Farhad Khalil-Manesh

Experimental model of lead nephropathy. II. Effect of removal from lead exposure and chelation treatment with dimercaptosuccinic acid (DMSA)

Male Sprague-Dawley rats were exposed to high-dose (0.5%) lead acetate for periods ranging from 1 to 9 months; then lead exposure was discontinued, and animals were sacrificed after 12 months. Controls were pair-fed. Two additional groups of low-dose (0.01%) and high-dose (0.5%) rats were exposed to lead for 6 months, then lead was discontinued and the rats were treated with three 5-day courses of 0.5% DMSA (dimercaptosuccinic acid) over the next 6 months. Controls were rats exposed to lead for 6 months, then removed from exposure for 6 months without receiving DMSA. Low-dose lead-treated rats showed no significant pathological changes with or without DMSA treatment, but exhibited a significant increase in GFR after DMSA. High-dose lead-treated animals showed no functional or pathological changes when lead exposure was discontinued after 1 month. However, when duration of exposure was 6 or 9 months, GFR was decreased and serum creatinine and urea nitrogen were increased as compared to controls. Tubulointerstitial disease was severe. Administration of DMSA resulted in an improvement in GFR and a decrease in albuminuria, together with a reduction in size and number of nuclear inclusion bodies in proximal tubules. However, tubulointerstitial scarring was only minimally reduced. It may be concluded that, except for brief initial exposure, discontinuation of high-dose lead exposure fails to reverse lead-induced renal damage. Treatment with the chelator, DMSA, improves renal function but has less effect on pathological alterations. As GFR improved after DMSA treatment in both low-dose and high-dose lead-treated rats, irrespective of the degree of pathological alterations, it may be concluded that the DMSA effect is most likely mediated by hemodynamic changes.

Experimental model of lead nephropathy. III: Continuous low-level lead administration

We sought to determine whether continuous low-level lead exposure (100 ppm lead acetate in drinking water) for periods of 1, 3, 6, 9, or 12 mo would produce adverse effects on kidney function or morphology in rats. Maximum blood lead levels in experimental animals were reached at 3 mo and averaged 29.4 +/- 4.1 micrograms/dl. Glomerular filtration rate, determined by single-injection 125I-iothalamate clearance, was found to be significantly increased above pair-fed controls at 1 and 3 mo, but it was normal at other time periods. Levels of urinary N-acetyl-beta-D-glucosaminidase exceeded levels found in controls at all time periods, except at 12 mo, when the normal increase with aging obscured differences between experimental animals and controls. In contrast, urinary ligandin (glutathione S transferase), a more specific marker of metal-associated proximal tubular injury, was normal at all time periods. Proximal tubular nuclear inclusion bodies were sparse and were observed only at 1 and 3 mo. There were no other pathological alterations in the kidneys, except at 12 mo, at which time mild tubular atrophy and interstitial fibrosis were seen. Therefore, low-level lead exposure in rats produced no significant changes in renal function and produced only mild alterations in renal morphology after 12 mo. The absence of changes in urinary ligandin accorded with the relative absence of morphological changes, whereas the observed increases in urinary N-acetyl-beta-D-glucosaminidase suggest that this enzyme may be an overly sensitive indicator of tubular injury.

Aluminum-Binding Protein in Dialysis Dementia. I. Characterization in Plasma by Gel Chromatography and Electrophoresis

A low molecular weight (approx. 8,000 daltons) protein has been found to be the major aluminum-binding protein in plasma of patients with dialysis dementia. Following treatment with desferrioxamine, the concentration of the low molecular weight protein and its aluminum content rise in parallel. The results suggest that aluminum exposure in dialysis dementia may result in the de novo synthesis of an aluminum-binding protein and that desferrioxamine may release aluminum in conjunction with its binding protein from tissue stores.

Aluminum-binding protein in dialysis dementia. II. Characterization in plasma by ultrafiltration.

Ultrafiltration experiments, using Amicon membranes with molecular weight exclusions of 1,000, 10,000 and 30,000 daltons, have revealed that Desferal, both in vitro and in vivo, markedly increases aluminum ultrafilterability in plasma from patients with dialysis dementia. Ultrafilterability was greater with the 10,000-dalton membrane (60%) as compared with the 1,000-dalton membrane (40%); the difference could be related to the presence of an 8,000-dalton aluminum-binding protein in the 10,000-dalton filtrate. These observations are pertinent to in vivo dialysis studies which have demonstrated enhanced aluminum clearance with high-permeability polyacrylonitrile dialysis membranes.

Na-K-ATPase inhibitor dissociated from hypertension-associated plasma protein

It has been demonstrated that human plasma contains a low molecular weight sodium-potassium-stimulated adenosine triphosphatase (Na-K-ATPase) inhibitor, which can be dissociated from a circulating protein with a molecular weight of approximately 12,000 daltons. The dissociated factor was found to have a molecular weight <500 daltons, and shared many characteristics with ouabain. Similar to ouabain, this factor was found to be a potent inhibitor of both the Na-K-ATPase and potassium-stimulated para-nitrophenyl phosphatase (K-pNPPase) enzyme systems, and to bind to both high- and low-affinity binding sites on Na-K-ATPase, but unlike ouabain did not cross-react with digoxin antibody. The factor was further separated by HPLC and electrochemical detection into two active compounds (p-NKAI-1 and p-NKAI-2). P-NKAI-1 was demonstrated on mass spectroscopy to have a molecular weight of 408 daltons. In a vasoconstrictor assay employing rabbit femoral artery segments, this compound was a direct vasoconstrictor and potentiated the vasoconstriction produced by norepinephrine. It behaved similarly to ouabain in counteracting the relaxing effect on rabbit femoral artery of increasing potassium concentrations in the tissue bath.

Progressively Decreasing Incidence of Membranoproliferative Glomerulonephritis in Spanish Adult Population

Spanish Society of Nephrology, Hospital Ramón y Cajal, Carretera de Colmenar, Km. 9,100, E-28034 Madrid (Spain) Dear Sir, 35η Several recent reports have called attention to the progressively decreasing incidence of membranoproliferative glomerulonephritis (MPGN) in the last decade [1–7]. In order to test this observation, we reviewed 8,545 renal biopsies in adult patients with primary glomerulonephritis (GN) examined at 33 nephrology units in Spain from January 1970 to December 1986. The study was entirely retrospective. The diagnosis was established on the basis of a kidney biopsy studied by light microscopy and immunofluorescence. Patients less than 14 years of age were excluded. MPGN was classified as type I (subendothelial deposits) or type II (dense intram-embranous deposits). A variance analysis was made to test the ‘null hypothesis’, that is to say two variables are independent. A marked reduction in the annual incidence of MPGN, expressed as a percentage of the total number of GN, was observed after 1976 (fig. 1). Thus, we compared the mean annual incidence of the various types of GN during three periods: period I (1970–1976), period II (1977–1981) and period III (1982–1986). As shown in table 1, in spite of the increased total number of patients submitted to biopsy, the incidence of MPGN (26.4,14.7 and 11.9% for the three periods, respectively) was significantly lower for each of the periods when compared with the preceding period (p < 0.001 for periods I vs. II; p < O.Ol for II vs. III). This reduced incidence was observed only in patients with type I MPGN (table 2), whereas the incidence of type II MPGN and its contribution to the total number of patients with primary GN (1.8,1.9 and 2% for the three periods, respectively) did not significatively vary (data from 23 hospitals). In addition, except for idiopathic nephrotic syndrome whose frequency remained unchanged, we observed variations in the incidence of three other primary GN. The incidence of crescentic GN between period I (4.8%) and period III (7.3%; p < O.Ol), membranous nephropathy in period I (8.1%) versus period III (11.6%; p < 0.01) and IgA 30–25–20–15–10–5Year: 1970 -71 -72–73–74–75–76 -77–78–79–80–81 -82–83 -84–85–86 6–7–8-12–15–17–19– 23–27–27–32–33–33–33–33–33–33 Number of hospitals Fig. 1. Annual incidence of MPGN in the Spanish adult population expressed as the percentage of the total number of GN throughout the 17-year study period. nephropathy (10.9, 19.9 and 22.3% for the three periods, respectively, p < 0.01) was found to increase significantly with time (table 1). The incidence of crescentic GN in period III was similar to that of the Milan study [4] and the increased frequency has also been previously reported [3].