Prevention of diabetic nephropathy: A diabetologist's ... - MedIND

Indian J Nephrol 2004;14: 157-162

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REVIEWARTICLE

Prevention of diabetic nephropathy: A diabetologist’s perspective V Viswanathan Diabetes Research Centre, [WHO Collaborating Centre for Research, Education and Training in Diabetes], Chennai

Abstract Diabetes mellitus causes considerable morbidity and mortality due to micro and macro vascular complications. One such complication is diabetic nephropathy which causes chronic renal failure in 30% of diabetic patients in India. Early diagnosis and detection of risk factors for diabetic nephropathy is important step for prevention of diabetic nephropathy. Key words: Diabetes, nephropathy, chronic renal failure and prevention

Diabetes mellitus is a major health problem1 and causes considerable morbidity and mortality primarily due to micro and macro vascular complications. The prevalence of diabetes is increasing globally and the maximum increase is expected to be in developing countries like India. By the year 2010, it is estimated that nearly 220 million people worldwide will have diabetes. India is facing a major health care burden due to the high prevalence of type 2 diabetes and there are indications that this would increase further in the next few decades. Diabetes is preventable and so are its complications. One such microvascular complication of diabetes is diabetic nephropathy. Nearly 30% of chronic renal failures in India are due to diabetic nephropathy2. Nonetheless attention towards diabetic nephropathy is not directed until the patient has progressed towards the stage of renal failure. Nephropathy due to diabetes can be diagnosed very easily and can be prevented. This review article aims at describing diabetic nephropathy, its prevalence and pathogenesis and management.

Increased prevalence of diabetic nephropathy in South Asians Racial differences in the prevalence of diabetic renal disease have been reported. Asian subjects have significantly (p < 0.01) higher prevalence (52.6%) of diabetic end stage renal disease (ESRD) when compared with the Caucasians (36.2%)4. Migrant Asian Indians had 40 times greater risk of developing ESRD when compared with the Caucasians5. The prevalence of diabetic nephropathy in type 2 diabetic subjects is reported to be 5-9% from various Indian studies6,7,8. Patients with diabetic nephropathy, especially with type 2 diabetes, have a high cardiovascular risk. The risk for cardiovascular disease (CVD) was 3 fold higher in South Indian NIDDM subjects with nephropathy when compared with their non-nephropathic counterparts9. Thus, in type 2 diabetes, many patients may not reach end stage renal disease due to premature death from CVD.

Pathophysiology

Diabetic nephropathy is clinically defined by the presence of persistent proteinuria of > 500 mg/day in a diabetic patient who has concomitant diabetic retinopathy and hypertension and in the absence of clinical or laboratory evidence of other kidney or renal tract disease3.

The pathogenesis of diabetic nephropathy is multifactorial and genetic susceptibility has been proposed to be an important factor in the development and progression of diabetic nephropathy.

Address for Correspondence: Dr. Vijay Viswanathan Diabetes Research Centre WHO Collaborating Centre for Research, Education and Training in diabetes 4, Main Road, Royapuram Chennai – 600 013 INDIA Email : [email protected]

Three major histologic changes occur in the glomeruli in diabetic nephropathy (1) mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycosylation of matrix proteins, (2) glomerular basement membrane thickening occurs, (3) glomerular sclerosis is caused by

Two major causative factors have been implicated in the development of diabetic nephropathy: metabolic and hemodynamic.

Copyright © 2004 by The Indian Society of Nephrology

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intraglomerular hypertension. These different histologic patterns appear to have similar prognostic significance. Diabetes produces qualitative and quantitative changes in the composition of the capillary basement membrane and this altered material undergoes accelerated glycosylation and further rearrangement to form advanced glycosylation end-products (AGE), which stimulate protein synthesis10, further decrease degradability of the basement membrane11, increase its permeability12 and causes endothelial dysfunction13. Impaired endothelial function measured as elevated endothelin-1 levels and abnormal flow mediated dilatation has been demonstrated in south Indian type 2 diabetic subjects14,15.

Abnormal mechanisms involved in diabetic nephropathy The exact cause of diabetic nephropathy is unknown, but various mechanisms postulated are hyperglycemia (causing hyperfiltration and renal injury), AGE and activation of cytokines. Hyperglycemia increases the expression of transforming growth factor beta (TGFß) in the glomeruli and of matrix proteins specifically stimulated by this cytokine. TGFß may contribute to both the cellular hypertrophy and enhanced collagen synthesis observed in diabetic nephropathy. In a study from southern India16, it was shown that TGF- ß1 levels are elevated in type 2 diabetic subjects. Treatment with insulin and angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) appears to decrease the levels of TGF- ß1. Hyperglycemia also may activate protein kinase C, which may contribute to renal disease and other vascular complications of diabetes. In addition to the renal hemodynamic alterations namely decreased glomerular filtration rate and renal plasma flow, patients with overt diabetic nephropathy (dipstickpositive proteinuria and decreasing GFR) develop systemic hypertension. Hypertension is an adverse factor in all progressive renal diseases and seems especially so in diabetic nephropathy. The deleterious effects of hypertension are directed at the macro and microvasculature.

Genetics Familial factors may play a role in the development of diabetic nephropathy. Certain ethnic groups, particularly American blacks, Hispanics, and Native Americans, may be particularly pre disposed to renal involvement as a complication of diabetes. The author conducted a study17 to determine familial aggregation of diabetic nephropathy in South Indian type 2 diabetic subjects. It was found that proteinuria was present in 50% and microalbuminuria in 26.7% of the



diabetic siblings of probands with diabetic nephropathy. In contrast, the prevalence of proteinuria and microalbuminuria among diabetic siblings of probands with normoalbuminuria was 0% and 3.3% respectively (P=0.057 for microalbuminuria). Some evidence has suggested that polymorphism in the gene for the angiotensin-converting enzyme contributes in either predisposing to nephropathy or accelerating its course. In a study from south India18, it was shown that a positive association exists between the D’allele (ID and DD genotype) of the ACE polymorphism and proteinuria in South Indian type 2 diabetic patients. However, definitive genetic markers have yet to be identified. In summary, hyperglycaemia sets in motion a number of hemodynamic and metabolic abnormalities that eventuate in the typical histologic and clinical picture that is seen in patients with diabetic nephropathy.

Early diagnosis of risk factors for diabetic nephropathy Diabetic patients with microalbuminuria (MAU) are at a high risk for developing overt nephropathy and cardiovascular complications. Early screening for MAU in diabetic patients allows for aggressive intervention with a view to prevent ESRD.

Management of diabetic nephropathy Hypertension is the single most important factor that accelerates the progression of diabetic renal disease. Various drugs such as the a-blockers, b-blockers, calcium channel blockers, ACEI and ARB are available to target hypertension. But the key to initiate treatment is not to get everyone to one particular class of drug, but to treat effectively with the best drug for individual patients. Eventhough a-blockers, b-blockers and calcium channel blockers remain important anti-hypertensive agents in diabetic patients, they should be considered as secondor third line drugs in combination with ACEI and ARB. Studies like HOPE19, Steno20 and BRILLIANT study21 have demonstrated the effectiveness of ACEI in terms of reducing albumin excretion rate independent of their blood pressure lowering capacity. Recently, the IRMA22 and the IDNT23 trials conducted respectively in microalbuminuric and nephropathic type 2 diabetic subjects have shown that treatment with ARB (irbesartan) is renoprotective and slows the progression of glomerulopathy. This protection is independent of reduction in blood pressure with minimal drug specific serious adverse events. The IRMA trial showed that treatment with irbesartan reduced the number of patients attaining the primary end-point of developing overt nephropathy. This reduction


Prevention of diabetic nephropathy

was dose dependent, irbesartan 300 mg (5.2%) showing more beneficial effect than irbesartan150 mg (9.7%) and the placebo group (14.9%). Similarly the IDNT trial showed that the risk of developing the primary end- point (doubling of serum creatinine and onset of ESRD) in the irbesartan 300 mg group was 20 times lower than the placebo group and 23 times lower than the amlodipine treated group. Irbesartan was found to be renoprotective, independent of its beneficial effect in lowering 24-hour blood pressure in patients with type 2 diabetes and persistent microalbuminuria, in a sub-study of the IRMA 2 trial24. In a recent study by Herman et al.,25 it was shown that treatment with losartan in type 2 diabetic patients with nephropathy reduced the incidence of ESRD and resulted in decrease in cost associated with ESRD. Losartan significantly reduced the number of days with ESRD over 3.5 years when compared with the placebo and conventional therapy group. Table 1 shows the recommended blood pressure targets, non pharmacologic and pharmacological therapy recommended by National Kidney Foundation task force on cardiovascular disease in chronic renal disease (KDOQI)26. Early screening for microalbuminuria is the key for early detection of the devastating complication. Once

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identified, intensive treatment to control the blood sugar should be the primary objective. A target blood pressure of 1 g /d) or diabetic kidney disease:

< 125 / 75

Reduction in dietary salt

ACE – inhibitors or angiotensin - II receptor blockers (diuretics), or Calcium channel blockers in kidney transplant recipients

CKD Stages 1 – 4 without proteinuria (< 1 g / d):

< 135 / 85

Reduction in dietary salt

ACE – inhibitors or angiotensin - II receptor blockers (diuretics), or Calcium channel blockers in kidney transplant recipients

CKD Stage 5:

< 140 / 90

Reduction in dietary salt, Reduction in fluid intake and ultrafiltration in dialysis patients

Any, except diuretics in dialysis patients.


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diabetic nephropathy was very much less (11.5%) in the group that received more intensive treatment than in the conventionally treated group (43.5%) In the UKPDS study30, more than 4000 patients with freshly diagnosed type 2 diabetes were observed over 15 years, either under a conventional or under a more intensive treatment with oral antidiabetics and / or insulin. The study showed that with 12 years of blood glucose control, there was a risk reduction of 33% in the onset of microalbuminuria, 34% risk reduction in proteinuria and 74% risk reduction in two-fold increase of plasma creatinine. The above two studies highlighted the importance of blood glucose control to prevent the onset and progression of diabetic nephropathy. Dietary protein intake: Recommended dietary allowance of protein intake by American Diabetes Association (ADA)31 is 0.6 - 0.8 gm/kg body weight/day in patients with diabetic nephropathy. It is generally believed that an average Indian diet does not exceed this limit. However in a cross-sectional study by Vijay et al.32, it was shown that the prevalence of microalbuminuria and macroproteinuria did not differ among vegetarians and non-vegetarians. Eventhough the non-vegetarians had significantly higher mean protein intake when compared with vegetarians, both the groups did not exceed the recommended protein intake for patients with diabetic nephropathy. Therefore in South Indians, protein intake does not seem to be an important factor in the progression of diabetic nephropathy. Specific therapies: This includes modification and/or treatment of associated risk factors such as hyperlipidemia and cessation of smoking. Intensified multifactorial treatment are useful in slowing the progression of nephropathy. In the Steno type 2 diabetes randomized study, it was shown that intensive treatment with a stepwise implementation of behaviour modification, pharmacological therapy targeting hyperglycemia, hypertension, dyslipidaemia and microalbuminuria lowered the rate of progression to

nephropathy (OR = 0.27) when compared with a conventional therapy. Thus the treatment strategy should not only aim at attenuating high blood sugars and blood pressures but also treat comorbid conditions associated with diabetic nephropathy20.

Recent advances in the field of diagnosis and treatment of diabetic nephropathy Many new markers for earlier and better determination of kidney function are undergoing experimental investigations. One such marker is Cystatin C. This marker was found to be better than the conventional serum creatinine in estimating renal function33. Another marker namely, urinary transforming growth factor β34 is also found to be a predictor of diabetic kidney disease. Abnormally elevated levels of protein kinase C and endothelin-1 are noted in diabetic patients with nephropathy. Novel drugs such as protein kinase C inhibitor (LY333531)35, endothelin-1 inhibitors (FR 139317, PD142893)36,37, which can prevent renal failure are under experimental studies. The future for the treatment of diabetic kidney disease appears to be bright with latest advances in the field of science and technology.

Challenge for the present and the future: Prevention of diabetic nephropathy Various studies conducted by the author have shown that the major pathogenic features associated with diabetic nephropathy namely atherosclerosis demonstrated as increased carotid intimal media thickness38, endothelial dysfunction (increased endothelin1 levels and abnormal flow mediated dilatation)15 and non-dipping of blood pressure occurs at the stage of normoalbuminuria itself39. Only worsening of these parameters occurs at the stage of nephropathy. Intervention at the stage of normoalbuminuria might help in a great way to prevent diabetic nephropathy.

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