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Nephropathy

A Review of the Diagnosis and Therapy of Diabetic Nephropathy


By Niall G. McLaughlin, MD* ; Udayan Y. Bhatt, MD*; Gil A. Cu, MD* ; Ronald L. Mars* , MD; N. Stanley Nahman, Jr, MD* *Department of Internal Medicine, University of Florida Jacksonville Jacksonville Transplant Center, Shands Jacksonville
Diabetes is the most common cause of end stage renal disease (ESRD) in the United States, and in 2002, accounted for over 40% of patients on dialysis.1 In this group, 44,000 were new to renal replacement therapy. The cost of providing dialysis care to these patients was $76,515/patient-year. Thus, ESRD from diabetes persists as a huge cause of patient morbidity, and carries an equally heavy economic burden for society. Taken together, strategies to prevent and control diabetic nephropathy would be expected to result in a reduction in patient morbidity and mortality, as well as a significant cost savings. On this basis, the purpose of this essay is to review the diagnosis and therapy of diabetic nephropathy. The approach to diagnosis stems directly from the pathology and pathophysiology of the disease. Therapy is based upon controlling the pathologic effects of mesangial matrix expansion and proteinuria. Each of these facets of the disease is discussed in the following sections.

Pathology and pathophysiology of diabetic nephropathy


The pathology of diabetic nephropathy manifests histologically as diabetic glomerulosclerosis, and is characterized by glomerular basement membrane thickening and mesangial expansion with increased extracellular matrix deposition. In Type I diabetics, there is a direct relationship between the extent of mesangial expansion and clinical severity of disease.2 In this regard, Mauers seminal paper demonstrated a direct correlation between the degree of mesangial expansion, and magnitude of proteinuria, severity of hypertension, and degree of renal impairment.2 Taken together, these data suggest that clinical findings predict severity of glomerular damage, and underscore the necessity of understanding the mediators of mesangial expansion in this disease. Mesangial expansion in diabetic glomerulosclerosis may be considered the result of an imbalance between mesangial matrix protein production and degradation, favoring matrix protein accumulation. Overproduction of mesangial matrix proteins may be the result of glomerular hypertension and/or hyperglycemia-driven synthesis of prosclerotic cytokines such as transforming growth factor-B, angiotensin II, and/or other growth factors.3,4 Alternatively, elevated glucose levels may inhibit matrix protein degradation through non-enzymatic glycosylation and/or through the inhibition of protein degradative pathways.5 Thus, the mediators of mesangial expansion constitute reasonable therapeutic targets when crafting a treatment strategy for diabetic nephropathy. Understanding the natural history of diabetic glomerulosclerosis is important to designing therapeutic interventions, as well as gauging responses to therapy. In this regard, Parving demonstrated the deleterious effect of hypertension on renal function in proteinuric diabetics.6,7 Of equal or greater value in that report was the demonstration of the expected rate of loss of glomerular filtration rate (GFR) over time, in patients with diabetic nephropathy. Figure 1 (opposite page) is a schematic summary of the natural history of diabetic glomerulosclerosis, and demonstrates the relationship between albuminuria and the loss of GFR over time. The model is based on the following assumptions: (1) all macroscopic (dipstick positive) proteinuria is preceded by a phase of microalbuminuria (microalbumin 30-300 mg/day); (2) the appearance of dipstick positive proteinuria heralds the beginning of a linear, irreversible loss of GFR; and (3) GFR is lost, on average, at the rate of 1 ml/min/month. Clinicians can use these criteria to predict the behavior of the disease, expecting patients to need renal replacement therapy 7-8 years after the onset of dipstick positive proteinuria. Modulating the rate of loss of GFR

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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.

Clinical diagnosis of diabetic nephropathy


The diagnosis of diabetic glomerulosclerosis can be made with a renal biopsy. Light microscopic findings include increased mesangial matrix and thickening of the glomerular basement membrane. Immunofluorescence is characterized by increased staining of the glomerular and tubular basement membrane and Bowmans capsule for IgG and albumin in a linear pattern.8 The presence of diabetic glomerulosclerosis can also be inferred from the clinical presentation. For example, in the first placebo controlled, double blind study of the effect of ACE inhibitors diabetic nephropathy9 a diagnosis of diabetic glomerulosclerosis was inferred if a patient had diabetes at least 7-10 years, exhibited demonstrable diabetic retinopathy, and had macroscopic proteinuria (albuminuria> 300mg/day). Diabetics with heavy proteinuria, but lacking the disease for a sufficient period of time and/or retinopathy, may require renal biopsy. These patients may suffer from primary glomerulopathies such as membranous nephropathy, or other glomerular diseases.10 Diabetic glomerulopathy is the most common cause of nephrotic syndrome. Thus, early in the course of the disease, the serum creatinine is normal despite heavy proteinuria (> 3 grams/24 hours). In this regard, a diabetic patient presenting with elevated serum creatinine in the absence of macroscopic proteinuria should suggest additional diagnostic possibilities (such as other glomerulopathies) . The diagnostic utility of proteinuria is less useful in patients treated with angiotensin converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs), since both classes of drugs are known to reduce glomerular proteinuria.11, 12
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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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Six treatment targets


1. Tight blood glucose control
The DCCT demonstrated the importance of tight blood glucose control in slowing the development of proteinuria in Type 1 diabetics.13 In this regard, patients randomized to tight glucose control (HbA1C levels < 6.5%) versus regular control (8-9%), demonstrated 39 and 54% lower rates of development of microalbuminuria and macroalbuminuria, respectively, over the two years of the trial.

2. Blood pressure control


The importance of controlling hypertension to slow the decline in GFR at various levels of blood pressure was demonstrated by Parving.6 Patients with a blood pressure of 144/97 had an estimated loss of GFR of 0.91 ml/min/month. When the same patients were treated with an antihypertensive drug regimen to attain an average blood pressure of 128/ 84 using a diuretic, beta blocker and vasodilator, the rate of loss of GFR was reduced by ~ 57% to 0.39 ml/min/month. This altered rate of renal function loss is illustrated by the estimated time to the initiation of renal replacement therapy (dialysis or transplantation) after the onset of macroproteinuria in the two groups. The hypertensive group would be expected to progress to end stage renal disease in about 8 years (if normal GFR (100 ml/min) is lost at ~ 12 ml/min/year) whereas the treated group would not reach the same endpoint for about 22 years (rate of loss of GFR ~ 4.6 ml/min/year).

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

4. Dietary protein restriction


In some reports, dietary protein restriction has been shown to slow the loss of GFR in proteinuric diabetics,19 although the data are not conclusive.7 Protein restricted diets (0.6-0.8 g/kg body wt/day) decrease glomerular hypertension, the production of prosclerotic cytokines, proteinuria, and glomerulosclerosis,20 and remain a viable therapeutic option for compliant patients.

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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Medical therapy of diabetic nephropathy


The medical therapy of diabetic glomerulosclerosis includes strict control of blood glucose levels, aggressive blood pressure control, angiotensin II inhibition, and dietary protein restriction. Additional therapeutic targets include microalbuminuria and macroproteinuria. An approach to each of these parameters is discussed on the opposite page (Six treatment targets).

Renal replacement therapy: hemodialysis


Hemodialysis and peritoneal dialysis are the two forms of dialysis used to treat diabetic patients with end stage renal disease. Survival analysis shows the two modalities are comparable with regard to patient outcome.28 However, when compared to non-diabetics, diabetic patients on dialysis do substantially worse,29 with five-year survival rates as low as 5% for elderly type II diabetics.30 With meticulous management, others have shown three-year survival rates as high as 58%.29 The reasons for poor survival rates relate to the high incidence of preexisting cardiovascular disease, late referral both for predialysis care, as well as vascular access placement, malnutrition, and co-existing vascular problems (in particular, peripheral vascular disease with associated ischemic toes and feet).29 Furthermore, diabetes and smoking have been shown to be significant risk factors for atherosclerotic heart disease in dialysis patients, similar to what is seen in the general population.31 The anemia of chronic renal disease may further complicate the course of patients with significant coronary artery disease. Taken together, these data suggest that the survival of diabetic patients on hemodialysis may be optimized with aggressive attention to risk factors for cardiovascular disease (hypertension, dyslipidemia, smoking, etc.), awareness and therapy of diabetic foot problems, and early nephrology referral (as GFR falls or with progressive proteinuria) for vascular access placement and anemia management.

Renal replacement therapy: peritoneal dialysis


The second option for renal replacement therapy in diabetic patients with ESRD, is peritoneal dialysis. When compared to hemodialysis, fewer patients are treated with peritoneal dialysis. Patients opting for peritoneal dialysis tend to be healthier and more involved in their medical care. While no clear survival advantage for peritoneal or hemodialysis has been demonstrated, patients treated with peritoneal dialysis may experience labile blood glucose levels (attributed to the high glucose concentrations inherent to PD dialysate) and increased risk of malnutrition (secondary to excessive protein losses in dialysate effluent).32

Renal replacement therapy: transplantation


By far the best treatment for ESRD from diabetes is kidney transplantation. Kidney transplantation in diabetics with end-stage renal disease may include kidney transplantation alone, or combined kidney-pancreas transplantation. The former treats renal failure, the latter both renal failure and diabetes. Patient survival following kidney transplantation without a pancreas has consistently been demonstrated to be superior to any form of dialysis. Data from the Organ Procurement and Transplantation Network reported one-, three-, and five-year patient survival rates for transplanted diabetics of 90, 79 and 66%, respectively.33 This compares to a twoyear survival rate in diabetic patients on hemodialysis of ~ 58%.29 The improved survival of renal transplant patients over those treated with hemodialysis must be interpreted in light of the fact that healthier patients are selected for transplantation, whereas patients with extensive co-morbidities tend to remain on dialysis. Living donor transplants confer an allograft survival advantage over cadaveric donors, with three-year allograft survival rates of 88 and 78% for living and cadaveric donor transplants, respectively.33 However, both modalities are superior to dialysis with threeyear patient survival rates of approximately 88-94%.33 Preemptive transplantation is renal transplantation that is performed prior to instituting dialysis. Preemptive transplantation may confer a survival advantage that is superior to transplanting patients on dialysis. In this regard, the time spent on dialysis prior to transplantation portends worse survival rates for patients. For example, in patients on dialysis < 6 months, 12-24 months, or >48 months had mortality rates of 21%, 41%, and 72%, respectively.34, 35, 36 A similar trend for allograft survival was seen in cadaveric transplants performed in patients receiving hemodialysis for more than two years prior to the transplant. In those studies, the allograft survival rate was only 39% after ten years.35

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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