Diabetic nephropathy is characterized by proteinuria, decreasing glomerular filtration rate and increasing blood pressure. In the absence of urinary infection or other renal disease, proteinuria in the order of >0.5g/day is an indication of established diabetic nephropathy.
This degree of proteinuria is detectable by dipstick urine testing. However, it is recognized that this stage is preceded by a long phase of incipient nephropathy associated with microalbuminuria (30-300mg/day) that is not detectable on dipstick testing. As microal-buminuria presages diabetic nephropathy, it allows the possibility of interventional treatment to slow the rate of progression of nephropathy.
Histologically, the diabetic kidney is characterized by increased glomerular volume secondary to basement membrane thickening and mesangial enlargement, hyaline deposits and glomerular sclerosis due to mesangial expansion and/or ischemia. Nephropathy is commonly seen in type 1 diabetic patients, especially in those who develop diabetes before the age of 15 years. Around 35% of type 1 diabetic patients will develop nephropathy; the incidence of new cases of nephropathy declines after approximately 16 years of diabetes. However, because type 2 diabetes is much more common, the majority of diabetic patients proceeding to end-stage renal failure have this form of diabetes.
The hypertension of diabetic nephropathy appears to be of renal origin and to occur after the onset of microalbuminuria. As proteinuria also reflects widespread vascular damage affecting both small and large vessels, the condition is associated with a poor prognosis unless special strategies are adopted. The causes of death include not only end-stage renal failure, but also myocardial infarction, cardiac failure and cere-brovascular accidents. Type 2 diabetic patients with nephropathy are more likely to die because of major vascular disease than uremia.
Peripheral vascular disease, neuropathy and retinopathy (usually proliferative) are virtually universal in diabetic nephropathy. Indeed, if neuropathy and retinopathy are not present, an alternative cause of the proteinuria should be sought. The sudden development of nephrotic syndrome, a rapid decline in renal function, hematuria and short duration of type 1 diabetes also indicate the need to seek an alternative cause, with the use of renal biopsy if necessary. If there is a marked discrepancy in size between the kidneys on ultrasound scanning, investigations should be conducted to exclude renal artery stenosis which is common in diabetes especially in type 2 diabetes with other evidence of vascular disease. Angiotensin-converting enzyme (ACE) inhibitors should be avoided in this situation. Regular monitoring of glomerular filtration rate and plotting the inverse of serum creatinine against time will give an indication of the rate of progression of nephropathy; however, this may be slowed by vigorous treatment of the associated hypertension, preferably with ACE inhibitors, which have the additional benefit of reducing intraglomer-ular pressure.
There is evidence that establishing strict glycemic control and adopting a diet of moderate protein restriction may also retard the progression of established nephropathy. With declining renal function, insulin requirements fall and, as most sulfonylureas and metformin undergo renal excretion or metabolism, these compounds should not be used in patients with renal failure; in such cases, insulin treatment is preferable, although some agents, such as gliclazide, which are cleared predominantly through the liver may be relatively safe.
With aggressive treatment of hypertension and hyperlipidemia and improvement of glycemic control, the need for renal replacement therapy may be delayed for several years. However, late referral of diabetic patients with advanced diabetic nephropathy to a nephrologist should be avoided: referral should be instigated when serum creatinine levels start to rise and certainly before they reach 300 |imol/l. Renal physicians prefer to see such patients earlier rather than later. Although renal transplantation offers the best method of treatment in suitable patients, hemodialysis is indicated in patients unsuitable for transplantation, while awaiting transplantation or following graft failure. Dialysis may need to be started at lower creatinine levels than in non-diabetic patients because of a tendency to increased fluid retention and volume-dependent hypertension. Vascular access and arterio-venous fistulae failures are additional problems for diabetic patients, as is difficulty achieving blood glucose control during hemodialysis. However, the prognosis of diabetic patients receiving hemodialysis, although poorer than in non-diabetics, has improved dramatically over the past 20 years.
Long-term survival of diabetic patients with continuous ambulatory peritoneal dialysis (CAPD) is possible. Survival rates may be lower than in non-diabetic patients receiving CAPD. Advantages of CAPD include the facts that vascular access is not required and that good glycemic control may be achieved by the intraperitoneal route of insulin.
Renal transplantation is the treatment of choice for those <65 years who are free of significant cardiovascular disease, cerebrovascular disease and significant sepsis, and for whom a suitable donor may be found. Survival rates for diabetic patients who receive grafts from living donors are now almost the same as for non-diabetic patients, while results of cadaver transplantation, although less favorable, have improved greatly. Histologic changes compatible with diabetic nephropathy can be detected in most transplanted kidneys. In today's era, many diabetic patients with endstage renal failure who require a transplant receive both a kidney and a pancreas at the same time.
A major Finnish study of 20 005 patients with type 1 diabetes showed that during a follow-up of 35 years the overall incidence of end-stage renal failure was only 2.2% at 20 years and 7.8% at 30 years after diagnosis. The risk of end-stage renal failure was virtually zero for the first 15 years after diagnosis. These data suggest a greatly improved renal outlook for patients with type 1 diabetes, especially for the under 5s. Overall survival has also improved.
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