Diabetes and Chronic Kidney Disease: Prevention, Early Recognition, and Treatment
ABSTRACT: Diabetes care presents several challenges for both patient and clinician. But the challenge is significantly increased when it is complicated by chronic kidney disease (CKD). Fortunately, CKD is preventable and, if recognized early disease, progression can be halted. Cardiovascular disease is the major consequence of CKD and this also can be prevented. Primary care clinicians provide the majority of care for patients with diabetes so they are ideally suited to prevent, recognize, and provide initial treatment for CKD. This can be done by screening for diabetic kidney disease with urine microalbumin, obtaining serum creatinine levels to calculate glomerular filtration rate, closely monitor hemoglobin A1c, blood pressure, lipid levels, and appropriately treat abnormal levels to achieve evidence-based goals. This article reviews the epidemiology, cost, stages, screening, prevention strategies, and treatment options for patients with diabetes and CKD.
Diabetes is the leading cause of end-stage renal disease (ESRD) and accounts for nearly 45% of new cases of kidney failure in the United States.1 Kidney damage is detectable in approximately one-third of patients with type 2 diabetes at some time during the course of their disease and is associated with an excessive risk for cardiovascular (CV) morbidity and mortality. Chronic kidney disease (CKD) disproportionately afflicts certain racial and ethnic groups—with significantly higher prevalence rates in Hispanics, blacks, and Native Americans.2
In the United States, 20 million adults have CKD. Less than 2% progress to ESRD as most patients with CKD will die of a CV event before they progress to ESRD. Prevalence in people older than age 60 increased from 19% to 25% in the last decade and 40% of diabetic patients are at stage 1 and 2 CKD. The average cost for a patient with ESRD is $70,000 per year.3
Medicare spent $29 billion in 2009 for ESRD or 6% of the annual Medicare budget. Annual spending for the earlier stages of CKD for Medicare patients was $20,432 per patient. The annual per person cost attributable to CKD begins to increase in stage 2 at $1,700, $3,500 for stage 3, and $12,700 once the patient is in stage 4.4
STAGES OF CKD
Understanding the various stages of CKD helps the clinician make informed therapeutic decisions. Some medications used by patients with diabetes depend on renal clearance and should not be used or used with caution in the later stages of CKD. This will be discussed further in the section under medications. Staging kidney damage is accomplished by calculating the glomerular filtration rate (GFR). All diabetic patients should have a serum creatinine level on an annual basis. Once the creatinine level is obtained, the GFR can be calculated with a formula provided by the National Kidney Foundation (NFK).
Figure 1. Screenshot from iTunes showing glomerular filtration rate (GFR), chronic kidney disease epidemiology collaboration (CKD-EPI), and modification of diet in renal disease (MDRD).
Note: You can download free apps to use on your smartphone (Figure 1) or visit the NKF website (http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm) to calculate the GFR using the serum creatinine, age, gender, and race of the patient.
The Chronic Kidney Disease Epidemiology Collaboration equation (Figure 2) is considered more accurate in stages 1 to 3 and the Modification of Diet in Renal Disease is best for stages 4 to 5.5
Figure 2. Screenshot from CKD-EPI showing estimated glomerular filtration rate (eGFR) and chronic kidney disease epidemiology collaboration (CKD-EPI).
There are 5 stages for CKD progressing from stage 1 (mild) to stage 5 (severe). Knowing the stage of CKD aids the clinician with therapeutic decisions. The NKF provides the following definitions of the 5 stages of CKD (Table 1).
• Stage 1 CKD is defined as a GFR (≥90 mL/min/1.73 m2) but with some other evidence of damage to the kidneys, such as albuminuria.
• Stage 2 CKD is present when the GFR decreases from 60 to 89 mL/min/1.73 m2. The first 2 stages provide the warning that the clinician should be more concerned about preventing future damage. Better control of blood pressure and glycemia, reduced use of drugs like nonsteroidal anti-inflammatories, and more frequent screening for albuminuria and GFR are indicated. No adjustment of medication dose is usually required.
• Stage 3 CKD is considered the major drop in GFR and requires more vigilance by the clinician. Stage 3 is defined as a GFR of 30 to 59 mL/min/1.73 m2, clearly a substantial decrease in GFR. Stage 3 is divided into 3A and 3B. Stage 3B is considered a major milestone and consultation with a nephrologist is advisable.
• Stage 4 CKD is a GFR of 15 to 29 mL/min/1.73 m2. Stages 4 and 5 indicate severe renal damage.
• Stage 5 CKD is a GFR <15 mL/min/1.73 m2 or renal replacement therapy is required.
EARLY RECOGNITION
In most patients with early stage CKD, renal function/GFR declines slowly and the rate of decline varies among individuals. Because CKD stages 1 to 3 usually progress asymptomatically, detection of early-stage CKD requires laboratory testing. Most experts recommend GFR and urine microalbumin to evaluate deterioration kidney function or presence of glomerular damage in patients with CKD.
The Kidney Disease Outcomes Quality Initiative (KDOQI) recommends at least annual estimated GFR (eGFR) measurement in adults with CKD to predict onset of ESRD and evaluate the effect of CKD treatments.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends annual quantitative measurement of albuminuria in all patients with “kidney disease.” KDOQI also recommends more frequent monitoring of CKD patients with worsening kidney function.6
Measuring the amount of albumin in the urine aids with identifying early kidney damage. In some patients, microalbuminuria precedes a drop in GFR and in others the GFR decreases before the onset of microalbuminuria. The recommended test for albumin in the urine is a spot urinalysis for microalbumin creatinine ratio. Collections of urine for 24 hours are not practical and the spot urine is more reliable. The normal finding is <30 ug/mg. If the patient has an active infection, hematuria, or has engaged in strenuous exercise in the past 24 hours the test should be repeated.
When an abnormal finding is discovered the test should be repeated in 1 or 2 months before starting any kind of intervention, like an angiotensin receptor blocker (ARB) or an angiotensin-converting enzyme (ACE) inhibitor.7
The current guidelines from the American Diabetes Association (ADA) recommend the following8:
• Perform an annual test to assess urine albumin excretion in type 2 diabetic patients. Measure serum creatinine at least annually in all adults with diabetes regardless of the degree of urine albumin excretion. The serum creatinine should be used to estimate GFR and stage the level of CKD.
• Risk of CV disease (CVD) in CKD increases as the stage of CKD progresses and albuminuria appears. As noted in the heat diagram in Table 2, without albuminuria the risk of CVD disease does not significantly increase until stage 3B (pink) but once albuminuria appears risk increases at earlier stages of CKD.9
Reducing the Risk of Progressive Renal Disease
Control of blood pressure and hemoglobin A1c (HbA1c) are the most important factors to prevent diabetic nephropathy. Landmark studies have demonstrated that keeping HbA1c at 7% or less significantly reduces the risk of nephropathy.10,11 The risk of nephropathy is related to HbA1c levels in a curvilinear relationship. The highest levels of HbA1c have the highest risk. By lowering HbA1c levels even from 12% to 10%, the risk is reduced.12
Hypertension is seen in about 60% to 80% of patients with type 2 diabetes and it usually pre-dates the diagnosis of diabetes. There is significant association between the blood pressure and insulin sensitivity.13 Both the United Kingdom Prospective Diabetes Study and Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trials demonstrated a reduction in nephropathy and other diabetic microvascular complications.14,15
The target goal for blood pressure is controversial. The ADA recently changed its goals from 130/80 mm Hg to 140/80 mm Hg,8 but stated that in some cases 130/80 mm Hg may be a more appropriate goal. As most diabetic patients require 2 drugs to attain blood pressure control, it is considered acceptable to be at 140/80 mm Hg or less and a third drug is not needed to push the blood pressure lower. However, if the blood pressure remains >140/80 mm Hg, a third drug would be indicated.6
The most appropriate drug for treating hypertension in diabetes is an ACE or an ARB. Both of these drugs are associated with improvement and/or stabilization in renal function as well as a decrease or stabilization of albuminuria.16 An ACE or an ARB is not indicated if the patient is normotensive and has no albuminuria.
A few small studies have demonstrated that reducing low-density lipoprotein (LDL) cholesterol and obesity may also decrease the risk of CKD.17
Reducing the Risk of CV
Patients with diabetes already have an increased risk of CVD. Adding CKD to diabetes increases the risk. As previously mentioned, <2% of patients with CKD progress to ESRD. Most patients with CKD will die of a CV event before they progress to ESRD.3 The risk for a CV event increases significantly after stage 3B and in all stages once albuminuria is present as noted in Table 2.9 CV risk can be decreased with the use of lipid lowering therapy.
The Study of Heart Renal Protection demonstrated that lipid lowering therapy with a statin and ezetimibe decreased the incidence of CV events in CKD.18 The Heart Protection Study demonstrated that a 30% to 40% reduction from baseline LDL cholesterol levels is most beneficial for people with kidney disease.19
Glycemic Control in CKD
Keeping the HbA1c <7% is the goal to prevent CKD and the NKF recommends this as the goal in CKD. However, as CKD progresses and patients develop more comorbidities, an HbA1c goal between 7% and 8% is more appropriate.20 Once CKD progresses into the later stages (4 and 5), HbA1c is not as reliable to measure glycemic control because of anemia, erythropoiesis-stimulating agents, and red blood cell survival. The red blood cell lifespan may be reduced by 30% to 70%.21 Once the patient reaches stage 4 CKD, relying on HbA1c as the sole measure of glycemic control is not advisable.
Glycated albumin is proposed as a better measure of glycemic control in the later stages of CKD. Serum albumin has a half-life of approximately 20 days, so compared to the 60 to 90 days for HbA1c, it reflects a shorter glucose exposure. The testing interval for monitoring glycated albumin is monthly. Glycated albumin reflects glycemic control for 1 to 2 weeks before obtaining the sample.22,23
DIABETES MEDICATIONS IN CKD
Some medications that are commonly used to reduce hyperglycemia require a dosage reduction or discontinuation depending on the stage of CKD.
• Metformin. The foundation of diabetes treatment in type 2 is metformin. As renal function decreases, a dose reduction and eventually discontinuation is recommended to decrease the chance of lactic acidosis.24 Table 3 provides a guide for prescribing metformin by stage of CKD.24
• Sulfonylureas. Glipizide is the preferred second-generation sulfonylurea for patients with stage 3 to 5 CKD, although glimepiride can also be used if initiated at a low dose. Glyburide is substantially excreted by the kidney and should be avoided in patients with stage 3 to 5 CKD to avoid hypoglycemic reactions.25
• Thiazolidinediones (TZD). No dose adjustment is needed in patients with kidney impairment. These drugs also decrease urinary albumin.26 No evidence exists that this indicates improved kidney outcomes in patients with diabetic nephropathy. TZDs cause fluid retention and increase the risk of heart failure. Heart failure is more frequent in the later stages of CKD. Fracture risk is increased with TZDs adding to the increased fracture risk already present in CKD. Bladder cancer risk is also increased. Because of all these negative concerns, TZDs are not a preferred class of drugs for diabetes treatment in CKD.27,28
• Dipeptidyl peptidase-4 inhibitors. Sitagliptin, saxagliptin, and linagliptin are the 3 drugs currently available in this class of drugs in the United States. Sitagliptin and saxagliptin need dose adjustment because of their renal excretion. For sitaglipitin, the dose should be reduced to 50 mg/day when the GFR is between 49 and 30 and reduced to 25 mg/day when the GFR is <30. For saxagliptin, the dose should be reduced to 2.5 mg/day when GFR is <50. Linagliptin is metabolized in the liver so no dose adjustment is needed for decreased renal function.29
• Glucagon-like peptide-1 (GLP-1) receptor agonists. Exenatide twice daily and once weekly may be used without dose adjustment in patients with mild kidney dysfunction, GFR 50-80, and used with caution when the GFR is 30-50. Exenatide is not recommended for patients with severe kidney impairment and a GFR <30.30,31 Liraglutide does not require a dose adjustment at any stage of CKD.32 Because of the gastrointestinal side effects of these drugs and the potential of dehydration, GLP-1 receptor agonists should be used with caution in CKD.
• Insulin. Insulin therapy in CKD patients is no different from patients without CKD in stages 1 to 3A. However, once stage 3B is reached, insulin requirements may be lower because insulin clearance is lower and the risk of hypoglycemia is higher.33 One study in hospitalized patients suggested that insulin doses be reduced 50% in later stage CKD.34 Clinicians should make patients aware of need to decrease the insulin dose as CKD progress.
Primary care clinicians provide the majority of care for patients with diabetes. They are ideally suited to prevent, recognize, and provide initial treatment for CKD. This can be accomplished by yearly screening for with urine microalbumin, obtaining serum creatinine levels to calculate glomerular filtration rate, and keeping the hemoglobin A1c, blood pressure, and lipid levels at ADA recommended goals. Fortunately, CKD is preventable and, if recognized early, progression can be halted. ■
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The 3rd annual Cardiometablic Risk Summit will take place in Las Vegas this October 10-12, 2014. For more information and to reserve your spot, visit
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Edward Shahady, MD, is a clinical professor of family medicine at the Universities of Miami and Florida, and the medical director of the Diabetes Master Clinician program at the Florida Academy of Family Physicians Foundation.