Screening & Diagnosis for Diabetic Nephropathy

Screening for diabetic nephropathy

Therapeutic interventions and efforts to prevent the progression of nephropathy have the greatest impact if instituted very early in the course of the disease.[1] Therefore, it is recommended that all patients with diabetes receive routine screening tests for diabetic nephropathy so that appropriate treatments can be instituted as early as possible. These tests include blood pressure measurement, urinalysis, serum creatinine, and microalbuminuria testing.[2]

Therapeutic interventions and efforts to prevent the progression of nephropathy have the greatest impact if instituted very early in the course of the disease.[1] Therefore, it is recommended that all patients with diabetes receive routine screening tests for diabetic nephropathy so that appropriate treatments can be instituted as early as possible. These tests include blood pressure measurement, urinalysis, serum creatinine, and microalbuminuria testing.[2]

Risk factors for development and progression of diabetic nephropathy

Elevated blood pressure, poor metabolic control, and longer duration of disease are associated with greater likelihood or more rapid progression of diabetic nephropathy.[1] Members of certain ethnic groups (eg, African Americans) also have increased risk for developing end-stage renal disease (ESRD).[1]

Screening tests for diabetic nephropathy

Laboratory tests that are ordered as part of the initial diagnostic workup for diabetes include several that assess for diabetic nephropathy. These are provided in Table 1.

Table 1. Laboratory tests to order at the initial diagnosis of diabetes [3,4]

*Tests for diabetic nephropathy

Screening for microalbuminuria should be performed on diagnosis of type 2 diabetes. Microalbuminuria rarely occurs with short disease duration in type 1 diabetes; therefore, screening is recommended after 5 years of disease duration. Because microalbuminuria is also a marker for cardiovascular morbidity and mortality in diabetic patients, its presence is an indication to screen for possible vascular disease and to aggressively control cardiovascular risk factors.[1]

Screening for microalbuminuria can be performed by 3 methods:

1) Measurement of albumin:creatinine ratio in random spot collection

2) 24-hour collection with creatinine, allowing the simultaneous measurement of creatinine clearance

3) Timed (eg, 4-hour or overnight collection).

Microalbuminuria is said to be present if urinary albumin excretion is ≥30 mg/24h (Table 2).

Table 2: Albuminuria thresholds for 3 common tests of diabetic nephropathy<1

Clinicians should use assays indicated for detecting microalbuminuria, as standard laboratory urinary protein analyses are not sensitive enough to detect the low levels of protein indicative of microalbuminuria.[5] Reagent tablets or dipsticks specific for microalbuminuria may be used if other tests are not readily available. However, these methods are prone to false results because urinary creatinine levels are not used to adjust for variations in urine concentration [4,5]

Stages of diabetic nephropathy may be described by creatinine output or by clinical disease stage. The American Diabetes Association (ADA) categorizes disease stages by albumin:creatinine ratio, as measured by spot collection. Normoalbuminuria is <30 μg/mg, microalbuminuria is 30-299 μg/mg, and macroalbuminuria is ≥300 μg/mg. [4] Macroalbuminuria is also called clinical albuminuria. The ADA advises that because of variability in urinary albumin excretion, 2 of 3 specimens collected within a 3- to 6-month period should be abnormal before considering a patient to have crossed one of these diagnostic thresholds.[4] The ADA further notes that exercise within 24 hours, infection, fever, congestive heart failure, marked hyperglycemia, and marked hypertension may elevate urinary albumin excretion over baseline values.[4]

A 5-stage classification system proposed by Mogensen correlates the progressive functional and structural renal changes in type 1 patients with urinary albumin levels.[6] According to this system, stages 1 and 2 are associated with normal urinary albumin levels, stage 3 correlates with microalbuminuria, and stages 4 and 5 are characterized by macroalbuminuria.[6] The physical findings associated with Mogensen's proposed stages are described in further detail below.

Although nephropathies that are not of diabetic origin can occur in patients with diabetes, clinicians should maintain a high index of suspicion in patients with both kidney disease and diabetes.[7] Nephropathology often varies among patients with type 1 versus type 2 diabetes, but regardless of the type of diabetes, 20-30% of diabetes patients will develop some degree of nephropathy.[1,8]

Physical findings in diabetic nephropathy

Diagnosis of diabetic nephropathy

According to Mogensen's proposed classification system, stage 1 of diabetic nephropathy is characterized by enlarged kidneys and glomerular hyperfiltration resulting in polyuria; systemic blood pressure is usually normal.[6] Stage 2 may be clinically silent, with normal urinary albumin excretion (UAE) and systemic blood pressure, along with either normal or elevated glomerular filtration rate (GFR).[6] An estimate of GFR can be computed from creatinine clearance.[2,4] In stage 3, systemic blood pressure is often elevated, and microalbuminuria may be noted. [6] Stage 4 is characterized by clinical albuminuria and/or proteinuria.[6] Stage 5, otherwise known as end-stage renal failure, is associated with glomerulosclerosis, systemic hypertension, and markedly reduced GFR (below 10 mL/min).[6]

Increased urine output (polyuria) is one of the diagnostic hallmarks of early type 1 diabetes. While polyuria is typically present at diagnosis of type 1 diabetes, it may be absent in type 2 diabetes.[6]

Diabetic kidney disease is strongly associated with other diabetic complications for which patients should be monitored and treated.[9] Patients with clinical nephropathy almost always have retinopathy and coronary artery disease.[3]

Laboratory assessment for diabetic nephropathy

Table 3. Laboratory tests of renal function in diabetes [2]

* Diabetes with renal insufficiency is a risk factor for radiocontrast-induced nephropathy.[10]

Other laboratory tests

Blood urea nitrogen (BUN) is also used to assess renal function, and is especially important if creatinine values are suspect (eg, due to cephalosporins); however, creatinine is usually a better gauge of glomerular function.[2] Assays for protein C or protein S may be used to assess anticoagulant status in patients with diabetic nephropathy.[2]

Kidney ultrasound

Kidney size may be determined with ultrasound, but the procedure is neither common nor recommended for routine use in current clinical guidelines. Ultrasound imaging may also be used to guide needle insertion for kidney biopsies.[11] Obesity may interfere with image quality.[11]

Kidney biopsy

The precise reasons for performing renal biopsy vary among nephrologists, and there is ongoing discussion in the literature regarding the indications for performing this study. Renal biopsy is not routinely used to evaluate or to confirm a diagnosis of diabetic nephropathy, but it may be useful in evaluating rapid and unexpected deterioration of renal function in patients with confirmed diabetes.[11] Biopsies may be performed with or without ultrasound guidance. Nephropathological features often differ between patients with type 1 and type 2 diabetes and are even variable among type 2 patients. For example, a recent study of type 2 patients with microalbuminuria revealed 30% had normal renal structure, 40% had advanced tubulo-interstitial and/or vascular lesions, and only 30% had pathology similar to that seen in type 1 patients.[12]

Referral Criteria

The ADA recommends referral to a physician with experience in treating diabetic renal disease when a patient's estimated GFR (eGFR) falls below 60 mL/min/m² or when hypertension or hyperkalemia management become problematic.[4]

In addition, the following referral guidelines are provided by the Institute for Clinical Systems Improvement (ICSI).[3] Strongly consider referral to a nephrologist for patients with creatinine >1.5 mg or proteinuria >3 g/24 h. Nephrology consultations at this stage often include early patient education in preparation for ESRD, review and reinforcement of the medical regime, and preservation of arm veins for future vascular access.[3] Refer patients with creatinine clearance <30 mL/min for consultation regarding renal replacement therapy options. These patients may also benefit from more intensive nutritional interventions and management of anemia and bone disease.[3] Finally, the risk of nephropathy may be reduced in patients with chronic kidney disease by limiting protein intake to the Recommended Dietary Allowance (RDA) of 0.8 g/kg. [4]

References

1. Kramer H, Molitch ME. Screening for kidney disease in adults with diabetes. Diabetes Care. 2005;28:1813-1816.
2. Jacobs DS, DeMott WR, Oxley DK, eds. Laboratory Test Handbook. 5th ed. Hudson, Ohio: Lexi-Comp Inc; 2001.
3. Institute for Clinical Systems Improvement. Health Care Guidelines: Management of Type 2 Diabetes Mellitus. 9th edition. November 2004. Available from: http://www.icsi.org.
4. American Diabetes Association. Standards of Medical Care in Diabetes-2006. Diabetes Care. 2006;29(suppl 1):S4-S42.
5. American Diabetes Association. Nephropathy in Diabetes. Diabetes Care. 2004;27(suppl 1):S79-S83. 
6. Mogensen CE. Microalbuminuria, blood pressure and diabetic renal disease: origin and development of ideas. Diabetologia. 1999;42:263-285.
7. Hergesell O, Zeier M. Underdiagnosis of diabetes mellitus in chronic dialysis patients on the renal transplant waiting list. Transplant Proc. 2003;35:1287-1289.
8. Fioretto P, Mauer M, Brocco E, et al. Patterns of renal injury in NIDDM patients with microalbuminuria. Diabetologia. 1996;39:1569-1576.
9. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Part 7. Stratification of risk for progression of kidney disease and development of cardiovascular disease. Guideline 14. Association of chronic kidney disease with diabetic complications. Available at: http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p7_risk_g14.htm. Accessed June 2, 2006.
10. Asif A, Preston RA, Roth D. Radiocontrast-induced nephropathy. Am J Therap. 2003;10:137-147.
11. Michota FA Jr, ed. Diagnostic procedures handbook. 2nd ed. Hudson, Ohio: Lexi-Comp Inc; 2001.
12. Dalla Vestra M, Saller A, Bortoloso E, Mauer M, Fioretto P. Structural involvement in type 1 and type 2 diabetic nephropathy. Diabetes Metab. 2000;26(suppl 4):8-14.