Diabetic Nephropathy is the leading cause of end stage renal disease worldwide. Patients with diabetes currently account for 35% of all the patients in ESRD being treated in USA and 28 % of ESRD patients in India. Sixty three percent of patients with diabetic nephropathy have type II diabetes or NIDDM. The development of diabetic nephropathy has a dramatic increase on the morbidity and mortality of patients with diabetes. It is estimated that patients with type I diabetes mellitus and diabetic nephropathy as manifested by proteinuria have a hundred fold greater risk of dying relative to a non diabetic population. Diabetic patients without proteinuria have only a 2 fold increase in relative mortality. Proteinuria is the hall mark of diabetic nephropathy. Diabetic Nephropathy rarely develops before ten years duration of diabetes. The cumulative incidence of proteinuria in patients with type I diabetic (IDDM) after 40 years duration of diabetes is 40%. The annual incidence of diabetic nephropathy in IDDM peaks just before 20 years and thereafter declines. This suggests that the risk of developing diabetic nephropathy is not constant over the duration of diabetes. Thus if a patient survives 35 years of diabetes without developing nephropathy, the patient is at extremely low risk of doing so in future. Studies in type 2 diabetes (NIDDM) show similar results to those in IDDM.

Natural history :

Mogenson has classified Diabetic nephropathy into 5 stages. Stage 1 (0-2 Yrs) Stage of hyperfiltration and hyperperfusion. Stage of hyperfiltration and hyperperfusion is characterized by increased GFR, increase in renal size and reversible alluminuria unmasked by stress or exercise. The importance of these functional changes as the predictor of later development of overt renal disease remains controversial.

Stage 2 (2-5 Yrs) Stage of structural changes Structural changes - Characterized by increase in glomerular basement membrane thickness and increase in mesangial matrix.

Stage 3 (5-10 Yrs) Stage of Microalbuminuria Stage of Micro albuminuria or incipient diabetic nephropathy - defined as a urinary albumin excretion rate of 20-200 mg/min 30-300 mg/24 hrs. Microalbuminuria is predictive of development of overt proteinuria.

Stage 4 (10-15 Yrs) Stage of overt proteinuria Stage of overt proteinuria & renal failure - once proteinuria is established, renal function declines in exorably.

Stage 5 (15-25 Yrs) End stage renal disease Stage of ESRD - When GFR declines to less than 10 ml/min, the need for renal replacement in form of dialysis or renal transplantation is required.

Pathogenesis and Pathophysiology :

There is perhaps an interplay of genetic, metabolic and hemodynamic pathways.

Genetic factors :

Siblings of probands with diabetic nephropathy who have diabetes have a higher incidence of diabetic nephropathy. A family history of hypertension is also associated with increased risk of diabetic nephropathy. An association between RBC sodium-lithium counter transport activity, viewed as a marker of the risk for essential hypertension and development of diabetic nephropathy is supported by meta - analysis of various studies. Renal angiotension system has been incriminated. Polymorphism of genes such as ACE and angiotension type I receptor have been assessed. ACE gene polymorphism may represent a genetic determinant of renal response of an individual to inhibition of ACE.

Metabolic factors :

Normal kidneys transplanted into patients with diabetes develop diabetic lesions, whereas kidneys from patients with diabetes that were in advertently transplanted into non-diabetic ESRD patients resolved their diabetic lesions. DCCT and UKPDS trials have conclusively proven that intensive glycemic control results in a significant reduction in primary and secondary microvascular complications. These observations strongly support the notion that exposure to the diabetic milieu rather than an intrinsic defect in the kidneys predisposes patients to the development of diabetic nephropathy. Chronic effects of glucose in inducing tissue injury may occur via the generation of advanced glycation end products (AGE). AGE accumulate in various tissues including kidneys. Aminoguanidine, an inhibitor of AGE formation reduces accumulation of renal AGE and also retards the development of albuminuria and mesangial expansion. Several clinical studies are in progress. Another alternative approach would be to inhibit the effects of advanced glycation products involving the use of the thiazolium compound, phenyl acylthiazolium bromide. This agent can cleave performed AGE mediated tissue damage and may be of particular relevance in patients with established diabetic renal disease.

Another glucose dependent pathyway - polyol pathyway has also been implicated, though inhibitors of this pathyway have produced conflicting results. The activity of the enzyme - phospho-kinase C has been reported to be increased in various diabetic tissues and LY333531, an orally active inhibitor of B11 isoform of protein kinase C is being developed and awaiting clinical trials.

Hemodynamic Factors : Diabetic Nephropathy is commonly associated with systemic hypertension. Longitudinal studies in patients with IDDM have suggested that in the transition from normoalbuminuria to microalbuminuria, there is a modest rise in blood pressure of about 3 mm Hg per year best detected by ambulatory blood pressure monitoring. Micropuncture studies in animal models of diabetes show raised intra glomerular pressure. These renal hemodynamic changes may be partly due to the actions of vasoactive hormones such as angiotension II and endothelin. ACE inhibitors and angiotension II receptor antagonists, reduce elevated intraglomerular pressure and thus the beneficial effects of ACE inhibitors in diabetic nephropathy.

The hallmark of pathological changes in diabetic nephropathy is increased extracellular matrix accumulation. It has been postulated that the cytokine - Transforming factor - B (TGF - B) which is stimulated by glucose, AGE, Vasoactive, hormones such as angiotension II and endothelium, plays a pivotal role in the development of diabetic Nephropathy. It is likely that TGF-B plays an important part in mediating the interactive between metabolic, hemodynamic and even genetic factors.

Management and Treatment :

Several studies including DCCT and UKPDS have indicated that intensified glycemic control retards the rate of development of both microalbuminuria and overt proteinuria in patients of diabetes and normal albuminuria. Glycemic control is therefore an important goal to achieve in a diabetic and should be monitored by Glycosylated hemoglobin 3 monthly and should be kept below 7.%.

It is more than 20 years since Mogensen showed that antihypertensive treatment could attenuate the rate of decline in renal function in patients with diabetic nephropathy. In patients with early diabetic nephropathy manifested by microalbumenuria lowering of systemic blood pressure has been demonstrated to lower urinary albumin excretion rate. The current recommendation for target B.P. for patients with proteinuria is less than 125/75 mm Hg. ACE inhibitors have been clearly shown to be renoprotective, it is still not been established in clinical studies whether normotensive & normoaalbuminuric diabetics would benefit from ACE inhibtors.

Dietary protein restriction ( 0.8 gms/kg) has been shown to produce attenuation of progression of diabetic renal failure. However in Indian patients it is very important to keep in mind that malnutrition does not develop as it is one of the most important predictors of mortality in chronic renal failure including diabetic Nephropathy.

Many patients of diabetic nephropathy have macrovascular disease, hyperlipidemia, coronary artery disease & cerebro - vascular disease. Therefore the choice of anti hypertensive should take into consideration all these factors in an individual patient. Moreover patients on ACE inhibitors should be monitored for renal function deterioration & hyperkalemia.

The 40% of patients with diabetes who develop diabetic nephropathy must be identified as early as possible in their course, as interventions noted above can be implemented to slow and halt the progression of their renal disease at very early stages such as when patient has only microalbuminuria. Once persistent elevation of urine albumin is found, patient should be referred to a nephrologist for further evaluation. The nephrologist can also evaluate the patient to ensure that no other cause of proteinuria besides diabetic nephropathy is present. In addition to implementing specific therapeutic interventions it is very important to preserve the remaining renal function by avoiding other insults such as use of non-steroidal anti-inflammatory agents, the unnecessary uses of aminoglycosides and by properly managing urinary tract infection or obstructive uropathy due to diabetic cystopathy. Patients with diabetic nephropathy are at greater risk of developing acute renal failure secondary to exposure of IV contrast agents. Because of the high incidence of vascular complications diabetic patients are often candidates for radio contrast administration for cardiac catheterization or other diagnostic procedures. Avoiding radio contrast agents or minimizing their exposure plays an important role in preserving residual renal function. If exposure to radio contrast agent is necessary, ensuring adequate hydration & intravascular volume at the time of the study is critical.

Lastly patients with diabetes develop uremia and require renal replacement therapy earlier than patients with other renal diseases. Patients with diabetes often have a lower GFR for any given serum creatinine than a nondiabetic patient with renal insufficiency. Thus it is not uncommon for a patient with diabetes to be near ESRD even with a serum creatinine as low as 4-5 mg/dl. Diabetic patients also develop symptoms of uremia at higher GFR values (10-15 ml/mt) than patients with non-diabetic kidney disease. Establishing a vascular access for dialysis may be difficult because of co-existent vascular disease. Because diabetic patients have a high incidence of coronary artery disease, their transplantation evaluation may require extensive cardiac testing. For all these reasons, dialysis training and planning as well as transplant evaluation should begin early. Once patients reach ESRD, the diabetic patient has options of renal transplantation, peritoneal dialysis in form of continuous ambulatory peritoneal dialysis (CAPD) or maintenance hemodialysis. Each of these options need to be discussed with the patient and their family and therapy individualized.

In conclusion it is now incumbent on clinicians to carefully monitor diabetic patients for evidence of early renal disease. This means regular screening for microalbuminuria as per algorithm, now made convenient by advent of a reliable urine dipstick method such as micral and use of albumin creatinine ratio in early morning urine. It is hoped early diagnosis & early intervention in this group of patients might delay, if not prevent, the development of overt proteinuria and diabetic nephropathy.

Practice Guidelines :

(1) Measurement of Microalbuminuria

• Test for microalbuminuria in all IDDM patients of greater than 5 yrs every year and all NIDDM patients at the time of diagnosis and every year. If positive, confirm by a repeat test (either 24 hrs urine collection or by albumin creatinine ratio in early morning urine sample).
• Normal albumin excretion <30mg/24 hrs, Microalbuminuria 30-300 mg/24 hrs Proteinuria > 300 mg/24 hrs.
• Monitor blood sugar control by glycosylated hemoglobin every 3 monthly. Target HbA1c < 7%.
• Monitor Blood pressure. Target B.P. < 125/75.
  

(2) Guidelines for outlining of strategy based on Microalbuminuria Target

	Screening of diabetic patient for Micro albuminuria
	Microalbuminuria confirmed at least on 2 occasions.
	Is glycemic control Satisfactory ?
Glycemic control Satisfactory		Optimize glycemic control
Antihypertensive Therapy-ACEI		Microalbuminuria Confirmed on 2 occasions
	Target B.P.<125/75 Reduction of Microalbuminuria
Target achieved		Target not achieved
Treat associated risk factors (lipids)		Titrate dose of ACEI consider other anti hypertensives
	Continue monitoring albumin Excretion rate 3-6 monthly

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