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Diabetics are at increased risk for several types of kidney disease but the predominant cause of end stage renal disease in diabetics is diabetic nephropathy. It accounts for second most important cause of Renal disease constituting about 18.56% (Mani M.K. et al 1993).
Natural history of diabetic Kidney disease
Nephropathy is defined as persistent albuminuria of 300 mgm/day in the absence of other renal diseases. It is a complication developing after 10 years duration of diabetes mellitus often accompanied by hypertension & declining kidney function. Diabetic nephropathy is classified into 5 stages.
In stage 1 there is renal hypertrophy & hyp erf unction. Kidney size is large, Glomerular filtration rate is increased. Glycemic control caii reverse the changes, intracapillary glomerular capillary pressure is increased and urine shows no albuminuria.
In stage II there are renal lesions without clinical signs. Glomerular filtration rate is increased and yet there is no albuminuria. Histopathologically basement membrane thickening, with glomerular mesangium is increased- Basement membrane deposition of albumin degradation products with IgG, fibrin and platelets
In stage III (incipient nephropathy) there is microalbuminuria. This develops 7-15 yrs after the onset of diabetes mellitus. Microalbuminuria in urine is detected by radioimmunoassay. It is 20-200mcg/minute. This amount increases after exercise. Microalbuminuria is highly predictive of clinical nephropathy. In NIDDM it is not only a strong predictor of nephropathy but it is a risk factor of coronary artery disease.
Reversible microalbuminuria can occur with poor glycemic control in diabetics. At this stage urine albumin by heat test is negative or there is no macroalbuminuria.
Overt Diabetic Nephropathy is stage IV, where glomerular filtration rate is decreased, clinical nephropathy with hypertension, puffy face and pedal oedema develops. Urine examination for albumin shows massive albuminuria over 3 gm/day. Often such diabetics show associated retinopathy and neuropathy. In non-insulin dependant diabetics, diabetic nephropathy may be associated with coronary artery disease.
In the last stage (stage 5) also known as end stage renal failure. Glomerular filtration rate is decreased, blood pressure is increased.
Pathogenesis of Diabetic Nephropathy
In the pathogenesis of Diabetic Nephropathy various factors are implicated like hyperglycemia hypertension, high dietary protein intake, smoking, lipid abnormalities, familial and racial factors. Diabetic Nephropathy is said to be more in IDDM compared to NIDDM, more in males compared to females and longer the duration of diabetes greater is the chance of developing nephropathy.
Histopathologically there is diabetic glomerulosclerosis. Changes may be diffuse, nodular, capillary aneurysm and arteriolar hypertensive changes are seen.
Clinical presentation of Diabetic nephropathy - some salient features
Proteinuria is the hallmark of disease with fluid retention, hypertension & anemia. Retinopathy, peripheral vascular disease may be "associated with nephropathy.
With the onset of nephropathy there is increase in insulin sensitivity normally 40% of insulin is degraded by kidney with renal parenchymal disease the half life of insulin is prolonged, more insulin is circulating because less of insulin is degraded. This results in recurrent hypoglycemia and the dose of insulin has to be reduced. Other factors which may contribute to reduction in insulin dosage are poor intake of food and reduced gluconeogenesis.
It is advisable to avoid long acting oral antidiabetic drugs like chlorpropamide as kidneys are damaged the chlorpropamide excretion is delayed. Such patients tend to have prolonged hypoglycemia. Similar!}' long acting insulins are also to be avoided.
Patients have hypertension but often they have postural drop so that control of B.P. becomes difficult. This is related to hypoalbuminemia and associated autonomic neuropathy
Often these patients have hyperkalemia. Because insulin pushes potassium inside the cell, in a state of insulin deficiency and poor diabetic control there is hyperkalemia. Other contributory factors to hyperkalemia are reduced aldosterone, reduced renin and angiotensin levels. On the top of diabetic nephropathy at times acute renal failure may be superadded and confuse the clinical presentation. Such a situation arises in a diabetic during diabetic ketoacidosis with papillary necrosis.
Management of Diabetic Nephropathy
Firstly one has to find out whether the renal involvement in diabetes is related or not related to diabetes. Lack of antecedent nephrotic range proteinuria in the preuremic stage and presence of normal optic fundi point to non-diabetic etiology. Percutaneous kidney biopsy is appropriate in such a situation to establish the ctiological diagnosis.
The management of diabetic nephropathy is a team work between family physician, diabetologist and nephrologist. It is necessary to explain to the patient and his family the problem and patients co-operation is needed.
Screening for microalbuminuria in high risk diabetes mellitus is rewarding in the sense that one can identify the patients who are going to have overt diabetic nephropathy. At this stage tight control of diabetes preferably with insulin and maintaining 24 hours euglycemia is beneficial. Also blood pressure must be controlled. If urinary tract infection is there control and prevent further recurrent infections.
Dietary modification in terms of cutting down protein intake is an essential step. At this time we can increase carbohydrate, polysacchride and reduce protein. In the incipient nephropathy the best drug to control microalbuminuria is an ACE-inhibitor.
Avoid iatrogenic injury to kidney by not using contrast media, nephrotoxic drugs, such as aminoglycosides, amphotehcim B, Sulpha, and cisplatinum. If these drugs are essential in diabetics the patients should be well hydrated adequately, urinary output monitored and dosage of drugs should be optimum. Once the overt diabetic nephropathy develops, glucose control may not be beneficial in reversing the glomerular basement membrane changes. Now these changes are permanent. Control of B.R will no doubt prevent to some extent further glomerular changes. Choice of drugs in control of blood pressure are ACE inhibitor, diuretics, methyldopa, nifedepine and alphablokers.
ACE inhibitors reduce intracapillary glomerular pressure and reduce micro albuminuria and are useful. But in chronic end stage renal disorder and bilateral renal artery stenosis the drug is contraindicated. Methyldopa and nifedepine can be added if monotherapy fails, hydralazine can also be used as an adjuvant when the drugs are not effective.
Oedema has to be controlled by sodium restriction. Diuretics to be given if needed. Thiazide diuretics are better avoided as they produce hyperglycemia. Somatostatin is used in the treatment of incipient nephropathy (State III). A simple urinary infection in diabetes can flare up to severe necrotising papillitis.
Dialysis
Diabetics have poor vascular access so chronic haemodialysis becomes some times difficult. It is said continuous ambulatory peritoneal dialysis (CAPD) is more useful in diabetics. Disadvantage of CAPD is peritonitis. When anticoagulant therapy is given, in diabetic patients with proliferative retinopathy for dialysis it may lead to retinal haemorrhage. Associated CAD may be limiting factor. A diabetic may die due to CAD inspire of good efforts to control diabetic nephropathy.
Renal Transplantation
In diabetic nephropathy transplantation should be planned early at GFR of 5-15 ml/min rather than 5 ml/min. and not wait for end stage renal disease. When graft acceptance, patient survival, quality of life, rehabilitation, cost and availability are considered together, living related donor renal transplantation is now the Gold standard of treatment for end stage renal failure. 5 years survival in diabetics after transplantation is 44% while in non diabetics it is 72%. Diabetics who have received renal transplantation often die due to septicemia or myocardial infarction. Use of steroid to prevent rejection of transplantation may cause problems in diabetic control as steroids are diabetogenic. Recurrence of diabetic nephropathy which occur after 21/2 years of transplantation. Transplant kidney shows typical histological changes of diabetic nephropathy.
REFERENCES
1. Renal complications of Diabetes mellitus. page 122-141 practice of diabetes mellitus
edited by MMS Ahuja 1983.
2. Glomerular transplantation chapter 10. page 261-288 in clinical diabetes modern
management Stephen Podolsky 1980.
3. The nephrotic syndrome etiopathogenesis and role of renal biopsy. Page 263- 267
M.K. Mani in Medicine update Vol.3,1993. Edited by Prof. S. Chandra Sekharan
APICON 1993.
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