Diabetic kidney disease

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

General approach

In order to minimize the progression of DKD, treatment should be comprehensive and should involve simultaneous evaluation and management of hyperglycemia, hypertension, dyslipidemia, nutrition, and behavior. Management should involve a combination of lifestyle changes and pharmacotherapies, including those with proven renal and cardiovascular (CV) benefits.[48] Patient behavior and self-management significantly improves diabetic outcomes and DKD outcomes; behavioral strategies, including goal setting and action planning, should be used to support diabetes self-management and engagement in health behaviors.[1][65] Proper nutrition, with decreased intake of saturated fat, cholesterol, and salt, is beneficial.[29][66]

This topic covers the management of nonpregnant adults only. Specialist advice should be sought for the management of DKD in pregnant people.

Treatment of hyperglycemia: general principles

Treatments for hyperglycemia include insulin, other injectable agents, and oral hypoglycemic agents. Patients with type 1 diabetes always require treatment with insulin.

In patients with type 2 diabetes and DKD, special consideration should be given to the use of agents that reduce the risk of both chronic kidney disease (CKD) progression and CV events.[1][67] The benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for renal and CV outcomes have been found to be independent of metformin use, and thus these agents should be considered in people with CKD (as well as those with established or high risk of atherosclerotic cardiovascular disease [ASCVD] or those with established heart failure), independent of metformin use or hemoglobin A1c (HbA1c).[1][47][67][68][69] [ ] American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that most patients with type 2 diabetes and CKD benefit from early initiation of metformin plus an SGLT2 inhibitor, with additional drug therapy as needed for glycemic control.[48]

Patient preferences, comorbidities, and cost should guide selection of drugs, and prescription of certain glucose-lowering medications may be limited by estimated glomerular filtration rate (eGFR). Appropriate dose adjustments, based on eGFR, are important for medications that increase risk of adverse effects with low eGFR or undergo elimination through the kidney.[48] Insulin can be added or substituted as needed. Treatments and the combinations of drugs that are used need to be individualized for each patient.

In patients with CKD, there is a risk for hypoglycemia because of impaired kidney clearance of medications such as insulin (two-thirds of insulin is degraded by the kidney) or sulfonylureas, and because of impaired kidney gluconeogenesis. Caution should be taken when using these medications and patients counseled about the risk of hypoglycemia.[48]

Intensive lowering of blood glucose with the goal of achieving near-normoglycemia has been shown in large, randomized studies to delay the onset and progression of albuminuria and slow eGFR decline in people with type 1 and type 2 diabetes.[1][70][71][72][73][74][75][76][77][78] [ ] The main harm associated with lower HbA1c targets is hypoglycemia. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial of type 2 diabetes, mortality was higher among participants assigned to the lower HbA1c target, perhaps due to hypoglycemia and related CV events.[79] Among patients with diabetes and CKD, a U-shaped association of HbA1c with adverse health outcomes has been observed, suggesting risks with both inadequately controlled blood glucose and excessively lowered blood glucose.[80] However, as KDIGO guidelines note, these data have derived mostly from studies that used glucose-lowering agents known to increase hypoglycemia risk, and lower HbA1c targets may not necessarily lead to a significant increase in hypoglycemia rates when attained using medications with a lower risk of hypoglycemia.[47]

Both the ADA and KDIGO emphasize use of individualized glycemic targets that take into consideration key patient characteristics (such as age, disease progression, and macrovascular risk, as well as the patient's lifestyle and disease management capabilities) that may modify risks and benefits of intensive glycemic control.[48][81]

ADA guidelines recommend keeping HbA1c at <7% (<53 mmol/mol) for most adults with diabetes, suggesting that setting a glycemic goal during consultations is likely to improve patient outcomes.[1] Less stringent goals may be appropriate for very young children, older adults, people with frailty, people with a history of severe hypoglycemia, and those with limited life expectancies, advanced microvascular or macrovascular complications, or comorbid conditions.[1]
Based on randomized controlled trial (RCT) data, KDIGO recommends that individualized HbA1c targets should range from <6.5% to <8.0% (<48 mmol/mol to <64 mmol/mol) for patients with diabetes and CKD not treated with dialysis.[47] Targets in this range have been associated with improvements in survival, CV outcomes, and microvascular endpoints, as well as lower risk of CKD progression. It adds that safe achievement of targets at the lower end of this range (e.g., <6.5% or <7.0% [<48 mmol/mol or <53 mmol/mol]) may be facilitated by continuous glucose monitoring or self-monitoring of blood glucose and by selection of glucose-lowering agents that are not associated with hypoglycemia.[47]

Clinical properties of antihyperglycemic agents

Metformin

Recommended as a first-line therapy for most patients with type 2 diabetes and CKD who have eGFR ≥30 mL/minute/1.73 m².[48]
Proven to be a safe, effective, and affordable foundation for glycemic control.[48]
Cleared by renal filtration, and very high circulating levels (e.g., as a result of overdose or acute renal failure) have been associated with lactic acidosis. However, the occurrence of this complication is now known to be very rare, and metformin may be safely used in people with eGFR ≥30 mL/minute/1.73 m².[1] Metformin is contraindicated if eGFR is <30 mL/minute/1.73 m².[48][82] Dose reduction should be considered when eGFR is <45 mL/minute/1.73 m² in patients continuing on existing therapy. However, metformin should not be initiated in patients with an eGFR of 30-45 mL/minute/1.73 m².[48][67] Dose reduction may also be considered in some patients with eGFR 45-59 mL/minute/1.73 m² who are at high risk of lactic acidosis.[48]
One Cochrane review did not find enough evidence to show that metformin had any effect on kidney function, with the authors concluding that further evidence in the form of large, well‐designed randomized trials is needed to more robustly assess whether metformin can be a long‐term protective treatment in those with CKD.[83]

SGLT2 inhibitors

A consensus statement by the ADA and KDIGO recommends the use of SGLT2 inhibitors in most people with type 2 diabetes and CKD with eGFR ≥20 mL/minute/1.73 m², particularly in (but not restricted to) those with albuminuria.[48] This recommendation is independent of HbA1c and the use of other glucose-lowering agents, as the SGLT2 inhibitor is being used predominantly for its reno- and cardioprotective, rather than antihyperglycemic, effects. Most patients with type 2 diabetes and CKD will therefore benefit from first-line treatment with both metformin and an SGLT2 inhibitor.[47] SGLT2 inhibitor treatment without metformin may be reasonable for: patients with eGFR too low for safe prescription of metformin; those who do not tolerate metformin; or patients who do not need metformin to achieve glycemic targets.[48]
SGLT2 inhibitors reduce hyperglycemia and have added renal benefits through independent effects on renal tubular glucose reabsorption, weight, blood pressure (BP), intraglomerular pressures, albuminuria, and slowed glomerular filtration rate loss.[1][84] They are moderately to highly effective at glycemic control and very effective at reducing proteinuria and slowing the progression of DKD.[68][85][86] Studies suggest that they are effective in mild to moderate CKD.[87][88][89][90][91][92] They reduce the risk of serious hyperkalemia in people with type 2 diabetes and CKD without increasing the risk of hypokalemia.[93][94] Compared with usual care or placebo, they also reduce the risk for all-cause mortality by 12%, major adverse cardiac events (MACE; nonfatal myocardial infarction, nonfatal stroke, and CV mortality) by 10%, and hospitalization due to congestive heart failure by 36%.[95] They have been found to reduce the risk of renal and heart failure outcomes for all eGFR categories, although the greatest benefits in terms of kidney protection may be achieved by their early initiation in people with preserved eGFR.[96][97]
In the CREDENCE trial of canagliflozin versus placebo on renal outcomes in patients with type 2 diabetes with nephropathy, an eGFR 30-90 mL/minute/1.73 m², and albuminuria (ACR >300 mg/g), canagliflozin significantly decreased the risk of kidney failure and CV events.[98] A pooled analysis of the CANVAS and CREDENCE trials found that the risk for the primary kidney composite outcome (doubling of serum creatinine, end-stage kidney disease, renal death) was 37% lower in the canagliflozin group versus placebo, with no evidence of heterogeneity in the renoprotective effects of canagliflozin across a broad spectrum of participants with type 2 diabetes and varying levels of baseline kidney function.[99]
The DAPA-CKD trial demonstrated benefits of dapagliflozin in reducing progression of CKD and hospitalization for heart failure in both diabetic and nondiabetic patients down to an eGFR of 25 mL/minute/1.73 m².[100]
The EMPA-KIDNEY trial, which enrolled patients with eGFR as low as 20 mL/minute/1.73m², found that empagliflozin therapy led to a lower risk of progression of kidney disease or death from CV causes than placebo.[101] The trial was stopped early due to the effectiveness of the study medication.
In post-hoc analysis of the DECLARE-TIMI 38 CV outcome trial, dapagliflozin mitigated kidney function decline in patients with type 2 diabetes at high CV risk, including those with low KDIGO risk, suggesting a possible role for SGLT2 inhibitors in the early prevention of DKD.[102]
While the glucose-lowering effects of these drugs are blunted with eGFR <45 mL/minute/1.73 m², the renal and CV benefits are still seen at eGFR levels as low as 20 mL/minute/1.73 m², even with no significant change in glucose.[1]
Initiation of an SGLT2 inhibitor is generally not recommended (or should be done with caution) in patients with eGFR <20 mL/minute/1.73 m², but once initiated, the SGLT2 inhibitor may be continued at lower eGFR levels, unless it is not tolerated or kidney replacement therapy is initiated.[48] SGLT2 inhibitor initiation is associated with a reversible decline in eGFR, but this generally does not require drug discontinuation.[48] Concerns that these agents can cause acute kidney injury have been refuted by clinical outcome trials of advanced CKD.[98]
Indications for SGLT2 inhibitors are expanding rapidly; some are now indicated to help preserve kidney function and protect against end-stage renal disease (ESRD), even in the absence of diabetes mellitus and albuminuria, as well as to protect against CV death and hospitalization for heart failure.[103]

Dual SGLT1/SGLT2 inhibitor

Sotagliflozin is the first and only dual SGLT1/SGLT2 inhibitor.[104] It inhibits both renal SGLT2 (promoting significant excretion of glucose in the urine, in the same way as other already available SGLT2 selective inhibitors) and intestinal SGLT1 (delaying glucose absorption and therefore reducing postprandial glucose).[104]
Sotagliflozin is approved by the Food and Drug Administration (FDA) to reduce the risk of CV death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure, or with type 2 diabetes mellitus, CKD, and other CV risk factors.
The approval was based on two randomized, double-blind, placebo-controlled phase 3 cardiovascular outcome trials: SOLOIST-WHF (effects of sotagliflozin on clinical outcomes in hemodynamically stable patients with type 2 diabetes post worsening heart failure) and SCORED (effects of sotagliflozin on cardiovascular and renal events in patients with type 2 diabetes mellitus, cardiovascular risk factors, and moderately impaired renal function).[105][106]
Sotagliflozin has not been studied in patients with eGFR <25 mL/minute/1.73 m².

GLP-1 receptor agonists

Highly effective antidiabetic medications that have been shown to reduce the risk for all-cause mortality and major adverse CV events.[95][107] Notably, they retain glycemic efficacy and safety even in advanced CKD stages.[48] They may also improve renal outcomes independent of glucose-lowering effect and may have additional benefits of weight loss.[108][109][110] Their beneficial effect on renal outcomes appears to be inferior to that of SGLT2 inhibitors, however.[111]
Unlike for SGLT2 inhibitors, the evidence for GLP-1 receptor agonists in reducing heart failure has been inconsistent across trials. One meta-analysis found that they may prevent new-onset heart failure and mortality in patients with type 2 diabetes; however, they did not reduce heart failure hospitalizations and mortality in those patients with preexisting heart failure.[112]
A pooled analysis of two randomized controlled trials in patients with type 2 diabetes assessed the effect of liraglutide and semaglutide on the kidney outcomes of albuminuria change, annual slope of eGFR change, and time to persistent eGFR reduction from baseline; it concluded that these drugs offered kidney-protective effects that are more pronounced in patients with preexisting CKD.[113]
The landmark FLOW trial, a double-blind, randomized, placebo-controlled international trial comprising 3533 patients, with a median follow-up period of 3.4 years, was designed to assess the efficacy and safety of subcutaneous semaglutide in preventing major kidney outcomes (specifically kidney failure, substantial loss of kidney function, and death from kidney or CV causes) in individuals with type 2 diabetes and CKD.[114] Participants who received semaglutide had a 24% risk reduction for the composite primary endpoint compared with those who received placebo. This reduction risk was consistent across both kidney-specific and CV death outcomes. Secondary endpoints also showed significant improvements with semaglutide; specifically, the total eGFR slope was 1.16 mL/minute/1.73 m² per year slower, the risk of major CV events was decreased by 18%, and the risk of all-cause mortality was reduced by 20%.[114]
The ADA gives strong support to the use of GLP-1 receptor agonists in patients with type 2 diabetes and established ASCVD, multiple ASCVD risk factors, or DKD, in consideration of their primary CV and secondary kidney benefits in large CV outcome trials.[1] A consensus statement from the ADA and KDIGO recommends using a GLP-1 receptor agonist with proven CV benefit in patients with type 2 diabetes and CKD if they do not meet their individualized glycemic target with metformin and/or an SGLT2 inhibitor, or if these drugs are not tolerated/contraindicated.[48]
Experience with GLP-1 receptor agonists in patients with renal dysfunction is more limited than with SGLT2 inhibitors; therefore, they should be used with caution.[69] [ ] Acute kidney injury has been reported with semaglutide.[115]
Liraglutide, dulaglutide, and semaglutide are not renally excreted and are the preferred agents in this class. Exenatide is eliminated by renal excretion and should not be used in patients with severe renal impairment; the immediate-release formulation should not be used in patients with an eGFR <30 mL/minute/1.73 m², while the extended-release formulation should not be used in patients with an eGFR <45 mL/minute/1.73 m².

Combination therapy with an SGLT2 inhibitor and GLP-1 receptor agonist

If a patient is taking an SGLT2 inhibitor or GLP-1 receptor agonist and requires additional pharmacotherapy for glucose-lowering, combined therapy with an SGLT2 inhibitor plus a GLP-1 receptor agonist may be considered.[1]
This combination has been shown to be effective in improving glycemic control, and emerging evidence suggests that it may provide additive reduction in the risk of adverse CV and kidney events.[1][48][116][117]

Dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist

Tirzepatide is the first and only dual GIP/GLP-1 receptor agonist to receive approval; it has been approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
Suitable for patients with overweight or obesity without gastroparesis who desire weight loss, are willing to take injections, and can tolerate the common adverse effect of initial nausea. May be used in patients with renal impairment of any degree, and no dose adjustment is required.
Has been shown to have a greater effect on glucose levels and weight control than selective GLP-1 receptor agonists, without increased risk of hypoglycemia.[118][119][120] The SURPASS-3 trial demonstrated that in patients with type 2 diabetes, tirzepatide was superior to titrated insulin degludec, with greater reductions in HbA1c and bodyweight at week 52 and a lower risk of hypoglycemia.[121] The SURPASS-4 trial demonstrated that in patients with type 2 diabetes and elevated CV risk, tirzepatide, when compared with insulin glargine, demonstrated greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycemia.[122] Furthermore, in post-hoc analysis of SURPASS-4, tirzepatide slowed the rate of eGFR decline and reduced urinary ACR in clinically meaningful ways compared with insulin glargine.[123]
CV safety trials are under way.

Dipeptidyl peptidase-4 (DPP-4) inhibitors

Studies report that DPP-4 inhibitors may be renoprotective, although evidence is weak in comparison to that for SGLT2 inhibitors.[124] DPP-4 inhibitors show pleiotropic effects in in vitro models, reducing inflammation, fibrosis, and oxidative damage, suggesting potential kidney-protective effects.[125] Although existing trials suggest a possible benefit in the progression of DKD, further studies are needed to demonstrate kidney-specific benefits.[125] The ADA and European Association for the Study of Diabetes (EASD) report that at a class level, DPP-4 inhibitors have a neutral effect on progression of DKD.[67]
Sitagliptin, saxagliptin, and alogliptin can be used in patients with DKD, but the doses must be adjusted depending on the degree of renal dysfunction. Linagliptin can also be used in patients with DKD, including ESRD, though there is limited experience with its use. Linagliptin has the advantage that it is not renally cleared and thus a dose adjustment is not necessary.
According to a 2022 meta-analysis of randomized controlled trials, combining DPP-4 inhibitors with insulin is safe and effective for patients with DKD.[126]

Sulfonylureas and meglitinides

If other agents are required for glycemic control, glipizide is the sulfonylurea agent of choice due to its metabolite having little or no hypoglycemic activity.[66] Glimepiride is also acceptable, but glyburide should not be used, due to accumulation of active metabolites and increased risk of hypoglycemia.
Nateglinide is a meglitinide that is not renally cleared and is considered within its drug class to be safest for CKD.[127]

Thiazolidenediones

Although there is evidence showing that thiazolidinediones (e.g., pioglitazone) reduce hyperglycemia, albuminuria, and proteinuria in people with diabetes, the clinical significance of this finding is unclear.[128]
The ADA/EASD report that they have a neutral effect on progression of DKD.[1][67]
Thiazolidinediones are associated with fluid retention and should be avoided in patients with advanced CKD and in patients on dialysis.

Insulin

Treatment with insulin is required if there is evidence of ongoing catabolism (weight loss, hypertriglyceridemia, and ketosis), symptoms of hyperglycemia (polyuria and polydipsia), or when HbA1c or blood glucose levels are very high (i.e., HbA1c >10% and/or blood glucose ≥300 mg/dL [≥16.7 mmol/L]), regardless of background glucose-lowering therapy or disease stage.[1]
Intensification to insulin is also an option for individuals who are not meeting their glycemic targets on other antihyperglycemic agents; it is necessary in at least 20% to 30% of those with type 2 diabetes in order to achieve recommended treatment goals.
Of note, the ADA recommends that a GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist should be considered prior to insulin if injectable therapy is needed and the patient is not already being treated with one of these drugs.[1]
If insulin is used, combination therapy with a GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist (if the patient is not already on one of these agents) is recommended for greater glycemic efficacy, as well as the beneficial effects of these drugs on reducing weight and hypoglycemia risk (as lower insulin doses can be used), reducing CV events (GLP-1 receptor agonists), and slowing CKD progression (semaglutide).[1]

Glycemic management in advanced CKD (eGFR <30 mL/minute/1.73 m², with or without renal replacement therapy)

Glycemic management is particularly challenging for patients with eGFR <30 mL/minute/1.73 m², including those treated with dialysis, because of restrictions on drug use and lack of high-quality randomized controlled trials (RCTs) in this population.[48]

For type 1 diabetes, insulin remains the only approved therapy. Doses are titrated to achieve individualized glycemic goals but may need to be decreased in comparison with earlier stages of CKD due to reduced insulin clearance and other changes in metabolism with advanced CKD.[48]

In type 2 diabetes, advanced CKD is a risk factor for hypoglycemia and, when possible, drugs that control glycemia without increasing risk of hypoglycemia are preferred.

Metformin is contraindicated with eGFR <30 mL/minute/1.73 m² and with dialysis treatment.[48]
SGLT2 inhibitors can be initiated with eGFR 20-29 mL/minute/1.73 m² and continued at lower eGFR if previously initiated and well tolerated. However, they have minimal effects on glycemia in this range of eGFR and are of use mainly for kidney and CV benefits not mediated through glycemia.[48] Very few data are available evaluating use of SGLT2 inhibitors for patients receiving dialysis, and the glycosuric actions of SGLT2 inhibitors are likely insignificant with this degree of kidney failure. For this reason, KDIGO guidelines advise that they should be discontinued prior to initiation of dialysis treatment.[47]
GLP-1 receptor agonists have been studied with eGFR as low as 15 mL/minute/1.73 m² and retain glucose-lowering potency across the range of eGFRs and among dialysis patients.[48] They have been shown to reduce ASCVD events and albuminuria in large RCTs; they are thus theoretically appealing for people with type 2 diabetes and advanced CKD, but have not been prospectively tested for CV efficacy or safety in this population.[48] However, findings of a meta-analysis of the CV outcome trials showed that ASCVD risk was reduced at least as much among individuals with eGFR <60 mL/minute/1.73 m² compared with those with higher eGFR.[129] GLP-1 receptor agonists induce weight loss and can cause nausea and vomiting, so caution is warranted among patients with or at risk for malnutrition. Notably, in people who have obesity exceeding body mass index (BMI) limits required for kidney transplant listing, GLP-1 receptor agonists can be used to aid weight loss that may facilitate qualification for transplant.[48]
Tirzepatide can be used in patients with advanced DKD. No adjustment in dose is required. In people with renal impairment including ESRD, no change in tirzepatide pharmacokinetics was observed.[130]
Selected DPP-4 inhibitors can be used with eGFR <30 mL/minute/1.73 m² and with dialysis (a dose adjustment may be required) and provide a safe and effective option for treatment of patients who are not treated with GLP-1 receptor agonists.[48]
Thiazolidinediones improve insulin sensitivity, a common abnormality in advanced CKD, and retain antihyperglycemic effects in this population. Fluid retention and heart failure are concerns with low eGFR and require careful monitoring.[48]
Insulin and short-acting sulfonylureas are often necessary to control glucose when medications with less propensity to cause hypoglycemia are contraindicated, not tolerated, unavailable, or insufficient.[48]

While both ADA and KDIGO focus on HbA1c as the primary tool for assessing long-term glycemic control, both guidelines acknowledge limitations in its accuracy and precision as an indirect metric of glycemic status, particularly in advanced CKD and kidney failure treated by dialysis, and the inability of HbA1c to adequately capture glycemic variability and hypoglycemic events.[48] Continuous glucose monitoring (CGM) should be considered as an additional tool to assess overall glycemia and the effectiveness and safety of treatment among patients at risk for hypoglycemia.[48] Direct glucose estimations via self-monitoring of blood glucose should also be offered as a tool to guide medication adjustment, particularly in patients treated with insulin.[48][131]

Treatment of hypertension

Treatment of hypertension reduces progression of DKD.[1] Intensive blood pressure (BP) lowering provides protection against kidney failure, particularly among those with proteinuria.[132]

There is a lack of high-quality evidence regarding the optimal treatment goal for hypertension in people with diabetes.[133] However, US and European guidelines recommend a general BP target of <130/80 mmHg, providing this can be safely attained.[1][134][135][136] The departure in the guidelines from the previous BP target of <140/90 mmHg was in response to studies like the meta-analysis of data from the ACCORD-BP and SPRINT trials, which showed a reduction in a composite of unstable angina, myocardial infarction, acute heart failure, stroke, and CV death with intensive systolic BP targets of <120 mmHg compared with the traditional target of <140 mmHg.[137] Notably, the ADA recommends an individualized approach to BP targets, and recommends that patients and clinicians should engage in a shared decision-making process to determine individual BP targets, acknowledging that the benefits and risks of intensive BP targets are uncertain.[1]

Lower BP targets may be suitable in some cases, especially in patients with severely elevated albuminuria (ACR ≥300 mg/g), provided the patient's individual benefits and risks have been taken into account.[1] Of note, KDIGO guidelines recommend a lower systolic BP goal of <120 mmHg (when tolerated) in adults with hypertension and CKD, noting that evidence for the benefits of intensive BP control is less certain in patients with diabetes than those without.[138][139][140]

ACE inhibitors and angiotensin-II receptor antagonists

The ADA recommends that all individuals with type 1 or 2 diabetes and BP ≥130/80 mmHg should qualify for pharmacologic therapy to lower BP.[1]

First-line treatment of patients with diabetes, hypertension, and albuminuria should be with an ACE inhibitor, or an angiotensin-II receptor antagonist if an ACE inhibitor is not tolerated, titrated to the highest tolerated approved dose (a dose reduction may be required in patients with renal impairment).[1][48][133][136][141] Treatment with these drugs has been shown to reduce proteinuria and slow the progression of DKD in patients with type 1 and type 2 diabetes with moderately increased albuminuria.[142][143][144] [ ] The ONTARGET study demonstrated that angiotensin-II receptor antagonists and ACE inhibitors are equal in prevention of CV morbidity and mortality, myocardial infarction, and stroke.[145][146]

While ADA and KDIGO guidelines specify that ACE inhibitors and angiotensin-II receptor antagonists should be used in those patients with albuminuria who have coexisting hypertension, the KDIGO guidelines note that for patients with diabetes, albuminuria, and normal BP, treatment with an ACE inhibitor or angiotensin-II receptor antagonist may be considered.[1][47] Available data suggest that ACE inhibitors and angiotensin-II receptor antagonists are not beneficial for patients with neither albuminuria nor elevated BP.[47] The ADA comments that while ACE inhibitors or angiotensin-II receptor antagonists are often prescribed for moderately increased albuminuria (ACR 30-299 mg/g) without hypertension, trials have not been performed in this setting to determine whether they improve renal outcomes.[1] Moreover, two long-term, double-blind studies demonstrated no renoprotective effect of either ACE inhibitors or angiotensin-II receptor antagonists among people with type 1 and type 2 diabetes who were normotensive, with or without moderately increased albuminuria.[147][148]

Dual therapy with an ACE inhibitor and an angiotensin-II receptor antagonist has been extensively studied in patients with albuminuria, including DKD.[149] Dual blockade reduced proteinuria to a greater extent than monotherapy, and was associated with a decrease in BP, but also a small decline in GFR and increase in serum potassium.[150] However, two large clinical trials in diabetic patients with overt proteinuria (ALTITUDE, NEPHRON-D) have been stopped due to adverse safety events (hyperkalemia, acute kidney injury).[151][152] On the basis of this evidence, dual blockade should not be employed in patients with overt DKD.

ACE inhibitors and angiotensin-II receptor antagonists are generally well tolerated. However, dry cough is a known adverse effect of ACE inhibitor treatment, affecting about 10% of patients.[47] Angioedema has also been associated with the use of ACE inhibitors.[47] It has been postulated that these adverse effects are due to the inhibition of ACE-dependent degradation of bradykinin, and consideration can be given to switching affected patients to an angiotensin-II receptor antagonist.[47] The incidence of angioedema with angiotensin-II receptor antagonists is not significantly different from that of placebo.[153] ACE inhibitors and angiotensin-II receptor antagonists can also cause hypotension, hyperkalemia, and a rise in serum creatinine. Consequently, BP, serum potassium, and serum creatinine should be monitored in patients who are started on these medications or whenever there is a change in the dose of the drug. The changes in BP, potassium, and kidney function are usually reversible if medication is stopped or doses are reduced.[47]

Alternative first-line antihypertensive pharmacotherapy (for patients without albuminuria)

Patients with diabetes and hypertension are at lower risk of CKD progression when urine albumin excretion is normal (ACR <30 mg/g), and existing evidence does not demonstrate clear clinical benefit of renin-angiotensin system inhibition for CKD progression in this population.[47] CV risk reduction is the most important goal of BP management with normal urine albumin excretion, and multiple classes of antihypertensive agents (including ACE inhibitors or angiotensin-II receptor antagonists, diuretics, and dihydropyridine calcium-channel blockers) are appropriate first-line options in this setting.[47]

Additional antihypertensive pharmacotherapy (if BP not controlled on a single agent)

Additional antihypertensive therapy is required in most patients to reach BP targets.[154][155] Dihydropyridine calcium-channel blockers, thiazide-like diuretics, or beta-blockers are commonly used as add-on agents to ACE inhibitors or angiotensin-II receptor antagonists and may be used in combination as triple-therapy (i.e., with an ACE inhibitor or angiotensin-II receptor antagonist) if required.[155][156] Beta-blockers may mask symptoms of hypoglycemia, but may be used as add-on treatment in patients who require multiple agents to reach BP targets or in those with another indication for the use of beta-blockers (e.g., ischemic heart disease).[155]

Diuretics are almost always required to control BP in advanced DKD. While loop diuretics have long been the cornerstone of therapy in such patients, the CLICK trial demonstrated that chlorthalidone (a thiazide-like diuretic) with or without a loop diuretic is also effective.[157] Although diuretics are generally ineffective for BP management in patients on dialysis, in selected patients with residual renal function, loop diuretics may still be efficacious in preventing fluid overload and hypertension as adjunctive therapy to ultrafiltration during dialysis. Moderation of dietary sodium potentiates the renal and CV protective effects of angiotensin-II receptor antagonists.[158]

Management of hypertension in patients on dialysis

Management of hypertension is challenging in this population and requires specialist review.[159] There is insufficient evidence from data in the published literature to decide how best to manage BP in people with diabetes who are on dialysis.[160] Many factors affect BP in this population, including fluid status, salt intake, sympathetic nervous system activity, and the renin-angiotensin-aldosterone system.[160] People with diabetes who are undergoing hemodialysis often have autonomic dysfunction, which increases the risk of CV instabilities during dialysis; it causes severe orthostatic reduction in cerebral blood flow velocity and may subsequently increase the risk of cerebrovascular injury post hemodialysis. This makes management of hypertension in people with diabetes who are on dialysis even more challenging.[160]

Kidney Disease: Improving Global Outcomes (KDIGO) guidance does not make a recommendation for BP targets in patients on dialysis.[138] UK guidelines suggest a target BP of <140/90 mmHg between dialysis sessions for patients on hemodialysis. The same target is suggested for patients on peritoneal dialysis.[160] Individualization of the BP target may be indicated in patients with multiple comorbidities in order to reduce potential adverse events of BP lowering. Hypotension between dialysis sessions should be avoided in patients on hemodialysis.[160]

UK guidelines suggest using ACE inhibitors or angiotensin-II receptor antagonists (but not in combination) and/or dihydropyridine calcium-channel blockers and/or beta-blockers to reduce CV complications.[160] Diuretics are also recommended in people with diabetes who are on dialysis and have residual renal function.[160] Combination therapy with agents from different classes is required in most patients to reach BP targets.[154][155] There are few data on the effectiveness of renin-angiotensin system blockade in patients with diabetes and ESRD; however, use of these agents may improve CV outcomes and lower mortality.[161]

Role of nonsteroidal mineralocorticoid receptor antagonists

Despite guideline-directed therapies, people with type 2 diabetes and CKD with persistent albuminuria remain at increased risk for CV events and CKD progression.[1][47] Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has been shown to reduce both of these outcomes, irrespective of baseline atherosclerotic CV disease (ASCVD) history.[1] It is the first mineralocorticoid receptor antagonist to demonstrate positive kidney and CV outcomes in patients with CKD associated with type 2 diabetes.[162][163] It has also shown benefit in reducing all-cause mortality and new-onset hypertension.[164] By blocking mineralocorticoid receptor overactivation, a key driver of CKD progression and fibrosis, finerenone works on a pathway largely unaddressed by existing treatments for CKD in type 2 diabetes. Finerenone efficacy is not modified by baseline HbA1c, HbA1c variability, diabetes duration, or baseline insulin use.[165]

Guidelines recommend that for patients with type 2 diabetes and CKD with persistent albuminuria (≥30 mg/g) despite maximum tolerated doses of an ACE inhibitor or angiotensin-II receptor antagonist, finerenone should be added.[1][47][166] It can be used simultaneously with SGLT2 inhibitors.

In a 2020 double-blind trial of patients with diabetes and CKD treated with renin-angiotensin system blockade (FIDELIO-DKD), treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo, albeit with an increased risk of hyperkalemia.[167]
The FIGARO-DKD analyses demonstrate that finerenone reduces new-onset heart failure and improves other heart failure outcomes in patients with CKD and type 2 diabetes, irrespective of a history of heart failure.[168]
The FIDELITY prespecified pooled efficacy and safety analysis, which incorporated patients from both FIDELIO and FIGARO, showed a 14% reduction in composite CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure for finerenone when compared with placebo, as well as a 23% reduction in the composite kidney outcome, consisting of sustained ≥57% decrease in eGFR from baseline over ≥4 weeks, or renal death. The benefit was consistent across all age and sex subgroups.[169]

The main risk of finerenone is hyperkalemia, although finerenone has a lower risk of hyperkalemia and/or acute kidney injury compared with spironolactone. People with lower eGFR, higher serum potassium levels, or previous episodes of hyperkalemia are at increased risk for developing hyperkalemia. Accordingly, finerenone should be used with caution and with more frequent monitoring in people with these characteristics.[170] Finerenone should not be initiated if eGFR is <25 mL/minute/1.73m² and should be discontinued in people who have progressed to ESRD (eGFR <15 mL/minute/1.73m²). It should not be initiated if serum potassium level is >5.0 mmol/L. The risk of hyperkalemia increases with concomitant medications that can raise serum potassium, and finerenone should not be administered with potassium-sparing diuretics or other mineralocorticoid antagonists.[170] Other common (≥1/100 to <1/10) adverse effects include hypotension, decreased eGFR, and pruritus.[170]

Role of aldosterone antagonists

Joint ADA/KDIGO consensus guidelines recommend aldosterone antagonists, also known as steroidal mineralocorticoid receptor antagonists (e.g., spironolactone, eplerenone), only in patients with resistant hypertension (BP above target despite ACE inhibitors/angiotensin-II receptor antagonists, calcium-channel blockers, and thiazide-like diuretics) and eGFR ≥45 mL/minute/1.73 m².[48] These agents have established CV benefits in those with heart failure and are also useful for treating primary hyperaldosteronism in those with normal eGFR.[48] They also reduce albuminuria.[47] However, their effects on kidney disease progression (eGFR decline or kidney failure) have not been examined in larger trials, and hence their benefits on clinical kidney outcomes remain uncertain. Furthermore, their use increases the risk of hyperkalemia (2-3 fold) and acute kidney injury (2-fold). These adverse effects have limited the use of these agents in patients with DKD.[47]

Spironolactone should theoretically be promising in the treatment of DKD and has been shown to lower BP in these patients.[171] However, long-term data are lacking and there are concerns about hyperkalemia in the presence of decreased renal function.[172] In a study in which some subjects had substantial renal dysfunction, serum potassium >6 mEq/L was noted in 52% of patients treated with combined high-dose ACE inhibitors plus low-dose spironolactone.[173] Gynecomastia is another potential adverse effect.
In a large study of patients with moderately increased albuminuria with generally preserved renal function, eplerenone in combination with the ACE inhibitor lisinopril decreased albuminuria by about 40%; however, 8% of patients treated with the higher dose of eplerenone had to be withdrawn from the study due to hyperkalemia.[174]

Treatment of dyslipidemia

People with DKD have a high risk of CV events. Management of CV risk should therefore be a strong consideration in order to reduce mortality from ASCVD. Low-density lipoprotein cholesterol (LDL-C) is the most extensively studied modifiable risk factor associated with ASCVD. There is strong evidence that it is a causal factor in the pathophysiology of CVD, and that CVD risk reduction is proportional to the absolute and relative LDL-C reduction achieved.[175]

ADA/KDIGO consensus guidelines recommend a statin for all patients with type 1 diabetes or type 2 diabetes and CKD; moderate-intensity statin therapy for primary prevention of ASCVD; and high-intensity statin therapy for patients with known ASCVD and some patients with multiple CVD risk factors.[48] The Endocrine Society recommends that all adults with diabetes with CKD stages 1-4 and post renal transplant should receive statin therapy, irrespective of their CV risk score.[176] Guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) recommend that lipid treatment should be guided by CVD risk.[177]

For primary prevention of CVD in adults with diabetes without established CVD, the ADA recommends:[1]

Moderate-intensity statin therapy in all people ages 40-75 years. Consideration of statin therapy in patients ages 20-39 years with additional ASCVD risk factors.
High-intensity statin therapy in people ages 40-75 years at higher CV risk, including those with one or more CVD risk factors, to reduce LDL-C by ≥50% of baseline and to target an LDL-C goal of <70 mg/dL (<1.81 mmol/L).
Consider addition of ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibody (e.g., alirocumab, evolocumab) to maximum tolerated statin therapy in people ages 40-75 years at higher CV risk, especially those with multiple CVD risk factors and LDL-C ≥70 mg/dL (≥1.81 mmol/L).
For adults ages >75 years already established on statin therapy, it is reasonable to continue statin treatment. It may be reasonable to initiate moderate-intensity statin therapy in this age group following discussion of the potential benefits and risks.
In people intolerant of statin therapy, treatment with bempedoic acid is recommended as an alternative cholesterol-lowering therapy.

Given that CKD and albuminuria are classed as CVD risk factors, the majority of patients with DKD over 20 years of age should be treated with a statin based on this guidance.[1] Guidelines for lipid management differ for patients with diabetes who have established cardiovascular disease (i.e., secondary prevention). For further information, see Diabetic cardiovascular disease.

Statins may decrease the rate of reduction in GFR and moderately decrease progressive increase in proteinuria in CKD.[26] Consideration should be given to the renal clearance of the statin. Pitavastatin, pravastatin, and rosuvastatin all have at least partial clearance through the kidney, whereas atorvastatin, fluvastatin, lovastatin, and simvastatin are cleared via the liver.[176] All statins require dose adjustments in CKD, except for atorvastatin and fluvastatin.[176]

While statins have been shown to decrease mortality and CV events in CKD, their efficacy in patients with ESRD and in kidney or kidney-pancreas transplant recipients remains unproven.[25] In patients on dialysis, continuation of statins is recommended for those already taking them; however, they should not be initiated for primary prevention of CVD due to lack of evidence of benefit in this population.[177][178][179] Patients on dialysis with established CVD and/or with incident CV events (such as myocardial infarction) can appropriately receive statins.

If target LDL-C is not achieved with a statin alone, addition of ezetimibe or a PCSK9 inhibitor (e.g., alirocumab, evolocumab) can be considered.[1] In the SHARP study, a reduction of LDL-cholesterol with simvastatin plus ezetimibe reduced the incidence of major atherosclerotic events in a wide range of patients with advanced CKD.[179] Moderate-intensity statin with ezetimibe combination therapy has been shown to be a suitable alternative to high-intensity statin therapy if the latter cannot be tolerated, or if further reduction in LDL-C is required.[180]

Bempedoic acid, an adenosine triphosphate-citrate lyase inhibitor, is a novel oral LDL-C-lowering drug that works by inhibiting cholesterol synthesis.[135] The ADA advises that it may be considered for patients who cannot use, or tolerate, other evidence-based LDL-C-lowering approaches, or for whom those other therapies are inadequately effective.[1]

Icosapent ethyl, an omega-3 fatty acid, can be considered in patients with additional CV risk factors who are on a statin and have controlled LDL-C but elevated triglycerides (135-499 mg/dL [1.53 to 5.64 mmol/L]).[1] It has been shown to modestly reduce CV events.[181][182]

One systematic review and meta-analysis of fibrate therapy, which is an effective treatment for lowering very high triglyceride levels, concluded that it prevented CV events and decreased proteinuria in mild to moderate CKD.[183] Fibrates, however, are not generally recommended in patients with CKD, especially those with eGFR <30 mL/minute/1.73 m².

Smoking cessation

Smoking cessation is strongly recommended, as studies document a relation between smoking and loss of GFR. The mechanisms underlying the adverse renal effects of smoking are still incompletely understood. Beyond its effect on progression of renal failure, smoking is also an important CV risk factor in patients with CKD.[184]

ADA guidelines do not support e-cigarettes as an alternative to smoking nor to facilitate smoking cessation.[1]

For further information see Smoking cessation.

Nutrition

Medical nutrition therapy by a registered dietitian is recommended for patients with type 1 or type 2 diabetes.[29][185] An initial series of 3 to 4 encounters results in positive outcomes, including reductions in HbA1c, lipids, and weight, a positive adjustment in medications, and a decrease in comorbidities. In addition, patients should have a follow-up visit annually.[185]

High-protein diets should be avoided.[1][4][27] Every patient should be assessed individually to weigh the benefits of a moderate-protein diet (and associated avoidance of aminoaciduria and hyperfiltration); low-protein diets (0.6 g/kg) should be avoided due to the risks of malnutrition.[29][30] One Cochrane review was unable to show a benefit of low-protein diets on progression of DKD.[28] ADA and KDIGO guidelines suggest maintaining a protein intake of 0.8 g/kg body weight per day for those with DKD not treated with dialysis.[1][47] For patients on dialysis, higher levels of dietary protein intake should be considered as protein energy wasting is a major problem in this group.[1][186]

Limited intake of saturated fat, cholesterol, and sodium (<2 g/day) is beneficial.[1] Individualization of dietary potassium may be necessary to control serum potassium concentrations.[1][187] [ ] Although a multivitamin is recommended, high doses of B vitamins have been found to result in increased vascular events.[188]

Physical activity

KDIGO guidelines recommend that people with DKD undertake moderate-intensity physical activity for a cumulative duration of at least 150 minutes per week, or to a level compatible with their CV and physical tolerance.[47] A UK cohort study found that any level of leisure-time physical activity was associated with a lower risk of nephropathy in individuals with type 2 diabetes.[189] One meta-analysis reported that physical activity is effective for improving DKD and slowing its progression; however, more high-quality randomized controlled trials are required.[190]

Although dedicated trials among dialysis patients with diabetes are lacking, simple home-based exercise programs have been shown to be feasible and offer health benefits in those on dialysis.[47]

Management of obesity and overweight

The ADA recommends that weight management is a primary goal of treatment in patients with type 2 diabetes and overweight or obesity.[1] Weight loss strategies may include behavioral and lifestyle counseling, pharmacotherapy, and metabolic surgery. The ADA advises that any amount of weight loss will be beneficial, but that losing 3% to 7% of baseline weight improves glycemia and other cardiovascular risk factors. A sustained loss of >10% of body weight may result in disease-modifying effects and remission of type 2 diabetes.[1]

KDIGO guidelines recommend weight loss in patients with obesity, diabetes, and CKD, particularly those with eGFR ≥30 mL/minute per 1.73 m².[47] Additionally, weight loss will be required for those who exceed BMI limits for kidney transplant listing.[47][48]

When selecting an antihyperglycemic agent in those with type 2 diabetes mellitus, CKD, and obesity, a GLP-1 receptor agonist or tirzepatide may be preferred to promote intentional weight loss.[1][47]

More research is needed to determine the direct effect of weight loss interventions on renal function in patients with obesity and diabetes.[191]

Pancreas-kidney transplantation

Diabetes is the most common cause of ESRD requiring renal replacement therapy (RRT). RRT is associated with inflammation and significant morbidity and mortality. However, often patients are more concerned with day to day factors such as time constraints, and adverse effects such as cramps, fatigue, and central venous stenosis. Pancreas-kidney transplantation not only frees patients from the need for RRT but also has a significant survival benefit. With modern surgical and immunosuppressive protocols, 5-year patient survival is 95%, kidney survival is 90%, and pancreas survival is greater than 80%.[192]

Simultaneous pancreas kidney (SPK) recipients are generally younger (≤60 years) than kidney transplant recipients (≤70 years). They are usually patients with type 1 diabetes who have hypoglycemia unawareness or markedly uncontrolled diabetes; generally they are on insulin therapy (typically <1 unit/kg/day) and their C-peptide is <2 nanograms/mL. Patients with type 2 diabetes may be considered if they do not have significant insulin resistance (C-peptide >2 and BMI <30). In addition, recipients must have an eGFR <20 mL/minute/1.73 m² or be dialysis dependent. They must go through strict CV, psychosocial, and anatomic (computed tomography angiogram) clearance.[192]

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