Chronic diseases are the primary threat to global public health in the 21st century. In 2011, chronic kidney disease (CKD) joined diabetes, cardiovascular disease, chronic lung disease, and cancer as one of the five major chronic diseases threatening global public health.1 Diabetes is the leading risk factor for CKD in the United States (Figure 1).1,2 The estimated prevalence of diabetes in the United States is 8.3% of the population (25.8 million) and is increasing in all geographic areas.2 From 1995 to 2010, the age-adjusted prevalence of diabetes increased by 50% or more in 42 states; in 18 of those states, the increase was 100% or more (Figure 2).2 Primary care clinicians, including physician assistants (PAs), care for many patients with chronic diseases, including those with CKD and diabetes.3–5 Despite the rise in CKD prevalence, the incidence of end-stage renal disease (ESRD) due to diabetes has recently declined due to earlier therapeutic intervention in this population.1
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.
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chronic kidney disease; diabetes; guidelines; KDOQI; KDIGO; primary care
© 2014 American Academy of Physician Assistants.