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    Chronic Kidney Disease Management in the Patient With Diabetes Mellitus

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    Oct.28.2024

    Chronic Kidney Disease Management in the Patient With Diabetes Mellitus

    Summary

    Key Points

    • Early identification and management of CKD (chronic kidney transplant) in patients with diabetes are key to an optimal outcome
    • Multidisciplinary and patient-focused care to control hyperglycemia and blood pressure, optimize weight, provide dietary counseling, and encourage self-management to improve overall health can be particularly effective in early stages
    • RAS blockade should be considered for CKD in diabetes when patients have hypertension and/or proteinuria
    • Variety of agents are available for glycemic control, and where possible, regimens should be tailored to take advantage of those agents that have been shown to have favorable effects on renal outcomes (eg, SGLT2 inhibitors [sodium-glucose cotransporter 2] and, to a lesser extent, GLP-1 RAs [glucagonlike peptide 1 receptor agonists])
      • SGLT2 inhibitors and GLP-1 RAs are drug classes that have been shown to improve a broad spectrum of cardiovascular and kidney-specific outcomes in patients with type 2 diabetes
    • Nonsteroidal mineralocorticoid receptor antagonists, finerenone, is beneficial for reducing albuminuria and lowering cardiovascular risk in patients with diabetes and albuminuria

    Alarm Signs and Symptoms

    • Rapid decline or severely reduced kidney function
    • Rapid increase or profound elevation of proteinuria or albuminuria
    • Sudden unexplained development of swelling or generalized fluid overload
    • Uremic symptoms, though many are nonspecific and may have a more benign explanation

    Basic Information

    Terminology

    • Diabetic nephropathy: a pathologic entity in which histopathology may vary depending on how advanced the disease process is and whether it is type 1 or type 2 diabetes1,2
      • Pathologic findings may include:3
        • Glomerular lesions, such as thickening of basement membrane, mesangial expansion, and glomerular nodular sclerosis
        • Tubulointerstitial lesions, such as tubular atrophy and interstitial fibrosis or inflammation
        • Vascular lesions, such as arteriolar hyalinosis and large vessel atherosclerosis
    • Diabetic kidney disease: a clinical diagnosis, not necessarily confirmed by biopsy, in which evaluation leads to the determination that diabetes mellitus is the primary cause of kidney disease1,2
    • Albuminuria: presence of elevated amount of albumin level in urine as measured in untimed (most commonly) or timed collection4,5
      • When measured in untimed collection, result is indexed to simultaneous measurement of creatinine level in urine (UACR [urinary albumin to creatinine ratio])4
    • eGFR (estimated GFR): determined using a measured biomarker (eg, serum creatinine, cystatin C) and other patient characteristics (eg, age, sex) to quantify filtering capacity of the kidneys,4 most commonly expressed in mL/minute/1.73 m2
    • CKD (chronic kidney disease): a clinical diagnosis in which there is evidence of renal damage (most commonly in the form of albuminuria or proteinuria) and/or reduced kidney function (most commonly eGFR less than 60 mL/minute/1.73 m2)4
    • CKD in patients with diabetes mellitus: concurrence of both CKD and diabetes mellitus; commonly diabetes mellitus may be the etiology of CKD but not necessarily1,2

    Risk Models and Risk Scores

    • KDIGO guidelines (Kidney Disease: Improving Global Outcomes) provide a classification system for CKD that takes into account both eGFR and degree of proteinuria in an effort to inform prognosis4
      • GFR is classified as G1 (eGFR greater than 90 mL/minute/1.73 m2) to G5 (eGFR less than 15 mL/minute/1.73 m2)
      • Albuminuria is classified as A1 (UACR less than 30 mg/g) to A3 (UACR greater than 300 mg/g)
    • Relatively sophisticated calculators are available online6 and are fairly accurate for estimating the risk for a decline in kidney function or progression to end-stage kidney disease for people living with CKD
    • Additional equations for people with diabetes mellitus and CKD based on a simple demographic and readily available laboratory parameters have also been proposed in the literature7,8
    • A prediction model that can simultaneously predict the competing risks of death or progression to kidney failure over 5 years in patients with moderate to severe CKD has been shown to be accurate and is available online9,10

    Treatment

    Approach to Treatment

    • Once patients with diabetes mellitus have been diagnosed with CKD, efforts should be made to reverse or improve modifiable risk factors for adverse kidney and cardiovascular outcomes1,2
      • CKD, particularly albuminuria, is a marker for increased risk for cardiovascular disease5,11
    • Core components of management to address include:4,12,13
      • Blood pressure control
      • RAS inhibition (renin-angiotensin system)
      • Glycemic control
      • Cardiovascular disease prevention
      • Diet or nutrition
      • Physical activity
      • Body weight maintenance or reduction
      • Smoking cessation
      • Self-management education and support
      • Avoidance of nephrotoxic drugs

    Blood Pressure

    • Control of blood pressure is important to reduce cardiovascular mortality and slow CKD progression among all patients with diabetes14
    • Blood pressure goals in patients with diabetes mellitus should be individualized through a shared decision-making process that considers cardiovascular risk, potential adverse effects, and patient preferences12,15,16
      • At a minimum, aim for blood pressure of lower than 140/90 mm Hg for all patients with CKD and diabetes
      • For patients at higher cardiovascular risk (existing ASCVD [atherosclerotic cardiovascular disease]) or a 10-year ASCVD risk greater than 10% (American Heart Association guidelines) or 15% (American Diabetes Association guidelines), aim for blood pressure target lower than 130/80 mm Hg16,17
      • In cases where systolic blood pressure targets as low as less than 120 mm Hg can be attempted safely, there may be additional benefits, particularly regarding stroke prevention and further reduction in albuminuria, per KDIGO guidelines work group12,18
    • Advise all patients with hypertension and diabetes to monitor their blood pressure at home12

    Renin Angiotensin System Inhibition

    • RAS inhibition is a key target for patients with diabetes and established CKD because of the ability to reduce albuminuria, improve cardiovascular outcomes, and lower risk of progression to end-stage kidney disease4,12,19
    • ACE inhibitors and ARBs (angiotensin receptor blockers) are first line agents for RAS inhibition, because they improve hard cardiovascular and kidney-specific outcomes4,12,18,20
    • Evidence that the agents preserve kidney function is strongest among patients who have diabetes, hypertension, moderate to severe albuminuria, and reduced kidney function12,21,22,23,24,25
    • Some but not all guidelines recommend that ACE inhibitors or ARBs be prescribed for patients with albuminuria who do not have hypertension1,12
    • Initiation of ACE inhibitor or ARB is commonly associated with a rise in creatinine level and a proportionate drop in eGFR12,17,26
      • However, a drop in eGFR of less than 30% should not necessarily be viewed as a reason to discontinue
      • If the drop in eGFR is greater than 30%, consider a dose decrease or discontinuation and initiate evaluation for renal artery stenosis or other contributing cause
    • Hyperkalemia is a common adverse effect of RAS blockade and is often a dose-limiting factor12,27
      • Can be offset by pairing these agents with a diuretic (eg, chlorthalidone) that can counter the tendency for hyperkalemia12,27
      • Similarly, new potassium-binding resins, such as patiromer and sodium zirconium cyclosilicate, can be used to allow continuation of RAS blockade in patients who have been otherwise prone to hyperkalemia27,28
    • A second common adverse effect of ACE inhibitors is a cough caused by bradykinin; in most cases, an ARB may be used as a substitute4,17
    • Angioedema is an additional noteworthy adverse effect of ACE inhibitors
      • It is reasonable to consider an ARB in a person who has had ACE-inhibitor–induced angioedema if 6 weeks have passed since the ACE inhibitor was discontinued17

    Glycemic Control

    • Glycemic control is most commonly monitored by hemoglobin A1C level, although there may be limitations of the accuracy of this glycemic metric in advanced CKD1,2,29,30,31,32,33,34
      • In most cases, hemoglobin A1C target should be less than 8.0%; however, in many people, tighter control may be desirable30,35
      • Factors that influence the decision to tolerate higher hemoglobin A1C levels include:36
        • Severity of kidney disease
        • Presence of macrovascular complications of diabetes
        • A substantial burden of comorbidities
        • Short life expectancy
        • Impaired hypoglycemia unawareness
        • Propensity of antiglycemic therapies to cause hypoglycemia
        • Scarce resources for hypoglycemic management
      • In cases where strict hemoglobin A1C control (A1C level less than 6.5%) is desired or achievable, select agents do not pose risk for hypoglycemia
      • Hemoglobin A1C can be less reliable in patients with advanced CKD. For example, where there is a shortened RBC half-life, hemoglobin A1C level will underestimate average blood glucose levels1,35
      • Using fructosamine or glycated albumin to monitor blood glucose levels over time may be an alternative for some patients, although accuracy may be affected by certain conditions (eg, altered serum protein levels, hepatic disease, malnutrition, thyroid dysfunction, pregnancy)2
      • Continuous glucose monitoring and self-monitoring of blood glucose levels are tools that are used to measure interstitial or capillary blood glucose level by patients on a daily (or several times a day) basis; these measurements are used to self-adjust insulin doses30,35
    • Selection of glucose-lowering medications for patients with type 2 diabetes and CKD should take into account several factors, including the need to alter doses with diminished GFR, tendency to hypoglycemia, and direct effects on the kidneys1,2,37
      • Metformin is often considered as initial treatment for all patients with type 2 diabetes, including those with early CKD
      • SGLT2 inhibitors (sodium-glucose cotransporter 2) have been shown to have important renal and cardiovascular benefits for patients with type 2 diabetes for whom the medication has been initiated when eGFRs are greater than 20 mL/minute/1.73 m2, independent of glucose-lowering effects1,2,37,38,39
      • Some GLP-1 RAs (glucagonlike peptide 1 receptor agonists) (eg, liraglutide, dulaglutide, semaglutide) have been shown in cardiovascular outcome trials to reduce the risk of new or worsening nephropathy40,41,42,43
      • Both SGLT2 inhibitors and GLP-1 RAs reduce cardiovascular events in patients with type 2 diabetes and CKD
        • In EMPA-REG OUTCOME, CANVAS, DECLARE, LEADER, and SUSTAIN-6 randomized clinical trials, empagliflozin, canagliflozin, dapagliflozin, liraglutide, and semaglutide, respectively, each reduced cardiovascular events, evaluated as primary outcomes, compared with placebo41,42,44,45,46

    Lipids

    • Hyperlipidemia is an important risk factor for cardiovascular events in the general population and patients with diabetes47
    • It is advisable to obtain a lipid profile at the time of diagnosis of diabetes
      • American Diabetes Association guidelines recommend a lipid profile every 5 years after diagnosis16
    • Lifestyle modifications are recommended to address hyperlipidemia through increased physical activity and medical nutrition interventions, including eating patterns that are associated with lower cardiovascular risk such as Mediterranean diet or other plant-based diets that are low in saturated fat16,47
    • Determining who might benefit from treatment of lipids can be applied to anyone whose 10-year risk of a first ASCVD exceeds 10%16,47
      • Online calculators can be used to easily calculate the risk using lipid measurements and other clinical available variables48
    • Dose adjustment of statins based on serial monitoring of lipids is no longer generally recommended but may still have a role16,47
      • American Diabetes Association recommends lipid monitoring 4 to 12 weeks after initiation or a change in dose and annually thereafter, because it may help to monitor response to therapy and inform medication adherence16
    • Statins or statin-ezetimibe combination therapy is recommended in nondialysis-dependent CKD with the following considerations:49
      • In adults aged 50 years or older with eGFR less than 60 mL/minute/1.73 m2 but not treated with long-term dialysis or kidney transplant (GFR categories G3a-G5), treatment with a statin or statin-ezetimibe combination is recommended49
      • In adults aged 50 years or older with CKD and eGFR greater than 60 mL/minute/1.73 m2 generally with albuminuria (GFR categories G1 and G2), statins are advised49
      • In adults aged 18 to 49 years with CKD (not on long-term dialysis or with kidney transplant), statin treatment is recommended if there are other comorbidities, including:49
        • Diabetes mellitus
        • Known coronary disease (myocardial infarction or coronary revascularization)
        • Prior ischemic stroke
        • Estimated 10-year incidence of coronary death or nonfatal myocardial infarction greater than 10%
    • Statin use in patients on dialysis or with kidney transplant is not covered by these recommendations

    Nondrug and Supportive Care

    Lifestyle Modifications

    • Overall health of patient should be primary focus; adoption of a generally healthy lifestyle should be encouraged13,36,50,51
    • Encourage people with CKD to undertake physical activity compatible with cardiovascular health and tolerance, achieve a healthy weight, and stop smoking4

    Diet

    • Dietary recommendations and prescriptions should be individualized, balancing personal as well as cultural values and preferences against available resources2
      • Consume a diet that is low in processed meats and rich in vegetables and fruits; vegetable and fruit supplementation may preserve eGFR in patients with advanced CKD52,53
      • Minimizing consumption of carbohydrates, particularly simple carbohydrates, is a nonpharmaceutical strategy for improving glycemia13,51
      • Lower sodium diets (less than 2 g of sodium per day or less than 5 g of sodium chloride per day) may help control hypertension12,17,54
      • Advise dietary modification or caloric restriction to facilitate weight loss13,51
      • Lower protein diets (0.8 g/kg/day for those with diabetes and CKD not yet treated with dialysis) may help to slow the rate of progression in CKD, though care should be taken not to undermine successful strategies of glycemic control if caloric intake is maintained by consumption of simple carbohydrates)3,4,55,56,57,58,59
      • Recommendations vary across different clinical practice guidelines (National Kidney Foundation, International Society of Renal Nutrition and Metabolism, KDIGO, and American Diabetes Association) about precise amount of dietary protein intake in nondialysis-dependent CKD2,4,55,56,57,58,59
        • National Kidney Foundation KDOQI (Kidney Disease Outcomes Quality Initiative) 2020 updated nutrition guidelines provide one of the most rigorous sources of dietary recommendations58
        • KDIGO 2024 CKD guidelines support the incorporation of a plant-based diet to limit progression of CKD and mitigate the risk of certain CKD complications (eg, metabolic acidosis)4,60
        • It is also recommended that patients with CKD avoid processed meats and ultra-processed foods to limit progression of kidney disease4,60

    Physical Activity

    • Advise patients to engage in regular physical activity, with a goal of exercising for 150 minutes per week3,13,50,51
    • Functional health benefits related to quality of life are likely from both resistance and cardio training, whether measured by objective measures such as aerobic capacity and muscular performance or self-reported patient outcomes13,50,51,61
    • Maintaining and improving muscle mass may help with glycemic control50,51
    • Because patients with diabetes and CKD are at increased risk for adverse events (eg, falls, hypoglycemia) when engaging in physical activity, they should monitor and modify consumption of fluids along with regular monitoring of glucose levels, in accordance with type and intensity of their exercise program

    Body Weight Management

    • Obesity and overweight status are known CKD progression factors and worsen control of diabetes; hence, maintaining normal body weight should be a priority for patients with CKD and diabetes62
      • BMI targets serve as a starting point for weight classification
      • Additional measures (eg, abdominal circumference measurement) or more sophisticated measures of body composition may have a role for determining body composition in given patients63
    • Weight loss is advisable for patients who are obese or overweight to assist with glycemic and blood pressure control51,64,65
    • In a study of patients with type 2 diabetes, obesity, and CKD (GFR less than 40 mL/minute/1.73 m2), a weight loss program that led to 12% weight loss also reduced albuminuria by 36%, improved kidney function, and improved glycemic control66

    Smoking Cessation

    • Smoking poses a risk for the development of CKD, and patients who continue to smoke are at increased risk for progression of CKD3,13,67
      • All patients should be counseled to avoid tobacco products
      • Effective smoking cessation strategies include cognitive behavioral interventions and pharmacologic interventions4
    • Consequences of smoking on cardiovascular outcomes are magnified in patients with diabetes mellitus and CKD4,13,51

    Avoid Nephrotoxins

    • Avoid agents that carry the risk of either injury to kidneys, reduced kidney function, or worsening complications of kidney disease (ie, nephrotoxins)4
      • In outpatient clinical practice, NSAIDS are likely the most commonly encountered class of potentially nephrotoxic medications
        • NSAIDs can lead to reduction in eGFR, sodium retention, and increased risk of hyperkalemia and hyponatremia4
        • Less frequently, NSAIDs can independently lead to pathologic injury of kidneys, including chronic interstitial nephritis, acute interstitial nephritis, and membranous nephropathy
        • In some cases of CKD, NSAIDs can be used but more frequent monitoring of kidney function and electrolytes may be needed
      • Other OTC medications, including certain herbal supplements, carry the risk of nephrotoxicity4
      • Proton pump inhibitors carry some risk for the development of CKD and can cause interstitial nephritis68
        • Where possible, avoid proton pump inhibitors and other agents such as H2 blockers (eg, famotidine). However, in cases where overt nephrotoxicity is not suspected, proton pump inhibitors should be used
        • If severe gastrointestinal pathology (eg, Barrett esophagus or gastric ulcer) is defined or suspected, the risk-benefit ratio likely favors their continued use

    Drug Therapy

    • Can be categorized based on therapeutic intent, such as treatments to:
      • Improve glycemic control
      • Improve blood pressure
      • Slow progression of CKD and reduce proteinuria
      • Improve cardiovascular outcomes2,37,38
        • Some agents, such as SGLT2 inhibitors, may help to achieve multiple objectives
    • CKD complicates pharmacologic therapy as decreased eGFR can affect the metabolism of many agents and can lead to increased risk of adverse effects2,30
      • Some agents are not recommended below certain eGFR thresholds due to loss of efficacy and/or increased risk of adverse effects and toxicity
    • Treatments for glycemic control are covered in greater detail in other sections
      • Interactions between a given class of treatments and specific management aspects in CKD are highlighted here

    Antihypertensives

    • When treating patients with hypertension in the setting of CKD and diabetes, it is common that more than 1 agent is needed to reach blood pressure goals16,37
    • There are no well-powered trials comparing cardiovascular outcomes or survival for specific agents or antihypertensive classes in patients with both hypertension and CKD12
    RAS Inhibitors
    • Inhibition of RAS with ACE inhibitors or ARBs is a fundamental aspect of treating diabetic kidney disease, because this class of drugs has been shown to improve hard cardiovascular and kidney-specific outcomes4,12,19
    • First line agents for RAS inhibition are ACE inhibitors or ARBs, because they improve hard cardiovascular and kidney-specific outcomes4,12,19,20
    • Evidence that these agents preserve kidney function is strongest among patients who have diabetes, hypertension, moderate to severe albuminuria, and reduced kidney function12,21,22,23,24,25
    • Combining both ACE inhibitors and ARBs should be avoided due to increased risk of adverse effects with little additional benefit12,17
    • Combining ACE inhibitors or ARBs with direct renin inhibitors is likely not beneficial, may be harmful, and should be avoided based on safety signals from large clinical trials12
    Diuretics
    • Diuretics are often needed to reach blood pressure goals in CKD12,16,17
    • Diuretics are commonly paired with RAS blockade and have synergistic effects on blood pressure control12,17
    • 2 most commonly employed classes of diuretics (thiazide and loop diuretics) reduce potassium level; this effect can be used to offset the tendency toward hyperkalemia of RAS blockade12,16,17
    • Thiazide diuretics are the most commonly employed diuretic class for blood pressure control12
      • Thiazide diuretics have some risk of affecting glycemic control and inducing hyperuricemia, though these risks can generally be mitigated16
      • Monitoring for hyponatremia is important when using thiazide diuretics, particularly for older adults
      • Chlorthalidone and indapamide are longer acting than hydrochlorothiazide and are generally preferred due to reduced risk for metabolic (hyperglycemia, hyperuricemia) adverse effects17
      • Historically, thiazides were thought to lose efficacy with eGFR of less than 30 mL/minute/1.73 m2; however, more recent data showed continued efficacy for chlorthalidone down to eGFR69 of 15 mL/minute/1.73 m2
    • Loop diuretics are used for blood pressure control due to volume overload more frequently in CKD than in most other populations, particularly with advanced CKD12,15,70
      • Shorter-acting loop diuretics (eg, bumetanide, furosemide) need to be given at least twice a day when used for blood pressure control, whereas longer agents (eg, torsemide) can be given once a day
      • Loop diuretics are more effective for treating fluid overload than thiazide diuretics; this can be particularly important with profound proteinuria and related edema (nephrotic syndrome)
      • They do carry higher risk than thiazides for inducing overt hypovolemia
      • Kidney function and electrolytes need to be monitored after dose changes and then intermittently thereafter while the patient is on these agents
      • Combining loop diuretics with thiazide diuretics may have a role in overcoming diuretic resistance, but the risk of electrolyte changes (hypokalemia), volume depletion, and acute kidney injury increases
    Calcium Channel Blockers
    • Dihydropyridines are a subset of calcium channel blockers that do not slow heart rate and are the more common antihypertensive agents (eg, nifedipine extended-release, amlodipine)
    • Dihydropyridines are not generally thought to have specific nephroprotective effects in CKD in patients with diabetes. However, based on their efficacy in lowering blood pressure and neutral effects on metabolic profiles, they are frequently employed with favorable effects12
    • Lower extremity edema is a frequent adverse effect, and patients should be warned of this. Swelling will often improve with time and can frequently be managed without discontinuation of medication, though in severe cases, withdrawal of the agent is an appropriate course of action
    • Lower extremity edema may be decreased by initiating a calcium channel blocker after an ACE inhibitor or ARB has been started
    Mineralocorticoid Receptor Antagonists
    • Mineralocorticoid receptor antagonists may have added benefits in patients with diabetes and CKD with overt proteinuria or resistant hypertension5,12,71
      • Steroidal aldosterone receptor blocking agents (eg, spironolactone, eplerenone) have a role in resistant hypertension72
        • Can be useful as a third or fourth agent in resistant hypertension (often in addition to a diuretic, RAS blockade, and calcium channel blocker)
        • Hyperkalemia is a concern and potassium level needs to be carefully monitored, particularly in patients who are also on RAS blockade
      • For patients with type 2 diabetes and CKD who have albuminuria and normal potassium levels on maximum tolerated doses of ACE inhibitors or ARBs, addition of finerenone can be considered to improve cardiovascular outcomes and reduce the risk of CKD progression73,74
        • Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, was approved by FDA to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, nonfatal myocardial infarction, and hospitalization for heart failure in patients with CKD associated with type 2 diabetes73,74
        • When paired with a RAS blockade (as generally done in these studies), particular care should be taken to monitor and treat hyperkalemia as it develops73,74
        • In a controlled trial, the rate of hyperkalemia may be less than in real-world practice as was seen in earlier studies involving spironolactone75
        • Careful attention to potassium levels, with responsive adjustment of finerenone dose and/or addition of adjunctive medication classes that lower serum potassium level (diuretics, SGTL2 inhibitors, or potassium-binding resins), can allow for continued use in some cases76
      • Aldosterone synthase inhibitors have been investigated for control-resistant hypertension, and their role in the management of CKD independently of these treatment effects is being investigated in phase 3 trials77

    Antidiabetic Medications

    • Pharmacologic interventions for diabetes include a diverse group of agents, some of which have evidence for improved renal outcomes in addition to their effects on glycemia
    Insulin
    • Several different insulins and insulin delivery systems exist. These are the cornerstones of therapy in type 1 diabetes and have a defined role in type 2 diabetes, although in type 2 diabetes insulin is generally not first line therapy1,34,37
      • Kidney plays a key role in the metabolism of insulin and gluconeogenesis
      • Increased risk of hypoglycemia and prolonged drug effect with declining kidney function78
      • Care should be taken and doses adjusted accordingly with declining kidney function, particularly with eGFR of less than 30 mL/minute/1.73 m2 and even more so with eGFR of less than 15 mL/minute/1.73 m2 to avoid hypoglycemia
      • Continuous glucose monitoring may play an important role in patients with advanced CKD who require insulin therapy to avoid hypoglycemic episodes while improving glycemic control
      • Cost of insulin, especially insulin analogs, can be considerable
    Metformin
    • Metformin should be considered as potential first line therapy for patients with type 2 diabetes without moderate to advanced kidney disease1,2,37,38,39
      • Overall positive effect on glycemic control, generally favorable adverse effect profile, and low cost
      • Metformin is contraindicated with GFR of less than 30 mL/minute/1.73 m2, primarily because of increased risk in lactic acidosis, which, while rare, can potentially be fatal79
      • Dose reduction should be considered with eGFR of less than 45 mL/minute/1.73 m2 (approximately half dose)
      • Metformin should be held with potentially unstable patients and in particular when patients are admitted to hospital with acute illness
    Sodium-Glucose Cotransporter 2 Inhibitors
    • SGLT2 inhibitors have been shown to have important renal and cardiovascular benefits for patients with type 2 diabetes1,2,37,38,39,80
      • Block absorption at SGLT2 in proximal tubule1,2
      • SGLT2 inhibitors are not recommended or FDA approved for use in patients with type 1 diabetes due to higher risk of diabetic ketoacidosis37
        • European Medicines Agency initially approved SGLT2 inhibitors for use in patients with type 1 diabetes but rescinded that approval in 2021 due to the high frequency of diabetic ketoacidosis in those taking dapagliflozin81
      • Hemoglobin A1C improvement in the treatment of naive patients is about 0.9%, whereas when added to metformin (more typical in clinical trials), improvement is about 0.6%2,37
      • Cardiovascular or renal benefits are generally felt to be class effects, though selection of agents should be done in an evidence-based manner that considers the outcomes of randomized controlled trials for specific indications and the clinical need of each patient being treated2,37
      • SGLT2 inhibitors reduce albuminuria by approximately 20% to 30%1,2,37,38,39,80
      • SGLT2 inhibitors reduce the risk of kidney disease progression by approximately 30% to 40%
      • Most SGLT2 inhibitor studies were conducted with high baseline rates of RAS inhibitor utilization; however, the data suggest the favorable renal effects of SGLT inhibitors are still present in patients who have not tolerated RAS inhibitors80
      • Antiglycemic effects of SGLT2 inhibitors are less potent as eGFR declines1,2,37
      • However, cardiovascular and kidney benefits from SGLT2 inhibitors are maintained at lower eGFRs and are independent of antiglycemic effects2,11,82
        • SGLT2 inhibitors can be initiated if eGFR is higher than or equal to 20 mL/minute/1.73 m2. They can be continued below 20 mL/minute/1.73 m2 to reduce the risk of further eGFR decline, end-stage kidney disease, cardiovascular death, or hospitalizations for heart failure until kidney replacement therapy is required
      • Patients using SGLT2 inhibitors are at increased risk for urinary infections, fungal infections, and euglycemic diabetic ketoacidosis1,2
      • In one study, there appeared to be a potential risk for worsening of peripheral vascular disease,45 but this effect has not been seen in most studies
        • Nevertheless, it may be prudent to avoid initiating SGLT2 inhibitors in patients with active peripheral artery disease, particularly with ulceration2
    Glucagonlike Peptide 1 Receptor Agonists
    • GLP-1 RAs activate the receptors for the endogenous incretin GLP-1, lowering blood glucose with limited risk of hypoglycemia1,2
    • GLP-1 RAs are indicated for patients with type 2 diabetes who have not achieved glycemic control with metformin or for those who have a contraindication to use of metformin1,2,37
      • Evidence has accumulated for additional cardiometabolic benefits beyond improved glycemic control, and their use has expanded in recent years
      • Evidence for cardiovascular benefits exists for most agents (primarily long acting) in this class but not all2,83
    • There are data showing improved renal outcomes with the use of some GLP-1 RAs; however, the outcomes are limited to reductions in albuminuria and a slower rate of decline in eGFR1,2,41,84
      • For example, use of semaglutide results in a 24% reduction of kidney disease progression, major adverse cardiovascular events, and death in the FLOW trial85
    • GLP-1 RAs also show favorable effects on weight management (weight loss of 5%-10% body weight in patients with obesity, often maintained over the long term)2,37
      • Semaglutide and liraglutide have specific indications for weight loss even in patients without diabetes
    • Agents that are dual agonists function as GLP-1 RAs but also with glucose-dependent insulinotropic polypeptide activity (tirzepatide); these exhibit more pronounced glucose-lowering effects and yield even greater weight loss86
    • GLP-1 RAs are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or the syndrome of multiple endocrine neoplasia due to the potential risk of thyroid T-cell tumors
    • GLP-1 RAs can be associated with severe gastrointestinal adverse effects, particularly nausea and vomiting
    • Some of the GLP-1 RAs have the advantage of infrequent dosing (eg, weekly)37
    • GLP-1 RAs have been used with eGFRs1 as low as 15 mL/minute/1.73 m2
    Dipeptidyl Peptidase 4 Inhibitors
    • Decrease breakdown of GLP-11,2
    • Unlike GLP-1 RAs, dipeptidyl peptidase 4 inhibitors have not been shown to have renoprotective effects in clinical trials conducted thus far
    • Do not use along with GLP-1 RAs
    • Linagliptin does not require dose adjustment in CKD, whereas the others do
    Sulfonylureas
    • Have a long-standing role in type 2 diabetes, but this is decreasing due to their adverse effects and potential benefits of alternative agents1,2,37,78
    • Induce improved glycemic control by increasing secretion of insulin
    • Typical hemoglobin A1C improvement is 0.8% to 1.5%37
    • Adverse effects include hypoglycemia and weight gain34
    • Should generally be avoided with progressive CKD; adjust dose in patients with renal impairment1,2
      • Glipizide is safer, because it is not eliminated by the kidneys and does not have metabolically active metabolites
      • Glimepiride and glyburide pose increased risk of hypoglycemia
    • Primary advantage of this class of agent is relatively low cost
    Thiazolidinediones
    • Aid glycemic control by increasing insulin sensitivity1,2,37
    • Hemoglobin A1C improvement varies from 0.5% to 1.4%
    • Generally well tolerated but carry the risk of fluid retention and may increase fracture risk
    • Pioglitazone is the only agent currently available in the United States
    • This class has the advantage that it is relatively inexpensive and does not require dose adjustment for reduced kidney function
    Meglitinides
    • Meglitinides are agents that lead to a rapid, short-lived increase in insulin secretion with meals1,2,37
    • Hemoglobin A1C level improves by 0.5% to 0.8%2
    • Adverse effects include hypoglycemia and weight gain
    • Reduced postprandial hyperglycemia
    • Examples include nateglinide and repaglinide
      • Repaglinide is not eliminated by the kidneys, but dose adjustments are necessary for CrCl (creatinine clearance) 20 to 39 mL/minute87
      • Nateglinide has active metabolites that are eliminated by the kidneys; no dose adjustments are needed for kidney impairment
    α-Glucosidase Inhibitors
    • Function by delaying carbohydrate absorption in the small intestine1,26,37
    • Typical hemoglobin A1C improvement of 0.5% to 0.8%
    • Adverse effects include flatulence and diarrhea
    • Examples include acarbose and miglitol
      • Acarbose is minimally absorbed; however, it does have metabolites that are cleared by the kidneys and its use is not recommended if CrCl is less than 25 mL/minute
      • Miglitol is excreted via the kidneys, and its use is not recommended if CrCl is less than 24 mL/minute

    Additional Considerations

    • Other classes of blood pressure–lowering agents can be employed based on specific indications. β-blockers are ideal in cardiovascular disease; peripheral α-blockers are suitable in people with benign prostatic hypertrophy12
    • Agents that reduce proteinuria overlap significantly with these categories. However, even in the absence of hypertension, some agents such as RAS inhibitors may be indicated with a specific goal of reducing proteinuria1,4,19
    • Agents that lower cardiovascular risk have classically been typified by cholesterol-lowering agents such as HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A ) reductase inhibitors (statins)16
    • For patients with type 2 diabetes and diabetic kidney disease, use of SGLT2 inhibitor is recommended in those with eGFR 20 mL/minute/1.73 m2 or greater, irrespective of albuminuria status (both elevated and normal urinary albumin levels), to reduce CKD progression and cardiovascular events44,88,89
    • Finerenone, which has benefits on albuminuria, also has benefits for cardiovascular outcomes74
    • Table 1. Drug Therapy: Noninsulin antidiabetic agents and other medications for CKD management in patients with diabetes mellitus.ACR = albumin/creatinine ratio, ARB = angiotensin receptor blocker, ASCVD = atherosclerotic cardiovascular disease, CKD = chronic kidney disease, CrCl = creatinine clearance, CV = cardiovascular, DKA = diabetic ketoacidosis, eGFR = estimated glomerular filtration rate, ESKD = end-stage kidney disease, GI = gastrointestinal, GLP-1 = glucagonlike peptide 1, GU = genitourinary, HFrEF = heart failure with reduced ejection fraction, MI = myocardial infarction, RAS, renin-angiotensin system; SCr = serum creatinine, SGLT2 = sodium-glucose cotransporter 2, T2DM = type 2 diabetes mellitus.*There is limited evidence on the use of specific antihypertensive agents to treat high blood pressure in CKD. Multidrug regimens will be necessary in most patients with CKD to achieve therapeutic goals. Choice of specific agents or classes in CKD depends on the type of kidney disease and the presence of defined CVD. First line therapy is typically with a 3-drug combination of an ACEI or ARB, a calcium channel blocker, and a thiazide-like diuretic. A β-blocker is indicated for specific cardiovascular conditions. If the 3-drug combination is not adequate for blood pressure control, additional therapy, including a mineralocorticoid receptor antagonist, long-acting α-blocker, or β-blocker, can be used as well as hydralazine, minoxidil, or central-acting agents.D2†Variable composite outcome that includes loss of eGFR, ESKD, and related outcomes.D1
      MedicationTherapeutic useDosageSafety concernsNotable adverse reactionsSpecial considerations
      Antihypertensive agents*
      ACE inhibitors
      BenazeprilFirst line in patients with albuminuria (ACR ≥ 30 mg/g, G1-G4, A2 and A3), with or without hypertension; may also consider in patients with hypertension and no albuminuriaD1,D2
      Slows progression of CKD and decreases proteinuriaD3      		Initial dose, eGFR ≥ 30 mL/minute/1.73 m2: 5-10 mg PO once dailyD4
      Initial dose, eGFR < 30 mL/minute/1.73 m2: 5 mg PO once dailyD4
      Titrate to maximum tolerated doseD2
      Max dose: 80 mg/day PO in 1-2 dosesD1,D5      		Contraindicated in patients with history of angioedemaD4
      Use with caution in patients with renal artery stenosis or obstruction in the outflow tract of left ventricle (ie, aortic stenosis, hypertrophic cardiomyopathy)D4,D6
      Patients whose kidney function is dependent on the RAS (eg, those with heart failure, CKD) may be at risk of developing acute kidney injuryD4
      Drug interactions: may need to avoid or adjust dosage of certain drugsD4      		Agranulocytosis
      Angioedema
      Cough
      Hepatoxicity
      Hyperkalemia
      Hypotension
      Nephrotoxicity
      NeutropeniaD4,D6,D7      		Monitor blood pressure, kidney function, serum potassium level, and WBC count closely during therapyD4,D7,D6
      If SCr level rises > 30%, evaluate potential contributing factors; dose reduction or discontinuation of therapy only as last resortD1,D2
      Parent compound not removed by hemodialysisD1
      LisinoprilFirst line in patients with albuminuria (ACR ≥ 30 mg/g, G1-G4, A2 and A3), with or without hypertension; may also consider in patients with hypertension and no albuminuriaD1,D2
      Slows progression of CKD and decreases proteinuriaD3      		Initial dose, CrCl > 30 mL/minute: 10 mg PO once dailyD5,D6
      Initial dose, CrCl 10-30 mL/minute: 5 mg PO once dailyD6
      Initial dose, CrCl < 10 mL/minute or on hemodialysis: 2.5 mg PO once dailyD6
      Titrate to maximum tolerated doseD2
      Max dose: 40 mg PO once dailyD6      		Contraindicated in patients with history of angioedemaD6
      Use with caution in patients with renal artery stenosis or obstruction in the outflow tract of the left ventricle (ie, aortic stenosis, hypertrophic cardiomyopathy)D6
      Patients whose kidney function is dependent on the RAS (eg, those with heart failure, CKD) may be at risk of developing acute kidney injuryD6
      Drug interactions: may need to avoid or adjust dosage of certain drugsD6      		Agranulocytosis
      Angioedema
      Cough
      Hepatoxicity
      Hyperkalemia
      Hypotension
      Nephrotoxicity
      NeutropeniaD4,D6,D7      		Monitor blood pressure, kidney function, serum potassium level, and WBC count closely during therapyD4,D6,D7
      If SCr level rises > 30%, evaluate potential contributing factors; dose reduction or discontinuation of therapy only as last resortD1,D2
      ARBs
      LosartanFirst line in patients with albuminuria (ACR ≥ 30 mg/g, G1-G4, A2 and A3), with or without hypertension; may also consider in patients with hypertension and no albuminuriaD1,D2
      Slows progression of CKD and decreases proteinuriaD3      		Initial dose: 50 mg PO once dailyD5,D8
      Titrate to maximum tolerated doseD2
      Max dose: 100 mg/day PO in 1-2 dosesD5,D8
      Adjust dose for mild to moderate hepatic impairmentD8      		Has not been studied in patients with severe hepatic impairmentD8
      Patients whose kidney function is dependent on the RAS (eg, those with heart failure, CKD) may be at risk of developing acute kidney injuryD8
      Drug interactions: may need to avoid or adjust dosage of certain drugsD8      		Hyperkalemia
      Hypotension
      NephrotoxicityD8      		Monitor blood pressure, kidney function, and serum potassium level closely during therapyD8
      If SCr level rises > 30%, evaluate potential contributing factors; dose reduction or discontinuation of therapy only as last resortD1,D2
      Not removed by hemodialysisD1
      Patients with ACE inhibitor–induced angioedema can receive ARB 6 weeks after ACE inhibitor is discontinuedD5
      ValsartanFirst line in patients with albuminuria (ACR ≥ 30 mg/g, G1-G4, A2 and A3), with or without hypertension; may also consider in patients with hypertension and no albuminuriaD1,D2
      Slows progression of CKD and decreases proteinuriaD3      		Initial dose: 80-160 mg PO once dailyD9
      Titrate to maximum tolerated doseD2
      Max dose: 320 mg PO once dailyD9      		Has not been studied in patients with severe hepatic impairmentD9
      Use with caution in patients with CrCl < 30 mL/minuteD9
      Patients whose kidney function is dependent on the RAS (eg, those with heart failure, CKD) may be at risk of developing acute kidney injuryD9
      Drug interactions: may need to avoid or adjust dosage of certain drugsD9      		Hyperkalemia
      Hypotension
      NephrotoxicityD9      		Monitor blood pressure, kidney function, and serum potassium level closely during therapyD9
      If SCr level rises > 30%, evaluate and manage potential contributing factors; dose reduction or discontinuation of therapy only as last resortD1,D2
      Not removed significantly by hemodialysisD1
      Patients with ACE inhibitor–induced angioedema can receive ARB 6 weeks after ACE inhibitor is discontinuedD5
      Calcium channel blockers
      Dihydropyridines
      AmlodipineFirst line as part of 2- or 3-drug combination antihypertensive regimenD2Usual dose: 2.5-10 mg PO once dailyD5,D10
      Adjust initial dose for older adults and hepatic impairmentD10      		Use with caution in patients with severe hepatic impairment or severe obstructive coronary artery diseaseD10Hypotension
      Peripheral edemaD5,D10      		Neutral effect glucose metabolismD11
      Dose-related edema more common in females than malesD5
      Nifedipine, extended-releaseFirst line as part of 2- or 3-drug combination antihypertensive regimenD2Initial dose: 30-60 mg PO once dailyD12,D13
      Usual dose: 30-90 mg PO once dailyD5
      Max dose: 90-120 mg PO once dailyD12,D13      		Contraindicated in patients with cardiogenic shockD13
      Avoid in patients with HFrEFD5
      Use with caution in patients with hepatic impairment, aortic stenosis, altered GI anatomy, or hypomotility disordersD12,D13
      Drug interactions: may need to avoid or adjust dosage of certain drugsD13      		GI obstruction or ulceration
      Headache
      Hypotension
      Peripheral edemaD12      		Dose-related edema more common in females than malesD5
      Diuretics
      Thiazide or thiazide-like diuretics
      ChlorthalidoneFirst line as part of 2- or 3-drug combination antihypertensive regimenD2,D3
      Fluid overloadD2,D3
      Preferred during earlier stages of CKD when GFR ≥ 30 mL/minute/1.73 m2 (G3 and lower)D2,D3,D14      		Initial dose: 25-100 mg PO once daily
      Max dose: 200 mg/dayD15      		Contraindicated in patients with anuria and with sulfonamide hypersensitivityD15
      Potential for exacerbation or activation of systemic lupus erythematosusD15
      Use with caution in patients with hepatic impairment or progressive liver diseaseD15      		Acute myopia
      Cholesterol or triglyceride level increased
      Electrolyte depletion
      Hyperglycemia
      Hyperuricemia
      Hypovolemia
      Secondary angle-closure glaucomaD15,D16,D17,D18      		Appears to retain effectiveness at GFRD2,D3 < 30 mL/minute/1.73 m2
      Longer acting than hydrochlorothiazide, resulting in better blood pressure control, but also higher incidence of hypokalemiaD3
      HydrochlorothiazideFirst line as part of 2- or 3-drug combination antihypertensive regimenD2,D3
      Fluid overloadD2,D3
      Preferred during earlier stages of CKD when GFR ≥ 30 mL/minute/1.73 m2 (G3 and lower)D2,D3,D14      		25-100 mg/day PO in 1-2 divided doses
      Max dose: 100 mg/dayD16      		Contraindicated in patients with anuria and with sulfonamide hypersensitivityD16
      Potential for exacerbation or activation of systemic lupus erythematosusD16
      Use with caution in patients with hepatic impairment or progressive liver diseaseD16      		Acute myopia
      Cholesterol or triglyceride level increased
      Electrolyte depletion
      Hyperglycemia
      Hyperuricemia
      Hypovolemia
      Secondary angle-closure glaucomaD15,D16,D17,D18      		Does not appear to retain effectiveness at GFRD2,D3 < 30 mL/minute/1.73 m2
      IndapamideFirst line as part of 2- or 3-drug combination antihypertensive regimenD2,D3
      Fluid overloadD2,D3
      Preferred during earlier stages of CKD when GFR ≥ 30 mL/minute/1.73 m2 (G3 and lower)D2,D3,D14      		Initial dose: 1.25 mg PO once daily
      Max dose: 5 mg PO once dailyD17      		Contraindicated in patients with anuria and with sulfonamide hypersensitivityD17
      Potential for exacerbation or activation of systemic lupus erythematosusD17
      Use with caution in patients with hepatic impairment or progressive liver diseaseD17      		Acute myopia
      Cholesterol or triglyceride level increased
      Electrolyte depletion
      Hyperglycemia
      Hyperuricemia
      Hypovolemia
      Secondary angle-closure glaucomaD15,D16,D17,D18      		Appears to retain effectiveness at GFRD2,D3 < 30 mL/minute/1.73 m2
      MetolazoneFirst line as part of 2- or 3-drug combination antihypertensive regimenD2,D3
      Fluid overloadD2,D3
      Preferred during earlier stages of CKD when GFR ≥ 30 mL/minute/1.73 m2 (G3 and lower)D2,D3,D14      		Usual dose: 2.5-20 mg PO once dailyD18Contraindicated in patients with anuria and in those with hepatic coma or precomaD18
      Potential for exacerbation or activation of systemic lupus erythematosusD18
      Use with caution in patients with severe renal or hepatic diseaseD18
      Patients allergic to sulfonamides may show hypersensitivity to metolazoneD18      		Acute myopia
      Cholesterol or triglyceride level increased
      Electrolyte depletion
      Hyperglycemia
      Hyperuricemia
      Hypovolemia
      Secondary angle-closure glaucomaD15,D16,D17,D18      		Appears to retain effectiveness at GFRD2,D3 < 30 mL/minute/1.73 m2
      Loop diuretics
      BumetanideAlternate therapy as part of 2- or 3-drug combination antihypertensive regimenD2,D3
      Fluid overloadD2,D3
      Typically used when GFR < 30 mL/minute/1.73 m2 (G4-G5)D2,D3,D14      		Initial dose: 0.5-2 mg PO once daily; may repeat dose at 4- to 5-hour intervals if initial diuretic response is not adequate
      Max dose: 10 mg/day in divided dosesD19      		BOXED WARNING: risk for electrolyte depletion and hypovolemiaD19
      Contraindicated in patients with anuria and in those with hepatic encephalopathy or severe uncorrected electrolyte depletionD19
      Initiation in hospital recommended for patients with cirrhosis and ascitesD19
      Patients allergic to sulfonamides may show hypersensitivity to bumetanideD19      		Electrolyte depletion
      Hyperuricemia
      Hypotension
      Hypovolemia
      Ototoxicity
      ThrombocytopeniaD19      		Lack of cross-sensitivity between furosemide and bumetanide allows for substitutionD19
      Diuretic potency is about 40 times > that of furosemideD19
      FurosemideAlternate therapy as part of 2- or 3-drug combination antihypertensive regimenD2,D3
      Fluid overloadD2,D3
      Typically used when GFR < 30 mL/minute/1.73 m2 (G4-G5)D2,D3,D14      		Initial dose: 20-80 mg PO; may repeat or increase dose by 20-40 mg/dose at 6-8 hours after previous dose if initial diuretic response is not adequate
      Max dose: 600 mg PO once daily or in 2 divided dosesD20      		Contraindicated in patients with anuriaD20
      Initiation in hospital recommended for patients with cirrhosis and ascitesD20
      Potential for exacerbation or activation of systemic lupus erythematosusD20
      Effect may be weakened, and ototoxicity potentiated in patients with hypoproteinemiaD20
      Use with caution in patients with severe symptoms of urinary retentionD20
      Patients allergic to sulfonamides may show hypersensitivity to furosemideD20      		Blood glucose level increased
      Electrolyte depletion
      Hyperuricemia
      Hypotension
      Hypovolemia
      OtotoxicityD20      		Lack of cross-sensitivity between furosemide and bumetanide allows for substitutionD19,D20
      TorsemideAlternate therapy as part of 2- or 3-drug combination antihypertensive regimenD2,D3
      Fluid overloadD2,D3
      Typically used when GFR < 30 mL/minute/1.73 m2 (G4-G5)D2,D3,D14      		Initial dose: 5-20 mg PO once dailyD21
      Dose range: 5-200 mg/day POD21      		Contraindicated in patients with anuria and in those with hepatic coma or hypersensitivity to povidoneD21
      Patients allergic to sulfonamides may show hypersensitivity to torsemideD21      		Blood glucose level increased
      Electrolyte depletion
      Hyperuricemia
      Hypotension
      Hypovolemia
      OtotoxicityD21      		Low risk of cross-sensitivity with sulfonamide allergyD22
      Mineralocorticoid receptor antagonists
      EplerenoneAdd-on therapy for resistant hypertensionD2
      Slows progression of CKD and decreases proteinuriaD23,D24      		Usual dose: 50-100 mg/day PO in 1-2 dosesD25
      Max dose: 50 mg PO twice dailyD25      		Contraindicated in patients with serum potassium level > 5.5 mEq/L at initiation, T2DM with microalbuminuria, SCr level > 2 mg/dL in males or > 1.8 mg/dL in females, or CrCl < 50 mL/minuteD25
      Drug interactions: may need to avoid or adjust dosage of certain drugsD25      		Gynecomastia
      Hyperkalemia
      Hypotension
      Vaginal bleedingD25      		Monitor serum potassium level before initiating therapy, within first week, at 1 month after initiation, then periodically thereafterD25
      Eplerenone is 1.3-2 times less potent than spironolactone on a mg-for-mg basisD23,D26
      More favorable adverse effect profile compared with spironolactone; less gynecomastiaD3,D26
      FinerenoneRisk reduction for sustained eGFR decline, ESKD, CV death, nonfatal MI, and hospitalization for heart failure in patients with CKD associated with T2DMD27,D28,D29eGFR ≥ 60 mL/minute/1.73 m2: 20 mg PO once daily
      eGFR 25-59 mL/minute/1.73 m2: 10 mg PO once daily
      eGFR < 25 mL/minute/1.73 m2: use not recommendedD27      		Contraindicated in patients with adrenal insufficiencyD27
      Do not initiate treatment in patients with serum potassium level > 5 mEq/LD27
      Avoid use in patients with severe hepatic impairment (Child-Pugh class C)D27
      Drug interactions: may need to avoid or adjust dosage of certain drugsD27      		Hypotension
      Hyponatremia
      HyperkalemiaD27      		Monitor serum potassium level before initiating therapy, 4 weeks after initiating therapy or dose adjustment, and then periodically thereafterD27
      SpironolactoneAdd-on therapy for resistant hypertensionD2,D3
      Slows progression of CKD and decreases proteinuriaD23,D24      		Usual dose: 25-100 mg PO once dailyD7
      Max dose: 100 mg PO once dailyD30      		Contraindicated in patients with hyperkalemia or Addison diseaseD30
      Drug interactions: may need to avoid or adjust dosage of certain drugsD30      		Electrolyte depletion
      Gynecomastia
      Hyperglycemia
      Hyperkalemia
      Hyperuricemia
      Hypotension
      Hypovolemia
      Kidney function worseningD30      		Monitor serum potassium level within 1 week of initiation or titration and periodically thereafterD30
      Monitor other serum electrolytes, uric acid, blood glucose, volume status, and kidney function periodicallyD30
      Spironolactone is 1.3-2 times more potent than eplerenone on a mg-for-mg basisD23,D26
      Noninsulin antidiabetic agents
      Biguanides
      Metformin, immediate-releaseFirst line with SGLT2 inhibitor for glycemic control in patients with T2DMD1,D31eGFR > 45 mL/minute/1.73 m2: initial dose: 500 or 850 mg PO once daily
      Increase by 500 or 850 mg/day every week as neededD1,D32,D33
      Max dose: 2550 mg/day PO divided twice daily; use doses > 1000 mg/day with caution in older adultsD32,D34
      Consider dose reduction to 1000 mg/day if the patient is at high risk for lactic acidosisD1,D32,D33,D34
      eGFR 30-44 mL/minute/1.73 m2: initial dose: 50% of recommended dose
      Max dose: 1000 mg/dayD1,D33
      eGFR < 30 mL/minute/1.73 m2: contraindicated due to risk of lactic acidosisD32      		BOXED WARNING: risk of lactic acidosis in high-risk patientsD32
      Contraindicated in patients with acute or chronic metabolic acidosisD32
      Avoid use in patients older than 80 years and in patients with hepatic impairmentD32,D34
      Drug interactions: may need to avoid or adjust dosage of certain drugsD32      		Diarrhea
      Lactic acidosis
      Nausea
      Vitamin B12 deficiencyD32      		Renally eliminatedD32
      Doses above 2000 mg/day may be better tolerated given 3 times dailyD32
      GI intolerance can be mitigated by gradual dose titrationD31
      Monitor kidney function at least every 3-6 months in patients with eGFRD1 30-59 mL/minute/1.73 m2
      Monitor hematologic parameters annually and vitamin B12 level at 2- to 3-year intervalsD32
      Metformin, extended-releaseFirst line with SGLT2 inhibitor for glycemic control in patients with T2DMD1,D31eGFR > 45 mL/minute/1.73 m2: initial dose: 500 mg PO once daily
      Increase by 500 mg/day every week as neededD1,D32,D33,D34,D35
      Max dose: 2000 mg/day; use doses > 1000 mg/day with caution in older adultsD32,D34,D35
      Consider dose reduction to 1000 mg/day if the patient is at risk for lactic acidosisD1,D33
      eGFR 30-44 mL/minute/1.73 m2: initial dose: 50% of recommended dose
      Max dose: 1000 mg/dayD1,D33
      eGFR < 30 mL/minute/1.73 m2: contraindicated due to risk of lactic acidosisD32      		BOXED WARNING: risk of lactic acidosis in high-risk patientsD32
      Contraindicated in patients with acute or chronic metabolic acidosisD32
      Avoid use in patients older than 80 years and in patients with hepatic impairmentD32,D34
      Drug interactions: may need to avoid or adjust dosage of certain drugsD32      		Diarrhea
      Lactic acidosis
      Nausea
      Vitamin B12 deficiencyD32      		Renally eliminatedD32
      If glycemic control is not achieved at maximum dose, consider dividing into 2 daily dosesD32
      GI intolerance can be mitigated by gradual dose titrationD31
      Monitor kidney function at least every 3-6 months in patients with eGFRD1 30-59 mL/minute/1.73 m2
      Monitor hematologic parameters annually and vitamin B12 level at 2- to 3-year intervalsD32
      SGLT2 inhibitors
      CanagliflozinFirst line with metformin for glycemic control in patients with T2DMD1,D31
      Risk reduction for progression of CKD, major CV events or death, and hospitalization for heart failure independent of eGFR or hemoglobin A1C levelD1,D31,D36,D37
      Decreases albuminuria and GFR loss†D1      		eGFR ≥ 60 mL/minute/1.73 m2: initial dose: 100 mg PO once dailyD37
      May increase to 300 mg PO once dailyD37
      eGFR 30-59 mL/minute/1.73 m2: 100 mg PO once dailyD33,D37
      eGFR < 20 mL/minute/1.73 m2: do not initiate therapy; may continue if eGFR falls after initiation in patients with albuminuria unless not tolerated or kidney replacement therapy is initiatedD33      		Use with caution in patients with history of diabetic foot ulcer or peripheral vascular disease due to increased risk of lower limb amputationsD37,D38
      Do not use in patients with severe hepatic impairmentD37
      Correct volume depletion before initiating therapyD37,D38,D39
      Do not use in patients with type 1 diabetes mellitus or for treatment of DKAD37,D38,D39
      Hold doses for at least 3 days, when possible, before major surgical procedures or proceduresD37,D38,D39
      Drug interactions: may need to avoid or adjust dosage of certain drugsD37,D38,D39      		Acute kidney injury
      Bone fractures
      Fournier gangrene
      GU infections
      Hypotension
      Ketoacidosis
      LDL-C level increasedD37      		Hepatic elimination; < 1% of unchanged drug excreted in urineD37
      Monitor patients for infection, new pain or tenderness, sores, or ulcers involving the lower limbsD37,D38
      Monitor kidney function at baseline and periodically thereafterD37
      SGLT2 inhibitors increase urinary glucose excretion, leading to positive urine glucose testsD37
      DapagliflozinFirst line with metformin for glycemic control in patients with T2DMD1,D31
      Risk reduction for progression of CKD, CV death, and hospitalization for heart failure independent of eGFR or hemoglobin A1C levelD1,D39
      Decreases albuminuria and GFR loss†D1      		eGFR ≥ 20 mL/minute/1.73 m2: 10 mg PO once dailyD33,D39
      eGFR < 20 mL/minute/1.73 m2: do not initiate therapy; may continue if eGFR falls after initiation unless not tolerated or kidney replacement therapy is initiatedD33      		Correct volume depletion before initiating therapyD37,D38,D39
      Do not use in patients with type 1 diabetes mellitus or for treatment of DKAD37,D38,D39
      Hold doses for at least 3 days, when possible, before major surgical proceduresD37,D38,D39
      Drug interactions: may need to avoid or adjust dosage of certain drugsD37,D38,D39      		Acute kidney injury
      Fournier gangrene
      GU infections
      Hypotension
      Ketoacidosis
      LDL-C level increasedD39      		Hepatic elimination; < 2% of unchanged drug excreted in urineD39
      Monitor kidney function at baseline and periodically thereafterD39
      SGLT2 inhibitors increase urinary glucose excretion, leading to positive urine glucose testsD39
      EmpagliflozinFirst line with metformin for glycemic control in patients with T2DMD1,D31
      Risk reduction for progression of CKD, CV death, and hospitalization for heart failure independent of eGFR or hemoglobin A1C levelD1,D31,D36,D38
      Decreases albuminuria and GFR loss†D1      		eGFR ≥ 30 mL/minute/1.73 m2: initial dose: 10 mg PO once dailyD1,D38
      Max dose: 25 mg PO once dailyD1,D38
      eGFR 20-29 mL/minute/1.73 m2: not recommended for glycemic control; however, may continue 10 mg PO once daily for CV and renal protectionD33
      eGFR < 20 mL/minute/1.73 m2: do not initiate therapy; may continue if eGFR falls after initiation unless not tolerated or kidney replacement therapy is initiatedD33      		Use with caution in patients with history of diabetic foot ulcer or peripheral vascular disease due to increased risk of lower limb amputationsD37,D38,D39
      Correct volume depletion before initiating therapyD37,D38,D39
      Do not use in patients with type 1 diabetes mellitus or for treatment of DKAD38
      Hold doses for at least 3 days, when possible, before major surgical proceduresD37,D38,D39
      Drug interactions: may need to avoid or adjust dosage of certain drugsD37,D38,D39      		Acute kidney injury
      Fournier gangrene
      GU infections
      Hypotension
      Ketoacidosis
      LDL-C level increasedD38      		Hepatic elimination; approximately 50% of unchanged drug excreted in urineD38
      Monitor patients for infection, new pain or tenderness, sores, or ulcers involving the lower limbsD37,D38
      Monitor kidney function at baseline and periodically thereafterD38
      SGLT2 inhibitors increase urinary glucose excretion, leading to positive urine glucose testsD38
      GLP-1 receptor agonists
      LiraglutideAdd-on or alternative therapy in patients with T2DM unable to achieve glycemic targets with metformin and SGLT2 inhibitor or with contraindications or intolerance to metformin and SGLT2 inhibitorD1,D31
      Risk reduction for major CV events, particularly in patients with ASCVD, and possibly progression of CKD independent of eGFR or hemoglobin A1C levelD1,D31,D36,D40
      Decreases albuminuriaD1      		Initial dose: 0.6 mg subcutaneously once daily for 1 week, then 1.2 mg once dailyD40
      Max dose: 1.8 mg subcutaneously once dailyD40      		BOXED WARNING: risk of thyroid C-cell tumors in rodents; human relevance not determinedD40
      Contraindicated in patients with personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2D40
      0.6-mg dose is for dose titration and is not effective for glycemic controlD40
      Drug interactions: may need to avoid or adjust dosage of certain drugsD40      		Acute kidney injury
      Cholelithiasis
      Cholecystitis
      Diarrhea
      Nausea
      Pancreatitis
      Serious hypersensitivity reactions
      VomitingD40      		Eliminated through proteolytic catabolism; intact drug not detected in urineD40
      Monitor kidney function in patients reporting severe GI adverse reactionsD40
      Semaglutide, injectionAdd-on or alternative therapy in patients with T2DM unable to achieve glycemic targets with metformin and SGLT2 inhibitor or with contraindications or intolerance to metformin and SGLT2 inhibitorD1,D31
      Risk reduction for major CV events, particularly in patients with ASCVD, and possibly progression of CKD independent of eGFR or hemoglobin A1C levelD1,D31,D36,D41
      Decreases albuminuriaD1      		Initial dose: 0.25 mg subcutaneously once weekly for 4 weeks, then 0.5 mg once weeklyD41
      May increase to 1 mg once weekly after 4 weeksD41
      Max dose: 2 mg subcutaneously once weeklyD41      		BOXED WARNING: risk of thyroid C-cell tumors in rodents; human relevance not determinedD41
      Contraindicated in patients with personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2D41
      0.25-mg dose is for dose-titration and is not effective for glycemic controlD41
      Drug interactions: may need to avoid or adjust dosage of certain drugsD41      		Acute kidney injury
      Cholelithiasis
      Cholecystitis
      Diarrhea
      Nausea
      Pancreatitis
      Serious hypersensitivity reactions
      VomitingD41      		Eliminated through proteolytic catabolism; approximately 3% of intact drug excreted in urineD41
      Monitor kidney function in patients reporting severe GI adverse reactionsD41
      Monitor for worsening diabetic retinopathy in patients with history of diabetic retinopathyD41
      Semaglutide, oralAdd-on or alternative therapy in patients with T2DM unable to achieve glycemic targets with metformin and SGLT2 inhibitor or with contraindications or intolerance to metformin and SGLT2 inhibitorD1,D31
      Risk reduction for major CV events, particularly in patients with ASCVD, and possibly progression of CKD independent of eGFR or hemoglobin A1C levelD1,D31,D36,D42
      Decreases albuminuriaD1      		Initial dose: 3 mg PO once daily for 30 days, then 7 mg PO once dailyD42
      May increase to 14 mg PO once daily after 30 daysD42
      Max dose: 14 mg PO once dailyD42      		BOXED WARNING: risk of thyroid C-cell tumors in rodents; human relevance not determinedD42
      Contraindicated in patients with personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2D42
      3-mg dose is for dose titration and is not effective for glycemic controlD42
      Drug interactions: may need to avoid or adjust dosage of certain drugsD42      		Acute kidney injury
      Cholelithiasis
      Cholecystitis
      Diarrhea
      Nausea
      Pancreatitis
      Serious hypersensitivity reactions
      VomitingD42      		Eliminated through proteolytic catabolism; approximately 3% of intact drug excreted in urineD42
      Monitor kidney function in patients reporting severe GI adverse reactionsD42
      Monitor for worsening diabetic retinopathy in patients with history of diabetic retinopathyD42
      Dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist
      TirzepatideAdd-on or alternative therapy in patients with T2DM unable to achieve glycemic targets with metformin and SGLT2 inhibitor or with contraindications or intolerance to metformin and SGLT2 inhibitorD31
      Benefit for pronounced improvement of glycemic control and weight lossD31      		Initial dose: 2.5 mg subcutaneously once weekly for 4 weeks, then 5 mg subcutaneously once weeklyD43
      May increase by 2.5 mg every 4 weeks as needed for glycemic controlD43
      Max dose: 15 mg subcutaneously once weeklyD43      		BOXED WARNING: risk of thyroid C-cell tumors in rodents; human relevance not determinedD43
      Contraindicated in patients with personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2D43
      Use not recommend in patients with gastroparesis and other severe GI diseaseD43
      2.5-mg dose is for dose titration and is not effective for glycemic controlD43
      Drug interactions: may need to avoid or adjust dosage of certain drugsD43      		Acute kidney injury
      Cholelithiasis
      Cholecystitis
      Constipation
      Nausea
      Pancreatitis
      Serious hypersensitivity reactions
      VomitingD43      		Eliminated through proteolytic catabolism; intact drug not detected in urineD43
      Monitor kidney function in patients reporting severe GI adverse reactionsD43
      Monitor for worsening diabetic retinopathy in patients with history of diabetic retinopathyD43

    Treatment Procedures

    Kidney Replacement Therapy

    • In the setting of progressive CKD that reaches kidney failure and a need for kidney replacement therapy, treatment procedures (dialysis or kidney transplant) become essential to sustaining life

    Persistent or Recurrent Disease

    • Treatment adherence is a major challenge for many patients for a variety of reasons (regimen complexity and cost); periodic evaluation for nonadherence and collaboration with patients to overcome barriers (especially financial) to care is essential90
    • Progressive loss of kidney function may occur even when treatment objectives are achieved. However, when disease progresses rapidly (dramatic worsening in proteinuria or decline in kidney function) without a clear precipitating event, diagnostic evaluation should be considered
      • Such steps include urinalysis, renal ultrasonography, targeted serologic evaluation, and in some cases renal biopsy to clarify pathology as nondiabetic kidney lesions (eg, glomerulonephritis) that may develop in patients with diabetes and kidney disease4
    • Bladder outlet obstruction should always be ruled out by sonographic evaluation due to high co-occurrence of autonomic neuropathy (and in males, prostatic hypertrophy)4

    Admission Criteria

    • CKD in diabetes is generally managed in the outpatient setting; regardless of treatment environment, a close follow-up with multidisciplinary collaboration is key to optimal outcomes
    • Patients may require admission if the course is complicated by severe electrolyte abnormalities (most commonly hyperkalemia and hyponatremia), volume overload, or kidney failure, whether through acute kidney injury or rapid progression of CKD
    • If patients exhibit progressive loss of kidney function, preparation for kidney replacement therapy (dialysis or transplant) should be undertaken principally in the outpatient setting4
      • However, if CKD progresses more rapidly than preparations permit, admission may be necessary to prevent clinical deterioration and to manage severe electrolyte abnormalities (eg, hyperkalemia)

    Follow-Up

    Monitoring

    • Blood pressure, kidney function, electrolytes, urine albuminuria, and glycemic control are essential to monitoring at all stages of CKD in patients with diabetes1
    • In progressive CKD (starting in late stage 3), monitoring for complications of CKD becomes important, including risk factors for metabolic bone disease (vitamin D, parathyroid hormone, phosphorus) and anemia (CBC, iron, total iron-binding capacity, ferritin)4
    • Albuminuria (UACR) should be measured serially over time1,4,5
      • Frequency of measurement should be at least annually in all patients
      • In patients with diabetes and CKD, albuminuria may be assessed more frequently for people at higher risk for progression and/or if the result of measurement will affect therapeutic decisions
      • Degree of albuminuria has a major prognostic effect on patients with CKD both in the absence of therapies with antiproteinuric effects and in the presence of such therapies (residual albuminuria)4
        • Patients with persistent proteinuria should be selected for escalation of therapies and/or referral to clinical trials for investigational therapies for diabetic kidney disease
    • Kidney function should be measured serially (at least annually) over time1,4
      • As kidney function declines, more frequent measurement of blood chemistry is advisable to identify electrolyte abnormalities
      • In stage 3 CKD, consider measuring kidney function more often than annually, particularly if using medications that are renally cleared

    Complications

    • CKD in patients with diabetes carries increased risk of electrolyte abnormalities, hypoglycemia, and resistant hypertension than in patients with diabetes without CKD1,2,36
    • Patients with diabetes or CKD are at increased risk for atherosclerotic disease; however, patients with both conditions (diabetes and CKD) are at higher risk than those with only 1 condition or the other7,16,91
    • CKD in patients with diabetes also carries risk of standard complications of CKD, such as mineral bone disorders, metabolic acidosis, and anemia of CKD4

    Prognosis

    Natural History

    • For patients with type 2 diabetes with risk factors for developing CKD, by 15 years after diabetes diagnosis92
      • 40% of patients develop albuminuria
      • In 30% of patients with type 2 diabetes, the GFR will lower to less than 60 mL/minute/1.73 m2

    Mortality

    • Among people with type 1 or type 2 diabetes, the presence of CKD markedly increases cardiovascular risk and mortality93
    • Degree of proteinuria is a major predictor of prognosis2,11,15,16,74
      • At any given level of eGFR, renal prognosis can vary dramatically based on the degree of proteinuria and initiation of and maintenance on therapies with proven cardiovascular and kidney benefits (eg, ACE inhibitor or ARB, SGLT2 inhibitor, finerenone, GLP-1 RA)
    • Older adults with CKD with a relatively low GFR may still have excellent renal prognosis, particularly when albuminuria is controlled (less than 300 mg/g) or absent (less than 30 mg/g)7,94,95

    Referral

    • In the early stages of diabetes, CKD management is generally conducted in a primary care setting
    • Referral to a nephrologist should be considered when:4
      • Cause of CKD is unclear
      • Unexplained acute kidney injury has occurred
      • Proteinuria is severe and/or persists despite appropriate antiproteinuric therapy and does not respond to blood pressure control or RAS blockade
      • Progression of CKD is rapid (eg, loss of eGFR in excess of 5 mL/minute/1.73 m2)
      • eGFR is less than 30 mL/minute/1.73 m2
    • Referral to kidney transplant program may be considered in suitable patients when eGFR is less than 20 mL/minute/1.73 m2 or earlier in patients who seem to be particularly at a high risk for progression4
    • Patients approaching the need for kidney replacement therapy should be evaluated and followed by a nephrologist. To improve access to and quality of patient-centered treatment options for kidney failure, efforts should be made to provide education on home dialysis treatment options and timely referral for consideration of kidney transplant4

    Author Affiliations

    Christos Argyropoulos, MD
    Associate Professor
    Division Chief
    University of New Mexico Health Sciences Center

    Darren Schmidt, MD
    Associate Professor of Medicine, Internal Medicine
    Department of Nephrology
    University of New Mexico Health Sciences Center

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