Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in several countries and the most common reason for the initiation of renal replacement therapy (RRT)/dialysis.^1,3 DN is characterized by persistent albuminuria (> 300 mg/d or 200 µg/min), a gradual decline in renal function/glomerular filtration rate (GFR), and hypertension.^1,2

Epidemiology

Twenty years after the onset of type 1 or type 2 DM the risk of proteinuria is 27-28%.³ The prevalence of DN is greater among African Americans, Asians and Native Americans compared to Caucasians.⁴ Furthermore, patients with a longer history of DM, old age, male sex, poor glycemic control and type 1 DM are at greater risk of nephropathy.^3,7

Risk factors

Microalbuminuria (urinary albumin excretion of 30-300 mg/24h or roughly 2.0-20 mg/mmol in males and 2.8-28 mg/mmol in females in a random urine sample measuring albumin to creatinine ratio) is a marker of glomerular damage, predicting the development of overt nephropathy (without intervention).¹ Hypertension, sustained hyperglycemia, dyslipidemia, hyperfiltration, smoking, hypovolemia, and non-steroidal anti-inflammatory use are other factors that lead to the progression of renal dysfunction in diabetic patients.^2,7 It’s important to acknowledge genetic susceptibility as a significant component of DN. The pathogenesis of DN is likely multifactorial and is a combination of both genetic and environmental factors.^4,10

Pathogenesis

Pathophysiological changes associated with DN include, renal and glomerular hypertrophy, hyperfiltration, mesangial cell hypertrophy and matrix accretion, glomerular basal membrane thickening, as well as functional alteration in glomerular filtration barriers.^2,4 These changes are a result of hyperglycemia, advanced glycosylation end-products (AGEs), growth factors, cytokines and glomerular hypertension.²

Symptoms and signs

There are seldom any symptoms present during the initial stages of DN, making the diagnosis of this disease quite challenging early in its course. Therefore, it’s important to check for hypertension (HTN) and microalbuminuria regularly in high risk/DM patients since at early stages the patients are asymptomatic and damage may go undetected. In later stages of DN, symptoms include frothy or foamy appearance of urine, fatigue, itching, headache, nausea, vomiting, decreased appetite, pulmonary and tissue edema.

Diagnosis

Not all patients with premature renal impairment will develop ESRD; however, the probability is substantially greater among patients with DM.⁷ Therefore, screen for early signs of microvascular renal damage to delay progression to kidney disease.⁷ Screening for albuminuria should be performed at the time of diagnosis in patients with type 2 DM.⁶ This is imperative as ~7% of patients with type 2 DM at diagnosis will already have microalbuminuria.⁴ Keep in mind that the diagnosis of type 2 DM can be quite variable from the onset of the disease.^5,6 Type 1 DM patients rarely develop microalbuminuria early and so screening for these individuals should commence 5 years into the duration of the disease.⁶ But patients with poor lipid and glycemic control, and HTN after the onset of puberty should be screened for microalbuminuria 1 year after DM diagnosis.⁴

A screening protocol for microalbuminuria is depicted in Figure 1. In the absence of albuminuria after initial screening, test for the presence of albuminuria annually. Microalbuminuria screening can be carried out by three methods: 1) measurement by a random urine spot collection of albumin-to-creatinine ratio; 2) collection with creatinine over 24-h simultaneously measuring creatinine clearance; and 3) timed collection (e.g., overnight or 4 hr).^6,7 Due to the known diurnal variation in albumin excretion, first-void or morning collections are best. Exercise, hyperglycemia, menses, heart failure, urinary tract infections, marked hypertension and acute febrile illness can result in elevated urinary albumin excretion.^6,7 Day-to-day variability in albumin excretion exists; therefore, before indicating a patient as having microalbuminuria, at least 2-3 collections over a 3-6-month period should show elevated levels.^6,7 Continued surveillance of microalbuminuria is suggested to gauge response to therapy and progression of disease.⁶

GFR is estimated by the Cockcroft and Gault Equation and is the most representative parameter of overall kidney function based on the patient’s serum creatinine, weight, gender and age.⁹ Many labs now report an estimated GFR (eGFR). The National Kidney Foundation in the U.S. has produced a system to classify stages of kidney disease based on GFR to enhance the identification and management of chronic renal disease (Table 2).⁸

Prevention and management

Prevention or slowing the progression of diabetic nephropathy is essentially treatment of its risk factors including HTN, hyperglycemia, ACEI/ARB use in most, and smoking cessation.⁴ Glycemic control (A1c < 7%), and strict BP control (< 130/80 mm Hg) are effective strategies in prevention and the progression of renal disease during all stages.⁵ Dietary protein restriction is also recommended (0.8-1.0 g/kg/day).⁷ At stage 3 and 4 (moderately/severely decreased GFR) additional management includes referring patients not meeting treatment goals to nephrology, monitoring for anemia and secondary hyperparathyroidism.⁵ Stage 5, end-stage renal failure requires assessment for dialysis and possible kidney transplantation.⁵ Remember to encourage a healthy lifestyle including physical activity, maintenance of a healthy body weight, and limiting sodium intake to less than 100 mmol (2g)/day.

Prognosis

Without specific intervention, approximately 80% of patients with type I DM and in 20-40% of those with type 2 DM with microalbuminuria will ultimately progress to macroalbuminuria.^2,3 Macroalbuminuria can be classified by the presence of proteinuria > 0.5 g/24 h.⁴ Figure 2 represents a typical temporal progression of kidney disease over a period of approximately 30 years.⁵ DN proved to be associated with poor outcomes, with diabetes accounting for the majority of new ESRD cases.^1,3,10 Type 1 DM patients with proteinuria have a 40-fold greater risk of mortality than those without.³ The prognostic significance of proteinuria is less pronounced in type 2 DM patients, although patients with proteinuria have a 4-fold risk of death than their counterparts.³ Therefore, trying to identify normoalbuminuric patients at greatest risk for DN will allow for earlier aggressive intervention strategies before reaching a microalbuminuric state and any further progression to ESRD.¹¹ Fortunately, survival continues to improve as a result of cumulative research, advancements in pharmacological treatment, and improved management.

When to refer

You should refer to a nephrologist when the cause of renal failure is in doubt, there’s an abrupt decline in renal function, acute renal failure, persistent estimated GFR < 30 mL/min/1.73 m¹, progressive decline of kidney function, ratio of urine protein to creatinine > 100 mg/mmol (about 900 mg/24 h), or urine albumin to creatinine ratio > 60 mg/mmol (about 500 mg/24h), or any other features that may suggest an alternative cause such as fever, rash, and/or purpura, or inability to achieve treatment targets.

Future promises

Detection of DN using urinary proteomics is currently being explored.¹² Significant increase in plasma proteins and accompanying degradation products can be observed in the urine, reflecting alterations in the filtration barrier due to a change in protease activity, and structural damages of tubuli and glomeruli (later stages of DN).¹² Another marker in urinary proteomics is the decrease of extracellular matrix degradation products in urine, indicating early stages and fibrosis onset.¹² Urinary proteomics can address current challenges in DN such as detection of high-risk patients (before microalbuminuria), early detection of disease, forecasting response to treatment and prediction of prognosis.¹² Urinary proteomic biomarkers will increase our knowledge and understanding of pathophysiology and molecular mechanisms responsible for disease onset and development.¹² What’s more, new, alternative drugs may be produced to target these events more effectively, and thus prevent disease onset entirely.¹²

Useful websites

Canadian Hypertension Education Program (CHEP) — www.hypertension.ca

Canadian Diabetes Association (CDA) — www.diabetes.ca

Canadian Society of Nephrology (CSN) — www.csnscn.ca

References

1. Rossing P. Diabetic Nephropathy: Worldwide Epidemic and Effects of Current Treatment on Natural History. Current Diabetes Reports 2006;6:479,483.
2. Djordjevi´c V. Hypertension and nephropathy in diabetes mellitus: what is inherited and what is acquired? Nephrol Dial Transplant 2001;16(Suppl 6):92-3.
3. Shlipak M. Diabetic nephropathy: preventing progression. BMJ 2009;01(606):1-18.
4. Gross JL, et al. Diabetic Nephropathy: Diagnosis, Prevention, and Treatment. Diabetes Care 2005;28:176-88.
5. Seaquest ER, Ibrahim HN. Approach to the Patient with Type 2 Diabetes and Progressive Kidney Disease. JCEM 2010;95:3103-10.
6. Molitch ME, et al. Nephropathy in Diabetes. Diabetes Care 2004;27:S79-83.
7. Evans TC, Capell P. Clinical Diabetes: Diabetic Nephropathy. ADA 2000;18.
8. Levin A, et al. Guidelines for the management of chronic kidney disease. CMAJ 2008;179(11):1154-62.
9. Traynor J, et al. How to measure renal function in clinical practice. BMJ 2006;333(7571):733-7.
10. Tanaka N, Babazono T. Assessing genetic susceptibility to diabetic nephropathy. Nephrology 2005;10:S17-21.
11. Caramori ML, Fioretto P, Mauer M. The need for early predictors of diabetic nephropathy risk. Is albumin excretion rate sufficient? Diabetes 2000;49:1399-1408.
12. Mischak H, Rossing P. Proteomic biomarkers in diabetic nephropathy — reality or future promise? Nephrol Dial Transplant 2010;25:2843-5.
13. Abboud H, Henrich, WL. Stage IV Chronic Kidney Disease. NEJM 2010;362:56-65.