared to placebo.
Similarly, IDNT reported that irbesartan was associated with lower risk of a doubling of
serum creatinine, serum creatinine ≥6.0 mg/dL, KFRT, or death compared to amlodipine or
placebo among patients with hypertension and CKD attributed to type 2 diabetes. Finally, in
AASK, use of ramipril was independently associated with 22% and 38% lower risks of the
clinical composite outcome (GFR decline ≥50% or ≥25 ml/min/1.73 m2 from baseline,
KFRT, or death) compared to metoprolol and amlodipine, respectively.

Current literature does not support the use of dual blockade with an ACE-I and ARB in
diabetic kidney disease. VA NEPHRON-D, which randomized veterans with type 2 diabetes
and CKD G2-G3bA3 to losartan plus lisinopril or losartan alone, was terminated early due
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to safety concerns with the combination therapy group having a markedly higher risk of
hyperkalemia (HR, 2.8 [95% CI, 1.8–4.3]) and acute kidney injury (AKI) (HR, 1.7 [95% CI,
1.3–2.2]) compared to the monotherapy group. Additionally, there was no significant
difference in risk of kidney function decline between the two treatment groups, though
follow-up was short (Table 3).

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Decreased sodium intake may enhance the renoprotective effects of RAAS inhibitors. A
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meta-analysis of 11 studies (23 cohorts with 516 participants) reported that dietary sodium
restriction (average decrease of 92 mmol/d) was associated with a 32% lower urine albumin
excretion (UAE). The reduction in UAE was greater in cohorts with concomitant RAAS
blockade therapy than in cohorts without (pooled mean differences of −41.9% and −17.2%,
respectively; p = 0.01 for interaction), suggesting a synergistic effect of low sodium intake
with RAAS inhibition. In a post-hoc analysis of 500 participants in REIN and REIN II trials
receiving ramipril therapy, a diet with >14 g/d of salt was associated with 3.3-fold and 2.4-
fold greater risks of kidney failure compared to diets of <7 g/d and 7–14 g/d of salt,
respectively. Importantly, the proteinuria-reducing effects of ramipril were greatest in the
low sodium diet group. In another post-hoc analysis of the RENAAL study and IDNT
(n=1,177), ARB therapy was associated with a 43% lower risk of a renal event, defined as a
doubling of serum creatinine or KFRT, compared to non-RAAS inhibitor therapy among
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participants in the lowest tertile of 24-hour urinary sodium-creatinine ratio with no

significant difference in risk between the two treatment groups for higher tertiles of sodium
intake (P < 0.001 for interaction; Figure 1). Given these findings, patients on RAAS
inhibitors for treatment of albuminuria should be encouraged to follow a low sodium diet.

For patients intolerant of ACEI/ARB therapy, a MRA can be considered. A recent meta-
analysis of 31 randomized controlled trials evaluated the efficacy and safety of MRAs
(spironolactone, eplerenone, canrenone, or finerenone) compared to active control or
placebo in reducing albuminuria. In the 18 trials (n=2,036) that examined UACR as an
outcome, proportional change in UACR from baseline to end of treatment was 22% lower in
MRAs compared to active control and placebo. The effect persisted when comparing MRAs
to placebo (n=1,436 in 11 trials) in patients on ACE-I/ARB therapy. When comparing
MRAs to renin-angiotensin blockers, there was no significant difference in change in
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albuminuria (n=201 in 2 trials) but risk of incident hyperkalemia was 70% higher (n=855 in
5 trials). Although reduction in albuminuria is not a universally accepted surrogate endpoint
for KFRT, the FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2
Diabetes Mellitus and Diabetic Kidney Disease) trial of patients with type 2 diabetes and
CKD (>98% on concomitant ACE-I or ARB therapy) reported that finerenone conferred an
18% lower risk of composite kidney outcome (sustained decline in eGFR by ≥40% or to <15
ml/min/1.73 m2, KFRT, or death from kidney causes) compared to placebo. Thus, MRAs
reduce albuminuria and may also slow CKD progression. These benefits, however, must be
balanced against the potential risk of hyperkalemia.

In Question 3, (b) changing atenolol to an ARB is the correct answer. ACE-I and ARB have
been shown to slow progression of CKD in patients with diabetes while beta-blockers have
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not. In the management of hypertension, beta-blockers are add-on therapy after the use of
1st-line agents such as ACE-I or ARB and thiazide diuretics. Adding an ARB to the current
regimen is less desirable, as this may result in hypotension in a patient with BP already
controlled to goal. In Question 4, (c) increasing the lisinopril dose is the best answer.
Combination ACE-I and ARB therapy is associated with an increased risk of adverse
outcomes. Although MRA may reduce albuminuria when combined with an ACE-I or ARB,
no randomized controlled trials have been performed to support changing an ACE-I to an

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MRA with the intent of slowing progression to KFRT. Exchanging chlorthalidone for
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indapamide is not anticipated to slow this progression.

Additional Readings
• Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group.
KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of
Chronic Kidney Disease. Kidney Int Suppl. 2013;3(1):1–150.*ESSENTIAL
READING

• The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia).

Randomised placebo-controlled trial of effect of ramipril on decline in
glomerular filtration rate and risk of terminal renal failure in proteinuria, non-
diabetic nephropathy. Lancet. 1997;349(9069):1857–1863.
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• Brenner BM, Cooper ME, De Zeeuw D, et al; Effects of Losartan on Renal and
Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy. N
Engl J Med. 2001;345(12):861–869.*ESSENTIAL READING
• Wright JT, Bakris G, Greene T, et al; Effect of Blood Pressure Lowering and
Antihypertensive Drug Class on Progression of Hypertensive Kidney Disease:
Results from the AASK trial. JAMA. 2002;288(19):2421–2431.*ESSENTIAL
READING

• Lewis EJ, Hunsicker LG, Clark WR, et al; Renoprotective Effect of the
Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy due to
Type 2 Diabetes. N Engl J Med. 2001;345(12):851–860.

• Fried LF, Emanuele N, Zhang JH, et al; Combined Angiotensin Inhibition for the
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Treatment of Diabetic Nephropathy. N Engl J Med. 2013;369(20):1892–

1903.*ESSENTIAL READING

• D’Elia L, Rossi G, Schiano di Cola M, et al; Meta-Analysis of the Effect of

Dietary Sodium Restriction with or without Concomitant Renin-Angiotensin-
Aldosterone System-Inhibiting Treatment on Albuminuria. Clin J Am Soc
Nephrol. 2015;10(9):1542–1552.
• Vegter S, Perna A, Postma MJ, et al; Sodium Intake, ACE Inhibition, and
Progression to ESRD. J Am Soc Nephrol.2012;23(1):165–173.*ESSENTIAL
READING

• Lambers Heerspink HJ, Holtkamp FA, Parving HH, et al; Moderation of dietary
sodium potentiates the renal and cardiovascular protective effects of angiotensin
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receptor blockers. Kidney Int. 2012;82(3):330–337.

• Alexandrou ME, Papagianni A, Tsapas A, et al; Effects of mineralocorticoid

receptor antagonists in proteinuric kidney disease: a systematic review and meta-
analysis of randomized controlled trials. J Hypertens. 2019;37(12):2307–
2324.*ESSENTIAL READING

• Bakris GL, Agarwal R, Anker SD, et al; Effect of Finerenone on Chronic Kidney
Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020;383(23):2219–2229.

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Glycemic control
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Case 4: A 48 year-old man with type 2 diabetes is seen for routine follow-up. He has stable
CKD (G3aA2 for 3 years) in addition to retinopathy, hypertension, and hyperlipidemia. He
is currently taking losartan 50 mg daily, metoprolol 75 mg twice daily, metformin 500 mg
twice daily, and atorvastatin 20 mg daily. His BP is 127/68 mm Hg with heart rate of 64
bpm. The remainder of the physical examination is unremarkable. Laboratory evaluation
demonstrates eGFR 52 ml/min/1.73 m2, UACR 35 mg/g, and hemoglobin A1c (HbA1c)
7.9%.

Question 5: Which one of the following interventions would be most likely

to slow progression of his CKD?
a. Increase losartan to reduce BP to <120/80 mm Hg
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b. Change metoprolol to a dihydropyridine calcium channel blocker

c. Increase metformin to target HbA1c <7%

d. No changes, as management of hypertension and glycemic control are at goal

For the answer to the question, see the following text.

The 2020 KDIGO guidelines on diabetes in CKD recommend that HbA1c goals be
individualized based on CKD severity, comorbidities, and hypoglycemia risk, among other
factors (Table 4). Dosing adjustments or discontinuation of glucose-lowering agents are
often necessary as CKD progresses. In particular, insulins, sulfonylureas, and meglitinides
are more likely to cause hypoglycemia in the patient with reduced kidney function.
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Most major randomized controlled trials suggest that intensive glycemic control reduces
albuminuria and possibly also kidney function decline in patients with diabetes (Table 5). In
the ADVANCE-ON and DCCT/EDIC studies, intensive glycemic control was associated
with a 46% lower risk of KFRT or death from kidney disease and 50% lower risk of incident
eGFR <60 ml/min/1.73 m2, respectively. A large meta-analysis of the ADVANCE,
ACCORD, UKPDS, and VADT trials showed that more intensive glycemic control was
associated with a 20% lower risk of developing a primary kidney event (i.e., incident eGFR
<30 ml/min/1.73 m2, UACR >300 mg/g, KFRT, or death from kidney disease), mostly due
to a reduction in risk of albuminuria. Participants with more intensive control were also
more likely to have regression of UACR from >300 to 30–300 mg/g (HR, 1.23 [95% CI,
1.03–1.48]), regression of UACR from 30–300 to < 30 mg/g (HR, 1.15 [95% CI, 1.03–
1.28]), and maintenance of UACR < 30 mg/g (HR, 1.16 [95% CI, 1.08–1.25]).
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For Question 5, (c) targeting a HbA1c of 7% or less is the best option among those listed to
help slow CKD progression. In patients with CKD G4-G5 or significant competing
comorbidities where risk of hypoglycemia is higher and benefits of intense control less well-
established, the HbA1c target should be individualized. The patient’s BP is currently
controlled to goal, and further reduction or substitution of a dihydropyridine calcium blocker
for a beta-blocker has not been shown to slow CKD progression.

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Additional Readings
Author Manuscript

• Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group.

KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic
Kidney Disease. Kidney Int. 2020;98(4S):S1-S115.*ESSENTIAL READING

• Bilo H, Coentrão L, Couchoud C, et al. for the Guideline Development Group;

Clinical Practice Guideline on Management of Patients With Diabetes and
Chronic Kidney Disease Stage 3b or Higher (eGFR<45 ml/min). Nephrol Dial
Transplant. 2015;30(Suppl 2):ii1-ii142.
• Ismail-Beigi F, Craven T, Banerji MA, et al; Effect of intensive treatment of
hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the
ACCORD randomized trial. Lancet. 2010;376(9739):419–430.

• Perkovic V, Heerspink HL, Chalmers J, et al; Intensive glucose control improves

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kidney outcomes in patients with type 2 diabetes. Kidney Int. 2013;83(3):517–

523.

• Wong MG, Perkovic V, Chalmers J, et al. for the ADVANCE-ON Collaborative

Group; Long-term Benefits of Intensive Glucose Control for Preventing End-
Stage Kidney Disease: ADVANCE-ON. Diabetes Care. 2016;39(5):694–700.

• The Diabetes Control and Complications Trial Research Group; The Effect of
Intensive Treatment of Diabetes on the Development and Progression of Long-
Term Complications in Insulin-Dependent Diabetes Mellitus. N Engl J Med.
1993;329(14):977–986.

• Epidemiology of Diabetes Interventions and Complications Research Group;

Sustained Effect of Intensive Treatment of Type 1 Diabetes Mellitus on
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Development and Progression of Diabetic Nephropathy. JAMA.

2003;290(16):2159–2167.

• The DCCT/EDIC Research Group. Intensive Diabetes Therapy and Glomerular

Filtration Rate in Type 1 Diabetes. N Engl J Med. 2011;365(25):2366–2376.

• UK Prospective Diabetes Study Group; Intensive blood-glucose control with

sulphonylureas or insulin compared with conventional treatment and risk of
complications in patients with type 2 diabetes (UKPDS 33). Lancet.
1998;352(9131):837–853.

• Duckworth W, Abraira C, Mortiz T, et al. Glucose Control and Vascular

Complications in Veterans with Type 2 Diabetes. N Engl J Med.
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2009;360(2):129–139.

• Zoungas S, Arima H, Gerstein HC, et al; Effects of intensive glucose control on

microvascular outcomes in patients with type 2 diabetes: a meta-analysis of
individual participant data from randomized controlled trials. Lancet Diabetes
Endocrinol. 2017;5(6):431–437.*ESSENTIAL READING

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SGLT-2 inhibitors
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Case 4, cont: The patient returns for follow-up. His CKD has steadily worsened over the
past 12 months. Laboratory studies reveal:

Parameter Present 6 mo prior 12 mo prior

Sodium, mEq/L 132 134 131

Potassium, mEq/L 5.3 5.2 5.4

Glucose, mg/dL 315 280 210

eGFR, mL/min/1.73 m2 46 51 52

UACR, mg/g 1,000 400 35

HbA1c 9.4% -- 7.9%

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Question 6: Which one of the following interventions would be the next

best step?
a. Start SGLT2 inhibitor to reduce albuminuria

b. Start SGLT2 inhibitor to achieve an HbA1c <7%

c. Do not start SGLT2 inhibitor because of risk for worsening hyperkalemia

d. Do not start SGLT2 inhibitor because of risk for worsening hyponatremia

Case 5: A 70 year-old woman with moderate obesity (BMI 32 kg/m2) and uncontrolled
diabetes mellitus (HbA1c 8.2%) returns to discuss management of her CKD G3aA2. Her
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history includes coronary artery disease and recurrent furunculosis requiring antibiotics
several times per year.

Question 7: In counseling her on the potential benefits and risks of therapy

with an SGLT2 inhibitor, for which one of the following adverse effects is
she at greatest risk?
a. Genitourinary fungal infections

b. Lower extremity amputation

c. Severe hypoglycemia
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d. Acute kidney injury

For the answers to the questions, see the following text.

In recent years, SGLT2 inhibitors have emerged as new and exciting therapies for delaying
CKD progression, particularly among patients with type 2 diabetes and/or albuminuria.
Current ADA and EASD guidelines recommend that SGLT2 inhibitors be considered in all
patients with type 2 diabetes at risk of CKD progression, regardless of cardiovascular
disease history (Table 1).

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Initial reports of the potential kidney protective effects of SGLT2 inhibitors came from
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cardiovascular outcome trials. These studies, however, primarily included individuals with
mild or no CKD and were limited by small numbers of kidney events. In 2019, the results of
the landmark CREDENCE trial were published. This trial, the first to examine the
association of a SGLT2 inhibitor with a primary kidney outcome, reported that among
patients with type 2 diabetes and CKD G2-G3bA3, randomization to canagliflozin was
associated with a 30% lower risk (95% CI, 18%−41%) of developing a composite outcome
(KFRT, sustained eGFR <15 ml/min/1.73 m2, doubling of serum creatinine from baseline,
death from kidney disease, or death from cardiovascular disease) compared to placebo.
Similar conclusions were obtained when considering individual components of the
composite outcome. Importantly, all participants were on an ACE-I or ARB, thus suggesting
that the benefits of canagliflozin extended beyond standard pharmacologic therapy (i.e.,
RAAS inhibition).
Author Manuscript

Neuen et al. performed a meta-analysis of four randomized-controlled trials that investigated

the effect of SGLT2 inhibitors on major kidney outcomes among patients with type 2
diabetes and eGFR ≥30 ml/min/1.73 m2: CREDENCE, CANVAS Program, EMPA-REG
OUTCOME, and DECLARE-TIMI 58. The majority of patients in the latter 3 trials did not
have baseline CKD (Table 6). Among 38,723 participants, use of SGLT2 inhibitors was
associated with a 33% lower risk of a composite outcome of dialysis, transplantation, or
death from kidney disease compared to placebo. Importantly, the benefits of SGLT2
inhibitors were statistically significant in all subgroups of baseline eGFR (30-<45; 45-<60;
60-<90; and ≥90 ml/min/1.73 m2). Estimated GFR decline was also slower in the SGLT2
inhibitor group versus placebo in CREDENCE (absolute difference, 2.74 [95% CI, 2.37–
3.11] ml/min/1.73 m2 per year), CANVAS Program (absolute difference, 1.18 [95% CI,
1.02–1.35] ml/min/1.73 m2 per year), and EMPA-REG OUTCOME (absolute difference,
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1.68 [95% CI, 1.02–1.35] ml/min/1.73 m2 per year).

More recently, the DAPA-CKD trial demonstrated that the renoprotective effects of SGLT2
inhibitors likely extend beyond patients with type 2 diabetes. This trial, which enrolled
individuals with CKD (32.5% without type 2 diabetes), was stopped early because of clear
efficacy of dapagliflozin over placebo for the primary outcome (sustained eGFR decline
≥50% from baseline, KFRT, sustained eGFR <15 ml/min/1.73 m2, or death from kidney or
cardiovascular cause), with an HR of 0.61 [95% CI, 0.51–0.72]. The benefits of
dapagliflozin were consistent in participants with and without type 2 diabetes. Safety
profiles were similar between the two treatment arms with the exception of volume depletion
(more common with dapagliflozin) and major hypoglycemia (more common with placebo).
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Several mechanisms have been proposed for how SGLT2 inhibitors improve kidney
outcomes. Blockade of SGLT-2, responsible for ~90% of glucose reabsorption that occurs in
the proximal tubule, promotes urinary excretion of glucose. However, SGLT-2 inhibitors are
associated with only modest HbA1c reductions, suggesting that the kidney effects are not
driven by improved glycemic control. Rather, increased distal delivery of sodium to the
macula densa (in tandem with glucose excretion) activates tubuloglomerular feedback,
leading to vasoconstriction of the afferent arteriole and ultimately a reduction in
intraglomerular pressure. SGLT-2 inhibitors also reduce systolic and diastolic BP, likely due

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 Chen et al. Page 12

to osmotic diuresis (from glucosuria), natriuresis, and possibly inhibition of sympathetic

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nervous system activity. Other potential mechanisms for the renoprotective effects of SGLT2
inhibitors include weight loss, lowering of serum uric acid levels, and reduction of
albuminuria.

Although SGLT-2 inhibitors are generally well-tolerated, some safety concerns warrant
mentioning. Genitourinary fungal infections, particularly in women, are the most commonly
reported adverse effect. Fournier gangrene, which occurs much more rarely, is another
potential severe complication. The US Food and Drug Administration (FDA) issued a black
box warning on canagliflozin regarding an increased risk of lower limb amputations based
on a nearly 2-fold higher risk of amputations in the CANVAS Program. In contrast, there
was no heightened amputation risk in CREDENCE. Still, it is prudent to perform regular
foot exams in all patients on SGLT-2 inhibitors, particularly those with a history of
neuropathy, peripheral vascular disease, and/or diabetic foot ulcers. An increased risk of
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fracture with SGLT-2 inhibitors was reported in CANVAS Program but not CREDENCE,
EMPA-REG OUTCOME, or DECLARE-TIMI 58. The role of SGLT2 inhibitors as a
precipitant for AKI remains controversial, with some published studies reporting protective
effects.

For Question 6, SGLT-2 inhibitors are associated with (a) a reduction in albuminuria and a
30–40% decreased risk of CKD progression. This class of medications is not commonly
associated with hyponatremia or hyperkalemia and results in only a small reduction in
HbA1c. For Question 7, while all choices have been reported with the use of SGLT-2
inhibitors, the most common is (a) genitourinary fungal infection.

Additional Readings
Author Manuscript

• Davies MJ, D’Alessio DA, Fradkin J, et al; Management of hyperglycaemia in

type 2 diabetes, 2018. A consensus by the American Diabetes Association
(ADA) and the European Association for the Study of Diabetes (EASD).
Diabetologia. 2018;61:2461–2498.
• Perkovic V, Jardine MJ, Neal B, et al; Canagliflozin and Renal Outcomes in Type
2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295–
2306.*ESSENTIAL READING

• Neuen, BL, Young T, Heerspink HJL, et al; SGLT2 inhibitors for the prevention
of kidney failure in patients with type 2 diabetes: a systematic review and meta-
analysis. Lancet Diabetes Endocrinol. 2019;7(11):845–854.*ESSENTIAL
READING
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• van Bommel EJM, Muskiet MHA, Tonneijck L, et al; SGLT2 Inhibition in the
Diabetic Kidney – From Mechanisms to Clinical Outcome. Clin J Am Soc
Nephrol. 2017;12(4):700–710.
• Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al; Dapagliflozin in Patients
with Chronic Kidney Disease. N Engl J Med. 2020; 383(15):1436–1446.

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• Neal B, Perkovic V, Mahaffey KW, et al; Canagliflozin and Cardiovascular and

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Renal Events in Type 2 Diabetes. N Engl J Med. 2017; 377(7): 644–657.

GLP-1 receptor agonists

Case 5: A 60 year-old man with type 2 diabetes mellitus and CKD G4A3 (eGFR 27 ml/min/
1.73 m2) has stable UACR (1,800 mg/g for 1 year). BP is 126/70 mm Hg and HbA1c is
9.0%. Medications include lisinopril 40 mg daily, diltiazem sustained release 180 mg daily,
and insulin glargine.

Question 8: Which one of the following interventions would be appropriate

to manage risk factors associated with CKD progression?
a. Addition of a GLP-1 receptor agonist to reduce HbA1c but at an increased risk
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for hypoglycemia

b. Addition of metformin rather than a GLP-1 receptor agonist due to the favorable
side-effect profile of metformin

c. Addition of a GLP-1 receptor agonist to slow progression to kidney failure

without change in albuminuria

d. Addition of a GLP-1 receptor agonist to reduce BP to <120/80 mm Hg

For the answer to the question, see the following text.

The GLP-1 receptor agonists are another novel class of diabetes medications that improve
kidney outcomes. In the AWARD-7 trial, dulaglutide 0.75 mg or 1.5 mg weekly resulted in
slower eGFR decline over 52 weeks compared with daily insulin glargine among
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participants with type 2 diabetes, CKD G3-G4, and UACR >300 mg/g. Furthermore, UACR
reduction occurred with dulaglutide in a dose-dependent manner. Among participants with
baseline UACR ≤300 mg/g, no significant differences in eGFR decline were observed
between the three treatment arms. In a meta-analysis of five cardiovascular outcome trials
(ELIXA; LEADER; SUSTAIN-6; EXSCEL; REWIND), Kristensen et al. reported that
GLP-1 receptor agonists were associated with a 17% lower risk of a composite kidney
outcome (new-onset UACR >300 mg/g, a doubling of serum creatinine, ≥40% decline in
eGFR, KFRT, or death from kidney disease), with an HR of 0.83 [95% CI, 0.78–0.89].
However, when considering the more restrictive outcome of worsening kidney function,
defined by a doubling of serum creatinine or ≥40% eGFR decline (except for EXSCEL
which also included KFRT or death from kidney disease), there was no statistically
significant protective effect of GLP-1 receptor agonists (HR, 0.87 [95% CI, 0.73–1.03]).
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GLP-1 receptor agonists act by binding to the GLP-1 receptor, enhancing glucose-dependent
insulin secretion, delaying gastric emptying, and decreasing appetite. Modest improvements
in body weight, BP, and lipid parameters have also been reported. Prior studies suggest that
multiple cell types (e.g., glomerular, tubular, and vascular) within the kidney have GLP-1
receptors but the mechanisms by which GLP-1 receptor agonists improve kidney outcomes

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 Chen et al. Page 14

are less clear. Altered renal hemodynamics, increased natriuresis, and reductions in
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inflammation and reactive oxidative species have all been proposed.

The most frequent side effect of GLP-1 receptor agonists is nausea, which usually resolves
after 4–8 weeks of continued therapy. Diarrhea, hypoglycemia (particularly if used in
combination with insulin therapy), tachycardia, gallbladder disease, pancreatitis, and
retinopathy may also occur. Other major safety concerns include increased risks of
pancreatic and thyroid cancer. Although Kristensen et al. did not find an association of
GLP-1 receptor agonist therapy with severe hypoglycemia, pancreatitis, pancreatic or
thyroid cancer, the trials excluded individuals with a personal or family history of medullary
thyroid carcinoma or multiple endocrine neoplasia type 2, and the FDA label warns against
the use of GLP-1 receptor agonists in these patients.

Although no trial has directly compared SGLT2 inhibitors with GLP-1 receptor agonists, a
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meta-analysis of 8 cardiovascular trials found a 38% (HR, 0.62 [95% CI, 0.58–0.67) and
18% (HR, 0.82 [95% CI, 0.75–0.89]) lower risk of new-onset UACR >300 mg/g, doubling
of serum creatinine, ≥40% decline in eGFR, KFRT, or death from kidney disease for SGLT-2
inhibitors and GLP-1 receptor agonists, respectively. When incident UACR >300 mg/g was
not included in the outcome, SGLT2 inhibitors were associated with a 45% lower risk (HR,
0.55 [95% CI, 0.48–0.64]) whereas no association was observed for GLP-1 receptor agonists
(HR, 0.92 [95% CI, 0.80–1.06]). Thus, SGLT2 inhibitors appear to be more effective in
slowing kidney disease progression and should be considered before GLP-1 receptor
agonists (Figure 2).

For Question 8, studies best support (a) a reduction in UACR following addition of a GLP-1
receptor agonist. There is an increased risk of hypoglycemia when used concurrently with
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insulin, and a reduction in the rate of progression to kidney failure has not been shown.
While GLP-1 receptor agonists may result in a small reduction in BP, lowering to <120/80
mm Hg has not been shown to slow CKD progression. Initiating metformin would be
inappropriate at this eGFR.

Additional Readings
• Tuttle KR, Lakshmanan MC, Rayner B, et al; Dulaglutide versus insulin glargine
in patients with type 2 diabetes and moderate-to-severe chronic kidney disease
(AWARD-7): a multicenter, open-label, randomized trial. Lancet Diabetes
Endocrinol. 2018;6(8):605–617.
• Kristensen S, RØrth R, Jhund PS, et al; Cardiovascular, mortality, and kidney
outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a
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systematic review and meta-analysis of cardiovascular outcome trials. Lancet

Diabetes Endocrinol. 2019;7(10):776–785.*ESSENTIAL READING
• Muskiet MHA, Tonneijck L, Smits MM, et al; GLP-1 and the kidney: from
physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol.
2017;13:605–628.

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• Zelniker TA, Wiviott SD, Raz I, et al; Comparison of the Effects of Glucagon-
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Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors

for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2
Diabetes Mellitus. Circulation. 2019;139(17):2022–2031.*ESSENTIAL
READING

• Li J, Albajrami O, Zhuo et al; Decision Algorithm for Prescribing SGLT2

Inhibitors and GLP-1 Receptor Agonists for Diabetic Kidney Disease. Clin J Am
Soc Nephrol. 2020;15(11):1678–1688.

Chronic metabolic acidosis and dietary protein restriction

Case 6: A 63 year-old woman with CKD G4A2 and osteopenia returns for follow-up,
having been last seen 4 months ago. She underwent left nephrectomy 30 years ago following
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trauma. She reports no interval symptoms and weight has been stable. Her eGFR has slowly
declined from 33 to 28 ml/min/1.73 m2 over the past 2 years, with her last two total carbon
dioxide values in the range of 19 – 21 mmol/L. On physical examination, BP 118/65 mm
Hg, lungs are clear, and she has trace pedal edema.

Question 9: Which one of the following is most accurate in treating

metabolic acidosis associated with CKD?
a. Modest dietary protein restriction should decrease urine ammoniagenesis

b. Dietary supplementation with sodium bicarbonate should decrease bone mineral

density

c. Modest dietary protein restriction should increase skeletal muscle catabolism

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Case 7: A 58 year-old man with IgA nephropathy has progressive CKD over the past 18
months. eGFR is 29 ml/min/1.73 m2 with total carbon dioxide ranging 18 – 20 mmol/L.

Question 10: Which one of the following interventions has the greatest
efficacy in improving metabolic acidosis?
a. Increase daily fruit intake to 4 servings

b. Add sodium bicarbonate 650 mg tablet once daily

c. Ensure 2 servings of pasta daily

d. Replace one serving of red meat with one serving of fish daily
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For the answers to the questions, see the following text.

Metabolic acidosis is a common complication of CKD due to impairments in the kidney’s

ability to excrete acid. Dietary composition also influences acid-base balance, with animal-
derived proteins contributing primarily hydrogen ions, and fruits and vegetables contributing
alkali. Thus, treatment of metabolic acidosis in patients with CKD typically relies on three
strategies: reduction of dietary animal protein, increased consumption of fruits and

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 Chen et al. Page 16

vegetables, and administration of oral alkali salts. Metabolic acidosis is a risk factor for
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KFRT, decreased bone mineralization, and sarcopenia. Correction of metabolic acidosis may
slow CKD progression. A systematic review of 13 small, primarily open-label clinical trials
suggested that both oral alkali supplementation and dietary interventions slow GFR decline,
with a meta-analyzed effect on mean GFR decline of >3 ml/min/1.73 m2 per year for both
strategies. However, only four of the 13 studies had durations more than 1 year, and four had
durations of 6 months or less. The largest randomized controlled trial of dietary protein
restriction to date (MDRD Study) suggested a more modest effect size that failed to
demonstrate statistical significance. Among participants randomized to usual-protein, low-
protein, or very-low-protein diet (1.3 vs. 0.58 vs. 0.28 g/d per kilogram of body weight), the
difference in mean GFR decline over a mean follow-up of 2.2 years was 0.8 ml/min per year
for very-low-protein vs. low-protein (p=0.07) and 0.4 ml/min per year for the low-protein vs.
usual-protein diets (p=0.30).
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Despite little clinical trial evidence, the KDIGO guideline suggests consideration of dietary
protein restriction to <1.3 g/d per kilogram of body weight for patients with or at risk for
CKD G3 and 0.8 g/d per kilogram of body weight per day for patients with CKD G4-G5,
given the theoretical benefit. Patients with CKD and bicarbonate <22 mmol/l should also be
treated with oral alkali therapy to maintain bicarbonate concentrations in the normal range,
recognizing the risks of increased BP and edema. Diets enriched in fruits and vegetables
may provide as much or more alkali than bicarbonate supplementation and, in one small
study, were similarly effective in slowing eGFR decline (Figure 3).

Returning to Question 9, chronic metabolic acidosis is associated with progression of CKD,

stimulates increased renal ammoniagenesis, increases bone resorption, and is associated with
the development of sarcopenia. Therefore, the best answer is (a) as reducing protein intake
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will decrease dietary acid production. For Question 10, the best answer is (a) since 4
servings of fruits and vegetables provide more alkali than low dose sodium bicarbonate.
Carbohydrates and animal meats contribute to net acid production, although replacing
servings of red meat with fish may have other health benefits.

Additional Readings
• Raphael KL; Metabolic Acidosis in CKD: Core Curriculum 2019. Am J Kidney
Dis. 2019;74(2):263–275.
• Banerjee T, Crews DC, Wesson DE, et al; High Dietary Acid Load Predicts
ESRD among Adults with CKD. J Am Soc Nephrol. 2015;26(7):1693–1700.

• Navaneethan SD, Shao J, Buysse J, Bushinsky DA; Effects of Treatment of

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Metabolic Acidosis in CKD: A Systematic Review and Meta-Analysis. Clin J

Am Nephrol. 2019;14(7):1011–1020.
• Klahr S, Levey AS, Beck GJ, et al; The Effects of Dietary Protein Restriction
and Blood Pressure Control on the Progression of Chronic Renal Disease.
NEJM. 1994;330(13):877–884.*ESSENTIAL READING
• Jain N, Reilly RF. Effects of dietary interventions on the Incidence and
Progression of CKD. Nature Reviews Nephrology. 2014;10(12):712–724.

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• Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group.

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KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of
Chronic Kidney Disease. Kidney Int Suppl. 2013;3:1–150.*ESSENTIAL
READING

• Goraya N, Simoni J, Jo CH, Wesson DE; Treatment of metabolic acidosis in

patients with stage 3 chronic kidney disease with fruits and vegetables or oral
bicarbonate reduces urine angiotensinogen and preserves glomerular filtration
rate. Kidney Int. 2014;86(5):1031–1038.

Avoidance of nephrotoxins
Case 8: A 62 year-old woman with recent diagnosis of ovarian cancer presented to the
emergency room with urinary tract infection and atrial fibrillation. Her medical history is
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notable for CKD G4A1 in the setting of hypertension and chronic hepatitis B. Home
medications include lisinopril, tenofovir disoproxil fumarate, and multivitamin. CT of the
abdomen/pelvis demonstrates a large ovarian mass with peritoneal carcinomatosis.

Question 11: Which one of the following medications is safest to use in

setting of CKD G4?
a. Gentamicin

b. Amiodarone

c. Tenofovir disoproxil fumarate

d. Cisplatin
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Case 9: A 74 year-old man with CKD G4A2 in the setting of diabetes mellitus and IgA
nephropathy is hospitalized for a non-healing lower extremity ulceration. His eGFR is
currently 23 ml/min/1.73m2, as compared to 26 one month prior. You are consulted prior to
planned lower extremity angiography for recommendations to reduce the risk for contrast-
associated AKI.

Question 12: Which one of the following interventions is most appropriate

prior to administration of intra-arterial iodinated IV contrast in hospitalized
patients with diabetes and CKD?
a. Oral N-acetylcysteine
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b. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor

c. Vitamin C

d. Normal saline hydration

For the answers to the questions, see the following text.

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Nephrotoxins can contribute to CKD progression by causing AKI, chronic interstitial

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nephritis, tubular dysfunction, or glomerular changes. Avoidance of nephrotoxins is not

always possible, especially in the hospital or acute care setting; thus, an individualized
approach that carefully weighs the risks versus benefits for each patient is necessary. Many
chemotherapeutic (e.g., platinum-based agents, gemcitabine, immunotherapies) and
antimicrobial agents (e.g., aminoglycosides, colistin, amphotericin B, tenofovir disoproxil
fumarate) require special attention in CKD given their potential for harm to the kidney
and/or need for dose adjustments. Despite known toxicities, alternative drug options may not
be appropriate due to susceptibility patterns or decreased efficacy. In such cases, counseling
patients on the potential worsening of CKD, close monitoring of kidney function, and dose
adjustments as needed is a reasonable approach. Other potential nephrotoxins include
gastrointestinal agents (e.g., phosphate-containing bowel preparations, proton-pump
inhibitors), pain relievers (e.g., nonsteroidal anti-inflammatory agents), and herbal
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supplements or remedies. Although proton-pump inhibitors do not necessarily need to be

stopped in patients with CKD, providers should review need and candidacy for alternative
therapy (e.g., H2-blockers) regularly.

Contrast-associated AKI remains a concern among patients with CKD, particularly those
with eGFR <30 ml/min/1.73 m2 or diabetes. Proposed mechanisms of injury include
vasoconstriction leading to renal ischemia, direct tubular toxicity, and oxidative stress from
free radical generation. High-osmolar (>1,200 mOsm/kg) ionic contrast agents are more
likely to be nephrotoxic than low-osmolar (700–850 mOsm/kg) or iso-osmolar (~290
mOsm/kg) nonionic agents. AKI risk is thought to be higher with arterial compared to
venous contrast administration. However, patients with CKD should not be denied necessary
tests that require contrast for diagnosis and management. Fundamental risk reduction
measures include: 1) use of minimum dose of contrast necessary; 2) use of low- or iso-
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osmolar agents; 3) expansion of intravascular volume as tolerated with intravenous normal

saline before, during, and after the procedure; and 4) avoidance of concurrent nephrotoxins.

Returning to Question 11, the best answer is (b) because amiodarone does not require
discontinuation or dose adjustment in CKD G4. For Question 12, while all listed agents have
been reported to reduce the risk of contrast associated kidney injury, the best answer is (d) as
periprocedural hydration with normal saline is the most widely accepted prophylaxis.

Additional Readings
• Chen TK, Knicely DH, Grams ME; Chronic Kidney Disease Diagnosis and
Management: A Review. JAMA. 2019;322(13):1294–1304.*ESSENTIAL
READING
Author Manuscript

• Perazella MA. Pharmacology behind Common Drug Nephrotoxicities. Clin J Am

Soc Nephrol. 2018;13(12):1897–1908.
• McCullough PA, Choi JP, Feghali GA, et al; Contrast-Induced Acute Kidney
Injury. J Am Coll Cardiol. 2016;68(13):1465–1473.

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Uric acid–lowering therapies

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Prior studies have reported an association between elevated serum uric acid levels and
increased risk of CKD progression. Whether uric acid directly causes CKD progression or is
an indirect marker of some other process is unclear. Two recent trials, PERL and CKD-FIX,
investigated whether treatment with allopurinol slowed eGFR decline. The PERL study
enrolled patients with type 1 diabetes and early diabetic kidney disease (mean GFR 68
ml/min/1.73 m2 and median UAE rate 60 mg/d) and showed no difference in GFR slope
over 3 years between allopurinol and placebo groups. The CKD-FIX study, which included
individuals with more advanced CKD (mean eGFR 32 ml/min/1.73 m2 and median UACR
717 mg/g), also reported no significant difference in eGFR change between allopurinol and
placebo over two years (−3.33 and −3.23 ml/min/1.73 m2 per year; mean difference, −0.10
[95% CI, 1.18–0.97] ml/min/1.73 m2 per year). Of note, baseline uric acid levels in both
trials were not markedly elevated (PERL: 6.1 mg/dL; CKD-FIX: 8.2 mg/dL). Another
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randomized clinical trial of febuxostat in patients with CKD G3 and asymptomatic

hyperuricemia (mean uric acid ~7.8 mg/dL) similarly found no difference in eGFR slopes
compared to placebo.

Additional Readings
• Doria A, Galecki AT, Spino C, et al. for the PERL Study Group; Serum Urate
Lowering with Allopurinol and Kidney Function in Type 1 Diabetes. N Engl J
Med. 2020;382(26):2493–2503.
• Badve SV, Pascoe EM, Tiku A, et al. for the CKD-FIX Study Investigators.
Effects of Allopurinol on the Progression of Chronic Kidney Disease. N Engl J
Med. 2020;382(26):2504–2513.
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• Kimura K, Hosoya T, Uchida S, et al; Febuxostat Therapy for Patients With

Stage 3 CKD and Asymptomatic Hyperuricemia: A Randomized Trial. Am J
Kidney Dis. 2018;72(6):798–810.

Weight loss and bariatric surgery

Case 10: A 54 year-old man has CKD G4A1 in the setting of diabetes mellitus and
hypertension. His weight has been stable for the past year after losing 15 pounds.
Medications include lisinopril 40 mg daily and a GLP-1 receptor agonist. His BP is 125/70
mm Hg and BMI is 32 kg/m2. Labs demonstrate an eGFR 27 ml/min/1.73 m2, UACR 25
mg/g, HbA1c 7.2%, and serum uric acid 8.1 mg/dL. The kidney failure risk equation
(KFRE) predicts a 4.6% risk of kidney failure at 2 years.
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Question 13: Which one of the following interventions would be most

appropriate to reduce risk of progression to kidney failure?
a. Referral for bariatric surgery

b. Start allopurinol

c. Start a 2nd anti-hypertensive agent to lower BP to <120/80 mm Hg

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d. No additional therapy
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For the answer to the question, see the following text.

In observational studies, higher BMI has been associated with substantially greater risk of
developing hypertension and diabetes and a more modest risk for CKD. Mechanisms for the
latter association may be through the development of hypertension/diabetes, or there may
independent effects through inflammation and hemodynamic alterations in the glomerulus.
Weight loss through lifestyle modification or bariatric surgery may improve kidney
outcomes. A meta-analysis of four small studies suggested a benefit of weight loss achieved
through non-surgical interventions on reduction in albuminuria; however, only two of the
studies were clinical trials, with 40 and 18 participants each. A post-hoc analysis of the Look
AHEAD trial of people with type 2 diabetes who were overweight or had obesity and
suggested a 31% reduction in risk of developing very-high-risk CKD (defined as G4,
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G3bA2-3, or G3aA3) associated with intensive lifestyle intervention, which aimed to reduce
caloric consumption and increase physical activity. Interestingly, the effect of the
intervention was only partially mediated by weight loss and reductions in HbA1c and
systolic BP. A propensity-matched study of 985 patients who underwent bariatric surgery
compared with 985 controls with obesity suggested that long-term GFR decline was
attenuated in the bariatric surgery group, with a 57% lower risk of doubling of serum
creatinine, an eGFR<15 ml/min/1.73 m2, or KFRT over a median follow-up of 4 years.
Thus, it appears that weight loss may confer benefits for both GFR decline and worsening
albuminuria, although clinical trial evidence is lacking.

In Question 13, of the options shown, response (d), or no additional therapy, would be the
most appropriate intervention. Bariatric surgery at this BMI or a BP goal <125/70 mm Hg
have not been shown to slow progression to kidney failure. And, as discussed in the previous
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section, randomized controlled trials have not shown a benefit of uric acid lowering therapy
in preserving kidney function.

Additional Readings
• Chang AR, Grams ME, Ballew SH, et al; Adiposity and Risk of Decline in
Glomerular Filtration Rate: Meta-Analysis of Individual Participant Data in a
Global Consortium. BMJ. 2019;364:k5301.

• The Look AHEAD Research Group; Effect of a long-term behavioural weight

loss intervention on nephropathy in overweight or obese adults with type 2
diabetes: a secondary analysis of the Look AHEAD randomised clinical trial.
Lancet Diabetes Endocrinol. 2014;2(10):801–809. *ESSENTIAL READING
Author Manuscript

• Navaneethan SD, Yehnart H, Moustarah F, et al; Weight Loss Interventions in

Chronic Kidney Disease: A Systematic Review and Meta-Analysis. Clin J Am
Soc Nephrol. 2009;4(10):1565–1574.
• Chang AR, Chen Y, Still C, et al. Bariatric Surgery is Associated with
Improvement in Kidney Outcomes. Kidney Int. 2016;90(1):164–171.

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Support:
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TKC is supported by a NIH/NIDDK K08DK117068 and a George M. O’Brien Center for Kidney Research Pilot
and Feasibility Grant from Yale University (under Award Number NIH/NIDDK P30DK079310). MEG is supported
by NIH/NIDDK R01DK115534.
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Figure 1:
Kaplan-Meier curves for renal events by tertiles of 24-hour urinary sodium-creatinine ratio
(<121 mmol/g; 121 to <153 mmol/g; ≥153 mmol/g) among RENAAL and IDNT trial
participants on non-RAASi-based therapy and ARB therapy. Renal event defined as a
doubling of serum creatinine from baseline or KFRT (RENAAL and IDNT) or serum
creatinine ≥6.0 mg/dL (IDNT only). Adapted from Heerspink et al 2012 (Kidney Int. https://
doi.org/10.1038/ki.2012.74) with permission of the copyright holder. Original graphic ©
2012 International Society of Nephrology. Abbreviations: Non-RAASi=non-renin-
angiotensin-aldosterone system inhibitor; ARB=angiotensin receptor blocker.
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 Chen et al. Page 23
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Figure 2:
Proposed algorithm for SGLT2 inhibitor and GLP-1 receptor agonist use in chronic kidney
disease. Metabolic risks factors include uncontrolled diabetes or obesity/weight gain. Based
on information in Li et al 2020 (Clin J Am Soc Nephrol. https://doi.org/10.2215/
CJN.02690320). Abbreviations: SGLT2=sodium/glucose cotransporter 2; GLP-1=glucagon-
like peptide 1; eGFR=estimated glomerular filtration rate; UACR=urinary albumin-
creatinine ratio; ASCVD=atherosclerotic cardiovascular disease; HF=heart failure.
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 Chen et al. Page 24
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Figure 3:
Mean (± standard errors) estimated glomerular filtration rates among patients with CKD G3
randomized to usual care, sodium bicarbonate supplementation, base-producing fruits and
Author Manuscript

vegetables. Reproduced from Goraya et al 2014 (Kidney Int. https://doi.org/10.1038/

ki.2014.83) with permission of the copyright holder. Original graphic © 2014 International
Society of Nephrology. Abbreviations: crGFR=plasma creatinine-based glomerular filtration
rate; cysGFR=plasma cystatin C-based glomerular filtration rate; HCO3=sodium bicarbonate
supplementation; F+V=fruits and vegetables.
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Table 1:

Summary of guidelines for slowing kidney function decline in patients with CKD.

Guidelines BP Control RAAS Inhibition Glycemic Control Diet

Chen et al.

KDIGO 2012 Goal BP: ≤140/90 mm Start ACEI or ARB if diabetes and UACR 30– a Goal <2 g/d of sodium; protein
Hg (if UACR <30 mg/g) 300 mg/g; start ACEI or ARB if UACR ≥300 Goal HbA1c ~7.0% ; avoid HbA1c <7.0% if at risk of intake <1.3 g/kg/d if at risk for
or ≤130/80 mm Hg (if mg/g hypoglycemia; allow HbA1c >7.0% if comorbidities, CKD progression; protein intake
UACR ≥30 mg/g) limited life expectancy, or at risk of hypoglycemia 0.8 g/kg/d if GFR<30 ml/min/
1.73 m2

AHA/ACC 2017 Goal BP: <130/80 mmHg Start ACEI if HTN and eGFR <60 ml/min/1.73 n/a Sodium reduction if HTN
m2 or UACR ≥300 mg/g; use ARB if above
indications and ACEI not tolerated

ADA and EASD 2018 n/a n/a Goal HbA1c ≤7.0% but should be individualized; n/a
(for patients with type 2 consider SGLT2i if at risk for CKD progression;
diabetes) consider GLP-1RA if SGLT2i not tolerated or
contraindicated

ERBP 2015 (for patients Goal SBP: <140 mmHg Start ACEI if diabetes and cardiovascular Goal HbA1c ≤8.5% if comorbidities, limited life n/a
with CKD G3b+) indication expectancy, or at risk of hypoglycemia; goal HbA1c
≤7.0–8.0% otherwise

None of the guidelines included recommendations relating to uric acid.

a
The 2020 KDIGO Diabetes in CKD guideline recommends an individualized HbA1c target of <6.5% to <8.0%.

Abbreviations: AHA, American Heart Association; ACC, American College of Cardiology; BP=blood pressure; SBP=systolic blood pressure; ACEI=angiotensin-converting-enzyme inhibitor;
ARB=angiotensin-receptor blocker; eGFR=estimated glomerular filtration rate; UACR=urinary albumin-creatinine ratio; HbA1c=hemoglobin A1c; SGLT2i =sodium/glucose cotransporter 2 inhibitor;
GLP-1RA =glucagon-like peptide 1 receptor agonist; NA=not available; KDIGO=Kidney Disease: Improving Global Outcomes; ADA=American Diabetes Association; EASD=European Association for
the Study of Diabetes; ERBP=European Renal Best Practice; HTN, hypertension

Based on KDIGO CKD Work Group 2013 (Kidney Int Suppl, https://doi.org/10.1038/kisup.2012.77); KDIGO Diabetes Work Group 2020(Kidney Int, https://doi.org/10.1016/j.kint.2020.06.019); Whelton
et al 2018 (Hypertension, https://doi.org/10.1161/hyp.0000000000000065); Davies et al 2018 (Diabetologia, https://doi.org/10.1007/s00125-018-4729-5); Bilo et al 2015 (Nephrol Dial Transplant, https://
doi.org/10.1093/ndt/gfv100).

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Table 2:

Summary of major clinical trials on intensive versus standard BP control and kidney function decline.

AASK trial and cohort (n=1,094) MDRD Study (n=840) REIN-II (n=335) SPRINT (n=9,361)
Chen et al.

Kidney-related GFR 20–65 ml/min/1.73 m2; UPCR Scr 1.2 (F) or 1.4 (M) to 7.0 mg/dL or CLcr Proteinuria 1–3 g/d & CLcr <45 ml/min/1.73 m2or eGFR 20–60 ml/min/1.73 m2;
inclusion criteria ≤2.5 g/d <70 ml/min/1.73 m2; Proteinuria <10 g/d Proteinuria ≥3 g/d & CLcr <70 ml/min/1.73 m2 Proteinuria <1 g/d

Follow-up Range: 8.8–12.2 y Mean: 2.2 y Median: 1.6 y Median: 3.3 y

% with diabetes 0% 0% with “diabetes mellitus requiring insulin 0% with “type 1 diabetes mellitus” 0%
therapy”

Intervention MAP ≤92 vs. 102–107 mm Hg MAP 92 vs. 107 mm Hg BP <130/80 vs. DBP <90 mm Hg SBP <120 vs. <140 mm Hg

Subgroups UPCR ≤0.22 UPCR >0.22 GFR 25–55 GFR 13–24 Proteinuria 1–3 g/d Proteinuria ≥3 g/d eGFR 20–59 eGFR >60
g/g g/g ml/min/1.73 m2 ml/min/1.73 m2 ml/min/1.73 ml/min/1.73
m2 m2
Mean baseline 51.1 40.0 a a ~32.9–35.9 ~31.1–41.7 ~47.8–47.9 ~81.1–81.3
eGFR, ml/min/ 38.6 18.5
1.73 m2

Baseline UPCR Median: 0.04 Median: 0.68 Median: 0.15 g/g Median: 0.63 g/g Mean: ~1.7–1.8 g/d Mean: ~4.9 g/d n/a n/a
or UPE g/g g/g

Baseline UACR n/a n/a n/a n/a n/a n/a Mean; ~41.1–44.1 mg/g

Kidney function HR: 1.18 (0.93– HR: 0.73 (0.58– −1.6 (−0.8, 3.9) −0.5 (−0.4, 1.4) HR: 1.06 (0.51–2.20) HR: 1.09 (0.55–2.19) HR: 0.89 HR: 3.49
c 1.50) 0.93) ml/min/3 y ml/min/y (0.42–1.87) (2.44–5.10)
decline

p-interaction 0.02 b b n/a n/a

0.02 0.01

a
denotes GFR;
b
for interaction with baseline proteinuria (<1 g/d vs. 1-<3 g/d vs. ≥3 g/d);
c

Am J Kidney Dis. Author manuscript; available in PMC 2022 June 01.

defined in each study as follows: AASK (HR for doubling of serum creatinine, KFRT, or death); MDRD Study (mean difference in rate of GFR decline); REIN-II (HR for KFRT); SPRINT, baseline eGFR
20–59 ml/min/1.73 m2 (HR for first occurrence of ≥50% reduction in eGFR, maintenance dialysis, or kidney transplantation); SPRINT, eGFR ≥60 ml/min/1.73 m2 (HR for ≥30% reduction in eGFR to a
level <60 ml/min/1.73 m2). Values in parentheses are 95% CI. Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; GFR= glomerular filtration rate; eGFR=estimated
glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; UPCR=urinary protein-creatinine ratio; UPE=urine protein excretion; UACR=urinary albumin-creatinine ratio; HR=hazard ratio;
REIN, Ramipril Efficacy in Nephropathy; SPRINT, Systolic Blood Pressure Intervention Trial; n/a=not available.

Based on information in Appel et al 2010 (NEJM, https://doi.org/10.1056/nejmoa0910975); Klahr et al 1994 (NEJM, https://doi.org/10.1056/nejm199403313301301); Ruggenenti et al 2005 (Lancet, https://
doi.org/10.1016/s0140-6736(05)71082-5); The SPRINT Research Group 2015 (NEJM, https://doi.org/10.1056/nejmoa1511939).
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Table 3:

Summary of major clinical trials on ACEI and ARB therapy on kidney function decline.

REIN, Stratum 2 (n=166) RENAAL (n=1,513) AASK (n=1,094) IDNT (n=1,715) VA NEPHRON-D (n=1,448)
Chen et al.

Kidney-related inclusion CLcr 20–70 ml/min/1.73 m2; Scr 1.3–3.0 mg/dL; GFR 20–65 ml/min/1.73 m2; Scr 1.0 (F) or 1.2 (M) 3.0 mg/dL; eGFR 30-<90 ml/min/1.73 m2;
criteria proteinuria ≥3 g/d UACR ≥300 mg/g UPCR ≤2.5 g/d proteinuria ≥900 mg/d UACR ≥300 mg/g

Follow-up Mean: ~1.3 y Mean: 3.4 y Range: 3.0–6.4 y Mean: 2.6 y Median: 2.2 y

% with diabetes 0%* 100% 0% 100% 100%

% with HTN 87% c 100% 100% n/a

93%

Intervention Ramipril vs Placebo Losartan vs Placebo Ramipril vs Metoprolol vs Irbesartan vs Placebo vs Losartan + Lisinopril vs Losartan
Amlodipine Amlodipine + Placebo

Mean baseline eGFR, GFR 37.4–40.2 ml/min/1.73 b GFR 45.6 ml/min/1.73 m2 b eGFR ~53.6–53.7 ml/min/1.73
GFR, or Scr Scr ~1.9 mg/dL Scr ~1.7 mg/dL
m2 m2
Baseline UPCR or UPE Mean: 5.1–5.6 g/d n/a Median: 0.08 g/g Median: ~2.9 g/d Median: ~1.6–2.1 g/g

Baseline UACR or UAE n/a Median: ~1,237–1,261 n/a Median: ~1.9 g/d Median: 847 mg/g
mg/g

Kidney function 0.53 vs 0.88 ml/min/mo; HR: 0.84 (0.72–0.98) Risk Reduction for ramipril: RR for Irbesartan: 0.81 (0.67– HR: 0.88 (0.70–1.12)
decline** a 22% (1%−38%) vs. Metoprolol, 0.99) vs. Placebo, 0.76 (0.63–
p=0.03 38% (14%−56%) vs. Amlodipine 0.92) vs. Amlodipine

a
Analysis among 117 participants with at least 3 GFR measurements;
b
eGFR or GFR not available;
c
Percent receiving anti-HTN drugs at baseline;
*
None with “insulin-dependent diabetes mellitus”

Am J Kidney Dis. Author manuscript; available in PMC 2022 June 01.

Abbreviations: ACEI=angiotensin-converting-enzyme inhibitor; ARB= angiotensin-receptor blocker; GFR=glomerular filtration rate; eGFR=estimated glomerular filtration rate; UPCR=urinary protein-
creatinine ratio; UPE=urine protein excretion; UACR=urinary albumin-creatinine ratio; UAE=urine albumin excretion; RR=relative risk; Scr= serum creatinine; RENAAL, Reduction in End Points in Non-
Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan; VA NEPHRON-D, Veterans Affairs Nephropathy in Diabetes Study; CLcr, creatinine clearance; IDNT, Irbesartan Diabetic
Nephropathy Trial; HTN, hypertension; REIN, Ramipril Efficacy in Nephropathy; F, female; M, male; n/a=not available.
**
defined in each study as follows: RENAAL (HR for SCr doubling, KFRT, or death); IDNT (RR for SCr doubling, SCr≥6.0 mg/dL, KFRT, or death); AASK (GFR decline ≥50% or ≥25 ml/min/1.73 m2
from baseline, KFRT, or death); VA NEPHRON-D (HR first occurrence of absolute decline in eGFR ≥30 ml/min/1.73 m2 if eGFR at randomization ≥60 ml/min/1.73 m2, relative decline in eGFR ≥50% if
eGFR at randomization <60 ml/min/1.73 m2; eGFR <15 ml/min/1.73 m2, KFRT; or death).

Based on information in The GISEN Group 1997 (Lancet, https://doi.org/10.1016/S0140-6736(96)11445-8), Brenner et al 2001 (NEJM, https://doi.org/10.1056/nejmoa011161), Wright et al 2002 (JAMA,
https://doi.org/10.1001/jama.288.19.2421), Lewis et al 2001 (NEJM, https://doi.org/10.1056/nejmoa011303), Fried et al 2013 (NEJM, https://doi.org/10.1056/nejmoa1303154).
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Table 4:

Factors to consider when determining hemoglobin A1c targets in patients with diabetes and chronic kidney
Author Manuscript

disease.

Factors Goal hemoglobin A1c

<6.5% <8.0%
CKD severity Lower (e.g., G1) Higher (e.g., G5)

Macrovascular complications None or mild Severe

Comorbidities None or few Many

Life expectancy Long Short

Hypoglycemia awareness Good Diminished

Resources for hypoglycemia management Available Limited

Likelihood of treatments causing hypoglycemia Low High

Author Manuscript

Based on information in KDIGO Diabetes Work Group 2020 (Kidney Int, https://doi.org/10.1016/j.kint.2020.06.019). Abbreviations: CKD, chronic
kidney disease; G, glomerular filtration rate category
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 Chen et al. Page 29

Table 5:

Summary of major clinical trials on intensive versus standard glycemic control on kidney outcomes.
Author Manuscript

ADVANCE ACCORD UKPDS VADT (n=1,791) DCCT (n=1,441) EDIC

(n=11,140) (n=10,251) (n=3,867) (n=1,349)
Kidney- Not specified Scr ≤132.6 Scr ≤175 μmol/L Scr ≤1.6 mg/dL Scr <1.2 mg/dL Scr <1.2 mg/dL
related μmol/L or CLcr >100 or CLcr >100
inclusion ml/min/1.73 m2; ml/min/1.73 m2;
criteria UAE <40 mg/d UAE <40 mg/d

Follow-up Median: 5 y Mean: ~3.5 y Median: ~10 y Median: 5.6 y Mean: 6.5 y Mean: ~8 y

Diabetes type Type 2 Type 2 Type 2 Type 2 Type 1 Type 1

Diabetes Median: 7 y Median: ~10 y “newly Mean: ~11.5 y a Mean: ~12 y

duration diagnosed” Mean: ~2.6 &
b
~8.6–8.9 y

Intervention HbA1c ≤6.5% HbA1c <6.0% Median HbA1c Median HbA1c HbA1c <6.05% None (obs
vs. standard* vs. 7.0%−7.9% ~7.0% vs. ~7.9% ~6.9% vs. 8.4% vs. standard follow-up of
DCCT)
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Mean ~7.5% ~8.1% 7.08% ~9.4% a d e

baseline ~8.8% & ~8.9– ~7.4 & 9.1
HbA1c b
9.0

Baseline Mean eGFR Median eGFR n/a Mean Scr ~1.0 Mean CLcr Mean CLcr ~122
eGFR, CLcr, ~78.0–78.3 ~90 ml/min/1.73 mg/dL a mL/min
or Scr ml/min/1.73 m2 m2 ~127–128 &
b
~128–130
mL/min
Baseline Median UACR Median UACR n/a n/a a Median UAE
UACR or ~14.9–15.0 ~1.54 mg/mmol Mean UAE ~12 d e
b 8.6 & 10.1
UAE* μg/mg & ~19–21 mg/d mg/d

Kidney UACR ≥30 UACR ≥30 mg/g: UACR >30 mg/g: Any ↑ in Risk reduction: Risk reduction:
c μg/mg: HR, 0.91 HR, 0.79 (0.69– RR, 0.70 (0.46– albuminuria: 9.1% 39% (21%−52%) 59% (39%
outcome (0.85–0.98); 0.90); UACR 1.07); vs. 13.8% for UAE ≥40 −73%) for UAE
UACR >300 ≥300 mg/g: HR, “Proteinuria”: RR, (p=0.01); From mg/d; 54% (19% ≥40 mg/d; 84%
μg/mg: HR, 0.70 0.69 (0.55–0.85); 0.58 (0.23–1.43); normal to UACR −74%) for UAE (67%−92%) for
(0.57–0.85); KFRT or SCr Pcr doubling: RR, ≥30 mg/g: 10.0% ≥300 mg/d UAE >300 mg/d
KFRT: HR, 0.35 >291.72 μmol/L: 1.25 (0.16–9.55) vs. 14.7%
Author Manuscript

(0.15–0.83) HR, 0.95 (0.73– (p=0.03); Scr f

Risk reduction: 50% (18%, 69%) for
1.24) doubling: 8.8%
sustained eGFR <60 ml/min/1.73 m2
vs. 8.8% (p=0.99)

a
primary prevention cohort and
b
secondary intervention cohort of the DCCT;
c
for UKPDS, from 0–15 years of follow-up with outcome assessed every 3 years;
d
intensive and
e
conventional groups of original DCCT;
f
over median follow-up of 22 years (includes DCCT and EDIC years 1–16);
*
based on local guidelines;
Author Manuscript

**
Baseline UPCR information not available.

Abbreviations: eGFR=estimated glomerular filtration rate; UPCR=urinary protein-creatinine ratio; UACR=urinary albumin-creatinine ratio;
UAE=urine albumin excretion; CLcr=creatinine clearance; HbA1c=hemoglobin A1c; RR, relative risk; obs, observational; ADVANCE, Action in
Diabetes and Cardiovascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ACCORD, Action to Control
Cardiovascular Risk in Diabetes; DCC, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and
Complications; UKPDS, UK Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial; n/a=not available.

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 Chen et al. Page 30

Based on information in Perkovic et al 2013 (Kidney Int, https://doi.org/10.1038/ki.2012.401), Ismail-Beigi 2010 (Lancet. https://doi.org/10.1016/
s0140-6736(10)60576-4); UKPDS Group 1998 (Lancet. https://doi.org/10.1016/S0140-6736(98)07019-6); Duckworth et al 2009 (NEJM, https://
doi.org/10.1056/nejmoa0808431), DCCT group 1993 (NEJM, https://doi.org/10.1056/nejm199309303291401); EDIC group 2003 (JAMA. https://
doi.org/10.1001/jama.290.16.2159), DCCT/EDIC group 2011 (NEJM, https://doi.org/10.1056/nejmoa1111732).
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Author Manuscript
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Table 6:

Summary of trials on SGLT2 inhibitors with kidney outcomes in patients with and without type 2 diabetes.

Trial CREDENCE (n=4,401) CANVAS Program EMPA-REG OUTCOME DECLARE-TIMI 58 DAPA-CKD (n=4,304)
Chen et al.

(n=10,142) (n=7,020) (n=17,160)

Study or Participant Characteristics

Inclusion criteria eGFR 30–<90 ml/min/1.73 eGFR ≥30 ml/min/1.73 m2 eGFR ≥30 ml/min/1.73 m2 CLcr ≥60 ml/min eGFR 25–75 ml/min/1.73
m2; UACR >300–5000 mg/g m2; UACR 200–5,000 mg/g

SGLT2i Canagliflozin Canagliflozin Empagliflozin Dapagliflozin Dapagliflozin

Median follow-up, y 2.6 2.4 3.1 4.2 2.4

Baseline ACEI or ARB use 4,395 (99.9%) 8,116 (80%) 5,666 (81%) 13,950 (81%) a b
1354 (31%) ; 2,870 (67%)

eGFR

≥90 ml/min/1.73 m2 0 (0%) 2,476 (24%) 1,538 (22%) 8,162 (48%) 0 (0%)

60–<90 ml/min/1.73 m2 1,809 (41%) 5,625 (55%) 3,661 (52%) 7,732 (45%) 454 (11%)

45–<60 ml/min/1.73 m2 1,279 (29%) 1,485 (15%) 1,249 (18%) 1,265 (7%) 1,328 (31%)

30–<45 ml/min/1.73 m2 1,313 (30%) 554 (5%) 570 (8%) N/A 1,898 (44%)

<30 ml/min/1.73 m2 0 (0%) 0 (0%) 0 (0%) 0 (0%) 624 (14%)

Missing 0 (0%) 2 (<0.1%) 2 (<0.1%) 1 (<0.1%) 0 (0%)

UACR

<30 mg/g 0 (0%) 7,007 (69%) 4,171 (59%) 11,644 (68%) c

n/a

30–300 mg/g 0 (0%) 2,266 (22%) 2,013 (29%) 4,030 (24%) n/a
>300 mg/g 4,401 (100%) 760 (7%) 769 (11%) 1,169 (7%) n/a

Am J Kidney Dis. Author manuscript; available in PMC 2022 June 01.

Missing 0 (0%) 109 (1%) 67 (1%) 317 (2%) n/a

Relative Risk or Hazard Ratio comparing SGLT2i to placebo

Dialysis, Tx, or death from kidney 0.72 (0.54–0.97) 0.56 (0.23–1.32) 0.90 (0.30–2.67) 0.42 (0.20–0.87) N/A
disease

Dialysis, Tx, or sustained eGFR < 15 0.68 (0.54–0.86) 0.77 (0.30–1.97) 0.60 (0.18–1.98) 0.31 (0.13–0.79) 0.64 (0.50–0.82)
mL/min/1.73 m2 **

Substantial loss of kidney function*; 0.66 (0.53–0.81) 0.53 (0.33–0.84) 0.54 (0.40–0.75) 0.53 (0.43–0.66) 0.56 (0.45–0.68)
Dialysis, Tx, or sustained eGFR < 15
mL/min/1.73 m2 **; or death from
kidney disease
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a
on ACEI;
b
on ARB;
c
n=2079 (48%) with UACR>1,000 mg.

All participants in CREDENCE, CANVAS Program, EMPA-REG OUTCOME, and DECLARE-TIMI 58 were with type 2 diabetes. In DAPA-CKD, 67.5% of participants were with type 2 diabetes.
Chen et al.

*
defined as a doubling of serum creatinine with the exception of DECLARE-TIMI 58 (sustained 40% decline in eGFR) and DAPA-CKD (sustained 50% decline in eGFR).
**
except for the EMPA-REG OUTCOME trial, which did not include sustained eGFR < 15 mL/min/1.73 m2.

Abbreviations: SGLT2i =sodium/glucose cotransporter 2 inhibitor; ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin-receptor blocker; eGFR=estimated glomerular filtration rate;
UACR=urinary albumin-creatinine ratio; Tx, transplantation; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; CANVAS, Canagliflozin
Cardiovascular Assessment Study; EMPA-REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; DECLARE-TIMI 58, Dapagliflozin Effect
on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; n/a=not available. Based on information
in Neun et al 2019 (Lancet Diabetes Endocrinol, https://doi.org/10.1016/s2213-8587(19)30256-6) and Heerspink et al 2020 (NEJM, https://doi.org/10.1056/nejmoa2024816).

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