Approach to Chronic Kidney Disease in the Diabetic Patient

C H A P T E R

51 Approach to Chronic Kidney Disease in the Diabetic Patient Farsad Afshinniaa, Frank C. Brosius, 3rd a,b a

Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States; b Division of Nephrology, University of Arizona College of Medicine, Tucson, AZ, United States increase.1 The reasons for continued growth in ESRD from diabetic kidney disease (DKD) include the inability to identify patients at high risk of progression of chronic kidney disease (CKD) at relatively early stages, as well as the lack of substantial advances in the treatment of DKD during the past 25 years. It is likely that the incidence of DKD will increase again as the recent major increase in type 2 diabetes, especially in children and young adults, leads to more nephropathy over the next two decades.2 The diagnostic and prognostic biomarkers of DKD in current clinical practice (S[Cr], cystatin C, estimated glomerular filtration rate [eGFR], and urinary albumin excretion) lack desired sensitivity and specificity, but new useful biomarkers will likely be available soon. Moreover, our general understanding of pathogenic signaling pathways leading to progressive DKD continues to expand.3 There is new evidence of the substantial therapeutic effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors and other new interventions in slowing the progression of DKD.4 Continued elucidation of the various molecular signaling pathways and networks that lead to DKD will allow us to test and develop even better diagnostic biomarkers and more effective preventive and therapeutic strategies in the not-too-distant future.3

Abstract The diagnosis of diabetic kidney disease (DKD) is generally made clinically, either by increased urinary albumin excretion (>30 mg/day) or declining glomerular filtration rate, usually in the presence of diabetic retinopathy. All diabetic patients should undergo annual measurements of serum creatinine concentration (S[Cr]) and urinary albumin concentration and have their estimated glomerular filtration rate (eGFR) calculated. Control of blood glucose to achieve an HbA1c of 7%, and blood pressure aimed at a level less than 130/80 mm Hg, as tolerated, can delay or prevent onset of DKD. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are first-line treatments in hypertensive and nonhypertensive DKD patients, especially those with increased urinary albumin excretion. The use of sodiumglucose cotransporter 2 inhibitors also prevents DKD progression in patients with both preserved and decreased eGFR. Lipid-lowering therapy is beneficial in the primary prevention of cardiovascular events in DKD patients. Dietary protein restriction should also be considered for DKD patients. All patients with stage 4 or 5 CKD should be evaluated for potential renal replacement therapy (RRT) by a nephrologist. Proper candidates should be prepared for end-stage renal disease therapy by discussing modalities of RRT, including renal transplantation, providing necessary education, creating dialysis access when appropriate, and making necessary referrals.

INTRODUCTION Over 44% of the new cases of end-stage renal disease (ESRD) in the US are attributed to diabetes mellitus (DM), making it the leading cause of ESRD in the US1 and in many parts of the world. According to the 2017 US Renal Data System report, in spite of stabilization of adjusted incidence rates, the total number of patients with ESRD from diabetes has continued to

Chronic Renal Disease, Second Edition https://doi.org/10.1016/B978-0-12-815876-0.00051-6

NATURAL HISTORY OF DKD Glomerular hyperfiltration, i.e. a higher-than-normal glomerular filtration rate (GFR), occurs shortly after diagnosis in most patients with type 1 DM. Hyperfiltration is due to the relative vasodilation of renal glomerular afferent arterioles, leading to increased glomerular

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pressure and a resultant increase in GFR. Hyperfiltration is improved or eliminated with good glycemic control.5 Hyperfiltration also occurs in early type 2 diabetes,6 but its presence is less consistent. Although hyperfiltration predicts albuminuria and a generally worse prognosis in diabetic patients, there are no convincing long-term prospective studies that establish whether hyperfiltration, per se, causes enhanced glomerular or tubular pathology and progression of DKD. The most common initial indicator of DKD is albuminuria, defined as urinary albumin excretion over 30 mg/day. Abnormal urinary albumin excretion usually develops between 5 and 15 years after the diagnosis of diabetes in many type 1 patients who develop nephropathy, and is not present at the onset of diabetes,7 unless some other kidney disease is present. In contrast, up to 20% of patients with type 2 diabetes may have increased albumin excretion at the time of diagnosis, suggesting the presence of another cause of CKD, such as obesity-related glomerulopathy, or early DKD. Historical data suggest that, without treatment, up to 80% of albuminuric patients with type 1 diabetes develop more significant levels of albuminuria (>300 mg/24 h, historically called macroalbuminuria). Of such patients, 50e75% reach ESRD within 10e20 years. In type 2 diabetes, in contrast, approximately 40% of patients with albuminuria show further increases in albuminuria levels and 20% reach ESRD within the same time frame.8 Over the past decade or more, it has become evident that the natural history presented above is not always followed by patients with progressive DKD. In the Diabetes Control and Complications Trial and the follow-up Epidemiology of Diabetes Interventions and Complications study of participants with type 1 diabetes, 28% of the patients with an estimated GFR <60 mL/min/1.73 m2 did not have abnormal albuminuria.9e11 It appears that somewhere between 5% and 30% of type 1 DKD patients develop only transient albuminuria or never develop albuminuria, yet still develop progressive nephropathy that is similar pathologically to that in patients with albuminuria and progressive DKD.12,13 Similarly, a progressive decline in GFR to ESRD in the absence of albuminuria progression occurs in up to 50% of type 2 diabetic patients.14,15 These changes in DKD patterns may be the result of widespread use of agents such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) that reduce proteinuria but fail to retard progression of disease in some patients. Moreover, enhanced hypertension control in diabetic patients can reduce albuminuria and may have contributed to the generalized reduction in albuminuria seen in DKD patients. Finally, a number of type 2 diabetic patients develop albuminuria before the onset of their diabetes. In some of these individuals,

this reflects the presence of generalized endothelial dysfunction rather than glomerular pathology.16 In addition, kidney disease can result directly from obesity, insulin resistance, and the metabolic syndrome,17,18 all of which routinely precede the onset of type 2 diabetes. The type of kidney pathology seen in such individuals diverges in several aspects from that of DKD.19,20 Little is known about the prognosis for kidney disease in such patients in the absence of diabetes. Finally, there is evidence that a number of patients, especially those with type 2 diabetes, develop either nondiabetic kidney diseases or a modified form of DKD, and therefore follow a different clinical course than “typical” DKD patients.

DIAGNOSIS OF DKD The diagnosis of DKD is made provisionally by detection of persistently elevated albuminuria and/or decline in eGFR in patients with type 1 DM 5 or more years after the onset of DM, or in patients with type 2 DM at or after the time of diagnosis. The American Diabetes Association (ADA) recommends that urinary albumin excretion and eGFR be assessed at least once a year in patients with type 1 diabetes with duration of
5 years, in all patients with type 2 diabetes, and in all diabetic patients with comorbid hypertension.21 Urinary albumin excretion has a wide intraindividual variability, due to a number of reasons, including exercise within 24 h, fever, urinary tract infection, uncontrolled hypertension, marked hyperglycemia, menstruation, and congestive heart failure, all of which can elevate albuminuria independently of kidney damage. Because of this variability, the diagnosis of albuminuria requires its detection in at least 2 out of 3 tests performed over a period of 3e 6 months. To detect albuminuria, measurement of a random spot urinary albumin:creatinine ratio (UACR) is preferred for convenience. According to the ADA, timed or 24-hour collections are more burdensome and add little to prediction or accuracy.21 Once the diagnosis of persistent albuminuria is established, yearly or more frequent measurement of albumin:creatinine ratio (ACR) or urinary protein:creatinine ratio (UPCR) should be performed for monitoring of clinical response or assessment of progression of CKD.21 S[Cr] values and estimation of GFR should be obtained at baseline and at least annually. Most eGFR formulae are based on S[Cr] and the patient’s age, gender, and ethnicity. Both the Modification of Diet in Renal Disease (MDRD)22 and Chronic Kidney DiseaseEpidemiology Collaboration (CKD-EPI)23 formulae provide reasonable estimates of true GFR in patients with GFRs significantly below normal. However, such creatinine-based formulae are increasingly inaccurate

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when the GFR is above 60 mL/min22,23 and appear to systematically underestimate measured GFR.24 They also are inaccurate in patients with cachexia where S [Cr] is substantially influenced by muscle mass. In these circumstances, use of a cystatin C-based eGFR formula may be helpful25 and may better predict cardiovascular events in diabetic populations26 although its superiority over the creatinine-based CKD-EPI formula for estimation of true GFR has not been uniformly confirmed.27 Longitudinal data also suggest that the degree of decline in GFR in diabetic patients may be underestimated using eGFR formulae.28 The diagnostic evaluation of DKD requires a baseline history, a thorough physical examination, including accurate measurement of resting seated blood pressure, assessment of retinopathy, and laboratory evaluation that includes measurement of urinary albumin, and estimation of GFR. Genitourinary complications such as neurogenic bladder, papillary necrosis, and hydronephrosis are common in diabetic patients, so obtaining a baseline kidney ultrasound may be informative. In patients with type 1 diabetes, the diagnosis of DKD is made largely on clinical grounds, as a patient with a history of diabetes for over 10 years and albuminuria, and some degree of diabetic retinopathy has greater than a 90% likelihood of manifesting DKD,29 and other types of kidney disease are unusual in this group. In contrast, diabetic retinopathy coexists less frequently with early DKD in type 2 diabetic individuals. In some reports, over 50% of type 2 diabetic patients were found to have evidence of other types of kidney disease, often in addition to DKD.30,31 However, these reports have been based on kidney biopsies performed for clinical reasons and have been limited by their lack of racial diversity. Therefore, it is not clear that they are representative of typical type 2 diabetic patients. There is a general impression that the prevalence of nondiabetic forms of CKD in North American patients with type 2 diabetes is lower than the figures suggested by these reports. More precise data will be obtained as more trials that include kidney biopsies of diabetic patients are performed, such as are planned by the Kidney Precision Medicine Project (https:// kpmp.org). At present, there needs to be an individualized and nuanced approach to the diagnosis of nephropathy in type 2 diabetic patients, including the performance of kidney biopsies, particularly in those patients who manifest nephropathy very early in the course of their diabetes, develop early and progressive nephrotic range proteinuria, demonstrate substantial glomerular hematuria (as demonstrated by dysmorphic red blood cells or red blood cell casts), or who have a rapid decline in GFR.

MANAGEMENT OF DKD Glycemic Control The ADA recommends a target HbA1c of <7% to prevent or retard nephropathy and other microvascular complications of diabetes.32 As red blood cell survival is reduced in progressive CKD, reliance on HbA1c should be limited, and the clinician should depend more on random or continuous home blood glucose monitoring in patients with advanced CKD and ESRD.33 The role of intensive control of blood sugar in prevention of DKD was tested in two landmark trials.34,35 The DCCT/EDIC studies showed a 39% decrease in development of albuminuria of <300 mg/ day and a 54% reduction in rate of albuminuria of >300 mg/day in type 1 diabetic patients.34 The United Kingdom Prospective Diabetes Study (UKPDS) revealed a 25% risk reduction in the composite microvascular complication endpoint in the groups that underwent intensive control of blood sugar compared to patients receiving what was standard control in the 1980s and early 1990s in type 2 diabetes.35 A smaller trial in Japanese type 2 patients, the Kumamoto trial, revealed a 60% reduction of albuminuria >300 mg/day with intensive glycemic control in type 2 diabetes.36 Both DCCT and UKPDS cohorts showed that intensive therapy early in the course of diabetes led to a substantial and significant reduction in the incidence of microvascular complications for decades after the difference in glycemic control between the two groups had been eliminated. This phenomenon, known as “metabolic memory,” may be responsible for the reduction in the annual incidence of DKD development over the last two decades.37,38 However, some prominent investigators have argued that intensive control has merely delayed the onset of DKD and not altered the percentage of patients who ultimately develop this complication, or the rate by which it progresses.39 It appears that the most beneficial impact of tight glycemic control is achieved if applied early in the course of diabetes. In elderly patients (aged over 65 years) and in those with longstanding diabetes and cardiovascular disorders, evidence does not support intensive lowering of blood sugar.40,41 In fact, there is some evidence for harm associated with intensive lowering of blood sugar in patients with type 2 diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed no significant reduction in cardiovascular events but revealed a higher mortality by targeting HbA1c below 6% compared to its conventional target of 7e7.9%.41 There is no identified cut-point for HbA1c below which the beneficial effect of blood glucosee lowering strategies levels off, but increased risk of

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hypoglycemia and mortality at lower levels of HbA1c can be counterproductive. Therefore, the appropriate target HbA1c should be individualized according to features such as age, stage of CKD, and comorbid conditions, reserving control of blood sugar with HbA1c <7% for younger patients without other comorbidities and levels >7% for older patients with advanced stages of CKD and cardiovascular comorbidities. As recommended by the ADA, metformin is the firstline pharmacologic agent for treatment of hyperglycemia in patients with type 2 diabetes,4 including those with DKD. Metformin is effective, safe, and inexpensive, and may reduce the risk of cardiovascular events and death.42,43 Compared to sulfonylureas, metformin has beneficial effects on A1C, weight, and cardiovascular mortality.42 In the past, metformin was felt to be contraindicated in CKD patients with S[Cr] >1.5 mg/dL, because of its structural similarity to phenformin, which caused lactic acidosis in diabetic patients. However, there is substantial evidence that this prohibition was overly restrictive. Importantly, significant lactic acidosis appears to be no more common in patients prescribed metformin than in those who received other glucoselowering agents.44 In response to these observations in 2016, the Food and Drug Administration (FDA) changed the guidelines for metformin use with the following points: (1) metformin use in CKD patients should be based on eGFR and not S[Cr]; eGFR screening should be performed before and at least annually during metformin treatment; (2) metformin can be used when the eGFR is <60 mL/min/1.73 m2, should be monitored closely when eGFR is <45 mL/min/1.73 m2, should be stopped when the eGFR reaches 30 mL/min/1.73 m2, and should not be started between eGFRs of 30 and 45 mL/min/1.73 m2; (3) metformin should be held before iodinated contrast procedures if the eGFR is 30e60 mL/min/1.73 m2 or if there is any liver disease, alcoholism, or heart failure, or if intraarterial contrast is used. If held, recheck the eGFR 48 h after the procedure and restart metformin when renal function is stable (https://www.fda.gov/Drugs/ DrugSafety/ucm493244.htm). In addition, periodic measurement of vitamin B12 should be considered with long-term use of metformin, especially in the presence of anemia and peripheral neuropathy, as it may be associated with vitamin B12 deficiency.4 In addition to lifestyle modification, antihyperglycemic therapy, and metformin, addition of agents with proven effect on reduction of cardiovascular events, such as SGLT2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, should be considered for glycemic control in patients with type-2 diabetes and established atherosclerotic cardiovascular disease.4 SGLT2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin) lower glucose levels by blocking glucose

reabsorption by the proximal renal tubules. In addition to glucose-lowering properties, and cardiovascular protection, they also promote weight loss and reduce blood pressure. In the EMPA-REG OUTCOME trial, the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke was significantly lower in the empagliflozin arm.45 In the CANVAS trial, canagliflozin showed a similar cardiovascular protection by lowering major cardiac events compared to standard care.46 There is also a strong indication from these trials that SGLT2 inhibitors prevent eGFR decline and development of albuminuria. More convincing renal protection has recently been reported by the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial which studied the effects of canagliflozin treatment in macroalbuminuric patients with DKD and eGFR between 30 and 90 mL/min/1.73m2 already receiving maximum tolerated standard treatment (including ACEIs or ARBs). In this trial, canagliflozin reduced the development of ESRD, doubling of S[Cr] and cardiovascular or renal death by 30%.47 While currently SGLT2 inhibitors are approved only for patients with eGFRs >45 mL/min/1.73 m2 this restriction may well be altered in the near future based on the demonstrated efficacy of canagliflozin on renal outcomes in participants with eGFRs down to 30 mL/min/1.73 m2. It should be noted that SGLT2 inhibitors are contraindicated all type 1 diabetic patients, due in part to the higher incidence of diabetic ketoacidosis in patients using these drugs.48,49 GLP-1 receptor agonists, such as lixisenatide, liraglutide, semaglutide, exenatide, lower glucose by stimulating glucose-dependent insulin secretion, suppressing glucagon secretion, slowing gastric emptying, and reducing appetite.50 Liraglutide, in the LEADER trial,51 and semaglutide, in the SUSTAIN-6 trial,52 were shown to decrease the rate of major cardiac events, and both are approved by the FDA as adjunct agents for lowering blood glucose in patients with type 2 diabetes.53,54 It is yet unclear whether GLP-1 receptor agonists prevent progression of CKD to ESRD. Like the SGLT2 inhibitors, GLP-1 agonists are contraindicated in patients with eGFR <30 mL/min/1.73 m2 and cannot be prescribed for type 1 diabetic patients.

Blood Pressure Control and ACEI and ARB Therapy in DKD In patients with type 1 diabetes, hypertension usually develops around or after the time of the appearance of DKD, but in type 2 diabetes patients it frequently precedes the onset of DKD, often as a manifestation of the metabolic syndrome or due to obesity.8 Home blood

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pressure measurement in hypertensive patients has been endorsed by a number of international societies and often provides a better picture of blood pressure control by providing more numerous readings and elimination of the “white coat” effect.55,56 Reliance on home BP measurements requires adequate education regarding proper timing and technique, but many studies have demonstrated the reliability of such data and its superiority over routine clinic BP measurement.57,58 Such monitoring appears to result in improved BP control when coupled with cointerventions, systematic medication titration, education, and lifestyle counseling.59 As autonomic dysfunction is a common finding in patients with diabetes, orthostatic BP measurements should be obtained. Reduction of BP in hypertensive patients with DKD has been uniformly found to reduce the incidence of major cardiovascular events and to delay the progression of DKD.60e64 The optimal range of BP control in hypertensive patients with diabetes has been an area of controversy, and the subject of several clinical trials in the past decade. The ADA currently recommends that most patients with diabetes should have an average seated BP of <140/90 mm Hg, although lower BP targets may be appropriate for individuals at high risk of cardiovascular disease.65 This necessitates initiation of at least one antihypertensive medication besides lifestyle modification, if the confirmed measure of office BP is
140/90 mm Hg, and two antihypertensive medications if the level is
160/100 mm Hg.65 The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for BP control, which were last updated in 2012, also recommend reduction of BP to 140/90 mm Hg, using blood pressureelowering agents if the daily urinary albumin excretion is <30 mg, but recommend further reduction to 130/80 mm Hg if daily albumin excretion is >30 mg.66 Conversely, the newer American Heart Association/American College of Cardiology guidelines issued in 2017 argue for more aggressive control of BP and redefine hypertension as an average seated BP of 130/80 mm Hg or above.67 Other than the KDIGO guidelines, none of these are specific for CKD patients, and none of the current guidelines have specific guidelines for DKD. The ACCORD trial showed no consistent benefit of lowering systolic BP to <120 mm Hg vs. to <140 mm Hg for diabetic patients including those with early DKD.68 Specifically, this study found no significant difference in the composite outcome of fatal and nonfatal major cardiovascular events in patients randomized to a systolic blood pressure of <120 mm Hg compared to a less-intensive target of range of <140 mm Hg. Although intensive lowering of blood pressure was associated with a significantly lower incidence of stroke, it was also associated with a

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significantly higher number of severe adverse outcomes including deaths, life-threatening events, persistent or significant disabilities, hospitalizations, and prolongations of hospital stay, which were numerically greater than the reduction in the number of strokes.68 Conversely, the SPRINT study, which studied participants at high cardiovascular risk (including CKD patients) but not diabetic patients, found a significant improvement in cardiovascular outcomes with lowering of systolic BP to 120 mm Hg.69 Our conclusion from these conflicting data is that BP control in DKD patients needs to be individualized. The lower the systolic BP, the lower will be the likely cardiovascular risk, but the higher will be the risk of adverse events, including acute kidney injury. Therefore, a more aggressive target than BP of 140/90 mm Hg should be individually applied, with the active participation of the patient until more definitive data from future randomized controlled trials (RCTs) are obtained (Table 51.1). Uncontrolled hypertension is a major contributing factor to progression of DKD.70 In established DKD patients with hypertension and albuminuria >300 mg/ day, well-designed RCTs have shown a beneficial effect of ACEIs or ARBs compared to other antihypertensives on the progression of DKD.60,63,64 The Collaborative Study Group trial of patients with type 1 DKD randomized to either captopril 25 mg three times a day or placebo showed a reduction in the primary endpoint of doubling of S[Cr] by 56%, and the combined endpoints of death, dialysis, and transplantation by 50%.63 ARBs were tested in most clinical trials of type 2 DKD, because these studies came after ACEI therapy was already standard of care for treatment of DKD. In general, these studies showed a less-dramatic effect on the progression of DKD in type 2 patients than did the ACEI studies in type 1 patients. For example, the Irbesartan Diabetic Nephropathy Trial (IDNT) randomization of DKD subjects with hypertension to three subgroups (irbesartan 300 mg/day, amlodipine 10 mg/day, or placebo), revealed a 20% reduction with ARB treatment in the primary composite outcome (doubling of S[Cr], development of ESRD, or death) compared to placebo, and 23% reduction compared to amlodipine, over a mean follow-up period of 2.6 years.64 In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study (RENAAL), type 2 DKD subjects were randomized to losartan vs. placebo. The risk of doubling of S[Cr] was reduced by 25% and incident ESRD by 28% in the losartan group.60 This difference in effect size in type 1 and type 2 DKD was assumed to be due to differences in the patient populations tested. Although there has never been a head-to-head comparison of ACEIs and ARBs, there is no evidence that one class works better than the other for DKD associated

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51. APPROACH TO CHRONIC KIDNEY DISEASE IN THE DIABETIC PATIENT

Recommendations for Management of Diabetic Kidney Disease (DKD).

Management Item

Recommendation

Prevention

The target for adequate glycemic control is an HbA1c of 7%. An average seated blood pressure of <140/90 mm Hg should be maintained. Metformin is the first-line agent for glycemic control in type 2 diabetic patients with eGFR >45 mL/min/1.73 m2. Given recent findings regarding their cardiovascular and renal protective effects, SGLT2 inhibitors should be considered as second line agents for this subset of type 2 diabetic patients. ACEI or ARB therapy is not recommended for primary prevention of DKD. However, ACEIs and ARBs are among the recommended agents for treatment of hypertension in type 1 and type 2 diabetic patients without nephropathy.

Screening and Diagnosis

Measurement of S[Cr] and monitoring for albuminuria (UACR >30 mcg/mg) should be performed annually starting 5 years after diagnosis of type 1 diabetes and at the time of diagnosis of type 2 diabetes. Confirm persistent albuminuria by two of three positive tests within a 3e6-month period after eliminating spurious causes of albuminuria. Type 1 diabetes: Persistent albuminuria and/or elevated S[Cr] (reduced eGFR) along with diabetic retinopathy is consistent with the diagnosis of DKD. Type 2 diabetes: Persistent albuminuria and/or elevated S[Cr] (reduced eGFR) with diabetic retinopathy is consistent with the diagnosis of DKD. Kidney biopsy should be considered when diagnoses other than DKD are suspected.

Treatment

Control of BP to a seated average BP of <140/90 mm Hg will prevent progression of DKD and the incidence of major cardiovascular events. Targeting a BP level of <130/80 mm Hg is encouraged when safe for individual patients. ACEIs or ARBs are the first-line antihypertensive therapy for nonpregnant hypertensive patients with DKD to reduce the incidence of major cardiovascular events and progression of DKD. Combined ACEI and ARB therapy is not recommended. Normotensive nonpregnant patients with DKD should also be treated with an ACEI or ARB, as tolerated, to reduce progression of DKD. Diuretics, mineralocorticoid receptor antagonists, calcium channel blockers, and beta blockers can be used in combination with ACEIs or ARBs to control blood pressure. A daily protein intake of 0.8 g/kg body weight is recommended for all nondialysis-dependent DKD patients. Lifestyle modification including exercise, weight loss, smoking cessation, and dietary consultation. Reduction of daily protein intake to 0.8e1.0 g/kg body weight should be considered in DKD patients with eGFR >30 mL/min/1.73 m2 and further reduction to 0.8 g/kg/body weight is recommended in patients with stage 4 or 5 DKD. Preparation for renal replacement therapy, including referral to a nephrologist at stage 4 CKD to allow adequate time for required education, and choice of therapy including transplantation, and creation of dialysis access, if indicated is recommended. Lifestyle modification including exercise, weight loss, smoking cessation, and dietary consultation should be recommended.

ACEI, angiotensin-converting enzyme inhibitor; UACR, urine albumin:creatinine ratio; ARB, angiotensin receptor blocker; CKD, Chronic kidney disease; eGFR, estimated glomerular filtration rate; S[Cr], Serum creatinine; SGLT2, sodium-glucose cotransporter 2.

with either type 1 or type 2 diabetes. ACEIs are often used preferentially due to lower cost and more extensive track record. However, in general the choice of class and specific agent for treatment should depend on tolerability, affordability, and physician and patient preference. An increase in the level of S[Cr] of approximately 30% above baseline with initiation of renine angiotensinealdosterone system blockade is expected and is associated with better preservation of renal function in the long term. However, a more severe decline in renal function, particularly if associated with flash

pulmonary edema, may reflect underlying renal artery stenosis. In these rare circumstances ACEI or ARB therapy should be immediately halted. Sometimes, at advanced stages of CKD, ACEIs or ARBs may be withdrawn to help extend the time off dialysis, to mitigate severe hyperkalemia or for other reasons. However, the relative benefits of this approach vs. maintaining ACEI or ARB therapy is not known. To date there have been no published studies assessing the benefits of ACEI/ARB therapy in cardiovascular risk reduction or CKD progression in advanced nondialysis CKD. An

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ongoing clinical trial, the STOP ACEI study, should help elucidate the relative benefits and risks of ACEIs/ARBs on renal function and cardiovascular outcomes use in advanced CKD.71 Because dual therapy with an ACEI and an ARB results in more complete inhibition of angiotensin II signaling, better control of blood pressure, and a greater reduction in proteinuria, it was hoped that dual ACEI and ARB therapy would lead to even better outcomes in DKD than seen with use of either class of agents alone. However, several randomized controlled trials in the last decade have shown this not to be the case. Both the ONTARGET72 and NEPHRON-D73 studies of dual ACEI and ARB therapy showed no significant improvement in cardiac or renal outcomes with combined therapy. Although the ONTARGET trial included few patients with DKD, the NEPHRON-D study focused on this population. In both studies combination therapy was significantly associated with adverse events, including hyperkalemia, hypotension, and acute kidney injury. Thus, dual therapy with an ACEI and ARB is not generally indicated for patients with DKD. Control of blood pressure in patients with diabetes usually requires prescription of two or more antihypertensive medications. Thiazide diuretics in combination with an ACEI or ARB have been shown to provide additional benefit by providing better reduction of blood pressure, lowering the risk of hyperkalemia, and better augmentation of the antiproteinuric effects of RAAS blockade.74 Although increased insulin resistance and hyperuricemia often accompany thiazide treatment, the favorable cardiovascular outcomes in diabetic subjects who received the thiazide-like diuretic, chlorthalidone, compared to those who received amlodipine or lisinopril in the ALLHAT study suggest that such metabolic side effects are outweighed by the protective effects of the diuretic.75 The combination of thiazides with loop diuretics may provide better diuresis and blood pressure control, particularly in patients with salt-sensitive and volume-sensitive hypertension and in more advanced stages of CKD. Mineralocorticoid receptor antagonists (MRAs), including spironolactone, eplerenone, and finerenone, appear to be underutilized in patients with DKD who are already on ACEI/ARB therapy. Aldosterone has a direct detrimental effect on renal function in diabetes independent of its effects on BP, possibly by enhancing MAP kinase activity and increasing TGF-b expression. Both processes have been implicated in the development of tubulointerstitial fibrosis.76,77 Patients may develop a rebound increase of aldosterone levels within weeks to months of initiation of ACEI or ARB treatment, a process referred to as aldosterone escape.78,79 Patients with aldosterone escape appear to have a faster decline of renal function.80

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The addition of MRAs to ACEIs or ARBs in the treatment DKD patients has been tested in a few small RCTs. Collectively, these studies suggest significant sustained decline in proteinuria, better control of hypertension, and better preservation of renal function.81e84 Although a significant decline in eGFR occurred immediately after initiation of MRAs in this setting, eGFR then stabilized as opposed to the continuous decline of kidney function found in patients receiving placebo.84,85 It appears possible to minimize side effects such as hyperkalemia and gynecomastia while maintaining beneficial effects.81 Two ongoing clinical trials, FIGARO-DKD and FIDELIO-DKD, will determine whether the MRA, finerenone, in addition to standard ACEI or ARB therapy will improve cardiovascular or renal outcomes in participants with progressive DKD (https://clinicaltrials. gov/ct2/show/NCT02545049). Calcium channel blockers (CCBs) are often used, either with or without ACEIs or ARBs, for BP control in patients with DKD. The safety, efficacy, and similar impact of both dyhidropyridine and nondihydropyridine CCBs on cardiovascular mortality, cardiovascular events, and stroke compared to diuretics, betablockers, or their combinations have been demonstrated in several RCTs.75,86,87 However, in type 2 diabetic hypertensive participants with or without DKD, there was a higher incidence of fatal and nonfatal myocardial infarction, in those treated with nisoldipine compared to those receiving ACEI or ARB therapy.88 Similarly, there was a higher rate of the composite outcomes of doubling of S[Cr], ESRD, or death with amlodipine than with irbesartan in the IDNT study of patients with moderate DKD, though this rate was not higher than those treated with placebo.64 However, a trial of over 11,000 patients with hypertension (approximately 1100 with CKD, and approximately 60% with diabetes) who were at high risk for cardiovascular events showed that the addition of amlodipine compared with the addition of hydrochlorothiazide to maximal ACEI therapy resulted in a major improvement in both cardiovascular and prespecified kidney endpoints.89,90 Thus, it appears that therapy with CCBs may be beneficial in DKD patients already treated with an ACEI or ARB. A recent large comparative effectiveness study from four integrated health care systems reinforced this approach. The study showed that CCBs have the best add-on effect to ACEI or ARB therapy in diabetic patients who have better cardiovascular and renal outcomes.91 In this study, CCBs were associated with a lower risk of significant kidney events, a similar risk of cardiovascular events, and a suggestion of a lower risk of death, over 5 years of follow-up, compared with thiazide diuretics. Although beta blockers were also associated with a lower risk of significant kidney events, they

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were associated with a higher risk of cardiovascular events compared with thiazide diuretics. These more recent studies are in accord with the now common practice of adding a CCB as the second antihypertensive agent after maximizing ACEI or ARB therapy in patients with DKD. Beta blockers appear to be a less-favorable class of antihypertensive medications, due to their reduced effectiveness in preventing cardiovascular events, as well as their adverse metabolic side effects, such as an unfavorable lipid profile, hypoglycemic unawareness, and erectile dysfunction. However, they may help reduce sympathetic overactivity in CKD and therefore may be an effective adjunct therapy in DKD patients who require an additional antihypertensive medication after achieving maximal RAAS blockade92 or when secondary prevention of cardiac outcomes is warranted. Direct renin inhibitors also appear to be a lessfavorable class of antihypertensives as they have no advantage over ACEI or ARB therapy and can cause significant adverse effects in combination with ACEIs or ARBs.93,94 Thus, current FDA guidelines recommend avoidance of aliskiren in conjunction with ACEIs and ARBs in patients with DKD (https://www.fda.gov/ Drugs/DrugSafety/ucm300889.htm). Several trials have demonstrated that preemptive treatment with ACEIs or ARBs in normotensive diabetic patients without albuminuria does not reduce the incidence or severity of DKD. Therefore, ACEIs and ARBs are not recommended for primary prevention.95,96 However, in normotensive diabetic patients with albuminuria, ACEIs or ARBs may be beneficial for patients at high risk of progression of DKD. Such high risk conditions include increasing albuminuria, decreasing GFR, increasing blood pressure, presence of retinopathy, worsening lipid profile, increasing uric acid, family history of hypertension, macrovascular disease, or DKD.96 Moreover, the ADA recommends ACEIs, ARBs, thiazide diuretics, or dihydropyridine CCBs as first-line pharmacologic therapy for hypertension in diabetic patients without nephropathy.65

Lipid Control The ADA recommends the use of lifestyle modification in all patients with diabetes, consisting of application of weight loss (when indicated), the reduction of saturated fat, trans fat, and cholesterol intake, increase of dietary n-3 fatty acids, viscous fiber, and plant stanols/sterols intake, and increased physical activity aimed at improving lipid profile.65 For patients with atherosclerotic cardiovascular disease at all ages, highintensity statins (atorvastatin 40e80 mg/day or

rosuvastatin 20e40 mg/day) should be added to lifestyle modification regardless of lipoprotein levels. For patients with diabetes aged <40 years with atherosclerotic cardiovascular disease risk factors, any patients between 40 and 75 years, and those >75 years without atherosclerotic cardiovascular disease, use of moderate intensity statins can be considered (atorvastatin 10e20 mg/day, rosuvastatin 5e10 mg/day, simvastatin 20e40 mg/day, or pravastatin 40e80 mg/day).65 In patients with atherosclerotic cardiovascular disease, if LDL is
70 mg/dL on maximally tolerated dose of statins, addition of another LDL lowering agent such as ezetimibe or PCSK9 inhibitor to the therapeutic regimen should be considered.65 Despite demonstrated effectiveness of lipid-lowering medications in preventing cardiovascular events in patients with diabetes, similar efficacy in diabetic CKD patients has been demonstrated only in the last decade.97e102 The Study of Heart and Renal Protection (SHARP) examined the effects of dual treatment with simvastatin and ezetimibe in CKD and dialysis patients, including those with diabetes.97 This study clearly showed that the combination of simvastatin and ezetimibe led to a significant reduction in major atherosclerotic cardiovascular events but did not appear to reduce the progression of CKD. Despite the observed beneficial effect in nondialysis CKD patients, a subgroup analysis in dialysis patients revealed no cardiovascular benefit with use of statins.97 This is consistent with results from the 4D, AROURA, and ALERT trials in which no cardiovascular survival benefit was noted in ESRD patients with use of statins.103e105 The reasons for the lack of beneficial effects from statins on cardiovascular outcomes in dialysis patients are poorly understood and could be due, in part, to impaired reverse cholesterol transport system in ESRD106 or may be due to differences in the type of cardiovascular events that affect dialysis patients. Gemfibrozil and fenofibrate are also used frequently in DKD patients. The Diabetes Atherosclerosis Intervention Study and the Fenofibrate Intervention and Event Lowering in Diabetes Study reported a decrease in albuminuria and its regression toward normoalbuminuria with the use of fenofibrate.107,108 In post hoc analysis of the Veterans’ Affairs High-Density Lipoprotein Intervention Trial, gemfibrozil reduced the primary composite outcome of coronary death and nonfatal myocardial infarction, but not the need for revascularization or allcause mortality in CKD.109 Gemfibrozil when combined with statins increases the risk of increased transaminases and rhabdomyolysis. Gemfibrozil therefore should not be given combined with statins. It is not recommended for use in patients with severe reduction in GFR as well.

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Dietary Protein Restriction High intake of nondairy animal protein may accelerate reduction of renal function.95 A number of studies, mostly conducted in the 1980s or 1990s, showed that moderate protein restriction reduced the progression of established DKD in terms of GFR decline, albuminuria, and occurrence of ESRD in both type 1 and type 2 diabetic patients.110e112 Generally, dietary protein was restricted to 1 g/kg body weight/24 h or less in these studies. As current management of DKD has emphasized blood pressure control and ACEI or ARB treatment, it is unclear whether dietary protein restriction provides much additional benefit. Indeed, relatively small studies reported after 2001 have not confirmed a significant improvement in outcomes with similar degrees of dietary protein restriction.113 However, modest dietary protein restriction may be helpful in a number of DKD patients and will likely do no harm. The ADA currently recommends a daily dietary protein intake of approximately 0.8 g/kg in individuals with nondialysis-dependent DKD.21

Other Lifestyle Modifications In addition to calorie and protein intake, dietary evaluation and recommendations should emphasize sodium restriction in hypertensive DKD patients, as well as in potassium and phosphorus intake when CKD progresses. Exercise should be part of lifestyle modification as tolerated. Supplementation with monounsaturated and polyunsaturated fats have improved glycemic control, lowered blood pressure, reduced albuminuria, and altered high-risk inflammatory biomarkers in the general population and may be beneficial in patients with diabetes and CKD.33 Smoking cessation and weight loss are integral parts of lifestyle modification, as smoking cessation ameliorates progression of early stage DKD.114 Weight loss has beneficial renal effects by reducing proteinuria and decreasing blood pressure in patients with mild to moderate CKD with or without diabetes.115,116 Aspirin (dose of 75e162 mg/day) is indicated for primary prevention of cardiovascular morbidities in all patients with cardiovascular risk factors (aged >50 years with family history of premature atherosclerotic cardiovascular disease, hypertension, dyslipidemia, smoking, or albuminuria), as well as for secondary prevention in patients with a history of atherosclerotic cardiovascular disease.65 Similarly, lowdose daily aspirin is indicated in all pregnant patients with type 1 and type 2 diabetes, starting from the end of the first trimester until the birth of the baby, aimed at reducing the risk of preeclampsia.117

DIABETES IN ESRD Between 2001 and 2015, adjusted mortality rates in the dialysis and kidney transplant populations declined by 28% and 3%, respectively. After accounting for changes in population characteristics, the adjusted mortality rates decreased by 40% for transplant recipients. These decreases in mortality likely reflect improved care along with an increase in the number of prevalent ESRD patients. In spite of this trend, up to 21.7% of diabetic patients die in the first year after initiation of dialysis and have a 5-year survival rate of only 37.9%,118 giving ESRD patients with diabetes the highest mortality among all ESRD patients. Preparation for ESRD should start at least 6 months before the start of renal replacement therapy (RRT) is contemplated. Preparation should include education of patients and families regarding the process, prognosis, and different modalities of RRT and projected lifestyle changes. Consultation with a nephrologist for patients who reach stage 4 CKD reduces costs, improves quality of care, and delays dialysis.119 Decision-making about the modality of RRT should be similar to that in other ESRD patients. Survival rates are much better in patients receiving kidney transplants compared to those treated with dialytic modalities.120,121

SUMMARY DKD remains the leading cause of ESRD in the US and most developing countries. Table 51.1 provides a summary of the approach to prevention, screening, diagnosis, and treatment of diabetic nephropathy. Excellent glycemic control with an HbA1c of 7% can prevent or delay the development of DKD. Treatment with an SGLT2 inhibitor should be strongly considered for those patients with eGFR >45 ml/min/1.73 m2. Treatment of elevated blood pressure to <140/90 mm Hg can also reduce the development and progression of nephropathy. Targeting a BP of <130/80 mm Hg should be considered when it is safe and tolerable. ACEI or ARB therapy is not recommended for primary prevention of DKD in normotensive patients with diabetes as it does not forestall nephropathy. However, ACEIs and ARBs are among the recommended agents for treatment of hypertension in type 1 and type 2 diabetic patients without nephropathy. Diabetic patients should be monitored for the development of DKD. Measurement of S[Cr], calculation of eGFR, and monitoring for albuminuria (UACR >30) should be performed at least annually starting 5 years after diagnosis of type 1 diabetes, and at the time of diagnosis of type 2 diabetes. Persistent albuminuria should

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be confirmed by 2 of 3 positive tests within a 3e6-month period, after eliminating spurious causes of albuminuria. The presence of persistent albuminuria and/or reduced eGFR along with diabetic retinopathy is consistent with the diagnosis of DKD in type 1 diabetic patients. The presence of persistent albuminuria and/or reduced eGFR with diabetic retinopathy is also generally consistent with the diagnosis of DKD in type 2 diabetic patients. However, there is a higher incidence of non-DKD in type 2 diabetic patients. Thus, other diagnoses should be considered, especially if there are acute or subacute increases in albuminuria or acute or subacute decreases in eGFR. Additional evaluation, including kidney biopsy, should be considered when a diagnosis other than DKD is suspected. Control of blood pressure to a seated blood pressure of less than 140/90 mm Hg will prevent progression of DKD and decrease the incidence of major cardiovascular events. Reducing blood pressure to <130/80 mm Hg is encouraged if tolerated and not contraindicated for other medical reasons. Use of an ACEI or ARB as the first-line antihypertensive therapy is recommended for nonpregnant hypertensive patients with DKD to reduce the incidence of major cardiovascular events and progression of DKD. Combined ACEI and ARB therapy is not recommended. Normotensive nonpregnant patients with DKD should also be treated with an ACEI or ARB, as tolerated, to reduce progression of DKD. Diuretics, MRAs, CCBs, and beta blockers can be used in combination with ACEIs or ARBs to control BP. Reduction of daily protein intake to 0.8 g/kg body weight is recommended in DKD patients who are not treated with dialysis. Lifestyle modification, including exercise, weight loss, smoking cessation, and dietary consultation should be incorporated into a multidisciplinary approach to treatment for DKD patients. Preparation for RRT, including referral to a nephrologist, should begin when patients reach stage 4 CKD to allow adequate time for required education, and choice of RRT including transplantation, and creation of dialysis access, as indicated.

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97. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377:2181e92. 98. Chonchol M, Cook T, Kjekshus J, Pedersen TR, Lindenfeld J. Simvastatin for secondary prevention of all-cause mortality and major coronary events in patients with mild chronic renal insufficiency. Am J Kidney Dis 2007;49:373e82. 99. Colhoun HM, Betteridge DJ, Durrington PN, et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis 2009;54:810e9. 100. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005e16. 101. Shepherd J, Kastelein JJ, Bittner V, et al. Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study. J Am Coll Cardiol 2008;51:1448e54. 102. Tonelli M, Keech A, Shepherd J, et al. Effect of pravastatin in people with diabetes and chronic kidney disease. J Am Soc Nephrol 2005;16:3748e54. 103. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395e407. 104. Holdaas H, Fellstrom B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361:2024e31. 105. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:238e48. 106. Vaziri ND. Lipotoxicity and impaired high density lipoproteinmediated reverse cholesterol transport in chronic kidney disease. J Ren Nutr 2010;20:S35e43. 107. Ansquer JC, Foucher C, Rattier S, Taskinen MR, Steiner G. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis 2005;45:485e93. 108. Davis TM, Ting R, Best JD, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 2011;54:280e90. 109. Tonelli M, Collins D, Robins S, Bloomfield H, Curhan GC. Gemfibrozil for secondary prevention of cardiovascular events in mild to moderate chronic renal insufficiency. Kidney Int 2004;66: 1123e30. 110. Hansen HP, Tauber-Lassen E, Jensen BR, Parving HH. Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy. Kidney Int 2002;62:220e8. 111. Pijls LT, de Vries H, Donker AJ, van Eijk JT. The effect of protein restriction on albuminuria in patients with type 2 diabetes mellitus: a randomized trial. Nephrol Dial Transplant 1999;14: 1445e53.

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112. Zeller K, Whittaker E, Sullivan L, Raskin P, Jacobson HR. Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med 1991;324:78e84. 113. Wheeler ML, Dunbar SA, Jaacks LM, et al. Macronutrients, food groups, and eating patterns in the management of diabetes: a systematic review of the literature, 2010. Diabetes Care 2012;35: 434e45. 114. Phisitkul K, Hegazy K, Chuahirun T, et al. Continued smoking exacerbates but cessation ameliorates progression of early type 2 diabetic nephropathy. Am J Med Sci 2008;335:284e91. 115. Afshinnia F, Wilt TJ, Duval S, Esmaeili A, Ibrahim HN. Weight loss and proteinuria: systematic review of clinical trials and comparative cohorts. Nephrol Dial Transplant 2010;25:1173e83. 116. Navaneethan SD, Yehnert H, Moustarah F, Schreiber MJ, Schauer PR, Beddhu S. Weight loss interventions in chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2009;4:1565e74. 117. American Diabetes A. 13. Management of diabetes in pregnancy: standards of medical care in diabetes-2018. Diabetes Care 2018;41: S137e43. 118. USRDS. Chapter 6: mortality. 2015. https://www.usrds.org/2015/ download/vol2_06_Mortality_15.pdf. 119. Smart NA, Dieberg G, Ladhani M, Titus T. Early referral to specialist nephrology services for preventing the progression to end-stage kidney disease. Cochrane Database Syst Rev 2014: CD007333. 120. Rabbat CG, Thorpe KE, Russell JD, Churchill DN. Comparison of mortality risk for dialysis patients and cadaveric first renal transplant recipients in Ontario, Canada. J Am Soc Nephrol 2000;11: 917e22. 121. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725e30. 122. Couser WG. Primary membranous nephropathy. Clin J Am Soc Nephrol 2017;12:983e97. 123. Winkelmayer WC, Owen Jr WF, Levin R, Avorn J. A propensity analysis of late versus early nephrologist referral and mortality on dialysis. J Am Soc Nephrol 2003;14:486e92. 124. Yang JY, Huang JW, Chen L, et al. Frequency of early predialysis nephrology care and postdialysis cardiovascular events. Am J Kidney Dis 2017;70:164e72. 125. Mehrotra R, Devuyst O, Davies SJ, Johnson DW. The current state of peritoneal dialysis. J Am Soc Nephrol 2016;27:3238e52. 126. Shafi T, Mullangi S, Jaar BG, Silber H. Autonomic dysfunction as a mechanism of intradialytic blood pressure instability. Semin Dial 2017;30:537e44. 127. Tennankore KK, Na Y, Wald R, Chan CT, Perl J. Short daily-, nocturnal- and conventional-home hemodialysis have similar patient and treatment survival. Kidney Int 2018;93:188e94. 128. Schjoedt KJ, Astrup AS, Persson F, et al. Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial. Diabetologia 2009;52: 46e9.

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QUESTIONS AND ANSWERS Question 1 A 58-year-old man is referred for evaluation of kidney disease associated with diabetes. He reports having type 2 diabetes for over 25 years. His diabetes has been under good control. He has chronic hypertension and hyperlipidemia. Six months ago S[Cr] was 1.0 mg/dL and UPCR was 0.12. On a routine clinic visit he is asymptomatic. His medications include lisinopril 20 mg a day, furosemide 20 mg a day, insulin glargine 10 units SQ at night, and atorvastatin 40 mg every night. On physical examination, seated blood pressure is 139/88 mm Hg, heart rate 80 beats per minute, weight 108 kg, and BMI 33 kg/m2. There is no retinopathy or JVD. Heart sounds are normal and lungs are clear. Abdomen is soft and nontender without evidence of organomegaly. There is 3þ lower extremity pitting edema. The following labs are obtained: Serum chemistries S[Na] 136 mEq/L Serum potassium concentration (S[K]) 4.8 mEq/L S[Cl] 103 mEq/L tCO2 22 mEq/L BUN 38 mg/dL S[Cr] 1.5 mg/dL Glucose 183 mg/dL HbA1C 7.8% LDL cholesterol 160 mg/dL HDL cholesterol 34 mg/dL UPCR 5.3 Urine microscopy: no cells, casts, crystals, or other abnormalities Which one of the following is correct in this patient? A. Addition of losartan 25 mg/day further reduces major cardiovascular events in presence of heavy proteinuria B. Addition of valsartan 40 mg/day preserves kidney function over the long-term by reducing glomerular hyperfiltration C. Addition of ezetimibe to atorvastatin delays progression of CKD by better control of the lipid profile D. A multidisciplinary approach incorporating life-style modification with weight loss, optimization of blood pressure, and blood sugar will result in halting progression of proteinuria E. Work up for nondiabetic glomerulopathies including age-specific cancer screening and, potentially, a kidney biopsy should be performed. Answer: E

The subacute onset of proteinuria in the absence of diabetic retinopathy and the presence of type 2 diabetes without nephropathy for 25 years suggest causes of kidney disease other than DKD. Membranous nephropathy is the most common primary glomerulopathy in Caucasian men of this age122 and is frequently observed in association with malignancy. Therefore, age-specific cancer screening is appropriate in this case. After serologic and other blood and urine testing, a kidney biopsy is likely indicated to help diagnose the glomerulopathy, especially because eGFR has decreased. The ONTARGET study suggests that dual therapy with ACEI and ARB does not improve the composite outcome of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure compared to single agent therapy in high-risk patients.72 Such therapy may also result in increased frequency of hypotension, hyperkalemia, and renal insufficiency. This makes Answers A and B incorrect. The beneficial effect of lipid-lowering agents in diabetes is mainly by primary prevention of major cardiovascular events. The SHARP trial found no evidence that ezetimibe plus a statin delayed progression of CKD,97 making C an incorrect answer. A multidisciplinary approach is necessary and essential in management of DKD. However, such an approach may not necessarily halt progression of proteinuria, making Answer D incorrect.

Question 2 A 45-year-old man with newly diagnosed type 2 diabetes does not have a history of hypertension, coronary artery disease, stroke or peripheral arterial disease. He does not report blurred vision. On physical examination his sitting blood pressure is 116/78 mm Hg, pulse 78 beats per minute, weight 110 kg, and BMI 32 kg/m2. Examination of retinas, heart, lungs, abdomen, and extremities is unremarkable. Neurologic examination is normal. Serum chemistries S[Na] 142 mEq/L S[K] 4.2 mEq/L S[Cl] 108 mEq/L tCO2 24 mEq/L BUN 20 mg/dL S[Cr] 1.0 mg/dL glucose 221 mg/dL HbA1C 8.5% Urinalysis: no protein or blood by dipstick. Spot UACR is 0.07. Urine microscopy: no cells, casts, crystals, or other abnormalities.

VII. CHRONIC KIDNEY DISEASE AND SYSTEMIC ILLNESSES e CLINICAL CONSIDERATIONS

QUESTIONS AND ANSWERS

Which one of the following is correct in this patient? A. Initiation of lisinopril reduces the risk of the new onset of microalbuminuria B. In type 2 diabetes losartan is more effective than lisinopril in reducing the risk of DKD C. Intensive lowering of blood glucose is an effective preventive strategy to delay incident DKD D. Intensive lowering of blood glucose prolongs longevity by decreased risk of major cardiovascular events E. Metformin is contraindicated as it increases risk of lactic acidosis in diabetic patients Answer: C The role of intensive lowering of blood glucose in primary prevention of DKD has been shown in both type 1 and type 2 diabetes.34,35 Several studies have shown that in normotensive diabetic patients without albuminuria, ACEI or ARB treatment does not reduce the incidence of DKD, making Answer A and B incorrect. In type 2 diabetes intensive lowering of blood sugar does not reduce cardiovascular events.40,41 A number of systematic reviews and meta-analyses revealed safety of metformin along with no evidence for increased risk of lactic acidosis compared to other oral hypoglycemic agents.42e44 Therefore, metformin is not contraindicated in type 2 diabetic patients with normal or moderately reduced kidney function.

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D. Initiation of an ACEI or ARB is indicated given the presence of high urinary albumin excretion E. Decrease of blood pressure to less than 120/ 80 mm Hg as compared to her current blood pressure delays progression of CKD Answer: D Initiation of ACEI or ARB treatment in nonpregnant type 2 diabetic patients with persistently increased urinary albumin excretion is recommended even in normotensive patients. In type 2 diabetes up to 40% of patients with microalbuminuria develop overt proteinuria, of whom 20% may progress to ESRD over 10e20 years.8,9 Thus, Answers A and B are incorrect. The DCCT/EDIC and UKPDS studies have shown that the sustained tight control of blood sugar early during the course of diabetes in both type 1 and type 2 diabetic patients leads to prolonged preservation of kidney function even if such tight control does not persist.37,38 This phenomenon is referred to as metabolic memory. Therefore, tight control of blood sugar is most beneficial earlier during the course of diabetes before increased albumin excretion occurs, rather than after development of DKD, making C incorrect. The ACCORD-BP trial found no evidence for improved preservation of renal function or delay in progression of CKD with more intensive treatment of BP to <120/80 mm Hg compared to less-intensive treatment of BP to <140/90 mm Hg,68 making Answer E incorrect.

Question 3 A 55-year-old woman with recently diagnosed type 2 diabetes is referred for counseling regarding kidney disease in diabetes. She denies a prior history of hyperlipidemia, or heart or lung disease. She has an older sister with a history of diabetes and advanced CKD. She had a UACR of 88 noted on annual screening 4 months ago. Currently, on physical examination her blood pressure is 130/85 mm Hg, heart rate 86 beats per minute, weight 85 kg, and BMI 31 kg/m2. Examination of heart, lungs, abdomen, and extremities is unremarkable. S[Cr] is 1.2 mg/dL. UACR is 106. Which one of the following is correct in counseling her regarding clinical course of kidney disease in diabetes? A. The probability of progression of DKD to ESRD is over 50% in her lifetime B. Without specific treatment of nephropathy, the likelihood of development of ESRD increases to over 80% C. Sustained intensive control of blood sugar should now be employed as excellent glycemic control is most effective at delaying progression of DKD rather than preventing its occurrence

Question 4 A 61-year-old woman had type 2 diabetes diagnosed 15 years ago. She does not comply with a low-salt diet and often eats in restaurants. She denies chest pain, orthopnea, or dyspnea on exertion. Recently she has had difficulty in control of her blood pressure. Her home medications include 20 mg lisinopril daily, 25 mg hydrochlorothiazide daily, 15 units insulin glargine daily at night, 20 mg simvastatin daily, and 81 mg aspirin daily. On physical examination her seated blood pressure is 164/95 mm Hg, heart rate 88 beats per minute. There is no rub or murmur, but there is mild jugular venous distension. There are bibasilar crackles. Abdomen is soft with normal bowel sounds. Lower extremities have 2þ pitting edema. Serum chemistry S[Na] 134 mEq/L S[K] 4.5 mEq/L S[Cl] 102 mEq/L tCO2 23 mEq/L BUN 42 mg/dL, S[Cr] 2.1 mg/dL

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glucose 193 mg/dL HbA1C 8.1% CKD-EPI eGFR: 29 mL/min/1.73 m2 UPCR 2.5 Urine microscopy: no cells, casts, crystals, or other abnormalities Which one of the following is NOT correct in management of the patient? A. Consultation with a nephrologist at this point may reduce cost, improve quality of care, and retard progression to ESRD B. Initiation of spironolactone at 25 mg/day will further reduce proteinuria C. Continued decline of GFR with initiation of spironolactone will preclude effective use of this medication D. Combination of a thiazide with a loop diuretic will be more effective than use of a thiazide alone in control of her blood pressure E. Addition of direct renin inhibition with aliskiren would be associated with an increased risk of adverse renal outcomes and nonfatal stroke Answer: C Short-term randomized clinical trials have shown that treatment with MRA such as spironolactone can acutely reduce the GFR in diabetic subjects, which stabilizes over time, compared to continued decline of GFR in placebo-treated subjects.81,84 This may potentially translate to better preservation of kidney function and therefore does not preclude its use. Referral to a nephrologist is indicated by the time patients with CKD progress to stage 4, as studies have shown long-term outcomes and planning for ESRD are better in this setting.123,124 Therefore, Answer A is a true statement. Initiation of MRA can further reduce proteinuria and provide better control over blood pressure81e84; therefore, Answer B is a true statement. In salt-sensitive hypertension a combination of a thiazide and a loop diuretic may provide better diuresis and control of hypertension74; hence Answer D is true. Dietary counseling to reduce salt intake should accompany treatment with diuresis. The ALTITUDE trial of aliskerin in DKD was terminated early due to higher incidence of hypotension, hyperkalemia, renal complications, and nonfatal stroke in association with aliskiren; hence Answer E is a true statement.

Question 5 A 51-year-old man with a history of type 1 diabetes for over 35 years presents with progressive DKD. He does not report a change in appetite, presence of a sleep

disturbance, reduced energy level, metallic taste, shortness of breath at rest, or orthopnea. His S[Cr] has slowly and steadily increased to 3.5 mg/dL from 2.8 mg/dL last year. His UPCR is increased to 9 from 3.5 last year. Which one of the following is correct in discussion of preparation of the patient for RRT? A. Preparation for ESRD including choice of RRT, vein mapping, and access creation should start at stage 4 CKD in anticipation of progression to ESRD because starting these processes early will improve morbidity and mortality after onset of ESRD B. There is no reason to push for early listing for kidney transplantation in the absence of a living kidney donor because deceased donor kidney transplantation is not associated with improved survival compared to maintenance hemodialysis (HD) in patients with ESRD from long-lasting diabetes C. HD is the preferred modality for this patient because peritoneal dialysis (PD) is associated with increased risk of hyperglycemia, hypertriglyceridemia, and weight gain D. When dialysis is initiated more aggressive ultrafiltration should be well-tolerated by this patient because diabetic patients are more likely to be volume overloaded than patients with other causes of ESRD E. In-center HD is preferred because short daily home HD provides inadequate clearance compared to traditional in-center HD. Answer: A Preparation for ESRD should start when stage 4 CKD is reached. If the decision is made for HD as the preferred modality of RRT, patients should undergo vein mapping and be referred for access creation in anticipation of progression to ESRD. Ideally, patients should start HD through an established arteriovenous fistula (or a graft when a fistula is not feasible). However, urgent indications for initiation of dialysis, delays in access creation and maturation, or absence of nephrologist involvement in ESRD planning may lead to initiation of HD using a catheter. HD using tunneled catheters is associated with higher risk of infective complications and therefore is less favorable. Deceased donor kidney transplantation provides significant survival benefit in diabetes compared to other modalities of RRT,120,121 so Answer B is incorrect. Although increased risk of hyperglycemia, hypertriglyceridemia, and weight gain is associated with PD in diabetic patients, PD outcomes are not clearly worse than HD outcomes and choice of modality of RRT is not different in DKD compared to other etiologies of ESRD,125 so Answer C is incorrect. Patient preference

VII. CHRONIC KIDNEY DISEASE AND SYSTEMIC ILLNESSES e CLINICAL CONSIDERATIONS

QUESTIONS AND ANSWERS

after consultation with the nephrologist should guide modality choice. Autonomic dysfunction is a common complication in diabetic patients, which makes effective ultrafiltration with dialysis more difficult and challenging,126 so Answer D is incorrect. Short daily dialysis has similar patient/treatment survival compared with traditional in-center dialysis127 and can be preferable when ultrafiltration of large volumes with each dialysis becomes difficult, making Answer E incorrect.

Question 6 A 32-year-old woman with type 1 diabetes for 25 years developed albuminuria at age 24 and has been on lisinopril 40 mg daily ever since. Her medication regimen includes humulin insulin via an insulin pump, which she has been adjusting over the past 2 months due to large glycemic swings, hydrochlorothiazide 25 mg daily, atorvastatin 10 mg daily. Her urinary albumin excretion is now greater than 800 mg/day. Her home blood pressure readings are between 120 and 130/ 60e70 mm Hg. On physical examination her seated blood pressure is 125/75 mm Hg, heart rate 96 beats per minute. There is no rub, murmur, or jugular venous distension. Lower extremities have 1þ pitting edema. The following labs are obtained: Serum chemistries S[Na] 136 mEq/L S[K] 4.5 mEq/L S[Cl] 101 mEq/L tCO2 25 mEq/L BUN 42 mg/dL S[Cr] 1.6 mg/dL glucose 142 mg/dL HbA1C 9.4% UACR 874 Urine microscopy: no cells, casts, crystals, or other abnormalities Which one of the following is correct regarding the assessment and treatment of her albuminuria?

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A. Increasing lisinopril dose to 60 mg daily will further reduce albuminuria and blood pressure B. Addition of spironolactone to reduce albuminuria will likely increase S[K] to >6.0 mEq/L and is therefore contraindicated C. The increased albuminuria does not predict further progression of her CKD toward ESRD so does not need to be treated D. Albuminuria can vary especially with swings in glycemic control. ACR should be rechecked before making a therapeutic change E. An increase in hydrochlorothiazide dose to 50 mg daily will improve blood pressure and albuminuria Answer: D Exercise, infection, fever, congestive heart failure, marked hyperglycemia, and marked hypertension may each cause increases in urinary albumin excretion. Thus, if albuminuria increases rapidly since the last check, these potentially confounding factors should be corrected if present and the urine albumin:creatinine (or protein:creatinine) level should be rechecked before committing a nonhypertensive patient to an additional medication. Increasing lisinopril above 40 mg daily does not result in improved proteinuria or blood pressure control in type 1 diabetic patients128; hence Answer A is incorrect. Addition of spironolactone can cause a further increase in S[K] in diabetic patients with CKD treated with either an ACEI or an ARB, but this increase is usually <0.5 mEq/L. In two RCTs in patients with diabetic nephropathy, S[K] increased no more than 0.8 mEq/L after add-on spironolactone therapy for up to 52 weeks.84 Hence, Answer B is incorrect. If validated and persistent, the increased albuminuria in this patient would be associated with a greater risk of progression to ESRD, so Answer C is incorrect. Hydrochlorothiazide at doses above 25 mg has little increased efficacy on blood pressure control and does not directly improve albuminuria, so Answer E is incorrect.

VII. CHRONIC KIDNEY DISEASE AND SYSTEMIC ILLNESSES e CLINICAL CONSIDERATIONS