Among HIV-infected patients with renal disease other than HIVAN, viral suppression and the use of antiretroviral therapy are not associated with a beneficial effect on renal function; thus, additional therapeutic strategies may need to be utilized. Because renal histology is associated with prognostic differences, these data provide outcomes information that will improve the clinical utility of renal biopsy among HIV-infected patients with renal disease.
Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.
Kidney disease is an important complication of HIV, particularly in minority populations. We describe the burden of chronic kidney disease among 1239 adults followed at an urban AIDS center, with an estimated prevalence of 15.5% (n = 192). Independent predictors of kidney disease included older age, black race, hepatitis C virus exposure, and lower CD4 cell count. These data suggest that chronic kidney disease remains a common complication of HIV infection in the era of antiretroviral therapy.
The rise in the number of patients with HIV-associated nephropathy and HIV-infection with end-stage renal disease (HIV؉ ESRD) continues to be a substantial concern for the ESRD program. In order to assess the impact of highly active antiretroviral therapy (
Studies were designed to determine the cause of the reduced glomerular filtration rate (GFR) in early cisplatin-induced acute renal failure. Rats were studied 72 h following a single intraperitoneal injection of cisplatin (5 mg/kg) or vehicle (0.9% NaCl). Whole kidney GFR and blood flow were lower in cisplatin-treated animals than in controls (0.30 +/- 0.06 vs. 1.17 +/- 0.06 ml X min-1 X g kidney wt-1 and 5.30 +/- 0.62 vs. 8.25 +/- 0.43 ml X min-1 X g kidney wt-1, respectively; P less than 0.001), as were superficial nephron GFR and stop-flow pressure (20.2 +/- 2.1 vs. 34.5 +/- 2.0 nl X min-1 X g kidney wt-1 and 29.0 +/- 1.9 vs. 39.8 +/- 1.3 mmHg, respectively; P less than 0.001). After volume expansion, renal plasma flow increased in control rats, whereas whole kidney and single nephron GFR did not change. In experimental animals, whole kidney filtration rate rose to 0.58 +/- 0.07 ml X min-1 X g kidney wt-1, single nephron filtration rate increased to 29.9 +/- 3.5 nl X min-1 X g kidney wt-1 (P less than 0.005), and renal plasma flow increased to 5.62 +/- 0.60 ml X min-1 X g kidney wt-1 (P less than 0.05). Intratubular hydrostatic pressure was not different in the two groups before or after volume expansion. The results of these studies show that the reduced GFR in early cisplatin-induced renal failure is due, in part, to reversible changes in renal blood flow and renal vascular resistance.
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