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is the cornerstone of all therapies of diabetic glomerulosclerosis, and is discussed further below. Recognizing deviations from the predicted loss of GFR in otherwise stable patients may result from readily reversible causes, such as acute renal failure. Effective therapies for diabetic nephropathy may be assessed by comparing changes in renal function to the expected decline of 1 ml/min/month. Understanding the natural history of diabetic glomerulosclerosis may allow for predicting prognosis, as well as gauging responses to therapy.
Figure 1 Graphic representation of the natural history of diabetic glomerulosclerosis. Initially there is glomerular hyperfiltration and microalbuminuria. Note: Microalbuminuria is followed by macroalbuminuria (dipstick (+) proteinuria). The onset of macroproteinuria heralds the beginning of a
relentless decline in GFR at approximately 1 ml/minute/month (at a blood pressure of 140/90(6)). If GFR is 75 ml/minute at the onset of macroproteinuria, and dialysis is indicated at a GFR of 10 ml/minute, 65 months would pass from the onset of proteinuria to the need for renal replacement therapy. The goal of therapy is to slow the rate of loss of GFR. Reducing the rate of loss of GFR from 1 ml/minute/month to 0.5 ml/min/month would translate into a doubling of the time for the need for dialysis (130 months). Modified from Molitch, Diabetes Care 17:756, 1994.
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3. Angiotensin II inhibition
The ACE inhibitor trial in diabetic nephropathy was the first randomized, placebo controlled trial that showed the beneficial effect of ACE inhibitors in the treatment of diabetic glomerulosclerosis.9 Subsequent studies have confirmed this observation for both ACE inhibitors and ARBs.12, 14 Most agree that ACEi are first line therapy for diabetic glomerulosclerosis,12 but ARBs are regarded by some as equivalent.12 The beneficial effect of angiotensin II inhibition may result from: a) a decline in glomerular hypertension (with slowing of mesangial expansion),15 b) a reduction in proteinuria (with an expected decrease in proteinuria-associated prosclerotic events),16 and/or c) a decrease in angiotensin II stimulated TGF- synthesis.17, 18
5. Microalbuminuria
Microalbuminuria predates the development of macroscopic proteinuria. Macroscopic proteinuria is a major risk factor for progression to ESRD,16 thus measures to reverse microalbuminuria may retard development of clinical nephropathy. Patients with microalbuminuria treated with ACEi demonstrate slower progression to macroproteinuria and renal failure.7 ADA guidelines suggest assessing for microalbuminuria (normal < 30 mg/24 hours or less 30 mcg/mg creatinine for a spot urine collection) at the time of diagnosis in all type 2 diabetics, in all type I diabetics with disease duration > 5 yrs, and annually thereafter in both groups.21 Early and aggressive therapy of microalbuminuria, taken along with angiotensin II inhibition, is expected to slow disease progression.
6. Macroproteinuria
Heavy proteinuria is a risk factor for progressive renal failure,16 including diabetic nephropathy.22 There is abundant evidence that abrogating proteinuria with dietary and antihypertensive interventions,23 and/or ACE inhibitors,1 and/ or ARBs,14, 24,25 results in a slower loss of GFR in proteinuric states. In this regard, combination therapy with both ACE inhibitors and ARBs may provide benefit over ACE inhibitors alone.26 Finally, nephrotic diabetics treated with ACE inhibition, and exhibiting a reduction in proteinuria to < 1 gm / day, demonstrated stable renal function for up to 8 to 15 years.7, 27 Taken together, therapeutic measures directed at reducing macroscopic proteinuria would be expected to slow the progression of diabetic nephropathy, and angiotensin II inhibition is the mainstay of therapy for attaining that goal.
[The authors acknowledge the support of NIH grant DK 10064, the American Heart Association - Southern/Ohio Valley Research Consortium, Dialysis Clinic Inc., and the Di vision of Nephrolo gy Research and Development Fund, University of Florida Jacksonville]
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Summary
The rising incidence of diabetes means that clinicians can expect to find an increased rate of diabetic nephropathy, and increasing numbers of patients requiring renal replacement therapy. Understanding the natural history of diabetic nephropathy, the early recognition of diabetic complications, and timely initiation of therapy to slow progression, are cornerstones in the management of this condition. Aggressive treatment of hyperglycemia and hypertension, the use of angiotensin II inhibitors, and timely therapy of micro and macroproteinuria are essential features of optimal therapy. For patients reaching end stage renal failure, renal replacement options include dialysis and kidney transplantation, with transplantation conferring a substantial survival advantage.
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References
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