Diabetic nephropathy is a microvascular complication of diabetes.6 Characterized by albuminuria (a level of more than 300 mg/dL) and decreased glomerular filtration rate (GFR), diabetic nephropathy often is present in patients when type 2 diabetes is diagnosed.6 In patients with type 1 diabetes, the prevalence of diabetic nephropathy is estimated at 25%, with the onset 7 to 10 years after diagnosis of diabetes.7 As kidney disease progresses, renal mass diminishes.6 The stages of CKD, as defined by National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI), are based on the estimated GFR (Table 1), which is contingent on sex, age, race, weight, and serum creatinine.8 Although the mechanisms for increased risk are not fully understood, stage 3 or higher CKD is an independent risk factor for cardiovascular (CV) events and death.9 Patients with diabetes and stages 3 to 5 CKD also are at increased risk of hypoglycemia due to decreased kidney gluconeogenesis, impaired clearance of insulin and oral agents such as the sulfonylureas, and decreased breakdown of insulin in peripheral tissues.6
PRIMARY CARE MANAGEMENT OF CKD
In 2007, the National Kidney Foundation published guidelines to assist clinicians in managing patients with diabetes and CKD.10 The primary health outcome addressed by the KDOQI guideline update is all-cause mortality. Secondary health outcomes include ESRD, CV death and nonfatal CV events, vision loss, amputation, and severe hypoglycemic events.11 Since the original publication, a significant body of high-quality evidence has emerged, resulting in updates to three of the nine practice guidelines (Table 2).11 Guideline statements are graded by strength of recommendation (Table 3) and quality of the supporting evidence (Table 4).11
KDOQI GUIDELINE UPDATES
Management of hyperglycemia and general diabetes care in CKD (Guideline 2). The KDOQI update provides clearer guidance by stratifying target A1C level by the patient's risk of hypoglycemia and comorbidities. Three studies published since the original KDOQI guideline demonstrate that glycemic control to near-normal levels (an A1C of less than 7%) prevents or decreases progression of diabetic kidney disease endpoints in patients with type 2 diabetes.12–14 The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) demonstrated a 21% reduction of the endpoints of new macroalbuminuria, doubling of serum creatinine, need for kidney replacement therapy, or death.12 The Veterans Affairs Diabetes Trial (VADT) demonstrated a 37% reduction in macroalbuminuria and a 32% reduction in microalbuminuria.13 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study showed a 32% reduction in macroalbuminuria and a 21% reduction in microalbuminuria.14
As a result, for patients at lower risk of hypoglycemia (stages 1 to 3 CKD), the recommendation for a target A1C level of 7% to prevent or delay progression of microvascular complications of diabetes, including kidney disease, is upgraded to Level 1A.11 Hypoglycemia risk increases with decreased renal function, particularly at stages 4 and 5 CKD, and in patients with diabetes treated to an A1C of less than 7%.6,15,16
For patients at higher risk of hypoglycemia, the three studies demonstrate similar endpoint outcome reductions in CV events, CV death, and ESRD among conventional versus intensive treatment groups.12–14 Therefore, the KDOQI recommends that patients at risk of hypoglycemia not be treated to a target A1C of less than 7% (Level 1B), and suggests an A1C greater than 7% in patients with stages 4 and 5 CKD who have limited life expectancy or significant comorbidities (Level 2C).11 CKD has a significant effect on drug selection and monitoring of pharmacotherapeutic effects in patients with diabetes.17 As the patient's renal function declines, some oral agents (except thiazolidinediones) require dose adjustment, and many are not recommended at stages 3 through 5 CKD. Insulin remains the core of therapy for control of glucose in patients with diabetes and advanced CKD, and in particular, for those on dialysis.17 See the KDOQI guideline update for a complete list of drug dosing recommendations.11
Management of dyslipidemia in diabetes and CKD (Guideline 4). The KDOQI now recommends use of statins or a statin and ezetimibe combination to lower low-density lipoprotein (LDL) cholesterol in all patients with diabetes and stages 1 to 4 CKD, including those who have had renal transplant (Level 1B).11 This recommendation is based on evidence from the Assessment of Lescol in Renal Transplant (ALERT) trial, which demonstrated a 35% relative reduction in cardiac death or nonfatal myocardial infarction (MI); and the Study of Heart and Renal Protection (SHARP) trial, which demonstrated 17% relative reduction in major atherosclerotic events, arterial revascularization, and nonhemorrhagic stroke in CKD patients treated to target LDL cholesterol.18,19 These trials found no evidence that lowering LDL cholesterol prevents progression of kidney disease.18,19 Statin therapy to lower LDL cholesterol in a subgroup of patients with type 2 diabetes and ESRD who were on hemodialysis did not show reductions in CV death, MI, or stroke.19 Furthermore, the Die Deutsche Diabetes Dialysis Studie (4D) and post hoc analysis of A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis (AURORA) demonstrated an increased risk of fatal and hemorrhagic stroke in patients on hemodialysis treated with statins.20,21 Therefore, the KDOQI continues to recommend not initiating statins in patients with diabetes who are already in ESRD and on dialysis (Level 1B).11 For patients already on a statin who develop ESRD, evidence from these studies is insufficient to provide a recommendation whether statin therapy should be discontinued.11 High-dose statin therapy carries a greater risk of myopathy, particularly in patients with stages 3 to 5 CKD. Lower-dose statin and statin plus ezetimibe combination therapy are recommended for patients with reduced renal function.11
The recently published Kidney Disease-Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease addresses managing lipid status in patients with CKD.22 KDIGO recommendations specific to patients with diabetes and CKD focus on adults ages 18 to 49 years with CKD who are not treated with chronic dialysis or kidney transplantation. In this population, statin therapy is recommended for patients with one or more of the following chronic conditions:
* known coronary disease
* previous ischemic stroke
* estimated 10-year incidence of coronary death or nonfatal MI of more than 10%.22
Consistent with the KDOQI guideline, initiation of statins or a statin/ezetimibe combination is not recommended in patients already on dialysis or who have had transplantation; lower-dose statin therapy is recommended for patients with stages 3 through 5 CKD.22
Management of albuminuria in normotensive patients with diabetes (Guideline 6). Hypertension in patients with diabetes is defined by the JNC 8 as BP greater than 140/90 mm Hg.23 Normoalbuminuria is less than 30 mg of albumin per gram of creatinine (Table 5).8 Studies in patients with diabetes show no evidence for the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) as primary prevention of diabetic kidney disease in normotensive normoalbuminuric patients.24–26 Therefore, the KDOQI no longer recommends use of these medications solely for primary prevention of diabetic kidney disease in this population (Level 1A).11 For patients with diabetes who are at high risk of diabetic kidney disease or its progression and are normotensive with microalbuminuria, use of an ACE inhibitor or ARB is suggested (Level 2C).11 When ACE inhibitors or ARBs are used, titration up to the maximum dose for hypertension is recommended. No specific target dose of ACE inhibitors or ARBs is recommended in normotensive patients with diabetes who have albuminuria. A meta-analysis of 33 clinical trials with 68,405 patients demonstrated increased risk of hypotension, hyperkalemia, and impaired renal function associated with combination therapy with an ACE inhibitor and ARB. Therefore, dual blockade of the renin-angiotensin system using combination therapy is not recommended.27
IMPLICATIONS FOR PRACTICE
As the authors of the KDOQI guidelines note, unanswered questions remain. Recommendations for future research related to each of the updated guidelines include:
* determining the effects of glycemic control on early and late GFR loss and health outcomes in patients with CKD (guideline 2)11
* establishing LDL cholesterol levels for treatment and initiation of lipid-lowering therapy as well as targets for primary and secondary prevention of CV disease in patients with diabetes by CKD stage (guideline 4)11
* evaluating the relative roles of ACE inhibitors, ARBs, renin blockers, and mineralocorticoid receptor blockers on progression of kidney disease in patients with albuminuria (guideline 6).11
Because the updated clinical practice guideline for managing BP in patients with CKD was published after the KDOQI diabetes guideline update, the KDOQI guideline does not incorporate the new BP guidelines.28 Future KDOQI updates will likely incorporate the KDIGO recommendations.
The KDOQI update provides a review of the current evidence for best practices in the management of diabetes and CKD. Primary care clinicians, including PAs, play a crucial role in preventing or delaying the progression of CKD in patients with diabetes. Beginning this year, certified PAs will transition to a new certification maintenance process involving performance improvement continuing medical education. In this process, PAs complete a quality improvement project related to their clinical practice at least twice in every 10-year certification maintenance cycle.29 PAs caring for patients with diabetes can use the KDOQI diabetes and CKD guideline, along with the 2012 update, to develop clinical policies and performance measures to fulfill this requirement.
Under the updated guidelines, key benchmarks for glycemic control and management of dyslipidemia and albuminuria are:
* a target A1C of about 7% for patients with stages 1 to 3 CKD and diabetes, to prevent or delay progression of the microvascular complications of diabetes, including CKD
* not treating patients at risk for hypoglycemia, in particular those with stage 4 or 5 CKD, to an A1C of less than 7%
* initiating LDL cholesterol-lowering therapy (a statin or statin plus ezetimibe) to prevent major CV events in patients with stage 1 to 4 CKD and diabetes
* not using ACE inhibitors or ARBs as primary prevention of kidney disease in normotensive normoalbuminuric patients with diabetes.
These benchmarks also can be used by PAs who care for patients with CKD to develop performance improvement CME plans.
1. US Renal Data System. 2012 USRDS Annual Data Report: Atlas of Chronic Kidney Disease in the United States, vol. 1
. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2012.
2. Centers for Disease Control and Prevention. Increasing prevalence of diagnosed diabetes–United States and Puerto Rico, 1995–2010. MMWR Morb Mortal Wkly Rep
3. Shahinian VB, Saran R. The role of primary care in the management of the chronic kidney disease population. Adv Chronic Kidney Dis
4. Fox CH, Brooks A, Zayas LE, et al. Primary care physicians' knowledge and practice patterns in the treatment of chronic kidney disease: an Upstate New York practice-based Research Network (UNYNET) study. J Am Board Fam Med . 2006;19(1):54–61.
5. Tahir MA, Dmitrieva O, de Lusignan S, et al. Confidence and quality in managing CKD compared with other cardiovascular diseases and diabetes mellitus: a linked study of questionnaire and routine primary care data. BMC Fam Pract
. 2011;12:83. http://www.biomedcentral.com/1471-2296/12/83
. Accessed December 27, 2012.
6. Bakris GL. Recognition, pathogenesis, and treatment of different stages of nephropathy in patients with type 2 diabetes mellitus. Mayo Clin Proc
7. Steinke JM, Sinaiko AR, Kramer MS, et al. The early natural history of nephropathy in type 1 diabetes: III. predictors of 5-year urinary albumin excretion rate patterns in initially normoalbuminuric patients. Diabetes
8. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis
. 2002;39(2 suppl 1):S1-S266.
9. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension
10. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis
. 2007;49(suppl 2):S12-S154.
11. National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis
12. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med
13. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med
14. Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet
15. Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. Diabetes
16. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ
17. Abe M, Okada K, Soma M. Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice. Curr Drug Metab
18. Jardine AG, Holdaas H, Fellström B, et al. Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: post-hoc subgroup analyses of the ALERT Study. Am J Transplant
19. 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
20. Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med
21. Holdaas H, Holme I, Schmieder RE, et al. Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol
22. Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Management Work Group. KDIGO clinical practice guideline for lipid management in chronic kidney disease. http://kdigo.org/home/guidelines/lipids
. Accessed March 12, 2014.
23. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA
24. Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med
25. Bilous R, Chaturvedi N, Sjølie AK, et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med . 2009;151(1):11–20.
26. Haller H, Ito S, Izzo JL Jr, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med
27. Makani H, Bangalore S, Desouza KA, et al. Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials. BMJ. 2013;346:f360.
28. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Inter
Keywords:© 2014 American Academy of Physician Assistants.
chronic kidney disease; diabetes; guidelines; KDOQI; KDIGO; primary care