• Introduction
• Management
  • Dietary Treatment
  • Glycaemic Control
  • Other modalities
  • Kidney and Pancreas Transplantation
• References

Introduction

Diabetic nephropathy is an important microvascular complication of long standing non-insulin dependent diabetes mellitus (NIDDM) as well as insulin dependent diabetes mellitus (IDDM) associated with considerable morbidity and mortality. Prevalence of diabetes mellitus is on the rise and it is estimated that there are 30 million diabetics in India, of which 6.6 million are expected to develop diabetic nephropathy (DN)¹. Further, type 2 diabetes mellitus is 5 times more common and microalbuminuria is higher in Indians than Europeans². Overt diabetic nephropathy is preceded by a stage of microalbuminuria which cannot be diagnosed by the routine dip-stick method.

Majority of the epidemiological studies of diabetic nephropathy are available in insulin-dependent patients due to the earlier manifestation (<40 yr.) of diabetes in these patients leading to longer follow-up period. In IDDM, the prevalence of nephropathy peaks at 21 percent after 20 to 25 years of clinically detected diabetes and then declines to 10 percent. However, in NIDDM, prevalence of proteinuria increases steadily with duration of diabetes, ie, 20 to 35 percent in patients who have had diabetes for more than 20 to 25 years³.

The natural history of diabetic nephropathy is evident by the phase of glomerular hyperfiltration during which important abnormalities of renal function and structure (nephromegaly) take place. The next stage is the appearance of microalbuminuria, the excretion of albumin in the range of 30-300 mg/d, which appears to be due to decreased concentration of anionic heparin sulfate-proteoglycan in the glomerular basement membrane. If adequate therapeutic measures are not taken at the initial stage, there develops the stage of clinical nephropathy after a variable period, signaled by the appearance of persistent proteinuria (albumin excretion rate of >300 mg/day). At this stage there is a steady decline in renal function with glomerular filtration rate (GFR) falling, on an average, by about 1 ml/min/month. A plot of the reciprocal of serum creatinine level against time usually yields a straight line and allows prediction of the rate of deterioration. The average time between onset of persistent proteinuria and end-stage renal failure has been calculated as 7 to 15 years. Recently, association of ‘Ischaemic Nephropathy’ has also been reported along with DN. The hallmark of this condition is ischemia, which is caused by reduction in caliber of renal artery and can also result from multiple thrombi, dissection of aorta, or cholesterol embolism. In an autopsy study, bilateral disease was seen in 43 percent patients with diabetes mellitus and 30 percent of non-diabetic patients⁴. The risk of ischemic nephropathy in the setting of DN is further increased if the age of patient is more than 70 years and there is associated cigarette smoking and hypertension of recent onset⁵.

The earliest morphologic abnormalities in diabetic nephropathy are thickening of the glomerular basement membrane (GBM) and expansion of the mesangium due to the accumulation of extracellular martrix. The various stages of diabetic nephropathy are shown in Table I.

Table I : Various stages of diabetic nephropathy.

Various genetic, metabolic, and hemodynamic factors that appear to be important in the pathogenesis of DN are hyperglycemia, hypertension, microalbuminuria, ethnicity, gender, family history, duration of diabetes, smoking, and genetic susceptibility. Hypertension (HT) is a critical factor in development and progression of DN. It is an ominous sign because once HT develops, there is an accelerated decline in GFR and increase in albuminuria. Therefore if treated aggressively, it is a key factor in slowing the rate and extent of decline in renal functions because HT contributes to hyperfiltration and hemodynamic abnormalities⁶. Therefore current strategies designed to prevent progression of diabetic nephropathy include :

• Glycaemic control
• ACE inhibition (microalbuminuria)
• Blood pressure control
• Smoking cessation
• Protein restriction
• Cholesterol reduction (possibly)

Management

Blood pressure control

It has become apparent that progressive fall in GFR in IDDM patients correlates closely with both increasing albuminuria and blood pressure (BP). Further, reduction in BP slows the rate of decline of GFR and checks the increasing albuminuria. A prospective study of 6 years duration demonstrated that effective BP treatment decreased albumin excretion rate of 50 percent and the rate of decline of GFR from 0.9 ml/min/month to 0.29 ml/min/month⁷. Further, numerous studies have shown that lowering of BP in normotensive diabetics has clear renal benefits. Although appropriate BP goal in diabetics is not clearly defined, a lower target diastolic pressure of 80 mm Hg is aimed at. However, better end point of antihypertensive (anti HT) treatment is not the BP level but the rate of albumin excretion because this is the indicator that predicts the rate of decline in GFR⁸. Therefore, there is widespread consensus for using antihypertensive medication that has most beneficial effect on reducing microalbuminuria and using them in normotensive microalbuminuria cases. The other factors which need to be considered in choosing the drug are the side effect profile and its potential effect on cardiovascular mortality. The characteristics of an ideal antihypertensive drug are given in table II.

Table II : Characteristics of an ideal antihypertensive drug

Among the available choices of antihypertensives which have reno-protective property, other factors like neutral effect on lipid profile and improvement in insulin sensitivity; ACE-I (Angiotensin Converting Enzyme Inhibitors), Angiotensin II receptor antagonists, nondihydropyridine calcium channel blockers, adrenergic antagonists, and cardioselective B Blockers (Carvedilol) appear to offer most advantages⁹. However, the only class of drug which has shown benefit with regard to reduction in cardiovascular deaths are ACE-I and low dose diuretics¹⁰.

A number of studies have suggested that not only a benefit of antihypertensive treatment but a relatively greater beneficial effect of ACE inhibition on kidney is found over that achieved by BP control alone. Enthusiasm has been generated in the nephrological community by the recent evidence that ACE-I are superior to other antihypertensive agents in attenuating progressive loss of renal function. The idea of a specific nephroprotective effect of ACE inhibitors goes back to the observation of Anderson¹¹. There is improvement in glomerular membrane size, a selective property seems to be unique to ACE-I and is independent of systemic BP changes¹². One important confounder (with obvious consequences, for the management of renal patient) is sodium intake. High sodium intake obliterates the beneficial effect of ACE inhibitors on development of glomerulosclerosis in animals¹³ and on proteinuria in renal patients¹⁴. It emerges from this, that in order to obtain maximal benefit from ACE-I, dietary sodium restriction, with or without diuretics, is indispensable. More recently it has become obvious that ACE-I, besides efferent arteriolar vasodilatation have many non-hemodynamic effects which may well be relevant in inhibition of progression. These include inhibitory action on mesangial cell proliferation in vitro¹⁵ and glomerular growth in vivo¹⁶, as well as the effects on the electrical change of the glomerular membrane¹⁷, and even actions on non-glomerular cells, particularly interstitial fibroblasts¹⁸. These processes are relevant in the genesis of glomerular and interstitial scarring and in the development of proteinuria.

The non-dihydropyridine subclass of calcium channel blockers including diltiazem and verapamil, which cause vasodilatation of afferent arterioles have been shown to decrease protein excretion; several reports in literature have recommended continuation of these drugs with ACE inhibition at lower doses of each agent and hence achieved greater reduction in proteinuria and better results in reducing decline in GFR¹⁹. However, use of ACE-I should be monitored clinically, biochemically, and by using isotope studies, especially if serum creatinine is more than 2.5 mg percent. The increments in serum creatinine beyond 70 percent of the baseline value should raise suspicion and prompt treatment for predisposing factors listed in table III. The risk of hyperkalemia is usually not clinically important, if loop diuretics are administered concomitantly with ACE-I.

Table III : Side effects of ACE inhibitors in renal patients.

Therefore, anti-HT treatment appears to be protective and delays the progression of establishment of diabetic nephropathy. If started at the stage of microalbuminuria, it may even prevent, or at least retard, the amount of clinically overt renal disease. Aggressive anti-HT therapy has also been found to decrease albuminuria in the stage of overt nephropathy.

Dietary treatment

Restriction of protein intake has long been advocated in the treatment of CRF, and diabetic nephropathy is no exception. Meta-analysis of efficacy of protein restriction in both diabetic and non diabetic renal disease has confirmed that such restriction slows the progression of renal disease in general²⁰. Zeller et al demonstrated 3-4 fold decline in rate of fall of GFR on a protein restricted diet (0.6 g/kg/day)²¹. Effect on albumin excretion especially in microalbuminuric type 1 and 2 diabetics have also been demonstrated.

However, protein restriction should be avoided in hypercatabolic patients with advanced DN as it may cause malnutrition. The mode of action of low protein diet (LPD) is complex and unlikely to be mediated simply by hemodynamic changes. Although hemodynamic factors are important in the pathogenesis of nephropathy, and LPD reduces intraglomerular pressure and microalbumin exeretion but changes in other nutritional components such as phosphorus and lipids may also be contributing. Further, it is also clear that an important interaction exists between glycemic control and hemodynamic response of kidney to a protein load and strict glycemic control enhances the beneficial effect of LPD on renal functions^22,23. Therefore this approach is safe and is probably an effective primary or secondary preventive measure for DN. Protein restriction of 0.75-0.8 g/kg/day is widely recommended in type 1 diabetes.

Glycemic control

Poor glycemic control leads to accumulation of advanced glycosylation end products in tissues, hence DN is four times more common in IDDM patients with poor glycemic control. The onset of microalbuminuria correlates closely with glycemic control, with a gradual rise in rate as the glycosylated hemoglobin level increases from 6.1 to 8.1percent and a sharp rise occurring above 8.1 percent²⁴. However, blood glucose control appears to have limited impact on the progression of diabetic renal failure which suggests that there is a point of no return for kidney, beyond which the nephropathy process becomes self perpetuating and independent of diabetic metabolic abnormalities which initiated it. Therefore good glycemic control is of prime importance in the earlier stages of renal disease (ie, before the onset of overt proteinuria) and reduction in albumin excretion rate and annual decline in GFR have been obtained by strict control of the glucose levels and it is the blood glucose concentration rather than the method of its control which matters^25,26. However, whether this effect can be translated into prevention of end stage renal disease (ESRD) remains to be established. Further, it has been suggested that establishment of irreversibility of renal hypertrophy signifies the onset of phase of progressive renal disease.

Other Modalities

Lipid lowering agents

Nephropathy in NIDDM appears to alter the lipid profile in a more atherogenic direction and diabetics have 3 times increased risk of cardiovascular deaths. Further they have increased triglycerides and cholesterol levels and have tendency of premature atherosclerosis. Hyperlipidemia is known to accelerate renal injury by activation of cytokine dependent pathways and stimulation of macrophage proliferation leading to progression of incipient/overt nephropathy²⁷. Therefore, it is generally recommended that all NIDDM patients with LDL>160 mg percent and TG> 400 mg percent should be treated with HMG-CoA reductase inhibitors²⁸. Fibric acid derivatives have been studied in NIDDM patients with diabetic dyslipidemia, but in patients with renal involvement, these drugs can have significant untoward effects. Therefore HMG-CoA reductase inhibitors have been used in DN, without adversely affecting the glycemic control.

Aldolase reductase inhibitors

Some short term studies have shown decrease in GFR and albumin excretion in IDDM patients²⁹.

Antiplatelet drugs

Aspirin and dipyridamol have been advocated by some workers to delay progression of CRF in DN³⁰. However, long term studies would be required before these agents (lipid lowering agents, aldolase reductase inhibitors, and anti platelet agents are recommended for routine use in diabetes.

Kidney and Pancreas Transplantation

Patients with end stage renal failure due to DN are not ideal candidates for long term dialysis because of concomitant multiple organ dysfunction secondary to widespread arteriovascular disease. Renal transplantation may be successful in the younger diabetic, especially if a living related donor is available. Survival and rehabilitation for diabetics on renal transplantation, whether cadaveric or alive has been found to be distinctly superior to either continuous ambulatory dialysis (CAPD) or maintenance hemodialysis (HD). Advanced glycation end products (AGE) levels in diabetics with renal transplantation decrease after surgery and progression of microvascular disease is, therefore, retarded. Multiple small advances in the understanding of the pathogenesis of extra-renal vasculopathic complications coupled with safe immunosuppression have improved patient and graft survival in diabetic graft recipient to the degree that in two large series, they are equivalent to the results obtained in non-diabetics^31,32. However, renal transplantation should not be considered in situations like life-threatening systemic disease, infections, pre-existing cardiovascular and pulmonary disease, metastatic malignancies, and other chronic debilitating diseases. Transplantation with whole pancreas or segments has cured diabetes in a number of patients but is usually performed only when kidney transplantation is required. Islet cell transplantation has not yet been very successful in humans.

To conclude, there is no specific treatment for diabetic nephropathy. Meticulous control of diabetes can reverse microalbuminuria in some patients, and the progression of diabetic nephropathy may be slowed. Hypertension must be treated aggressively whenever present. Angiotension-converting enzyme inhibitors appear to slow progression of diabetic nephropathy. They should be used in hypertensive patients with diabetes and may even be of value in normotensive subjects with microalbuminuria. Once azotaemia sets in, treatment does not differ from that of other forms of renal failure. Kidney and pancreas transplantation would be the most ideal treatment. In those, who cannot have transplantation, continuous ambulatory peritoneal dialysis (CAPD) is advised, provided these patients have adequate visual acuity and are not invalid. Home hemodialysis reportedly has highest survival rate³³. However, it should be encouraged in all young patients.

Acknowledgement: Journal of Indian Academy of Clinical Medicine, January-June 2001; 2(1-2):78-83.

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