Rapid onset of diabetic nephropathy in three renal allografts despite normoglycemia.

Diabetes mellitus is the leading cause of end-stage renal disease in the United States. Renal transplantation is currently the treatment of choice for diabetic patients on renal replacement therapy. Current immunosuppression includes medications that are diabetogenic and place nondiabetic transplant recipients at risk for developing posttransplant diabetes mellitus and subsequent de novo diabetic nephropathy in the allograft. Here we present three patients who underwent a deceased donor renal transplant and developed posttransplant diabetes mellitus. In all three patients despite excellent glycemic control (HbA(1c) < or = 7%) and average tacrolimus trough levels less than 10 ng/ml, clinical and histologic de novo diabetic nephropathy developed within 2 years of the diagnosis of posttransplant diabetes mellitus. This is in contrast to other reported data in which the average time to onset of de novo diabetic nephropathy was approximately 10 years. Additionally, in other case series the average HbA(1c) was 8.4% in patients who developed diabetic nephropathy. It is possible that the metabolic milieu of transplant recipients warrants tighter glycemic control. The allograft is also susceptible to hyperfiltration injury which may accelerate the diabetic lesions even at normal glucose levels. Further studies are warranted to determine the optimum glycemic control in posttransplant diabetes mellitus.

Primary amyloidosis with multiple pulmonary nodular lesions and IgA nephropathy-like renal involvement.

A 66-year-old woman demonstrated multiple nodular lesions in the lungs without symptoms, and laboratory tests and transbronchial lung biopsy (TBLB) had been negative for malignancy, tuberculosis and sarcoidosis 15 years ago. She developed proteinuria and hematuria 10 years later. Renal biopsy revealed focal segmental mesangial proliferation with predominant IgA deposition in the paramesangium, suggesting IgA nephropathy. However, electron-microscopic observation revealed 8-12 nm fibril deposits in the interstitium and few in the mesangium that were positively stained with amyloid P protein and negative for amyloid A protein. Re-evaluation of previous TBLB samples showed apple-green birefringence with Congo-red staining that was resistant to potassium permanganate reaction. Electron-microscopic observation with high magnification and immunostaining for amyloid components led to a diagnosis of AL amyloidosis in this patient with predominant mesangial IgA deposition and slowly progressive nodular lesions in the lungs.

Tubulointerstitial nephritis associated with acute intermittent porphyria.

Progressive renal impairment associated with acute intermittent porphyria is not well recognized and the mechanism of renal damage remains unclear. We report a case of a 51-year-old female with acute intermittent porphyria and long-term follow-up who developed proteinuria and renal insufficiency. Her biopsy showed marked tubulointerstitial damage with mitochondrial abnormalities. Urinary excretion of lipid peroxidation was increased compared to healthy controls. The porphyrin precursors may increase lipid peroxidation products and damage mitochondria leading to tubulointerstitial nephritis.

Tissue-specific induction of E-selectin in glomeruli is augmented following diabetes mellitus.

We recently demonstrated that induction of adhesion molecules is tissue, cell type, and blood vessel size specific. We examined here whether the glomeruli, a peculiar vascular system, express adhesion molecules in a specific manner in the murine kidney. In addition, since serum levels of soluble adhesion molecules have been reported to be elevated in diabetic patients, we examined the influence of diabetes mellitus on the induction of adhesion molecules in the kidney. Analysis of E-selectin mRNA expression by in situ hybridization indicated that it was selectively induced in glomeruli by intravenous administration of interleukin-1beta, while ICAM-1 mRNA expression was seen diffusely in endothelium lining the small arteries and capillaries or in glomeruli, and VCAM-1 mRNA expression was most prominent in endothelial cells of larger blood vessels. Induction of E-selectin mRNA expression in glomeruli by proinflammatory stimuli was augmented in streptozotocin-induced diabetic mice as compared with control mice, while ICAM-1 or VCAM-1 mRNA induction was only slightly influenced. Furthermore, immunohistochemical analysis showed that selective expression of E-selectin in glomeruli was augmented predominantly in epithelial cells, depending on the duration of diabetes mellitus, in KK-Ay mice. These findings suggest that glomerulus-specific expression of E-selectin is related to the development of diabetic nephropathy.

Distribution of stanniocalcin 1 in rat kidney and its regulation by vitamin D3.

Stanniocalcin is a glycoprotein hormone first described in fish as a hypocalcemic factor, and recently its mammalian counterpart has been identified. Localization of stanniocalcin 1 and its regulation of expression were determined in control and 1alpha,25-dihydroxyvitamin D3-treated rats. Immunoreactivity for stanniocalcin 1 was detected in the loop of Henle, macula densa cells, distal convoluted tubule (DCT), and cortical collecting duct (CCD), and also faintly in the medullary collecting ducts. Pre-embedding electron-microscopic immunocytochemistry revealed stanniocalcin 1 in the apical membrane of cells of loop of Henle, DCT, and principal cells of CCD. The expression of stanniocalcin 1 was increased by elevated plasma calcium via 1alpha,25-dihydroxyvitamin D3 treatment. In conclusion, stanniocalcin 1 was expressed in the apical membrane of distal nephron segments and enhanced by vitamin D3.

Reduced albumin reabsorption in the proximal tubule of early-stage diabetic rats.

The aim of this study is to investigate the role of the proximal tubule in microalbuminuria in the early stage of diabetic nephropathy. Diabetes was induced in male Sprague-Dawley rats by an injection of streptozotocin (50 mg/kg, i.v.). After 2 weeks, albumin delivery in the proximal tubule was measured using micropuncture and the endocytosis process of FITC-labeled albumin was evaluated with immunoelectron microscopy. Albumin was significantly reabsorbed in the proximal convoluted tubule (PCT) of controls (0.39+/-0.05 ng/min at early PCT to 0.17+/-0.08 at late PCT, P<0.05), whereas albumin reabsorption was inhibited in diabetic rats (0.27+/-0.05 to 0.21+/-0.08). Immunogold study revealed that FITC-albumin was significantly less reabsorbed in endosomes and lysosomes of S1 segments in diabetic rats than in controls (endosome: 1.20+/-0.10 vs 2.16+/-0.15 microm-1, P<0.0001; lysosome: 0.26+/-0.03 vs 0.83+/-0.07, P<0.0001). The expression of megalin, an endocytosis receptor, was decreased at the apical membrane of PCT in diabetic rats. The lipid peroxidation production in the proximal tubule was significantly increased in diabetic rats. In conclusion, albuminuria in early-stage diabetic rats can be partly explained by a decreased albumin endocytosis with reduced megalin expression and with increased lipid peroxidation in the proximal tubule.