At a glance
- Data show that 40% of patients with diabetes mellitus also have chronic kidney disease (CKD).
- Urinary albumin excretion and serum creatinine should be evaluated at least annually in patients with type 2 diabetes.
- Indicators of CKD are significant risk factors for cardiovascular disease in people with type 2 diabetes.
- Lowering BP in type 2 diabetics with hypertension has been shown to stabilize renal function.
Approximately 24 million Americans have type 1 or type 2 diabetes mellitus (DM), and this number is expected to increase to 44 million by 2034.1 It is also estimated that an additional 57 million Americans have prediabetes (impaired fasting glucose and/or impaired glucose tolerance).2 Type 2 DM (T2DM) accounts for 90% to 95% of all cases of DM.3 In 2007, the direct medical cost for the treatment of patients with DM was $116 billion and the indirect cost for disability, work loss, and premature mortality was $58 billion.2
T2DM results in an increased risk for macrovascular (large-blood vessel) and microvascular (small-blood vessel)complications. Approximately 75% of patients with T2DM also have hypertension,4 which increases the risk for cardiovascular (CV) events.5 Coronary heart disease (CHD) is common in patients with T2DM; heart disease was noted on 68% of diabetes-related death certificates among people aged 65 years and older.4 Patients with T2DM have a two- to fourfold higher risk of death from CHD than nondiabetics.4 Peripheral vascular disease in patients with T2DM increases the risk for lower-limb amputation.6 Stroke is also common in patients with T2DM and is reported as the cause of death in approximately 16% of patients with this disease. Patients with T2DM have a two- to fourfold higher risk for stroke than nondiabetics.4
Microvascular disease also occurs frequently in patients with T2DM. Chronic kidney disease (CKD) is defined as kidney damage or a glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for three months or more7 and is present in more than 40% of adults with DM.4,8 In 2005, 46,739 people with DM began treatment for end-stage renal disease (ESRD) in the United States and Puerto Rico, and 178,689 people with DM and ESRD were undergoing chronic dialysis or had received a kidney transplant. Diabetic retinopathy results in up to 24,000 new cases of blindness annually in the United States and is the leading cause of new cases of blindness in adults.4 Neuropathy due to DM occurs in 60% to 70% of patients with T2DM.4
Epidemiology of CKD/RI with DM
Results from analyses using information from the Fourth National Health Education and Nutrition Survey (NHANES IV) and NHANES 2003-2006 indicated that 40% of patients with DM also had CKD.8,9 In addition, up to 42% of patients with undiagnosed DM have CKD.9
Risk factors for CKD/RI in patients with T2DM
Risk factors for susceptibility to, and initiation of, CKD can be categorized into two groups: clinical factors (e.g., DM, hypertension, autoimmune disease, systemic infections, urinary tract infections, urinary stones, lower-urinary tract obstruction, neoplasia, family history of CKD, recovery from acute renal failure) and sociodemographic factors (e.g., older age, African-American or American Indian race, exposure to certain chemical and environmental conditions, low income/education level).7 Elevated levels of total cholesterol and glycated hemoglobin (Hb A1c), poorly controlled DM with HbA1c elevations, and elevated blood pressure (BP) are significantly associated with impaired kidney function, increased albuminuria, and decreased renal function.10,11 It has also been shown that male gender and the presence of retinopathy are risk factors for CKD in patients with T2DM.10 African-Americans and Native Americans are more likely than whites to have early diabetic nephropathy, and African-Americans, Hispanics, Asian-Americans, and Native Americans are more likely than whites to have ESRD.12
The frequencies of microalbuminuria (urinary albumin excretion 30-299 mg/24 hr) and macroalbuminuria (urinary albumin excretion ≥300 mg/24 hr) are increased in patients with DM7 and are associated with an elevated risk for CKD.10,13 In a study looking at various risk markers (i.e., age, gender, cholesterol, serum creatinine, albuminuria, hemoglobin, and HbA1c), albuminuria was the strongest predictor of kidney disease. Patients with high baseline albuminuria (≥3.0 g/g creatinine) showed a 5.2-fold increase in renal end point (doubling of serum creatinine, ESRD, or death) and an 8.1-fold increase in risk for progressing to ESRD compared with patients whose baseline albuminuria was low (≤1.5 g/g creatinine).13
Screening for CKD in patients with T2DM
It is important that renal function be assessed in patients with T2DM because timely intervention can decrease the risk for, and slow the progression of, CKD. Urinary albumin excretion and serum creatinine should be evaluated at least annually in patients with T2DM.14 Microalbuminuria screening can be performed using the albumin/creatinine ratio (ACR) in a random spot urine test. Timed or 24-hour urine collections are bothersome and do not enhance accuracy.14 Persistent microalbuminuria (30-299 mg/24 hr) is an early clinical marker for the development of nephropathy in patients with T2DM.14
Serum creatinine concentrations should be used to estimate GFR using the Modification of Diet in Renal Disease (MDRD) equation or Cockcroft-Gault formula. However, the MDRD equation may be more accurate than the Cockcroft-Gault formula for diagnosing and stratifying CKD in patients with DM,14 probably because the MDRD was developed on the basis of results from patients with moderate-to-severe renal failure.15,16 Overall, the MDRD equation may provide more accurate and unbiased assessments of GFR in patients with DM than the Cockcroft-Gault formula.17 The MDRD method has many advantages. It is more accurate and precise than the Cockcroft-Gault formula in persons with a GFR <90 mL/min/1.73 m2. It was developed from a large database containing information on more than 1,000 patients with various kidney diseases, and was tested on a validation database containing information on more than 500 additional patients. Also, it does not take height or weight into account and has been validated in kidney transplant recipients and black patients with nephrosclerosis.18 Assessing renal function using estimated GFR (eGFR), regardless of the equation chosen, is much more effective than measuring serum creatinine.18
Urinary albumin concentration is a significant independent predictor of renal outcomes in patients with T2DM19 and might be considered for staging patients. However, the severity of albuminuria does not always correlate with GFR or rate of decline in this measure in patients with T2DM.20,21,22
Healthcare providers should be aware of the CV consequences of CKD in patients with T2DM
Indicators of CKD are significant risk factors for CV disease in patients with T2DM. Results from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial showed that a urinary ACR >300 mg/g and an eGFR <60 mL/min/1.73 m2 were independent risk factors for CV events.19 In fact, patients with these risk factors had a 3.2-fold higher risk for CV events compared with patients with neither risk factor.19 Similar results have been reported in earlier, smaller-scale studies.23,24,25
The presence of CKD in patients with or without DM is associated with an increased risk for acute myocardial infarction, cerebrovascular accidents and stroke, peripheral vascular disease, atherosclerotic vascular disease, and congestive heart failure.26,27 The risk for CV events, including death, in both groups increases progressively with rising albuminuria and declining GFR.28,29
Awareness of CKD/RI: clinicians
There is a significant lack of awareness by many clinicians of the incidence and effects of CKD in patients with T2DM, and this may contribute to the apparent underdiagnosis and undertreatment of this condition.30 For example, reliance on serum creatinine levels for the assessment of renal function may lead to CKD/renal impairment (RI) being missed in many patients. A cross-sectional study of 660 elderly subjects with normal serum creatinine concentrations (0.8-1.3 mg/dL in men and 0.6-1.0 mg/dL in women) indicated that 39% had a GFR <60 mL/min/1.73 m2 according to the Cockcroft-Gault formula, and 25% had this degree of RI according to creatinine clearance determined from a 24-hour urine collection.30 Thus, a substantial proportion of elderly patients have diminished GFR despite normal serum creatinine concentrations30 and may not be diagnosed with CKD based on routine evaluations of clinical laboratory values.
Awareness of CKD/RI: patients
Patients with T2DM are generally unaware of CKD/RI when it is present. Results from the NHANES III survey indicated that only 9.2% of all participants with stage 3 CKD and 19.1% of patients with DM and stage 3 CKD were aware of their renal insufficiency.31
Awareness of CKD/RI: glycemic control
Renal disease elevates the risk for hypoglycemia in patients with DM.32 A retrospective cohort analysis of 243,222 patients indicated that the frequency of hypoglycemia (plasma glucose <70 mg/dL) in patients with DM and CKD was twice that in patients with DM alone (10.72 vs 5.33 per 100 patient-months).33 This increase is thought to result from lower insulin requirements due to altered renal clearance, and renal accumulation of antidiabetic drugs.34,35