Classification and Management of Chronic Kidney Disease

Key Points

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The 2012 Kidney Disease Improving Global Outcomes classification system for chronic kidney disease (CKD) provides simple risk stratification and serves as a convenient framework for guiding management through different stages.
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Lifestyle measures including smoking cessation, weight loss, and dietary sodium restriction should form part of any strategy to achieve kidney protection and reduce cardiovascular risk in persons with CKD.
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Evidence from The Systolic Blood Pressure Intervention Trial indicates that a lower target for the treatment of systolic blood pressure may afford improved cardiovascular risk reduction but may also be associated with some increase in risk of acute kidney injury and hyperkalemia. The risks versus benefits of a lower blood pressure target should be evaluated in each individual.
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The first pillar of treatment to achieve optimal kidney protection is treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers as “first line” in persons with albuminuria.
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The second pillar of treatment for kidney protection is initiation of sodium-glucose cotransporter 2 (SGLT2) inhibitor in persons with type 2 diabetes and CKD and an eGFR of ≥20 mL/min/1.73 m ², irrespective of UACR. Likewise, SGLT2 inhibitors should be initiated in persons without diabetes and an eGFR between 20 to 45 mL/min/1.73 m ² irrespective of urine albumin-creatinine ratio (UACR) or an eGFR of >45 mL/min/1.73 m ² with a UACR ≥200 mg/g.
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In persons with type 2 diabetes, the third and fourth pillars involve treatment with a nonsteroidal mineralocorticoid receptor antagonist and a glucagon-like peptide 1 receptor agonist for treatment for kidney and cardiovascular protection.
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To achieve optimal kidney protection, careful attention should be paid to addressing all modifiable aspects of CKD to achieve target blood pressure, minimize proteinuria, and slow glomerular filtration rate decline.
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All persons with CKD should be regarded as having a high risk of cardiovascular disease and management offered to reduce this risk, including consideration of RAAS blockade, statin, and SGLT2 inhibitor use and, in those with type 2 diabetes, a glucagon-like peptide-1 receptor agonist and finerenone.

Chronic kidney disease (CKD) is a collective term covering all primary disease processes that result in structural or functional kidney abnormalities, with implications for health, persisting for at least 3 months. Abnormal urinalysis findings identifying proteinuria or hematuria and/or abnormal kidney structure or histologic features, with or without a decreased glomerular filtration rate (GFR), are the defining manifestations. The rationale for having a single term that encompasses a wide range of kidney pathologies is that damage to the kidneys results in shared pathophysiologic features and that many of the interventions to slow the progression of CKD and reduce the associated cardiovascular risk should be applied regardless of the etiology of CKD. This formal definition of CKD proposed in 2002 has had a profound impact on the practice of nephrology. Before this, it was difficult to compare the results of epidemiologic and clinical studies because each used a different definition, and imprecise terms such as chronic renal disease, impairment, insufficiency, and failure were used by different authors. Epidemiologic research based on the unified definition has revealed that CKD is common, affecting on average 13.4% of the adult population globally, and CKD has been identified as a leading cause of death in global burden of disease studies, though it should be noted that most epidemiologic studies rely on only a single abnormal GFR value for the diagnosis of CKD and therefore probably overestimate the true prevalence. Nevertheless, nephrology has changed from a specialty that focused largely on the treatment of rare and advanced kidney diseases, as well as kidney replacement therapy (KRT) to one that is now concerned with a condition, CKD, that affects a substantial proportion of the general population, and which may have modifiable disease trajectories. Of necessity, this has also resulted in the need for health care workers who are not nephrologists to gain knowledge of CKD and its management. Thus education of health care workers on the management of CKD has the potential to reduce the burden of disease and the need for KRT. This chapter reviews in detail the classification of CKD and the evidence-based treatments that should be offered to persons with CKD regardless of the underlying kidney pathology. Within this context, there are four broad aims:

1.
Attenuate GFR decline and thus prevent or delay the need for dialysis. It is perhaps self-evident, but the earlier that CKD progression can be halted, the greater is the possibility of maintaining kidney function as close to normal as possible.
2.
Prevent premature cardiovascular death at all stages of CKD.
3.
Recognize and manage complications of CKD as they arise, particularly in stages 4 and 5.
4.
Timely preparation for KRT or conservative and palliative care.

Because the pathophysiology associated with CKD changes as the condition progresses, we also propose a stepped care approach and consider how primary and secondary care clinicians should cooperate to provide optimal care for persons with CKD.

Classification of Chronic Kidney Disease

The original classification proposed in 2002 subdivided CKD into five stages according to the GFR, reflecting the observation that in the majority of cases, CKD progresses slowly through the stages before reaching end-stage kidney failure (ESKF). In 2008, a National Institute for Health and Care Excellence (NICE) guideline proposed that stage 3 (GFR 59–30 mL/min/1.73 m ²) be subdivided into stages 3a (GFR 59–45 mL/min/1.73 m ²) and 3b (GFR 44–30 mL/min/1.73 m ²), reflecting a broad consensus that there are important differences in clinical aspects and prognosis between these groups. The CKD staging system has two important implications: First, it suggests that if CKD is detected at an early stage, intervention may be possible to prevent or slow progression to more advanced stages. Second, it reflects the observation that as GFR declines, the risk profile of persons and associated complications changes. Thus the staging system provides a useful framework for structuring therapy and prioritizing interventions to produce a comprehensive strategy for the management of CKD. Although universally adopted, this classification system was limited by not reflecting the risk status of those classified, a feature that is present in many other disease classification systems. Following extensive epidemiologic investigations that identified reduced GFR and albuminuria as independent risk factors for adverse outcomes, the CKD classification system was revised by Kidney Disease Improving Global Outcomes (KDIGO) in 2012 and reaffirmed in the 2024 KDIGO guidelines for management of CKD. The GFR stages were preserved, though now termed categories G1 to G5, and new categories were added for albuminuria; categories A1 to A3, corresponding to the previously used descriptions of “normoalbuminuria,” microalbuminuria,” and “macroalbuminuria.” In addition, it was emphasized that the etiology of CKD should be included in the classification, giving rise to the term “CGA” classification (cause, GFR, albuminuria; Fig. 54.1 ). ^, According to this system, a person with immunoglobulin A (IgA) nephropathy, a GFR of 34 mL/min/1.73 m ², and a urine albumin-to-creatinine ratio (UACR) of 367 mg/g would be classified as “IgA nephropathy, category G3b A3.” Implementation of the CGA classification has been greatly aided by the global adoption of equations to derive an estimated GFR (eGFR) from the serum creatinine concentration and use of UACR on a random sample to quantitate albuminuria (see Chapter 23 ). Importantly, in this classification system, each category reflects a risk status for multiple adverse outcomes including ESKF, progression of CKD, cardiovascular events (CVEs), and all-cause mortality as indicated in the accompanying heat map. Thus the category is useful to guide the therapeutic approach at each stage and prompt referral for specialist care when indicated.

A chart showing the prognosis of chronic kidney disease by G F R and albuminuria categories according to K I D I G O 2012, with color-coded risk levels. The chart shows the prognosis of C K D by G F R and albuminuria categories, as described by K D I G O 2012. The table is divided into two parts. The left section includes G F R categories: G1 normal or high, greater than or equal to 90 milliliter per minute per 1.73 meter square, G2 mildly decreased, 60 to 89 milliliter per minute per 1.73 meter square, G 3a mildly to moderately decreased, 45 to 59 milliliter per minute per 1.73 meter square, G 3 b moderately to severely reduced, 30 to 44 milliliter per minute per 1.73 meter square, G 4 severely decreased, 15 to 29 milliliter per minute per 1.73 meter square, and G 5 kidney failure, less than 15 milliliter per minute per 1.73 meter square. The right section shows persistent albuminuria categories: A 1 normal to mildly increased, less than 30 milligram per gram or less than 3 milligram per millimole, A 2 moderately increased, 30 to 300 milligram per gram or 3 to 30 milligram per millimole, and A 3 severely increased, greater than 300 milligram per gram or greater than 30 milligram per millimole. — Fig. 54.1

Despite its global adoption, some commentators have questioned the utility of the CKD definition and classification, suggesting that the high prevalence of CKD reflects a normal aging process and pointing out that mildly reduced GFR (category G3a) in the absence of albuminuria is associated with minimal increase in risk, particularly in older persons. ^, Various solutions have been proposed to address this issue, including the introduction of an age-adjusted GFR threshold for defining CKD or a modification of the classification for different age groups, but to date, no consensus has been reached and the KDIGO classification is used worldwide.

Mechanisms of Disease Progression and The Rationale for Interventions to Achieve Kidney Protection

It has long been appreciated that regardless of the primary kidney disease, kidney damage tends to progress toward ESKF, especially if more than half of glomeruli have been lost. This suggests that a common pathway of mechanisms may promote kidney injury and establish a vicious cycle of nephron loss. In research efforts since the 1960s, investigators have identified glomerular hemodynamic factors (glomerular hypertension and hyperfiltration), multiple effects of angiotensin II, proteinuria, and proinflammatory and profibrotic molecules as key elements of this pathway (discussed in detail in Chapter 50). A common pathway underlies progressive kidney damage from kidney diseases of diverse causes, and recognition of this pathway has been vital in informing strategies to achieve kidney protection. Thus the interventions to slow CKD progression discussed in the following sections are each aimed at attenuating mechanisms of progression. In view of the redundancy that is characteristic of most biologic systems, it has become clear that to achieve optimal kidney protection, attempts should be made to inhibit the vicious cycle of common pathway mechanisms at multiple points ( Fig. 54.2 ).

A flowchart showing the relationship between primary renal disease, treatment strategies, and pathways leading to glomerular cell injury and inflammation. The flowchart outlines a treatment pathway for primary renal disease, illustrating how various factors and medications impact kidney function. The chart starts with the primary renal disease box, leading to an increase in nephron number, which subsequently increases blood pressure and increases protein concentration in the glomeruli. The flowchart indicates that controlling blood pressure with antihypertensives and sodium restriction is a key factor, as is managing glycemic control and promoting weight loss with G L P 1-R A and S G L T 2 inhibitors. These interventions also lead to a reduction in proteinuria, which can minimize glomerular cell injury. Another pathway shows that an increase in proteinuria can lead to further kidney damage. The chart also shows the use of A C E and A R B for managing blood pressure and decreasing proteinuria. Other factors, such as smoking cessation, statin use for dyslipidemia, and the control of aldosterone, inflammation, and fibrosis, contribute to managing kidney health. — Fig. 54.2

Interventions for Slowing Progression of Chronic Kidney Disease

Lifestyle Interventions

Exercise

All guidelines support healthy lifestyle advice and exercise for persons with CKD, citing the substantial literature that exists largely for the general population. A major issue for nephrologists and physicians managing CKD is that there has yet to be a dedicated randomized controlled trial (RCT) examining the effect of lifestyle interventions in persons with CKD. The most contemporary evidence comes from an ancillary analysis of the Lifestyle Interventions and Independence for Elders (LIFE) trial. The LIFE study randomized 1635 sedentary older adults aged 70 to 89 years to a moderate-intensity physical activity and exercise program versus a “successful aging” health education program and examined clinical outcomes at 2 years. The study included 1199 participants—of whom 796 (66%) had a cystatin C–based eGFR [eGFR _CysC] <60 mL/min/1.73 m ² and the outcomes of interest were the change in eGFR _CysC, as well as a rapid decline in kidney function, defined as the high tertile of change in eGFR _CysC of >6.7% per year. Compared with the education intervention, physical activity and exercise significantly slowed the rate of eGFR _CysC decline at 2 years (mean difference [MD], 0.96 mL/min/1.73 m ²; 95% confidence interval [CI], 0.02–1.91 mL/min/1.73 m ²) and lowered the odds of rapid kidney function decline by 20% (odds ratio: 0.79, 95% CI, 0.65–0.97). Subgroup analyses showed a consistent pattern of benefit in persons with and without CKD.

Beyond kidney function, evidence does exist for the value of lifestyle intervention and exercise regarding treating hypertension and preventing CVE. Therefore in the absence of dedicated clinical trials of lifestyle interventions in persons with CKD, it is reasonable to expect that a similar relative (and greater absolute) benefit might be gained in terms of CKD progression and CVE.

Smoking Cessation

Tobacco use is the most common cause of avoidable cardiovascular mortality worldwide; therefore not surprisingly, smoking cessation is one of the most promoted methods in management of cardiovascular risk in the general population and in persons with CKD. Evidence that smoking cessation helps prevent CKD progression is emerging. In the Multiple Risk Factor Intervention Trial (MRFIT), smoking was significantly associated with an increased risk for ESKF ¹⁵; in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, the rate of urine albumin excretion was correlated with the number of cigarettes smoked. Smoking has been identified as a risk factor for the development of microalbuminuria and overt proteinuria and for the progression of CKD in persons with type 1 and type 2 diabetes. In a large Swedish study, the risk for disease-specific types of CKD among smokers was compared with that among people who had never smoked. Overall, the association was modest, but an important finding was that the risk increased with high daily consumption (>20 cigarettes/day), long duration (>40 years), and a high cumulative “dose” (>30 pack-years) in comparison with participants who had never smoked. The increase in risk associated with smoking was highest for persons with CKD classified as nephrosclerosis and also glomerulonephritis. In the Jackson Heart Study, smoking was associated with a higher risk of rapid GFR decline (>30% decline from baseline) in a dose-dependent manner and in a combined analysis of five large U.S. cohort studies ( n = 954,029), smoking was associated with a doubling in the risk of death from ESKF. Finally, a meta-analysis of 15 community-based cohort studies observed an increase in the risk of developing CKD in former (hazard ratio [HR], 1.15; 95% CI, 1.08–1.23) and current smokers (HR, 1.34; 95% CI, 1.23–1.47), as well as an increased risk of ESKF in former (HR, 1.44; 95% CI, 1.00–2.09) and current smokers (HR, 1.91; 95% CI, 1.39–2.64), though smoking was not associated with the development of proteinuria.

Two large cohort studies have reported detailed data on the impact of smoking on CKD progression. In the CRIC study, smoking was associated with increased all-cause mortality and the combined endpoint of all-cause mortality and CKD progression, though not with CKD progression alone. In an analysis of data from the Study of Heart and Renal Protection (SHARP) trial, current and former smoking were associated with higher levels of proteinuria but not with CKD progression during a median follow-up of 4.9 years. Smoking was associated with significantly increased risks of CVE, cancer, and all-cause mortality. RCTs on the effect of smoking cessation on CKD progression have yet to be published, and few prospective data are available, but in one study of persons with diabetes, smoking cessation was associated with less progression to macroalbuminuria (proteinuria) and a slower rate of GFR decline in comparison to persons who continued smoking. In addition, the intermediate risk for adverse outcomes reported for ex-smokers versus current smokers in several of the aforementioned studies provides indirect evidence of benefit from smoking cessation. Further prospective studies are required, but published evidence strongly supports smoking cessation as an intervention to reduce the incidence and progression of CKD.

Pharmacotherapy to assist in smoking cessation is now well established. A meta-analysis of RCTs in the general population (69 trials involving a total of 32,908 persons) showed that varenicline, bupropion, and five nicotine replacement therapies were all more efficacious than placebo at promoting smoking abstinence at 6 and 12 months. In comparison with persons taking placebo, persons treated with these agents were 1.5 to 2.5 times more likely to quit smoking, depending on the specific agent. Indeed, combining varenicline and a nicotine replacement patch achieved an impressive higher continuous abstinence rate at 12 weeks (55.4% vs. 40.9%) and 6-month point prevalence abstinence rate of 65.1% versus 46.7% compared with varenicline treatment alone. An important finding is that people who smoke are more likely to stop smoking if offered a combination of interventions, such as behavioral support and pharmacotherapy. Multicomponent interventions are now part of many public health guidelines. We see no reason to exclude people with CKD from this advice.

Weight Loss

Obesity is the dominant risk factor for type 2 diabetes and is also a major risk factor for hypertension and progression of CKD. Evidence linking the metabolic syndrome and CKD has emerged; each element of the metabolic syndrome is associated with increased prevalence of CKD and microalbuminuria. In animal models (obese Zucker rats with type 2 diabetes), early progressive podocyte damage and macrophage infiltration are associated with hyperlipidemia and antedate both the development of glomerulosclerosis and tubulointerstitial damage. ^, In humans, there was a graded relationship between the number of components of the metabolic syndrome present and the corresponding prevalence of CKD or microalbuminuria.

Epidemiologic studies have identified obesity as a risk factor for CKD, ^, and in one study, obesity was an independent risk factor for progression of IgA nephropathy. Furthermore, the largest such study to assess risk of CKD in association with obesity demonstrated a strong biologic gradient: Increasing body mass index (BMI) was associated with increasing risk of ESKF. In comparison with persons with an “ideal” BMI (18.5–24.9 kg/m ²), the relative risk (RR) of ESKF was 3.6-fold for those with a BMI of 30 to 34.9 kg/m ², sixfold for those with BMI of 35 to 39.9 kg/m ², and sevenfold for those with BMI of 40 kg/m ² or higher. Controlling for baseline blood pressure and presence of diabetes attenuated the associations, but the gradient between increasing body size and ESKF risk remained strong.

Because these components are major factors in the initiation and progression of CKD, respectively, there has been significant focus on the potential for benefit from weight loss to reverse the features of the metabolic syndrome, as observed in the general population. Results of early studies support this assertion, inasmuch as weight loss in humans with obesity demonstrated reversal of glomerular hyperfiltration and albuminuria.

Moreover, there is evidence that weight loss of as little as 10 lb (4.5 kg) reduces blood pressure, prevents hypertension, or does both in a large proportion of overweight persons, although the ideal is to maintain normal body weight. In the Framingham Heart Study, weight loss of 5 lb (2.25 kg) or more was associated with reductions in cardiovascular risk of about 40% for both men and women and thus should be a clear goal for persons with CKD who are overweight. It also appears that the degree of weight loss, regardless of method (lifestyle changes or bariatric surgery), dictates the benefits of lowering blood pressure and reduction in glycemic markers. However, according to longer-term studies of lifestyle modification and of persons after bariatric surgery, blood pressure lowering benefits regress somewhat over time, although the vascular outcomes continue to be better than those in control groups. ^36,41,42

Kidney-protective effects associated with weight loss interventions (dietary caloric restriction, exercise, antiobesity medications, and bariatric surgery) were reported in a meta-analysis of data from 522 participants in five controlled and eight uncontrolled trials. In persons undergoing interventions to lose weight, those with proteinuria had a mean reduction of urine protein levels of 1.7 g/day; even among persons with microalbuminuria, mean reduction of urinary albumin excretion was 14 mg/day. Although these reductions were modest in comparison with those in persons with overt proteinuria, results of other studies of blood pressure and glycemic control interventions on microalbuminuria suggest that they will have long-term benefit in such persons. This was confirmed by a secondary analysis of the Look AHEAD trial in which 5145 overweight or obese persons with type 2 diabetes were randomly assigned to an intensive lifestyle intervention (ILI) or diabetes support and education (DSE). The trial was stopped early due to lack of any difference in the primary outcome, CVEs, but analysis of kidney outcomes showed a 31% reduction in the incidence of “high-risk CKD” as defined by the KDIGO classification system (HR, 0.69; 95% CI, 55–0.87) in the ILI versus DSE group, mediated in part by weight loss and improvements in hypertension and glycemic control. ⁴⁵

With respect to weight management in people with CKD, glucagon-like peptide 1 receptor agonists (GLP1RAs) have emerged as important pharmacotherapeutic options. GLP1RAs are long-acting analogs of the naturally occurring incretin hormone, glucagon-like peptide-1 (GLP1), which is responsible for glucose-dependent insulin secretion. Initially developed as glucose-lowering medications, GLP1RAs also has notable cardiometabolic benefits including weight loss. The effect of GLP1RAs on weight loss is mediated through its effect on GLP1 receptors in multiple brain regions ultimately reducing appetite and caloric intake and increasing satiety. Compared with lifestyle modification in people with type 2 diabetes, GLP1RAs reduce body weight by an average of 5.79 kg (MD–5.79, 95% CI:–6.3 kg to–5.3 kg), with particularly sizable weight loss with semaglutide (MD–11.40 kg, 95% CI:–12.5 kg to–10.3 kg). These benefits also extend to people with moderate kidney impairment, ^, without any evidence of a disproportionate increase in adverse events. Indeed, currently available GLP1RA formulations such as semaglutide, liraglutide, and dulaglutide have minimal renal excretion and do not require dose adjustment. These formulations have also been used off-label in people with ESKF, although dedicated studies on their safety and efficacy have yet to be conducted.

In addition to GLP-1, glucose-dependent insulinotropic polypeptide (GIP) is the only other known incretin hormone. In dedicated RCTs focused on weight management, tirzepatide, a coagonist of the GLP1 and GIP receptor, resulted in greater weight loss than the selective GLP1RA, semaglutide. A more detailed discussion of the kidney-specific effects of GLP1RAs and GIP receptor agonists is provided later in “Glucagon-Like Peptide-1 Receptor Agonists and Glucose-Dependent Insulinotropic Polypeptide Receptor Agonists.”

Bariatric surgery is an important adjunctive strategy for weight management, and its increased use in people with CKD has provided an opportunity to study its effect on kidney function. In one long-term study of 2144 persons who underwent bariatric surgery, kidney outcomes were assessed after 7 years on the basis of the change in CKD risk category as defined by the KDIGO classification. Among those with moderate risk at baseline, the risk category improved in 53% and deteriorated in 5% to 8%; in the high-risk group, improvement was observed in 56% and deterioration in 3% to 10%; in the very-high-risk group, 23% improved. eGFR initially improved with a peak at 2 years and then gradually declined. Albuminuria showed large and sustained decreases in moderate (median UACR 48–14 mg/g) and high-risk groups (median UACR 326–26 mg/g). In another study that included only persons with CKD stages 3 and 4 and propensity score matching with similarly obese persons who did not undergo bariatric surgery, eGFR was significantly higher by a mean of 9.84 mL/min/1.73 m ² in the surgery group after 3 years. These studies are limited by relying on eGFR to assess kidney function, but the finding that benefit was sustained over several years provides reassurance that the improvement was not simply an artifact due to early decrease in serum creatinine secondary to weight loss after surgery. In a meta-analysis that included 23 cohort studies and 3015 persons who underwent all forms of bariatric surgery, small but statistically significant improvements were observed in serum creatinine (mean decrease 0.08 mg/dL) and proteinuria (mean decrease 0.04 g/day). Finally, the Microvascular Outcomes after Metabolic Surgery (MOMS) RCT compared the effect of Roux-en-Y gastric bypass (RYGB) surgery versus best medical treatment in 100 participants with early stage CKD (eGFR ≥30 mL/min/1.73 m ² and UACR ≥30 mg/g), type 2 diabetes, and a BMI of 30 to 35 kg/m ². RYGB surgery resulted in a 28% increase in the percentage of participants with albuminuria remission at 2 years compared with medical treatment.

On the basis of available data, we recommend weight loss in obese persons with CKD through a combination of increased exercise, reduced caloric intake, pharmacologic therapies, and consideration of bariatric surgery if these are not successful.

Dietary Interventions

Dietary Sodium Restriction

Salt (sodium chloride) intake in many countries is 9 to 12 g/day. However, the World Health Organization and KDIGO recommendation for adults is to reduce salt intake to 5 g/day or less on the basis of substantial evidence from epidemiologic, migration, intervention, genetic, and animal studies that salt intake plays an important role in regulating blood pressure.

Essential hypertension is observed primarily in societies in which the average sodium intake exceeds 100 mEq/day (2.3 g sodium or ≈6 g sodium chloride) and is rare in societies in which the average sodium intake is less than 50 mEq/day (1.2 g sodium or 3 g sodium chloride). Furthermore, in a subanalysis of the Prospective Urban Rural Epidemiology (PURE) study—a prospective cohort study of 157,543 adults 35 to 70 years of age from 18 low-, middle-, and high-income countries—the association between sodium excretion and blood pressure was also nonlinear. Among all participants included in the PURE, each 1 g increase in estimated 24-hour sodium excretion was associated with a 2.11 mm Hg increase in systolic blood pressure and 0.78 mm Hg increase in diastolic blood pressure. The magnitude of this association was larger with higher sodium intake. Among persons with an estimated 24-hour sodium excretion >5 g per day, the increment in systolic blood pressure per 1 g change in sodium excretion was 2.58 mm Hg, compared with 1.74 mm Hg per gram of sodium excretion for 3 to 5 g per day, and 0.74 mm Hg per g of sodium excretion for <3 g per day ( P < 0.001 for interaction). The magnitude of the association between each gram of estimated 24-hour sodium excretion and systolic blood pressure was also larger for persons with hypertension than for those without hypertension and with increased age.

Accordingly, sodium restriction produces a significant reduction in blood pressure. ^, A meta-analysis of RCTs with a duration of at least 4 weeks concluded that reducing salt intake by 3 g/day is predictive of a linear fall in blood pressure of, on average, 3.6 to 5.6 mm Hg (systolic blood pressure [SBP]) and 1.9 to 3.2 mm Hg (diastolic blood pressure [DBP]) in hypertensive persons and of 1.8 to 3.5 mm Hg (SBP) and 0.8 to 1.8 mm Hg (DBP) in normotensive persons. Weight loss and reduced sodium intake are particularly beneficial in older people. In the Trial of Nonpharmacologic Interventions in the Elderly (TONE), reducing sodium intake to 80 mEq (2 g) per day reduced blood pressure over 30 months, and about 40% of participants on the low-salt diet were able to discontinue their antihypertensive medications.

In many persons with CKD, especially those with glomerular disease and severe proteinuria, hypertension behaves in a salt-sensitive manner. In one large observational study of persons without CKD at baseline, both high (>4.03 g/day of sodium) and low (<2.08 g/day of sodium) dietary sodium intake was associated with an increased incidence of CKD during follow-up of more than 10 years in 3106 hypertensive participants, but no association with sodium intake was observed in those without hypertension ( n = 4871). This supports that salt sensitivity is important in the association between sodium intake and CKD. The reason for the association with low sodium intake is unknown but may be confounded by associations between sodium intake and several other nutritional factors including potassium, total calorie, fat, protein, and carbohydrate intake, though the analysis was adjusted for these factors. A systematic review of 16 small studies that investigated the association of dietary sodium intake and CKD progression concluded that marked heterogeneity between the studies precluded meta-analysis. Nevertheless, the general trend observed was that increasing sodium intake is associated with worsening albuminuria. An analysis of 3757 participants with CKD from the CRIC study found that after 15,807 person-years of follow-up, the highest quartile of urinary sodium excretion (≥195 mmol/day) was associated with a significantly increased risk of CKD progression (HR, 1.54; 95% CI, 1.23–1.92) and all-cause mortality (HR, 1.45; 95% CI, 1.08–1.95) compared with the lowest quartile (<117 mmol/day).

High dietary sodium intake has also been shown to negate the antiproteinuric effects of treatment with angiotensin-converting enzyme (ACE) inhibitors. In a prospective, randomized, placebo-controlled crossover study, dietary sodium restriction increased the antihypertensive and antiproteinuric effects of therapy with angiotensin receptor blockers (ARBs), as monotherapy or in combination with a thiazide diuretic, in persons with nondiabetic CKD ( Fig. 54.3 ). Whereas the protocol aimed to restrict dietary salt intake to less than 50 mEq/day (1.2 g of sodium or 3 g of sodium chloride), these impressive results were observed with achieved sodium restriction of only 92 mEq/day. Furthermore, a post hoc analysis of data from the first and second Ramipril Efficacy in Nephropathy (REIN) trials found that medium and high sodium intake were associated with significant increases in the incidence of ESKF versus low sodium intake. Each 100-mEq/g increase in 24-hour urinary sodium/creatinine excretion was associated with a 1.61-fold (95% CI, 1.15–2.24) higher risk of ESKF, independent of blood pressure.

A two-part graph, labeled A and B, shows the effect of high and low sodium on mean arterial pressure and proteinuria after treatment with placebo, losartan, and losartan or H C T. The first graph, labeled A, the vertical axis represents mean arterial pressure in millimeters of mercury, ranging from 85 to 110, while the horizontal axis shows different treatment groups: placebo, losartan, and losartan by H C T. The bars show the results of high and low sodium conditions, with placebo having the highest mean arterial pressure, while losartan and losartan by H C T both lower the pressure under both sodium conditions. Asterisks indicate significant differences. In the second graph, labeled B, the vertical axis represents proteinuria in grams, ranging from 0 to 4, and the horizontal axis shows placebo, losartan, and losartan by H C T groups. Proteinuria levels are higher for placebo, with losartan and losartan by H C T showing reduced proteinuria, especially under low sodium conditions. — Fig. 54.3

Several small prospective studies have investigated the impact of dietary sodium restriction on blood pressure and proteinuria in persons with CKD. In a randomized placebo-controlled crossover study (achieved using low sodium diet of 60 to 80 mmol/day plus sodium chloride tablets [120 mmol/day] or placebo) in 20 people with stage 3 or stage 4 CKD, low sodium intake was associated with an average 10/4 mm Hg reduction in blood pressure, as well as reductions in albuminuria and proteinuria. In a similar randomized crossover study, dietary sodium restriction to less than 2 g/day for 4 weeks in persons with CKD stage 3 and 4 was associated with an average reduction in extracellular volume of 1.02 L, weight loss of 2.3 kg, and mean reduction in ambulatory SBP of 10.8 mm Hg but no improvement in albuminuria. By contrast, another study in persons with CKD stage 1–3 and persistent albuminuria greater than 300 mg/day despite treatment with ramipril 10 mg/day reported that dietary sodium restriction for 8 weeks was associated with a reduction in arterial pressure from a mean of 95 to 90 mm Hg and a significant decrease in albuminuria from a mean of 1060 to 717 mg/day. Creatinine clearance also decreased from a mean of 101 to 91 mL/min. Another study illustrated the challenges associated with achieving sustained reduction in sodium intake. In an RCT, persons with CKD assigned to a 3-month intervention of education and coaching, as well as self-monitoring, achieved a modest mean reduction in urinary sodium excretion of 30 mmol/day associated with a mean reduction in ambulatory DBP of 3.4 mm Hg and mean reduction in proteinuria of 0.4 g/day, but at 3 months after completion of the intervention there was no difference in urinary sodium excretion or ambulatory BP compared with controls, although proteinuria remained 0.3 g/day lower. Further long-term randomized trials are needed to define the role of sodium restriction in kidney-protective strategies, but even the incomplete evidence available supports a recommendation for moderate dietary sodium restriction to less than 5 g/day of salt in persons with CKD.

Food processing drastically changes the cationic content of natural foods, increasing sodium content and decreasing potassium content. On average, approximately 10% of dietary sodium chloride originates naturally in foods, whereas approximately 80% is the result of food processing, the remainder being discretionary (added during cooking or at the table). We advocate assessment of salt intake in individuals with CKD and advise reducing salt intake with the assistance of a dietitian to less than 5 g/day (<90 mmol/day of sodium) as recommended by KDIGO.

Dietary Protein Restriction

Dietary protein restriction as a kidney-protective strategy is based on the notion that reducing the excretory burden on the kidneys would slow the rate of progressive injury. Unfortunately, clinical studies have failed to provide clear evidence to support the use of protein restriction in human CKD.

The Modification of Diet in Renal Disease (MDRD) study was designed to provide a definite answer to the question of whether dietary protein restriction slows the progression of CKD. The study had two components: In study A, 585 persons with mostly nondiabetic CKD (GFR, 25–55 mL/min/1.73 m ²) were randomly assigned to follow either a diet with “usual” protein levels (1.3 g/kg/day) or a low-protein diet (LPD) (0.58 g/kg/day); in study B, 255 persons with GFRs of 13 to 24 mL/min/1.73 m ² were randomly assigned to follow either LPD (0.58 g/kg/day) or “very low” protein diet (VLPD; 0.28 g/kg/day) with keto-amino acid supplementation to prevent malnutrition. After a mean follow-up period of 2.2 years, there was no difference in the rate of GFR decline in study A and only a trend toward slower decline in the VLPD group in study B. Further analysis indicated, however, that the desired protein intake was not achieved in the randomized groups, and secondary analysis based on achieved dietary protein intake demonstrated that a reduction in protein intake of 0.2 g/kg/day was correlated with a 1.15-mL/min/year reduction in the rate of GFR decline, equivalent to a 29% reduction in mean rate of GFR decline. In addition, a post hoc two-slope analysis, in which presumptive acute effects of dietary protein restriction were taken into account, suggested a modest long-term benefit. However, long-term follow-up of the cohort in MDRD study A yielded disappointingly inconclusive results. In a more recent trial, 207 well-nourished persons without diabetes and with eGFR less than 30 mL/min/1.73 m ² and urine protein-to-creatinine ratio (PCR) less than 1 g/g were randomized to a vegetarian VLPD (<0.3 g/kg/day) with ketoanalog supplementation (ketoanalog diet [KD]) or standard (nonvegetarian) LPD (<0.6 g/kg/day). After 15 months the primary outcome of RRT or 50% reduction in eGFR was reached in 13% of those on KD versus 42% on LPD (adjusted HR, 0.1; 95% CI, 0.05–0.2). Those on the KD also evidenced a 3.2 mL/min/year slower rate of eGFR decline. Metabolic factors were also improved by the KD; serum bicarbonate and calcium were higher and phosphate was lower. There was no change in nutritional status in either group and no adverse reactions were reported. However, it is unclear what proportion of the benefit was attributable to the vegetarian VLPD versus the ketoanalog supplementation.

Fouque and Laville performed a Cochrane Database systematic review of all randomized studies, comparing two different levels of protein intake in adult persons suffering from moderate to severe CKD. A total of 2000 nondiabetic persons were identified in 10 studies (of a total of 40 studies) in which follow-up lasted at least 1 year. There were 281 renal deaths (progression to ESKF) recorded, 113 among participants following the LPD and 168 among those following the higher-protein diet (RR, 0.68; 95% CI, 0.55–0.84; P =.0002). The authors concluded that reducing protein intake in persons with CKD reduces the occurrence of renal death by 32% in comparison with higher or unrestricted protein intake. The most recent meta-analysis included 16 RCTs of persons with relatively advanced CKD (stage 4 and 5 in most cases) not receiving RRT. Inclusion required at least 30 participants per study. In studies comparing LPD (<0.8 g/day) with higher-protein intake, LPD was associated with a small but significant absolute risk reduction for ESKF (4%) and higher serum bicarbonate at 1 year (weighted mean difference [MD], 1.46 mEq/L) versus higher-protein diets. Similarly, in studies comparing VLPD with LPD, VLPD was associated with an absolute risk reduction for ESKF (13%) and higher GFR at 1 year (weighted MD, 3.95 mL/min/1.73 m ²) versus LPD. No studies reported increased risk of protein-energy wasting or other safety concerns associated with dietary protein restriction.

The caveats for these trials are that most were of short duration, the largest trial (MDRD) mostly excluded persons with diabetes, and compliance with LPDs was a factor in interpretation of some of the results. Furthermore, the proportion of participants treated with renin–angiotensin–aldosterone system inhibitors (RAASi) was variable and the trials were conducted before the availability of SGLT2 inhibitors. Available evidence suggests that LPD and RAASi may have synergistic kidney-protective effects, but this has not yet been adequately evaluated in an RCT. In addition to possible kidney-protective effects, dietary protein restriction results in reduced intake of sodium, phosphate, and acid, all of which may be beneficial in CKD.

In summary, published data indicate that there is likely some kidney-protective benefit from dietary protein restriction but conclusive evidence is lacking, in particular for additional benefit in persons already treated with RAASi and or SGLT2 inhibitors. The benefits are more apparent in persons with proteinuria and lower GFR, and the risks are greater in those at risk of malnutrition, such as elderly persons (age >75 years); those with below-average BMI (<20 kg/m ²), muscle wasting, or myopathic symptoms; and those with evidence of protein-energy wasting. We therefore recommend that the potential benefits and risks should be considered carefully on an individual basis and with the assistance of a trained kidney dietitian. The 2024 KDIGO guideline for the management of CKD recommends avoidance of a high-protein diet and maintaining dietary protein intake at 0.8 g/kg/day in adults with CKD. For further discussion of dietary aspects in kidney disease, see Chapter 55 .

Glycemic Control in Persons With Diabetes

The role of glycemic control in protecting the kidneys in persons with diabetes is discussed fully in Chapter 41 . In summary, the benefit of tight glycemic control in ameliorating diabetic nephropathy seems to decrease as CKD progresses; the greatest benefits are observed in stages 1 and 2. In addition to the kidney-protective effects, however, there is clear evidence that improving glycemic control can reduce the risk of developing other microvascular and macrovascular complications such as blindness and cardiovascular disease. Of importance is that these benefits were maintained for up to 30 years after the trial, even though intensive control regressed to standard control levels. ^, Achieving optimal glycemic control should therefore be an important goal for all persons with diabetes and CKD but should be balanced against the risk of developing hypoglycemia, which may be increased in the elderly and those with more advanced CKD. The KDIGO guidelines recommend a target hemoglobin A _1c of 7.0% (53 mmol/mol) to prevent or delay progression of microvascular complications, including diabetic kidney disease, unless persons have multiple comorbidities, have reduced life expectancy, or are at risk of hypoglycemia.

Despite the importance of glycemic control, new classes of glucose-lowering medications such as SGLT2 inhibitors and GLP1RAs have important beneficial effects on albuminuria, CKD progression, and CV events that are independent of glycemic control and HbA1c. The mechanism of action and the use of these medications for kidney protection are discussed more fully in subsequent sections (see “ Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors ” and “ Glucagon-Like Peptide-1 Receptor Agonists and Glucose-Dependent Insulinotropic Polypeptide Receptor Agonists ”).

Treatment of Hypertension

The treatment of systemic hypertension was the first intervention shown to significantly slow the rate of CKD progression, and it remains a fundamental kidney-protective strategy. Mogensen and Parving and colleagues pioneered the role of blood pressure control in studies of persons with type 1 diabetes, in whom the initiation of antihypertensive therapy significantly slowed the rate of GFR decline.

Similar observations were subsequently reported among persons with nondiabetic forms of CKD. In one of the earliest meta-analyses in nephrology, Kasiske and colleagues studied 100 controlled and uncontrolled studies that provided data on kidney function, proteinuria, or both before and after treatment with antihypertensive agents in people with diabetes. Reductions in proteinuria from antihypertensive agents that do not inhibit the renin–angiotensin–aldosterone system (RAAS) could be attributed entirely to changes in blood pressure. Furthermore, blood pressure reduction was associated with a relative increase in GFR (3.70 ± 0.92 mL/min for each 10-mm Hg reduction in mean arterial pressure [MAP]; P =.0002).

A large body of evidence supports the use of ACE inhibitors or ARB agents (RAAS inhibitors) as first-line antihypertensive therapy in persons with CKD (see the “ Pharmacologic Inhibition of the Renin–Angiotensin–Aldosterone System ” section under “ Interventions for Slowing Progression of Chronic Kidney Disease ”). In the meta-analysis by Kasiske and colleagues, multiple linear regression analysis indicated that ACE inhibitors decreased proteinuria independently of changes in blood pressure, treatment duration, type of diabetes or stage of nephropathy, and study design. In comparison with other agents, ACE inhibitors had an additional favorable effect on GFR that was independent of blood pressure changes (3.41 ± 1.71 mL/min; P = 0.05).

Despite the evidence supporting the use of RAAS inhibitors, data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) have been misinterpreted by some as implying that the choice of antihypertensive drug does not affect kidney outcomes in persons with CKD. Note that ALLHAT was designed to investigate the effect of antihypertensive drugs on cardiovascular rather than kidney outcomes in persons who had hypertension and at least one cardiovascular risk factor. There was no significant difference in the incidence of the primary outcome of fatal or nonfatal myocardial infarction among persons randomly assigned to receive treatment with a thiazide diuretic, a calcium channel blocker, or an ACE inhibitor. Whereas a post hoc analysis also showed no difference in the secondary outcome of ESKF or more than a 50% decrease in GFR, persons with serum creatinine levels exceeding 2 mg/dL (>170 μmol/L) were specifically excluded from the study, and therefore only a minority (5662 of 33,357) had CKD, mostly in stages 1 to 3. Furthermore, the presence of proteinuria was not assessed.

In addition to RAAS inhibitor therapy, thiazide and other diuretics are valuable and sometimes essential as additional antihypertensive agents to achieve optimal blood pressure control. Studies have shown that high dietary sodium intake may abrogate the antiproteinuric effect of ACE inhibitor treatment, but addition of a thiazide diuretic restores the antiproteinuric effect despite ongoing high sodium intake. Similarly, addition of a thiazide diuretic to ARB treatment reduced blood pressure and proteinuria in persons with IgA nephropathy. We therefore recommend a thiazide diuretic as second-line antihypertensive therapy in persons who have not achieved adequate blood pressure control with an ACE inhibitor or an ARB alone, and thiazides retain their efficacy even in people with stage 4 kidney disease.

Trials of Low Versus Usual Targets for Lowering Blood Pressure

Despite the importance of blood pressure control in achieving kidney protection, the optimal blood pressure target remains uncertain, particularly in elderly persons and those with mild proteinuria. In several RCTs, researchers have investigated whether blood pressure targets lower than previously recommended levels afford greater kidney protection than “usual” blood pressure control, but these studies have not provided a conclusive answer. In the MDRD study, the primary analysis showed no significant difference in the rate of GFR decline between persons randomly assigned to a low blood pressure target (MAP of <92 mm Hg [equivalent to <125/75 mm Hg] if 18 to 60 years or MAP <98 mm Hg or persons aged 61 years or older) versus a lower blood pressure target (MAP <107 mm Hg [equivalent to 140/90 mm Hg] or MAP <13 mm Hg, respectively). Persons assigned to achieve lower blood pressure, however, evidenced an early rapid decrease in GFR, probably related to kidney hemodynamic effects, that obscured a later slower rate of GFR decline. Furthermore, a secondary analysis did show benefits associated with the lower blood pressure target among persons with more severe baseline proteinuria (urine protein level >1 g/day). Further secondary analysis revealed that lower achieved blood pressure was also associated with a slower GFR decline, an effect that was more marked among persons with more severe baseline proteinuria. The authors concluded by recommending a blood pressure goal of <125/75 mm Hg (MAP, 92 mm Hg) for persons with CKD whose urine protein levels exceed 1 g/day and a goal of <130/80 mm Hg (MAP, 98 mm Hg) for those with urine protein levels of 0.25 to 1.0 g/day.

Findings of prolonged follow-up of the participants in the MDRD study suggest that the benefits of lower blood pressure may become evident only over a longer period. Analysis after almost 10 years revealed a significant reduction in the risk of ESKF (adjusted HR, 0.68) and a combined endpoint of ESKF or death (adjusted HR, 0.77) among persons randomly assigned to achieve the lower blood pressure targets. An important caveat is that treatment and blood pressure data were not available beyond the 2.2 years of the original trial. In the African American Study of Kidney Disease (AASK), no significant difference in the rate of GFR decline was observed among participants randomly assigned to achieve a MAP goal of 92 mm Hg or lower versus a goal of 102 to 107 mm Hg. One possible explanation for this outcome is that participants in the AASK generally had lower baseline proteinuria (mean urine protein excretion, 0.38–0.63 g/day). The results are therefore consistent with those of the MDRD study, which showed benefit only in persons with significant proteinuria. Likewise, in the REIN-2 trial, additional blood pressure reduction (blood pressure of <130/80 mm Hg vs. DBP of <90 mm Hg, regardless of SBP) failed to provide additional kidney protection in persons with nondiabetic CKD who were already receiving ACE inhibitor treatment. Possible explanations are that the degree of additional blood pressure reduction was modest (4.1/2.8 mm Hg) and that in the group undergoing intensive blood pressure reduction, the number of participants with moderate to heavy proteinuria was small.

The Systolic Blood Pressure Intervention Trial (SPRINT) is the largest randomized trial to date to compare the effect of different BP targets on cardiovascular and kidney outcomes in persons with CKD. The study included 9361 participants aged 50 years and over with BP 130 to 180 mm Hg and increased cardiovascular risk (including all with CKD) who were randomly allocated to a systolic BP target of <120 mm Hg or <140 mm Hg. Persons with diabetes, proteinuria of >1 g/day, adult polycystic kidney disease, previous stroke, and cardiac failure were excluded. The main trial was stopped early due to evidence of significant benefit in the primary outcome of CVE and all-cause mortality in the lower BP group. A prespecified subgroup analysis showed no evidence of effect modification by CKD status on the primary outcome of CVE or all-cause mortality. In the CKD subgroup, participants in the lower BP group evidenced a lower incidence of CVE (HR, 0.81; 95% CI, 0.63–1.05) and all-cause mortality (HR, 0.72; 95% CI, 0.53–0.99; Fig. 54.4 ). Importantly, these benefits were also observed in participants aged 75 years and older. There was no difference between treatment groups in the kidney outcome of 50% decline in GFR or ESKF after a median of 3.3 years. The lower BP target was associated with some initial decline in eGFR, likely due to increased use of RAASi, whereas a small initial increase in GFR was observed with the higher BP. Nevertheless, after excluding the first 6 months of observation, the low BP target was associated with a slightly higher rate of GFR decline (0.47 mL/min/year vs. 0.32 mL/min/year; P < 0.03). The lower BP target was associated with lower UACR at all time points to 48 months. There was no difference in all serious adverse events between the groups. However, the low BP target was associated with a higher incidence of hyperkalemia, hypokalemia, and AKI (predominantly stage 1 and 2 and most had recovery of kidney function). In summary, SPRINT found that a lower BP target than previously recommended was associated with a significant reduction in CVE and all-cause mortality. There was no benefit in kidney outcomes but also no evidence of harm (apart from a small increase in incidence of AKI). It should be remembered that persons with advanced or severe CKD (evidenced by proteinuria >1 g/day) and those with diabetes were excluded. The findings are therefore consistent with those of the MDRD and AASK studies, confirming that there is little medium-term kidney-protective benefit associated with low BP targets in mild and nonproteinuric CKD. However, the results do indicate significant survival and cardiovascular benefits with lower BP targets and suggest that the benefit of lower BP targets outweighs the risks in older people.

A three-part graph, labeled A, B, and C, shows cumulative hazard for different interventions with standard and intensive treatment groups over a 4.5-year follow-up period. The three-part graph shows cumulative hazard over time for standard and intensive treatments. In the first graph, labeled A, the cumulative hazard is plotted against years of follow-up on the horizontal axis, with cumulative hazard on the vertical axis. The lines represent the standard and intensive treatments. The number at risk decreases over time, as indicated at the bottom of the graph. The hazard ratio with its 95 percent confidence interval C I is given as 0.81, 0.63-1.05. In the second graph, labeled B, similar data is shown with a hazard ratio of 0.72, 0.53-0.99, again comparing standard and intensive treatments. In the third graph, labeled C, the cumulative hazard continues over time, with the standard treatment line and intensive treatment line, showing a hazard ratio of 0.90, 0.64-1.23 for this final comparison. — Fig. 54.4

Because not all the persons in the aforementioned trials received ACE inhibitor treatment, it remained unclear how important the level of blood pressure attained was in persons with CKD who were receiving a RAAS inhibitor. Several studies have sought to address this issue. Among persons with type 1 diabetes and established nephropathy who were receiving ACE inhibitor treatment, attainment of a “low” (MAP, 92 mm Hg) versus “usual” (MAP, 100–107 mm Hg) target blood pressure was associated with significantly milder degrees of proteinuria after 2 years, but there was no significant difference in GFR. The Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) trial was conducted to investigate the role of blood pressure control in children with CKD who were receiving treatment with an ACE inhibitor. This is an important trial inasmuch as the primary endpoint (time to 50% decline in GFR or progression to ESKF) was not as affected by the competing mortality effects that complicate studies in older persons. A total of 30% of the participants who received intensified treatment for blood pressure control reached the primary endpoint, in comparison with 42% of those who received conventional treatment for blood pressure control (HR, 0.65; 95% CI, 0.44–0.94; P = 0.02). Urine protein excretion gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood pressure control. Achievement of blood pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of CKD.

Results of secondary analyses of other studies also indicate that lower blood pressure is associated with more effective kidney protection in persons receiving RAAS inhibitor treatment. In the Irbesartan in Diabetic Nephropathy Trial (IDNT), greater kidney protection was observed in persons who achieved lower blood pressure: Achieved SBP >149 mm Hg was associated with a 2.2-fold increased risk of developing ESKF or of serum creatinine doubling, in comparison with an achieved SBP <134 mm Hg, independent of ARB treatment. Progressive lowering of SBP to 120 mm Hg was associated with improved kidney outcomes and improved rates of patient survival, an effect independent of baseline GFR. However, the lower blood pressure observed was not a primary aim of these studies, and it cannot be assumed that this observed association (between lower blood pressure and improved kidney and patient outcomes) is causative.

Several meta-analyses have combined data from multiple trials to examine the potential benefit of lower BP targets in persons with CKD. In one study that included 11 randomized trials with 1860 participants who had nondiabetic CKD and proteinuria >1 g/day, the lowest risk of progression was associated with an achieved SBP of 110 to 129 mm Hg, independent of ACE inhibitor treatment. A more recent analysis that included 8127 participants from nine trials (including SPRINT) did not show a significant difference between intensive and usual BP control on the annual rate of change in GFR (MD, 0.07; 95% CI, −0.16 to 0.29 mL/min/year), doubling of serum creatinine concentration or 50% reduction in GFR (RR, 0.99; 95% CI, 0.76–1.29), ESKF (RR, 0.96; 95% CI, 0.78–1.18), composite kidney outcome (RR, 0.99; 95% CI, 0.81–1.21), or all-cause mortality (RR, 0.81; 95% CI, 0.64–1.02). Intensive BP control did reduce mortality (RR, 0.78; 95% CI, 0.61–0.99) in a sensitivity analysis that excluded participants with diabetes. In addition, a trend toward a slower rate of GFR decline was observed in those with proteinuria >1 g/day. By contrast, another recent meta-analysis of 18 randomized trials involving 15,924 participants with and without diabetes reported a 14.0% lower risk of all-cause mortality associated with intensive BP lowering (odds ratio [OR], 0.86; 95% CI, 0.76–0.97; P =.01). These findings remained similar when data were reanalyzed without the data from SPRINT. The difference in results between meta-analyses is likely attributable to the inclusion of different trials in each, but they are broadly in keeping with the findings of the individual trials discussed earlier.

By contrast, several sources indicate that excessive lowering of blood pressure may be associated with adverse effects in some persons with CKD. In one meta-analysis, an achieved SBP lower than 110 mm Hg was associated with an increased risk of CKD progression (RR, 2.48; 95% CI, 1.07–5.77), and in IDNT, an achieved SBP lower than 120 mm Hg was associated with increased rates of all-cause mortality and no further improvement in kidney outcomes. In addition, secondary analysis of data from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) revealed that hypertensive persons with risk factors for cardiovascular disease who achieved an SBP of <120 mm Hg had a significantly higher rate of cardiovascular mortality than did those who achieved an SBP of 120 to 129 mm Hg. Similarly, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure study reported no difference in primary cardiovascular outcomes (nonfatal myocardial infarction, nonfatal cerebrovascular accident, or cardiovascular death) among persons with diabetes randomly assigned to achieve an SBP target of <120 mm Hg, in comparison with a conventional control target of <140/80 mm Hg. During follow-up, the mean SBP was 119.3 mm Hg in persons undergoing intensive therapy and 133.5 mm Hg in those undergoing standard therapy. Persons undergoing intensive therapy demonstrated a slightly lower stroke rate (annual rates of 0.32% vs. 0.53%) but a higher rate of treatment-related adverse events (3.3% vs. 1.3%). Specifically, there were significantly more instances of an eGFR of <30 mL/min/1.73 m ² among persons receiving intensive therapy than among those receiving standard therapy (99 vs. 52 events; P <.001), and no difference in the primary cardiovascular composite outcome.

Current guidelines differ somewhat in their recommendations for blood pressure targets. The KDIGO guidelines recommend a SBP of 120 mm Hg or less for diabetic and nondiabetic adults with stage G1-G4 or A2-A3 CKD who are not on dialysis. The 2017 American College of Cardiology/American Heart Association guidelines did not adopt the low systolic BP target of <120 mm Hg supported by SPRINT but did recommend a target of <130/80 mm Hg for persons with increased cardiovascular risk, including those with diabetes and/or CKD. We support the KDIGO recommendations with a caveat that treatment should be individualized and that low BP targets should be avoided in those at increased risk of adverse effects.

Clinical Relevance

Evidence from the Systolic Blood Pressure Intervention Trial (SPRINT) indicates that a lower target for the treatment of systolic blood pressure may reduce all-cause mortality and reduce cardiovascular risk but may also be associated with some increase in risk of acute kidney injury and hyperkalemia. The risks versus benefits of a lower blood pressure target should be evaluated in each individual and blood pressure targets should be discussed with patients as part of shared decision making.

Pharmacologic Inhibition of the Renin–Angiotensin–Aldosterone System

Numerous published clinical trials and meta-analyses provide clear evidence to support the use of pharmacologic inhibition of the RAAS with either ACE inhibitors or ARBs as an essential component of any strategy aiming to achieve maximal kidney protection in persons with CKD ( Table 54.1 ). Although ACE inhibitors and ARBs differ significantly in their effects on the RAAS, experimental studies indicate that both treatments produce similar changes in glomerular hemodynamics (for a given blood pressure change) and afford equivalent kidney protection in a variety of CKD models.

Table 54.1

Summary of Studies Showing the Kidney-Protective Effects of RAAS Inhibitors, SGLT2 Inhibitors, nsMRAs, and GLP1RAs in Diabetic and Nondiabetic Persons With Chronic Kidney Disease

CKD Type	Trial Outcome	Reference
Angiotensin-Converting Enzyme Inhibitors
Type 1 DM + CKD	↓︎ Risk of dialysis or death	Lewis et al.
Type 1 DM + microalbuminuria	↓︎ Risk of overt nephropathy	Mathiesen et al.
		Laffel et al.
		Viberti et al.
Type 1 DM + normoalbuminuria	No significant benefit	Mauer et al.
Type 1 DM + normoalbuminuria	No significant benefit	EUCLID Study Group
Type 2 DM + CKD	Benefit in 1 study only	Bakris et al.
Type 2 DM + microalbuminuria	↓︎ Risk of overt nephropathy	Ravid et al. ^,
		Sano et al.
		Trevisan and Tiengo
		Agardh et al.
		Ahmad et al.
		Ruggenenti
Type 2 DM + normoalbuminuria	↓︎ Risk of developing microalbuminuria	Ravid et al.
Nondiabetic CKD	↓︎ Doubling of creatinine level/ESKF	Ruggenenti et al. ^,
Angiotensin Receptor Blockers
Type 1 DM + normoalbuminuria	Small ↑︎ in albuminuria or no benefit	Mauer et al.
Type 1 DM + normoalbuminuria	Small ↑︎ in albuminuria or no benefit	Bilous et al.
Type 2 DM + normoalbuminuria	↓︎ Risk of developing microalbuminuria (small ↑︎ in rate of cardiovascular mortality)	Bilous et al.
Type 2 DM + normoalbuminuria		Haller et al.
Type 2 DM + microalbuminuria	↓︎ Risk of overt nephropathy	Parving et al.
Type 2 DM + CKD	↓︎ Risk of doubling of creatinine level	Lewis et al.
Type 2 DM + CKD	↓︎ Risk of ESKF	Brenner et al.
Sodium-Glucose Cotransporter 2 Inhibitors
Type 2 DM and nondiabetic CKD	↓︎ Risk of CKD progression, ESKF, or death from kidney failure	Perkovic et al. Heerspink et al. EMPA-KIDNEY
Nonsteroidal Mineralocorticoid Receptor Antagonist
Type 2 DM + albuminuria	↓︎ Risk of CKD progression, death from kidney failure, ESKF or transplantation	Bakris et al.
Glucagon-Like Peptide-1 Receptor Agonist
Type 2 DM + albuminuria	↓︎ Risk of CKD progression, death from kidney failure, ESKF or transplantation	Perkovic et al.

CKD, Chronic kidney disease; DM, diabetes mellitus; ESKF, end-stage kidney disease; GLP1RA , glucagon-like peptide-1 receptor agonist; nsMRA , steroidal mineralocorticoid receptor antagonist; RAAS , renin–angiotensin–aldosterone system; SGLT2 , sodium glucose cotransporter 2. CKD progression includes a sustained ≥40%-50% decrease in eGFR.

Diabetic Chronic Kidney Disease

In 1993, the Captopril Collaborative Study Group published results of the first large prospective RCT to clearly show specific kidney protection attributable to ACE inhibitor treatment, a landmark event in the development of strategies for achieving kidney protection in persons with diabetes and CKD. Persons ( n = 409) with type 1 diabetes and established nephropathy (urine protein excretion >0.5g/day; serum creatinine levels <2.5 mg/dL) were randomly assigned to receive captopril or placebo, and a blood pressure goal of <140/90 mm Hg was set for both groups. After a median follow-up period of 3 years, captopril treatment was associated with a 50% reduction in the risk of the combined endpoint of death, dialysis, and kidney transplantation and a 48% reduction in the risk of serum creatinine doubling. Because blood pressure control was not statistically different between the groups, the additional kidney protection was not attributable simply to the antihypertensive effects of ACE inhibitors.

These results prompted several further studies to investigate whether ACE inhibitors may also benefit persons with early stage nephropathy characterized by microalbuminuria. A meta-analysis of 12 such studies, including 689 persons with type 1 diabetes who were monitored for at least 1 year, revealed that ACE inhibitor treatment was associated with a significant reduction in the risk of progression to overt nephropathy (OR, 0.38) and three times the incidence of normalization of microalbuminuria.

ACE inhibitors also have benefits at earlier stages of nephropathy in people with type 2 diabetes. Several studies, including the diabetic subgroup analysis of the Heart Outcomes Prevention Evaluation (HOPE) study, demonstrated beneficial effects of ACE inhibitor treatment among persons with type 2 diabetes in decreasing microalbuminuria or in reducing the number of persons progressing from microalbuminuria to overt proteinuria (risk reduction, 24% to 67%). In addition, the HOPE study reported a 25% reduction in the combined primary endpoint of myocardial infarction, stroke, or cardiovascular death in ramipril-treated persons with type 2 diabetes and risk factors for cardiovascular disease.

Likewise, three large RCTs published simultaneously established a clear role for ARB therapy in achieving kidney protection for persons with type 2 diabetes. In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, 1513 persons with overt diabetic nephropathy were randomly assigned to receive ARB treatment or placebo and were monitored for a mean of 3.4 years. ARB treatment was associated with significant reductions in the incidence of serum creatinine doubling (RR reduction, 25%) and in ESKF (RR reduction, 28%).

In IDNT, 1715 persons with overt diabetic nephropathy were randomly assigned to receive treatment with the ARB irbesartan, amlodipine, or placebo. After a mean of 2.6 years, the risk of serum creatinine doubling was 33% lower with irbesartan than with placebo and 37% lower with irbesartan than with amlodipine. ARB treatment was associated with a 23% reduction in the risk of ESKF in comparison with placebo and amlodipine, but this reduction was not statistically significant. Of importance is that close matching of achieved blood pressure between groups in both these trials implies that, as with the ACE inhibitor studies, the additional renoprotective effects of ARB treatment could not be attributed merely to their antihypertensive effects.

In a third study, investigators examined the renoprotective effects of an ARB (irbesartan) in 590 persons with type 2 diabetes, hypertension, and microalbuminuria. Participants were randomly assigned to receive irbesartan at one of two different dosages (300 or 150 mg/day) or placebo. After 2 years, there were significant differences in the incidence of overt proteinuria (5.2%, 9.7%, and 14.9%), and the higher dose of irbesartan was associated with substantial reduction in the risk of overt nephropathy (HR, 0.30; 95% CI, 0.14–0.61) in comparison with placebo. This dose-dependent effect indicates that when ARBs are used to treat diabetes-associated microalbuminuria, the dose should be titrated up to the maximum antihypertensive dose.

A meta-analysis confirmed the results of individual trials by showing significant reductions in the risk of ESKF (RR, 0.78; 95% CI, 0.67–0.91) and in doubling of serum creatinine level (RR, 0.79; 95% CI, 0.67–0.93), as well as a reduction in risk of progression from microalbuminuria to macroalbuminuria (RR, 0.49; 95% CI, 0.32–0.75) among diabetic persons treated with ARB versus placebo. However, these trials did not demonstrate a reduction in all-cause mortality.

Preventing the onset of diabetic kidney disease

Evidence of kidney protection with RAASi therapy in persons with established diabetic kidney disease prompted further studies to investigate whether early initiation of RAASi treatment could prevent or delay the onset of diabetic kidney disease. Following several trials that reported mixed results, ^, three meta-analyses were conducted. One analysis included only studies of type 2 diabetes with albuminuria or proteinuria as an outcome; it revealed statistically significant reductions in albuminuria in association with ACE inhibitor treatment versus placebo. A second, larger analysis combined data from studies of type 1 and type 2 diabetes and revealed a reduced, albeit not statistically significant, risk of serum creatinine doubling (RR, 0.60; 95% CI, 0.34–1.05) or ESKF (RR, 0.64; 95% CI, 0.40–1.03) but stronger evidence of reduced risk of progression of microalbuminuria to macroalbuminuria (RR, 0.45; 95% CI, 0.28–0.71) with ACE inhibitor treatment versus placebo. All-cause mortality was significantly reduced in persons receiving ACE inhibitors (RR, 0.79; 95% CI, 0.63– 0.99). A third meta-analysis involved data from 16 studies of the effect of ACE inhibitor treatment on reducing the risk of microalbuminuria in type 1 and type 2 diabetes. This meta-analysis revealed a significantly reduced risk of developing microalbuminuria with ACE inhibitors in comparison with placebo (RR, 0.60; 95% CI, 0.43–0.84) or calcium channel blocker treatment (RR, 0.58; 95% CI, 0.40–0.84).

With respect to ARBs, several RCTs have been conducted to investigate the potential role of ARB treatment to prevent the development of microalbuminuria in persons with diabetes. In persons with type 1 diabetes, two trials showed no benefit. ^, In hypertensive persons with type 2 diabetes, treatment with olmesartan was associated with a 23% delay in the time to onset of microalbuminuria versus placebo. However, a small but significantly higher incidence of death from cardiovascular causes was observed, particularly in persons with a previous history of cardiovascular disease and in those with the greatest reduction in blood pressure.

On the basis of the above data, the KDIGO guidelines recommend treatment with an ACE inhibitor or ARB in all adults with diabetes and urine albumin excretion ≥30 mg/day or more (or equivalent). In people with diabetes, CKD, and normoalbuminuria, the KDIGO guidelines also provide expert opinion to support the use of ACE inhibitors or ARBs for the first-line treatment of hypertension, principally for the established cardioprotective benefits of RAAS inhibition There is little evidence to suggest a kidney-protective effect of ACE inhibitors or ARBs in people with diabetes, CKD, and normoalbuminuria. For further discussion of the management of diabetic nephropathy, see Chapter 41 .

Nondiabetic Chronic Kidney Disease

After reports of kidney protection with ACE inhibitor treatment in diabetic nephropathy, further studies sought to investigate the renoprotective potential of ACE inhibitors in nondiabetic forms of CKD. One early study demonstrated a 53% reduction in the risk of the composite endpoint (serum creatinine doubling or ESKF) in association with ACE inhibitor treatment, but significantly lower blood pressure in persons receiving ACE inhibitors versus placebo made it impossible to separate the beneficial effects of lowering blood pressure from any unique effects of ACE inhibitor treatment. By contrast, in the REIN study of 352 persons with nondiabetic CKD and urine protein levels exceeding 1 g/day, similar control of blood pressure was achieved in the participants randomly assigned to receive an ACE inhibitor or placebo. Among persons with at least 3 g/day of urine protein at baseline, the study was stopped early because the rate of decline in GFR in participants receiving the ACE inhibitor was significantly lower (0.53 vs. 0.88 mL/min/month) ¹³⁷; further analysis showed a significantly lower risk of the combined endpoint (serum creatinine doubling or ESKF) in the participants taking ACE inhibitors (RR, 1.91; 95% CI, 1.10–3.33 for the placebo recipients).

One-hundred eighty-six persons from the REIN study who had <3 g/day of urine protein were monitored for a median of 31 months after randomization. In findings similar to those of participants with more severe proteinuria, ACE inhibitor treatment significantly reduced the incidence of ESKF (for placebo recipients, RR, 2.72; 95% CI, 1.22–6.08), particularly among those with a GFR of <45 mL/min at baseline. After the randomized phase of the study, persons who had received placebo were switched to ACE inhibitors, and those taking ACE inhibitors continued treatment. In a finding consistent with those of the first phase of the study, there was a significant reduction in the rate of decline in GFR of persons switched to ACE inhibitors. In addition, persons continuing with ACE inhibitor treatment showed a further reduction in the rate of GFR decline. Participants who had received ACE inhibitors from the start of the REIN study had a significantly lower risk of reaching ESKF than those who switched to ACE inhibitors after the initial phase (for placebo recipients, RR, 1.86; 95% CI, 1.07–3.26). In fact, from 36 to 54 months of follow-up, no additional persons in the former group experienced ESKF. Of interest is that a small number of persons who continued taking ACE inhibitors exhibited an increase in GFR after prolonged treatment.

One RCT confirmed that the kidney-protective benefits of ACE inhibitor treatment may be observed even in advanced stages of CKD. Among 244 persons with a serum creatinine level of 3.1 to 5.0 mg/dL at baseline, treatment with ACE inhibitor versus placebo was associated with a 52% reduction in urine protein levels and a 43% reduction in the risk of the primary endpoint (serum creatinine doubling, ESKF, or death). A meta-analysis of 11 studies that included 1860 persons with nondiabetic CKD revealed that ACE inhibitor treatment was associated with significantly lower risks of ESKF (RR, 0.69; 95% CI, 0.51–0.94) and with the composite endpoint of serum creatinine doubling or ESKF (RR, 0.70; 95% CI, 0.55–0.88). Moreover, the benefits of ACE inhibitor treatment were greater in persons with more severe baseline proteinuria but were inconclusive in persons with urine protein levels of <0.5 g/day. A further analysis restricted to persons with autosomal dominant polycystic kidney disease showed greater reduction in proteinuria with ACE inhibitor treatment, but overall evidence of slowing CKD progression was inconclusive and was limited to persons with more severe proteinuria.

In addition to the kidney-protective benefits of ACE inhibitor treatment, the HOPE study reported substantial reductions in overall mortality (RR, 0.84) and cardiovascular mortality (RR, 0.74) among 9297 participants who were at increased risk of cardiovascular disease receiving an ACE inhibitor versus placebo. Although the HOPE study did not include large numbers of persons with nondiabetic CKD, cardiovascular disease remains the most widespread cause of morbidity and mortality among these persons, and the data therefore provide further support for the use of ACE inhibitor therapy in persons with CKD.

With respect to ARBs, no large RCTs have investigated the kidney-protective effects of ARBs versus other antihypertensive drugs in nondiabetic kidney disease. Nonetheless, it is reasonable to expect that ARBs will provide similar kidney-protective benefits in nondiabetic CKD to those observed in diabetic kidney disease.

On the basis of the evidence, the 2024 KDIGO guidelines recommend treatment with an ACE inhibitor or ARBs as the first-line antihypertensive in persons with all forms of CKD and albuminuria >30 mg/g. In normotensive persons, the KDIGO guidelines similarly recommend treatment with an ACE inhibitor or ARB in adults with CKD and urine albumin excretion exceeding 30 mg/g (or equivalent).

Combination Treatment With Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers

The differing mechanisms of ACE inhibitors and ARBs on the RAAS imply that in combination, they may have additive or synergistic effects. However, the added antihypertensive effects of combination therapy have made it difficult to separate the benefits of additional blood pressure lowering from added kidney protection directly attributable to dual blockade of the RAAS. Only one RCT yielded results indicating benefit associated with ACE inhibitor and ARB combination therapy in CKD with respect to serum creatinine doubling or ESKF incidence. Publication of that study was, however, withdrawn because of concerns about the conduct of the study and integrity of the data.

Furthermore, the results of the ONTARGET trial cast doubt on the benefit of dual therapy. In ONTARGET, 25,620 persons with hypertension and additional cardiovascular risk factors were randomly assigned to receive treatment with an ACE inhibitor alone, an ARB alone, or a combination of both. The primary analysis revealed no difference in CVEs between the randomized groups, but the number of events for the composite kidney outcome—need for dialysis, doubling of serum creatinine level, and death ¹⁴⁶—was increased with combination treatment (14.5%; HR, 1.09; 95% CI, 1.01–1.18; P = 0.037) versus single-agent treatment (ARB: 13.4%; ACE inhibitor 13.5%). This excess was attributable predominantly to more acute dialysis and to the combination of all types of dialysis and serum creatinine doubling. In addition, hyperkalemia (K >5.5 mmol/L) was more frequent with combination treatment (ACE inhibitor, 3.2%; ARB, 3.3%; combination, 5.6%; P < 0.001 for combination vs. ACE inhibitor).

A further RCT (VA NEPHRON-D) in 1448 people with type 2 diabetes and UACR of at least 300 mg/g was stopped early due to safety concerns. Analysis of available data found no benefit with respect to the primary outcome of CKD progression, ESKF, or death in participants randomized to combination versus monotherapy. Of concern, those receiving combination treatment showed a significantly higher incidence of AKI (12.2 vs. 6.7 events per 100 person-years; P < 0.001) and hyperkalemia (6.3 vs. 2.6 events per 100 person-years; P < 0.001).

In a meta-analysis of 59 RCTs comparing the efficacy and safety of combination versus single RAASi therapy in CKD, combination treatment was associated with significant improvement in urine albumin and protein excretion, as well as blood pressure control. These beneficial effects, however, were associated with a net 1.8 mL/min/1.73 m ² decline in GFR, a significant increase in serum potassium level (3.4% higher rate of hyperkalemia), and a 4.6% higher rate of hypotension. There was no effect on doubling of the serum creatinine level, hospitalization, or mortality.

The KDIGO guidelines do not recommend the use of combination ACE inhibitor and ARB therapy for kidney protection and NICE guidelines, and the 2017 American College of Cardiology/American Heart Association guidelines recommend against combination treatment.

Mineralocorticoid Antagonism

Aldosterone has been identified as an important factor in the pathogenesis of hypertension, cardiovascular disease, and progressive kidney injury through hemodynamic and profibrotic actions. Treatment with steroidal mineralocorticoid receptor antagonists (sMRAs) has produced kidney-protective effects in experimental and small clinical studies. One meta-analysis of their use in comparison with other RAAS inhibitors included data from 10 trials and 845 participants. In comparison with ACE inhibitor or ARB plus placebo, a nonselective MRA (spironolactone) added to ACE inhibitor or ARB treatment significantly reduced proteinuria (weighted MD, −0.80 g/day; 95% CI, −1.23 to −0.38) and blood pressure, but these developments did not translate into an improvement in GFR (weighted MD, −0.70 mL/min/1.73 m ²; 95% CI, −4.73 to 3.34). There was a significant increase in the risk of hyperkalemia with the addition of an sMRA (RR, 3.06; 95% CI, 1.26–7.41). A more recent meta-analysis of 27 studies confirmed that treatment with spironolactone alone or in combination with an ACE inhibitor or ARB was associated with reduction in proteinuria (standardized MD,–0.61 g/day; 95% CI,–1.08 to–0.13) and blood pressure (MD,–3.44 mm Hg; 95% CI,–5.05 to–1.83) but provided no data on reduction in CVEs or ESKF. In addition, spironolactone was associated with an increased risk of hyperkalemia (RR, 2.00; 95% CI, 1.25–3.20) and gynecomastia compared with ACE inhibitor or ARB (or both) (RR, 5.14; 95% CI, 1.14–23.23). The kidney-protective potential of eplerenone, a more selective sMRA, has also been evaluated. In one RCT that enrolled 336 persons with hypertension, UACR 30 to 599 mg/g, and eGFR of 50 mL/min/1.73 m ² or above, treatment with eplerenone for 52 weeks, added to ACE inhibitor or ARB therapy, resulted in a 17.3% decrease in UACR, whereas a 10.3% increase was observed in those who received placebo ( P =.02). Serum potassium was higher with eplerenone treatment, but no episodes of severe hyperkalemia (serum potassium > 5.5 mmol/L) were observed.

Given the off-target steroidal side effects of sMRAs, nonsteroidal (ns)MRAs were developed as selective and potent alternatives to block aldosterone. Currently, the only widely available nsMRA with proven kidney and cardiovascular benefits is finerenone, although other nsMRAs such as esaxerenone are approved for use only in Japan. In comparison with sMRAs such as spironolactone and eplerenone, finerenone exhibits greater selectivity for the mineralocorticoid receptor and is at least as potent as spironolactone in reducing binding of aldosterone to the mineralocorticoid receptor. Due to the bulky chemical structure of finerenone, it also exerts more potent blocking of mineralocorticoid receptor cofactor binding as compared with spironolactone and eplerenone; which may reduce downstream gene expression of proinflammatory and profibrotic genes. In addition, with respect to side effects, finerenone has minimal affinity for androgen receptors and does not produce untoward side effects such as gynecomastia. Additionally, dedicated head-to-head RCTs have shown that finerenone is associated with a lower incidence of hyperkalemia. The phase II mineralocorticoid Receptor Antagonist Tolerability Study (ARTS) compared the effect of finerenone with placebo and spironolactone in people with heart failure with reduced ejection fraction and moderate CKD and showed that the incidence of hyperkalemia (serum potassium ≥5.6 meq/L) was lower with finerenone as compared with spironolactone (3.7% vs. 12.7% respectively, P = 0.03). Furthermore, the incidence of investigator-reported kidney failure was lower with finerenone versus spironolactone (1.5% vs. 7.9%, P = 0.04).

With respect to clinical outcomes, finerenone reduces the risk of CKD progression. The Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes (FIDELIO-DKD) trial compared the effect of finerenone versus placebo on the primary composite of kidney failure, a sustained decrease of ≥40% in the eGFR from baseline, or death from renal causes. The study included people with type 2 diabetes and CKD, and the CKD eligibility criteria included people with a UACR of 30 to 300 mg/g, an eGFR of 25 to 60 mL/min/1.73 m ², and diabetic retinopathy, or people with a UACR 300 to 5000 mg/g and an eGFR of 25 to 75 mL per minute per 1.73 m ². Finerenone reduced the primary kidney composite endpoint by 18% versus placebo (HR 0.82, 95% CI 0.73–0.93), albeit with a 1.4% absolute increase in the risk of hyperkalemia-related discontinuation of study medication (2.3% for finerenone vs. 0.9% for placebo). Similar evidence of the kidney-protective benefit of finerenone was noted in the companion cardiovascular pivotal RCT, FIGARO-DKD, which compared finerenone to placebo in people with type 2 diabetes and CKD. In FIGARO-DKD, the CKD eligibility criteria included people with a UACR of 30 to 300 mg/g and an eGFR of 25 to 90 mL/min/1.73 m ² or people with a UACR of 300 to 5000 mg/g and an eGFR ≥60 mL/min/1.73 m ². Finerenone reduced the prespecified secondary kidney composite outcome of kidney failure, a sustained decrease of ≥40% in the eGFR from baseline, or death from renal causes by 13% (HR 0.87, 95% CI: 0.76–1.01) in people with type 2 diabetes and CKD. A pooled analysis of FIDELIO-DKD and FIGARO-DKD reinforced the finding for the kidney composite of kidney failure, a sustained decrease of ≥40% in the eGFR from baseline, or death from renal causes, as well as for hard outcomes such as ESKF (HR 0.80, 95% CI: 0.64–0.99; Fig. 54.5 ). Only a small minority of participants in these trials were also treated with an SGLT2 inhibitor, so it remains uncertain whether the benefits of treatment with finerenone are additive to those of SGLT2 inhibitors (discussed later).

A graph shows cumulative incidence over time for finerenone and placebo treatments, with hazard ratio and statistical data indicated The graph shows that the horizontal axis represents time to first event in months, ranging from 0 to 48 months. The vertical axis shows cumulative incidence in percentage, from 0 percent to 10 percent. Two lines represent the treatments, with one for finerenone and one for placebo. The number of patients at risk is shown at the bottom, decreasing as time progresses. The H R with its 95 percent C I is provided as 0.77, 0.67-0.88, and the p-value is 0.0002, indicating a statistically significant difference between the treatments. — Fig. 54.5

Given consistent evidence of efficacy in FIDELIO-DKD and FIGARO-DKD, the 2022 KDIGO guidelines for diabetes management in CKD recommend an nsMRA with proven kidney or cardiovascular benefit for people with type 2 diabetes, an eGFR ≥25 mL/min/1.73 m ², normal serum potassium, and UACR≥30 mg/g despite a maximal tolerated dose of RAS inhibitor.

An alternative strategy for aldosterone antagonism involves limiting its production in the zona glomerulosa of the adrenal gland through inhibition of aldosterone synthase, which is the enzyme that catalyzes the final rate-limiting steps for producing aldosterone from deoxycorticosterone. However, a challenge in the development of aldosterone synthase inhibitors (ASIs) is the similarity in the amino acid sequence between aldosterone synthase and cortisol synthase and the potential for ASIs to inhibit cortisol production and increase the risk of adrenal insufficiency. Two highly selective ASIs—baxdrostat and lorundrostat—have been studied in phase II RCTs focused on their blood pressure lowering effect and both agents have demonstrated efficacy in blood pressure lowering. Furthermore, a phase II RCT involved 586 people with CKD was completed for the highly selective ASi BI 690517, alone or in combination with empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor. BI 690517 administered at the 10-mg dose reduced UACR by 39% versus 3% with placebo. There was no increased risk of adrenal insufficiency. The phase III RCT of BI 690517, entitled EASi-KIDNEY, is under way and additional phase II RCTs of baxdrostat (NCT05432167) and larundrostat are ongoing to examine the efficacy of ASIs with respect to managing CKD.

Direct Renin Inhibitors

Direct renin inhibitors block the RAAS at its rate-limiting step (the conversion of angiotensinogen to angiotensin I) and may therefore achieve more complete blockade of the RAAS than do ACE inhibitors or ARBs. Direct renin inhibitors (e.g., aliskiren) are effective antihypertensive drugs and reduced proteinuria in experimental models of CKD ^, and RCTs. ^, However, a large randomized trial that included 8561 people with type 2 diabetes and albuminuria or cardiovascular disease was stopped prematurely after the second interim efficacy analysis. Despite greater lowering of blood pressure and albuminuria with a combination of direct renin inhibitor and ARB therapy, no benefit was observed with respect to the composite primary endpoint of CVE, CKD progression, ESKF, or death versus ARB monotherapy, but combination therapy was associated with a higher incidence of hyperkalemia and hypotension. ^, There is currently no evidence that direct renin inhibitor therapy, alone or in combination with ACE inhibitor therapy, affords more effective kidney protection than ACE inhibitor or ARB therapy alone.

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors

SGLT2 inhibitors block the reabsorption of glucose and sodium in the proximal tubule, thereby increasing delivery of these solutes to the macula densa, stimulating tubuloglomerular feedback and afferent arteriolar vasoconstriction. The net effect of these changes is a decrease in intraglomerular pressure, which manifests as an acute dip of 3 to 5 mL/min/1.73 m ² in eGFR following the initiation of SGLT2 inhibitors. Within 6 weeks of initiating SGLT2 inhibitors, eGFR stabilizes and the rate of eGFR decline slows, thereby affording kidney protection compared with placebo-treated patients. Other effects of SGLT2 inhibitors include improved glycemic control, reduced blood pressure, amelioration of arterial stiffness, and weight loss, although the kidney-protective effects of SGLT2 inhibitors are independent of metabolic benefits.

In dedicated kidney RCTs, SGLT2 inhibitors reduce the risk of hard clinical endpoints including CKD progression, ESKF, and reduction of albuminuria down to an eGFR of 20 mL/min/1.73 m ². To date, there have been three pivotal kidney RCTs of SGLT2 inhibitors, all of which were stopped early for efficacy. The CREDENCE trial enrolled 4401 adults with type 2 diabetes, eGFR 30 to <90 mL/min/1.73 m ², and UACR 300 to 5000 mg/g despite treatment with the maximum dose of an ACE inhibitor or ARB. The risk of the composite primary outcome of ESKF, doubling of serum creatinine, and cardiovascular or renal death was reduced by 30% in participants who received canagliflozin (HR, 0.70; 95% CI, 0.59–0.82; P < 0.001), and the risk of ESKF was reduced by 32% (HR, 0.68; 95% CI, 0.54–0.86; P = 0.002). The geometric mean UACR was also reduced by 31% (95% CI, 26%–35%). Likewise, the DAPA-CKD trial enrolled 4304 adults with and without type 2 diabetes, with an eGFR of 25 to 75 mL/min/1.73 m ², UACR of 200 to 5000 mg/g on a stable dose of an ACE inhibitor or ARB. The risk of the primary composite of a sustained decline in eGFR of ≥50%, ESKF, or death from renal or cardiovascular causes was reduced by 39% in participants who received dapagliflozin versus placebo (HR 0.61, 95% CI, 0.51–0.72, P < 0.001), and the risk of ESKF was reduced by 36% (HR, 0.64; 95% CI, 0.50–0.82). The geometric mean UACR was reduced by 29.3% (95% CI, 25.2%–33.1%). The EMPA-KIDNEY trial enrolled 6609 adults with and without type 2 diabetes, with an eGFR of 20 to <45 mL/min/1.73 m ² or an eGFR of 45 to 90 mL/min/1.73 m ² with a UACR of ≥200 mg/g. The risk of the composite primary outcome of progression of kidney disease (defined as ESKF, a sustained decrease in eGFR to <10 mL/min/1.73 m ², a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes was reduced by 28% (HR, 0.72, 95% CI, 0.64–0.82), and the risk of ESKF was reduced by 33% (HR 0.67; 95% CI 0.52–0.85). In meta-analyses of the pivotal RCTs, SGLT2 inhibitor treatment reduced the risk of kidney disease progression by 37% (relative risk (RR) 0.63, 95% CI 0.58–0.69) and also reduced the risk of acute kidney injury by 23% (RR 0.77, 95% CI 0.70–0.84), cardiovascular death or hospitalization for heart failure by 23% (RR 0.77, 95% CI 0.74–0.81) and cardiovascular death by 14% (RR 0.86, 95% CI 0.81–0.92). The treatment effects were consistent in people with and without diabetes and irrespective of the underlying cause of kidney disease ( Fig. 54.6 ). The treatment effects were also consistent across baseline eGFR or albuminuria. On an absolute basis, in adults with CKD, prevention of 1 kidney disease progression event can be achieved by treating only 91 adults with type 2 diabetes for 1 year and 67 adults without diabetes for 1 year with an SGLT2 inhibitor versus placebo. When combined with RAAS inhibitors, treatment with an SGLT2 inhibitor versus placebo also results in an additional 7.9 years without doubling serum creatinine or kidney failure in people with albuminuria without diabetes. Finally, at a population level, screening of adults 35 to 75 years old for albuminuria followed by treatment with an SGLT2 inhibitor would prevent ESKF requiring dialysis in 398,000 to 658,000 people over their lifetime, depending on the frequency of screening, and is cost-effective. To date, there are no dedicated kidney outcome studies of persons without diabetes who have the earliest stages of CKD (eGFR≥45 mL/min/1.73 m ² with UACR<200 mg/g). There are also limited data in people with single kidneys, polycystic kidney disease, or kidney transplants in whom SGLT2 inhibitor treatment is currently not indicated. Studies are forthcoming in people with type 1 diabetes who have concurrent CKD (NCT06217302).

A table presents data on baseline e G F R, event rates per 1000 patient-years, and R R for different treatment groups across various kidney disease categories. The table is divided into several categories, including Diabetic Kidney Disease or Nephropathy, Ischemic and Hypertensive Kidney Disease, Other Kidney Diseases or Unknown, and Any Diagnosis. The results are shown for different clinical trials: C R E D E N C E, S C O R E D, D A P A C K D, and E M P A KIDNEY. Each row includes data for both the S G L T 2 inhibitor and placebo groups. The R R values are provided for each condition and trial, with corresponding confidence intervals. The overall trend shows lower risk ratios for the S G L T 2 inhibitor compared to placebo, with some trial-specific variations. The heterogeneity across trials is also indicated in the table, with a note on the trend across groups of urinary A C R for any diagnosis. — Fig. 54.6

SGLT2 inhibitors have a favorable side effect profile. Common side effects include low blood pressure and volume depletion. Before starting these medications, it is relevant to make sure patients are not hypotensive or hypovolemia and to decrease or stop concomitant medications that have no benefit on hard clinical endpoints beyond blood pressure lowering, such as diuretics or calcium channel blockers. The risk of genital mycotic infection is increased with SGLT2 inhibitors, although this can be readily managed through counseling regarding the need for routine genital hygiene and the use of topical antifungals if needed. In the event of an infection, prescription of antifungal treatment is usually sufficient, without discontinuation of the SGLT2 inhibitor. However, if the infection is refractory to treatment, a temporary discontinuation of the SGLT2 inhibitor can be considered, followed by reinitiation at the same or a lower dose. There is no meaningful increase in the risk of urinary tract infections with SGLT2 inhibitors. ^, Less common but important side effects include diabetic ketoacidosis (HR 2.12, 95% CI, 1.49–3.04), although the absolute risk increase in people with type 2 diabetes is marginal, ranging from 0.3 to 1.5 events per 1000 person-years. In contrast, the risk of DKA is higher in people with type 1 diabetes, ranging from 4 to 7%, and this has been a barrier to the use of SGLT2 inhibitors in this population. Potential risk factors for DKA associated with SGLT2 inhibitor use include large changes in insulin dose, dietary carbohydrate restriction, surgical stress or intercurrent illness impairing oral intake, lean body habitus, and latent autoimmune diabetes in adults. Clinicians can therefore mitigate the risk of DKA through gradual dose titration of insulin dose, avoiding ≥20% one-time insulin dose reduction, discontinuation of SGLT2 inhibitors during acute illness or before elective surgery, and counseling of patients regarding the risk of DKA.

Given the favorable benefit-risk profile of SGLT2 inhibitors, the KDIGO diabetes guidelines recommend initiating SGLT2 inhibitors for preventing CKD progression and albuminuria lowering in persons with type 2 diabetes and an eGFR ≥20 mL/min/1.73 m ², irrespective of UACR. For people without diabetes, the 2024 KDIGO guidelines for the management of CKD recommend initiation of an SGLT2 inhibitor in persons with an eGFR ≥20 mL/min/1.73 m ² and a UACR≥200 mg/g or in people with CKD, an eGFR 20 to 45 mL/min/1.73 m ², or heart failure, irrespective of UACR. In persons stabilized on SGLT2 inhibition, these medications can be continued even after eGFR falls below 20 mL/min/1.73 m ² and used until ESKF, KRT, or eGFR <10 mL/min/1.73 m ².

Glucagon-Like Peptide-1 Receptor Agonists and Glucose-Dependent Insulinotropic Polypeptide Receptor Agonists

GLP1RAs are long-acting analogs of GLP1, a naturally occurring incretin hormone that is principally secreted from the enteroendocrine L cells of the distal ileum and colon in response to food intake. GLP1 exerts insulinotropic effects through receptors on pancreatic β cells, and in the context of diabetes, postprandial production of GLP1 is attenuated. GLP1RAs mimic the effect of GLP1 and agonize the GLP1 receptor in the pancreas and therefore stimulate endogenous insulin production with the net benefit of improving glycemic control. GLP1RA agents were initially developed as treatments for type 2 diabetes, although due to the presence of GLP1 receptors in multiple organ beds including the heart, vasculature, kidney, and central nervous system, these medications exert multiple systemic effects including weight loss as discussed earlier. Experimental studies have identified that GLP1RA treatment has kidney-protective effects in diabetic and nondiabetic animal models, at least in part due to anti-inflammatory effects mediated by inhibition of receptor for advanced glycation endproducts (RAGE).

With respect to CKD, the effect of GLP1RAs on the kidney was first demonstrated in dedicated kidney-specific analysis of pivotal cardiovascular outcome trials in persons with type 2 diabetes. In a meta-analysis of 6 cardiovascular outcome RCTs, involving 44,378 participants, GLP1RAs reduced the incidence of the composite kidney endpoint of development of macroalbuminuria, doubling of serum creatinine or at least 40% decline in eGFR, KRT, or death due to kidney disease by 21% as compared with placebo (HR 0.79; 95% CI, 0.73–0.87). GLP1RAs also reduced the incidence of the composite of doubling of serum creatinine or ≥40% decline in eGFR, by 14% compared with placebo (HR 0.86; 95% CI 0.72–1.02). These hypothesis-generating findings prompted the initiation of an RCT with primary kidney endpoints, the “Evaluate Renal Function with Semaglutide Once Weekly” (FLOW) trial, which compared semaglutide to placebo in people with type 2 diabetes and CKD, defined as an eGFR between 50 and 75 mL/min/1.73 m ² with a UACR between 300 and 5000 mg/g or an eGFR between 25 and 50 mL/min/1.73 m ² and UACR between 100 and 5000 mg/g. The primary outcome of FLOW was a kidney composite of an eGFR decline ≥50%, ESKF, or death from kidney disease or cardiovascular disease. The FLOW trial was stopped early for efficacy after a median follow-up of 3.4 years and reported a 24% reduction in the risk of the primary endpoint (HR 0.76; 95% CI, 0.66–0.88), as well as a 21% reduction in a secondary, kidney-specific endpoint (primary endpoint without cardiovascular death), 18% reduction in risk of first major CVE, and 20% reduction in all-cause mortality ( Fig. 54.7 ). The results were consistent across all subgroups including SGLT2i use at baseline, though the latter included only 15.6% of participants. GLP1RAs may also have kidney-protective effects in persons without diabetes. The “Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity” (SELECT) trial enrolled persons who were overweight or obese but without diabetes (21.3% with CKD). In this population, treatment with semaglutide treatment was associated with a 20% reduction in the primary endpoint of major CVEs. A prespecified secondary analysis reported a 22% reduction in the composite kidney endpoint of progression to eGFR <15 mL/min/1.73 m ², initiation of KRT, death due to kidney disease, eGFR decline of ≥50%, or progression to uACR >300 mg/g (HR 0.78; 95% CI, 0.63–0.96). Further trials with primary kidney endpoints are therefore warranted to specifically evaluate the kidney-protective effects of GLP1RAs in persons without diabetes.

A graph shows the percentage of participants over time for placebo and semaglutide, with a hazard ratio of 0.76 and statistical significance. The graph shows that the vertical axis represents the percentage of participants, ranging from 0 to 35 percent. Two lines represent the treatments: placebo and semaglutide. The semaglutide line shows a lower cumulative percentage of participants compared to the placebo group, indicating a reduced event rate with semaglutide. The H R is 0.76, with a 95 percent C I of 0.66to 0.88, and the p-value is 0.0003, indicating statistical significance. The graph highlights the benefit of semaglutide compared to placebo over the 48-month period. — Fig. 54.7

Alongside GLP-1, GIP is currently the only other naturally incretin hormone. GIP is produced in the intestinal K-cells, which are principally located in the duodenum and proximal jejunum. Similar to GLP1, GIP is released in response to food intake and in healthy individuals, GIP exerts its insulinotropic effect through receptors located on pancreatic β cells. In people with type 2 diabetes, mechanistic studies suggest there is no acute insulinotropic response to infusion of GIP. However, in a dedicated well-powered RCT, tirzepatide, a coagonist of the GLP-1 and GIP receptor, was superior to the selective GLP1RA semaglutide in reducing HbA1c in people with type 2 diabetes. There is also early evidence that tirzepatide may confer kidney protection. The SURPASS-4 RCT compared the effect of tirzepatide to insulin glargine in people with type 2 diabetes, BMI ≥25 kg/m ², and established cardiovascular disease or high risk of CVEs. In a post hoc analysis focused on kidney outcomes, tirzepatide reduced the incidence of the composite kidney endpoint of eGFR decline ≥40%, ESKF, death from kidney failure, or new-onset macroalbuminuria by 42% as compared with insulin glargine (HR 0.58, 95% CI 0.43–0.80). Dedicated kidney-specific RCTs of tirzepatide are needed to definitively establish its efficacy for kidney protection.

Clinical Relevance

Treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are “first line” in persons with albuminuria to achieve kidney protection. Sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment should be added for all persons with type 2 diabetes, CKD, and eGFR >20 mL/min/1.73 m ². For persons with CKD without diabetes, SGLT2 inhibitors should be added for those with eGFR 20 to 45 mL/min/1.73 m ², irrespective of albuminuria or ≥45 mL/min/1.73 m ² with albuminuria. For persons with type 2 diabetes and residual albuminuria, a nsMRA (finerenone) and a glucagon-like peptide-1 receptor agonist (GLP1RA)-like semaglutide should be added, unless contraindicated. Treatment with these medications should be started sequentially at a low dose and titrated upward. Serum creatinine and potassium should be checked approximately 2 weeks after initiation or dose titration. Additional monitoring is generally not required for GLP1-RA initiation.

Management of Hyperuricemia

A number of studies have highlighted evidence that elevated serum uric acid concentration is a risk factor for the development and progression of CKD. ^, It has also been associated with excess cardiovascular risk and hypertension in a cohort of community-based persons.

An early small randomized trial of allopurinol in 113 persons with CKD reported a 47% reduction in risk of CKD progression (defined as decrease in eGFR of >0.2 mL/min/month) in participants treated with allopurinol, as well as a 71% reduction in risk of new CVEs and 62% reduction in risk of hospitalization. Long-term follow-up of these participants demonstrated further benefit with a 68% reduction in risk of a kidney event (initiation of RRT or 50% reduction in GFR or doubling of serum creatinine) and a 57% reduction in risk of CVE. However, two subsequent large RCTs have found no evidence of benefit of serum urate lowering. First, the PERL trial randomized 530 people with type 1 diabetes, an eGFR of 40 to 99.9 mL/min/1.73 m ², and a serum urate of 267 μmol/L or higher to allopurinol versus placebo. Although allopurinol reduced serum urate versus the placebo group, the mean between-group difference in iohexol-based measured GFR was only–0.6 mL/min/1.73 m ². Likewise, the CKD-FIX randomized people with stage 3 or 4 CKD and no history of gout to allopurinol versus placebo. Eligible participants had an eGFR UACR of ≥265 mg/g or an eGFR decrease of at least 3 mL/min/1.73 m ² in the year preceding randomization. The study randomized 369 people, short of the intended target of 620 people, because of slow recruitment. There was no effect of allopurinol versus placebo in the change in eGFR from randomization to week 104. Furthermore, a meta-analysis that included 29 placebo-controlled trials of allopurinol, febuxostat, and other uric acid–lowering treatments (4471 participants with CKD) reported that all were effective in lowering serum uric acid concentration but only allopurinol improved GFR and none of the treatments lowered proteinuria. Therefore we do not recommend uric acid lowering in persons without gout as part of the management of CKD.

Treatment of Metabolic Acidosis

As the number of functioning nephrons declines, CKD leads to net retention of hydrogen ions, which begins when GFR falls below 40 to 50 mL/min/1.73 m ². Among persons in whom GFR decreases from 90 to <20 mL/min/1.73 m ², the prevalence of metabolic acidosis rises from 2% to 39% and is higher among younger persons and those with diabetes. As the patient approaches ESKF, the plasma bicarbonate concentration tends to stabilize between 15 and 20 mEq/L. Chronic metabolic acidosis has multiple adverse consequences, including increased protein catabolism, increased bone turnover, induction of inflammatory mediators, insulin resistance, and increased production of corticosteroids and parathyroid hormone. Several observational studies, including the CRIC study, have identified low serum bicarbonate as a risk factor for CKD progression, although post hoc analysis of data from persons with diabetic kidney disease enrolled in the RENAAL and IDNT studies found that an association between lower serum bicarbonate and kidney outcomes was not maintained after adjustment for baseline GFR.

The first study to show convincing kidney protection with bicarbonate supplementation was from a single center and involved 134 persons with advanced CKD (creatinine clearance rates between 15 and 30 mL/min/1.73 m ²) and baseline serum bicarbonate concentrations of 16 to 20 mEq/L. The participants were randomly assigned to receive treatment with oral bicarbonate or no treatment. After 2 years of follow-up, there was a lower mean rate of decline in creatinine clearance (1.88 vs. 5.93 mL/min/1.73 m ²) and a lower risk of ESKF among the persons who received the bicarbonate treatment than among the controls (6.5% vs. 33%). In a subsequent randomized, placebo-controlled trial in persons with a mean eGFR of 75 mL/min/1.73 m ², treatment with sodium bicarbonate for 5 years was associated with a slower rate of decline in eGFR (derived from plasma cystatin C measurements) compared with placebo or treatment with sodium chloride. Western diets are typically acid producing, but the addition of significant portions of fruits and vegetables can move this to a base-producing state. Further studies have reported that correction of acidosis with a diet rich in fruits and vegetables was as effective as sodium bicarbonate in ameliorating kidney damage in early (stage 1 or 2 CKD) and more advanced (stage 4 CKD) disease. Furthermore, a recent trial has reported benefits even in people with mild acidosis. People with stage 3 CKD and serum bicarbonate 22 to 24 mmol/L were randomized to oral bicarbonate supplementation, a diet rich in fruits and vegetables, or “usual care.” All participants received treatment with an RAAS inhibitor, and SBP was controlled to lower than 130 mm Hg. Both interventions achieved an increase in serum bicarbonate and were associated with a decrease in urinary angiotensinogen. After 3 years, both interventions were associated with less albuminuria and GFR decline than the “usual care” group. The KDIGO guidelines recommend bicarbonate supplementation using pharmacologic treatment, with or without dietary interventions, to prevent serum bicarbonate levels below 18 mEq/L, but further studies are required to further investigate whether this may also be beneficial in the setting of less severe acidosis.

Monitoring and Safety Considerations

Regular monitoring is essential for optimizing therapeutic interventions to slow CKD progression and ensure safety. Kidney function is best assessed with the use of eGFR, derived from a serum creatinine measurement with cystatin C where available, using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, recommended by KDIGO. This strategy allows direct monitoring of the rate of GFR decline and assessment of the therapeutic goal to reduce this decline to <1 mL/min/year, a rate associated with normal aging. Most laboratories now facilitate this monitoring by reporting eGFR with every serum creatinine measurement. In addition, monitoring allows for the detection of side effects of drug treatment, particularly electrolyte disorders (hyperkalemia and hyponatremia), as well as acute changes in kidney function related to volume depletion. The appropriate frequency for monitoring of persons with CKD should depend on the CKD stage, previous rate of GFR decline, risk of future GFR decline, and use of medication that may cause acute deteriorations in GFR or electrolyte disorders (especially RAAS inhibitors, diuretics, SGLT2is, and MRAs).

Initiation and Titration of Renin–Angiotensin–Aldosterone System Inhibitors

Despite clear trial evidence of the kidney-protective and cardioprotective effects of ACE inhibitors, ARBs, and nonsteroidal MRAs, some physicians remain hesitant about prescribing these medications to persons with stages 3 and 4 CKD. This caution results from concerns about kidney dysfunction induced by these drugs, with a potential rise in serum creatinine or potassium level (reviewed by Schoolwerth and colleagues and Palmer ²⁰⁸).

The initiation of therapy with RAAS inhibition may provoke an acute decline in GFR or hyperkalemia in persons with CKD, particularly in those with volume depletion, poor cardiac status, elderly persons, those with stage 4 or 5 disease, and persons with atherosclerotic renovascular disease. GFR and electrolytes should therefore be checked before and approximately 1 to 2 weeks after treatment is started or dosage is increased. On the basis of a review (but not a meta-analysis) of data for 12 RCTs, it has previously been recommended that an acute increase in serum creatinine of up to 30% after initiation of RAAS inhibitor therapy is acceptable because it is attributable to glomerular hemodynamic effects and correlates with slower subsequent annual decline in GFR. This advice has been questioned by analysis of data from a large database of 122,363 persons initiating RAAS inhibitor therapy in primary care. The analysis confirmed that a >30% increase in serum creatinine within 2 months after initiation of RAAS inhibitors (observed in 1.7% of participants) was associated with a significant increase in risks of ESKF, myocardial infarction, cardiac failure, and death, although the incidence rate ratio decreased with time after starting treatment. Importantly, the study also reported a graduated relationship between all of these adverse outcomes and acute increase in serum creatinine at all values ≥10% ( Fig. 54.8 ). An important limitation of this analysis is that data on proteinuria were not available. Nevertheless, these data indicate that a more cautious approach is warranted. A rapid initial rise in serum creatinine level or a more gradual progressive increase should prompt discontinuation of therapy and consideration of further investigation to exclude renovascular disease (see Chapter 47 ). It should be remembered that AKI can occur even if RAAS inhibition therapy has been successful for months or years, usually when provoked by factors such as volume depletion or nephrotoxic medications.

A forest plot showing incidence rate ratios for end-stage kidney disease, myocardial infarction, heart failure, and mortality associated with creatinine increase in different percentage ranges. The the left side, the creatinine increase categories are listed, ranging from less than 10 percent to more than 40 percent. The I R R with 95 percent C I are shown for each category, with the reference category set at less than 10 percent. For each outcome, the plot shows the I R R values along with statistical significance. For example, for end-stage kidney disease, the I R R increases as the creatinine increase categories rise, with values of 1.73, 1.41 to 2.13 for 10 to 19 percent, and 4.00, 2.46 to 6.63 for greater than 40 percent. The plot also includes p-values for trend, which indicate statistical significance for each outcome. — Fig. 54.8

ACE inhibitor or ARB treatment should be started at a low dose and titrated upward, with monitoring of creatinine and potassium levels 1 to 2 weeks after each increase. To avoid compromise from intravascular volume depletion, persons should be counseled to omit ACE inhibitor or ARB treatment during vomiting or diarrheal illnesses and to seek medical advice if these illnesses do not resolve within 48 hours. Likewise, it is important to ensure adequate hydration, omit or reduce diuretics for 48 to 72 hours if clinically appropriate, and avoid nonsteroidal anti-inflammatory drugs (NSAIDs) before starting an RAAS inhibitor. In general, we strongly advise discontinuation of NSAIDs because these are potent causes of AKI in persons with CKD. General guidance on risk factors for AKI and frequency of monitoring are given in Tables 54.2 and 54.3 .

Table 54.2

Overview of Chronic Kidney Disease Management by Stage

Features	Stages 1 and 2	Stage 3a	Stage 3b	Stage 4	Stage 5
Estimated GFR	≥60 mL/min/1.73 m ² + albuminuria or hematuria or structural kidney damage	45-59 mL/min/1.73 m ²	30-44 mL/min/1.73 m ²	15-29 mL/min/1.73 m ²	<15 mL/min/1.73 m ²
Frequency of monitoring	Annual	6-12 months	3-6 months	3-4 months	1-3 months
Laboratory testing	Annual electrolytes and estimated GFR Annual urine ACR (or other estimate of proteinuria) Baseline anemia and mineral and bone profiles Glucose, lipids, and HbA _1c See Table 54.3 for causes of AKI after initiation of ACE inhibitor or ARB therapy.				Check electrolytes and estimated GFR 1 week after new use or higher doses of ACE inhibitors or ARBs; otherwise, assess electrolytes/estimated GFR, mineral and bone, and anemia profiles every 3-6 months, depending on GFR decline.
Blood pressure targets	BP target <130/80 mm Hg with proteinuria BP target <140/90 mm Hg without proteinuria if no clinical or radiologic evidence of ARVD or previous episodes of AKI				Risk of AKI is increased in elderly persons (>75 years), those with CHF, and those with ARVD; 140/90 mm Hg may be more appropriate for these groups.
Blood pressure agents	ACE inhibitor or ARB if urine ACR ≥30 mg/g Most persons need 2-4 agents in total to achieve these targets, in a combination of ACE inhibitors or ARBs and 1 or more of the following: a diuretic (all classes), a calcium channel blocker, and a β-blocker.				Loop diuretics are now usually required for BP and edema control.
SGLT2 Inhibitors	SGLT2 inhibitors in all people with CKD and type 2 diabetes and eGFR ≥20 mL/min/1.73 m ² SGLT2 inhibitors in all people with CKD without diabetes and an eGFR between 20 and 45 mL/min/1.73 m ² irrespective of UACR or an eGFR of ≥45 mL/min/1.73 m ² with a UACR ≥200 mg/g				Continue SGLT2 inhibitor.
nsMRA	nsMRA for all people with CKD with type 2 diabetes and an eGFR ≥25 mL/min/1.73 m ², normal serum potassium concentration, and a UACR ≥30 mg/g despite maximum tolerated dose of ACE inhibitor or ARB				Continue nsMRA as tolerated.
Cardiovascular prevention	Statin if CVD risk ≥10% over 10 years HbA _1c <7.0% unless at risk for severe hypoglycemia GLP1RA as the preferred second-line glucose lowering medication for people with diabetes at high cardiovascular risk			Consider statin for all persons. GLP1RA for people with diabetes at high cardiovascular risk	Continue statin.
Bone and anemia complications	If PTH level rises progressively, commence phosphate restriction and then consider therapy with vitamin D or analog. If anemia is out of keeping with GFR, confirm or rule out gastrointestinal blood loss.				Give intravenous iron before ESA if hemoglobin count <10 g/dL. Maintain target hemoglobin count of 10-11.5 g/dL.
Lifestyle and nutritional management	Smoking cessation Moderate exercise up to 30-60 min/day 4-7 days/wk Target weight with BMI <25 kg/m ² Reduced salt intake as per DASH diet <5 g/day GLP1RA as the preferred second line glucose lowering medication for people with diabetes and requiring weight management				Limit dietary potassium excess. Weigh at each clinic and assess fluid overload, anorexia, physical function.
Specific RRT planning steps	Education regarding progression and role of conservative management regarding blood pressure targets and specific primary kidney disease treatment if indicated Hepatitis B vaccination if risk of progression is high			Education on RRT types and palliative care if CKD is progressing or patient is at high risk of progression. Hepatitis B vaccination.	AVF creation PD catheter insertion Enter on list for transplant.
Referral guidance from primary care physician to nephrologist	Progressive or abrupt fall in estimated GFR Proteinuria (urine protein levels >0.5 g/day; ACR >300 mg/g or >30 mg/mmol)			Refer unless patient is terminally ill	Refer unless patient is terminally ill.

ACE, Angiotensin-converting enzyme; ACR, albumin-to-creatinine ratio; AKI, acute kidney injury; ARB, angiotensin receptor blocker; ARVD, atherosclerotic renovascular disease; AVF, arteriovenous fistula; BMI, body mass index; BP, blood pressure; CHF, congestive heart failure; CKD, chronic kidney disease; CVD, cardiovascular disease; DASH, Dietary Approaches to Stop Hypertension; ESA, erythropoietin-stimulating agent; GFR, glomerular filtration rate; GLP1RA , glucagon-like peptide 1 receptor agonists ; HbA _1c , hemoglobin A _1c; PD, peritoneal dialysis; nsMRA , nonsteroidal Mineralocorticoid Receptor Antagonist; PTH, parathyroid hormone; RAAS, renin–angiotensin–aldosterone system; RRT, renal replacement therapy; SGLT2 , sodium-glucose cotransporter-2.

Table 54.3

Causes of Acute Kidney Injury After Initiation of Therapy With Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker

Blood Pressure Insufficient for Adequate Renal Perfusion

Poor cardiac output
Low systemic vascular resistance (e.g., as in sepsis)
Volume depletion (gastrointestinal loss, poor oral intake, excess diuretic use)

Presence of Renal Vascular Disease ^a

Bilateral renal artery stenosis
Stenosis of dominant or single kidney
Afferent arteriolar narrowing (caused by hypertension and cyclosporine)
Diffuse atherosclerosis in smaller renal vessels

Vasoconstrictor Agents (Nonsteroidal Anti-inflammatory Drugs, Cyclosporine)

Initiation and Titration of SGLT2 Inhibitors

Initiation of SGLT2 inhibitors is associated with an initial dip in eGFR, but this change reflects a decrease in intraglomerular pressure due to afferent arteriolar vasoconstriction. This initial dip in eGFR generally should not prompt discontinuation of an SGLT2 inhibitor. First, the efficacy of SGLT2 inhibitors on hard kidney outcomes is consistent, irrespective of the magnitude of the initial dip in eGFR. Second, SGLT2 inhibitors reduce the incidence of AKI and hyperkalemia, suggesting that this initial dip does not lead to long-term deleterious effects. In the SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium (SMART-C) meta-analysis, which includes 13 RCTs and 90,313 participants, SGLT2 inhibitors reduced the incidence of AKI by 23% (HR 0.77, 95% CI, 0.70–0.84). Likewise, in a meta-analysis of 6 RCTs, involving 49875 participants, SGLT2 inhibitors reduced the incidence of serum potassium ≥6 mmol/L by 16% (HR 0.84; 95% CI, 0.76–0.93; Fig. 54.9 ). This benefit was consistent irrespective of baseline kidney function, history of heart failure, and concomitant medications including RAAS inhibitors or diuretics. SGLT2 inhibitors may therefore be considered as an adjunctive treatment to facilitate ongoing treatment with RAAS inhibitors when hyperkalemia is a concern. With respect to laboratory monitoring of kidney function, there is no indication for routine monitoring of kidney function or electrolytes in most persons starting an SGLT2 inhibitor except in persons at high risk of AKI such as the elderly, people with BP <120/70 mm Hg, signs/symptoms of volume depletion, or people taking high-dose diuretics.

A forest plot showing the hazard ratio for various subgroups including H b A 1 c, e G F R, U A C R, heart failure, and medication use comparing S G L T 2 inhibitors and placebo. The forest plot overall results show a hazard ratio of 0.64 for S G L T 2 inhibitors. The plot is divided by subgroups, including H b A 1 c levels, e G F R both above and below 60 mL per min per 1.73 meter squares, U A C R, heart failure status, and use of R A A S inhibitors, diuretics, and M R A s. For each subgroup, the hazard ratios are displayed along with the 95 percent confidence intervals, demonstrating the relative effectiveness of S G L T 2 inhibitors compared to placebo in reducing the hazard of adverse events across these different groups. The study results indicate that S G L T 2 inhibitors are favored over placebo across most subgroups, with minimal variations in effectiveness depending on the subgroup, and no significant interaction between subgroups.

Tags: Ayodele Odutayo, Maarten W. Taal; David Cherney

May 3, 2026 | Posted by drzezo in NEPHROLOGY | Comments Off

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Classification and Management of Chronic Kidney Disease

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Classification of Chronic Kidney Disease

Mechanisms of Disease Progression and The Rationale for Interventions to Achieve Kidney Protection