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Although not all renal disease that diabetic patients develop is due to diabetic glomerulosclerosis, the great majority of patients progressing to advanced renal failure suffer from diffuse or nodular (Kimmelstiel Wilson′s) diabetic glomerulosclerosis. This condition has become the single most frequent cause of end-stage renal failure in the Western world. Recent studies indicate that an interplay between genetic predisposition and other factors such as hyperglycemia, blood pressure, age, gender, smoking and ethnicity, predispose to nephropathy both in type 1 and type 2 diabetes mellitus. It has also become clear that trace albuminuria ("microalbuminuria") provides a unique opportunity to recognize incipient renal involvement early on, particularly in type 1 and less specifically in type 2 diabetes. Increasing evidence indicates that early intervention delays progression of nephropathy. Factors which promote progression of nephropathy include hypertension, proteinuria, smoking, poor glycemic control and, less certainly, high dietary protein intake and hyperlipidemia. The most important strategies to combat the medical catastrophe of increasing numbers of diabetic patients with end-stage renal failure include (i) prevention of diabetes (mainly type 2), (ii) glycemic control to prevent onset of renal involvement and (iii) meticulous antihypertensive treatment to avoid progression of nephropathy. Survival of diabetic patients on dialysis and after transplantation is inferior to that of non-diabetic patients, mainly because of high rate of cardiovascular death. There is consensus that in the absence of major vascular disease the best treatment is renal transplantation in the type 2 diabetic patient and combined kidney and pancreas transplantation in the type 1 diabetic patient.

Angioten-sin II accelerates and renin-angiotensin system blockade halts progression; blockade with high doses even reverses established glomerulosclerosis. Aldosterone also accelerates progression of glomerulosclerosis, partially independently of angiotensin 1I. The purpose of this study was to assess the relative ability of an angiotensin receptor type I (A[T.sub.1]) blocker, a mineralocorticoid receptor blocker, and their combination to reverse glomerulosclerosis. Sprague-Dawley rats were subjected to subtotal renal ablation (SNX) or sham operation. Eight weeks after surgery, they were either euthanized or allocated to treatment with vehicle, losartan, spironolactone, their combination, or unspecific antihypertensive treatment (dihydralazine) for 4 wk. Renal morphology was evaluated by stereology in tissues obtained using pressure-controlled perfusion fixation. Systolic blood pressure was significantly higher in SNX compared with sham-operated animals and decreased in all treatment groups. Compared with wk 8 after SNX, the glomerulosclerosis index (GSI) had increased further by week 12 in the vehicle- and dihydralazine-treated groups but was significantly lowered in the SNX+losartan as well as in the SNX+losartan+spironolactone groups and had not progressed further in the SNX+spironolactone group. The study confirms the partial regression of established glomerulosclerosis in subtotally nephrectomized rats alter high-dose A[T.sub.1] receptor blockade. Nonhyperkalemic doses of spironotactone prevented the increase but failed to decrease the GSI below the 8-wk level and preserved podocyte numbers. Combining the A[T.sub.1] blocker with mineralocorticoid receptor blockade failed to further increase the regression of glomerulosclerosis. aldosterone escape: renin-angiotensin system

A multicenter, randomized, double-blind, prospective study of 1255 subjects with type 2 diabetes mellitus receiving maintenance hemodialysis who are randomly assigned to receive 20 mg of atorvastatin per day or matching placebo is presented. The finding indicate that atorvastatin has no statistically significant effect on the composite primary end point of cardiovascular death, nonfatal myocardial infraction, and stroke in patients with diabetes receiving hemodialysis.

1,25[(OH).sub.2][D.sub.3] has antiproliferative effects and promotes cell differentiation. This consideration has provided the rationale for studies in subtotally nephrectomized rats showing that 1,25[(OH).sub.2][D.sub.3] intefferred with glomerulosclerosis. The cellular mechanisms involved have remained obscure, however. It was the purpose of the present study to assess glomerular structure and cellular composition in subtotally nephrectomized (SNX) rats treated with nonpharmacological doses of 1,25[(OH).sub.2][D.sub.3]. Male Sprague-Dawley rats were sham operated (sham) or underwent SNX under general anesthesia and received either solvent or 1,25[(OH).sub.2][D.sub.3] (3 ng x 100 g body [wt.sub.-1] x [day.sub.-1] sc). Blood pressure (BP) and albuminuria were measured. After 16 wk, the remnant renal tissue was perfusion fixed and morphometric and stereological measurements were carried out. The expression of proliferating cellular antigen (PCNA), cyclin-dependent kinase inhibitor p27, Wilms tumor gene (WT1), and desmin, a marker of early podocyte damage, was investigated by immunohistology. BP, serum creatinine, and urinary albumin excretion were significantly higher in SNX than in sham rats. Albuminuria was significantly lower in SNX+1,25[(OH).sub.2][D.sub.3] compared with SNX+solvent rats. Mean glomerular tuft volume was significantly higher in SNX+solvent (2.69 [+ or -] 0.21 x [10.sub.6] [micro][m.sub.3]) than in sham rats (1.44 [+ or -] 0.17 and 1.28 [+ or -] 0.14 x [10.sub.6] [micro][m.sub.3]); it was significantly (P < 0.05) lower in SNX+1,25[(OH).sub.2][D.sub.3] rats (1.81 [+ or -] 0.16 x [10.sub.6] [micro][m.sub.3]). The main finding was a significantly higher number of podocytes in SNX+1,25[(OH).sub.2][D.sub.3] (88 [+ or -] 9) and sham (98 [+ or -] 17) compared with SNX+solvent rats (81 [+ or -] 8.7). In parallel, the increase in podocyte volume in SNX+solvent rats was abrogated by treatment with 1.25[(OH).sub.2][D.sub.3], and immunohistochemistry revealed less expression of desmin, PCNA, and p27, suggesting less podocyte injury and activation of the cyclin cascade. This study identifies the podocyte as an important target cell for the renoprotective action of 1,25[(OH).sub.2][D.sub.3]. This notion is suggested by less evidence of podocyte injury, decreased podocytes loss, and abrogation of podocyte hypertrophy, findings that may also explain less pronounced albuminuria and glomerulosclerosis. visceral glomerular epithelial cell; mesangial cell; glomerular endothelial cell; progression

Byline: Matthias Schaier (1), Sabine Liebler (1), Kerstin Schade (1), Fujio Shimizu (1,2), Hiroshi Kawachi (1,2), Hermann-Joseph Grone (3), Roshantha Chandraratna (4), Eberhard Ritz (1), Juergen Wagner (1) Keywords: Chronic glomerulonephritis; Retinoids; Retinoid receptor expression Abstract: Retinoids, derivatives of vitamin A, inhibit mesangial cell proliferation, glomerular inflammation, and extracellular matrix deposition in acute anti-Thy1.1 glomerulonephritis (Thy-GN) of the rat. We examined a model, chronic mesangioproliferative Thy-GN (MoAb 1-22-3), which is more akin to human disease. Treatment started on day 23 when Thy-GN had already been established. Nonnephritic control and Thy-GN rats were treated orally for 67 days with vehicle or with two doses of either the retinoic acid receptor [alpha]-specific agonist AGN 195183 (RAR[alpha] agonist) or the retinoid X receptor specific agonist AGN 194204 (RXR agonist). Doses of either the RAR[alpha] or the RXR agonist significantly reduced albuminuria and normalized blood pressure during the course of treatment. The glomerulosclerosis index, glomerular cell and interstitial cell counts, and area of the interstitial space were significantly lower in nephritic rats treated with the RAR[alpha] agonist or RXR agonist than with vehicle. The RAR[alpha] and RXR agonist significantly reduced the infiltration of the glomerulus by macrophages. The increase in glomerular TGF[beta]1 and prepro-ET.sub.1 gene expression in vehicle-treated nephritic rats was significantly attenuated by RAR[alpha] or RXR agonists. Glomerular expression of RXR[alpha] and RAR[alpha] receptor mRNA was significantly greater in vehicle-treated nephritic rats than in nonnephritic controls. Treatment with RAR[alpha] or RXR agonists tended to normalize retinoid-receptor gene expression. Our data indicate that both RAR[alpha] agonists and RXR agonists reduce renal damage in rats with established chronic glomerulonephritis. Receptor-specific retinoids may provide a novel therapeutic approach for the treatment of chronic glomerulonephritis. Author Affiliation: (1) Department of Nephrology, University Hospital, University of Heidelberg, Bergheimer Strasse 56a, 69115, Heidelberg, Germany (2) Department of Nephrology, University of Niigata, Niigata, Japan (3) Department of Experimental Pathology, German Cancer Research Center, Heidelberg, Germany (4) Allergan Pharmaceuticals, Irvine, California, USA Article History: Registration Date: 04/11/2003 Received Date: 06/05/2003 Accepted Date: 30/10/2003 Online Date: 08/01/2004

All patients with diabetes should have a urinalysis frequently to check for albumin in the urine. Albumin is a protein whose presence in urine is a sign of kidney dysfunction. A study published in 2003 showed that good control of blood sugar could stop the excretion of albumin in urine. This may be a sign that blood sugar control may prevent diabetic kidney disease. Diabetic kidney disease may also be a marker for cardiovascular disease in general.