Captopril reduces the proteinuric effect of human growth hormone in adriamycin nephrosis.

Developing male Sprague-Dawley rats (125 g) with adriamycin (doxorubicin hydrochloride) nephrosis (AN) were treated with growth hormone (GH) which may induce hyperfiltration potentiating glomerulosclerosis. Since captopril (CAP) reduces hyperfiltration, we studied its effects in GH-treated rats with AN. After 41, 76, and 90 days of therapy, urine protein excretion was significantly (P<0.05) reduced in GH-treated AN plus CAP compared with AN rats receiving GH alone. After 90 days, urine protein, creatinine ratio was significantly (P<0.05) increased in GH-treated AN (95.2+/-13.9) compared with untreated AN (64.8+/-7.8) and GH-treated AN rats plus CAP (41.8+/-8.8). The mean serum cholesterol level was significantly (P<0.05) reduced in GH-treated AN rats receiving CAP compared with AN rats receiving GH alone and untreated AN controls. Histologically tubular dilation was significantly (P<0.05) reduced in GH-treated AN rats plus CAP compared with AN rats receiving GH alone. Tubular atrophy and scarring were significantly (P<0.05) increased in AN rats treated with GH compared with untreated AN rats, and normalized in GH-treated AN rats plus CAP. We conclude that CAP reduces the proteinuric response of GH in rats with AN and ameliorates tubular injury.

Synergistic effects of fish oil diet and dimethylthiourea in acute adriamycin nephrosis.

The synergistic effects of combining fish oil (FO) diet, which reduces thromboxane A production, with the free radical scavenger, dimethylthiourea (DMTU), were evaluated in acute adriamycin nephrosis, because proteinuria in adriamycin nephrosis is mediated by increased renal thromboxane A and free radical production. The effects of combined evening primrose oil (EPO) and DMTU were compared with the DMTU + FO combination because EPO increases prostaglandin E but not thromboxane A. After 7, 14, and 21 days, proteinuria was significantly (p < 0.05) reduced in rats receiving either DMTU + corn oil (CO) or DMTU + FO compared with untreated control rats. However, after 21 days, rats receiving DMTU + FO had significantly reduced urine protein excretion compared with those receiving DMTU + CO (103.9 +/- 20 mg daily vs 351.8 +/- 29.8 mg daily; P < 0.05). In contrast to FO, rats receiving EPO + DMTU had similar urine protein excretion to rats receiving DMTU + CO after 21 days (170.2 +/- 20.34 mg daily vs 179.45 +/- 26.38 mg daily). The mean serum cholesterol concentration was significantly (P < 0.01) reduced in rats receiving DMTU + FO (195.2 +/- 23.8 mg/dL) compared with DMTU + CO (377.9 +/- 28.5 mg/dL). Serum triglyceride levels also were significantly (P < 0.01) reduced in rats receiving DMTU + FO (52.5 +/- 26.4 mg/dL) compared with DMTU + CO (100.5 +/- 36.9 mg/dL). No significant differences in serum cholesterol concentrations or triglycerides occurred between rats receiving DMTU + CO and DMTU + EPO. Renal glutathione content was significantly (P < 0.05) increased by 23% in normal rats receiving FO diet and by 34% in rats receiving combined DMTU + FO compared with CO alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of tuberculosis in children with idiopathic nephrotic syndrome.

Forty black South African children (mean age 4.7 +/- 2.6 years) with idiopathic nephrotic syndrome due to focal glomerulosclerosis (FSGS) were evaluated. Tuberculosis (TB) was found in 37.5% of children with FSGS (FSGS-TB) compared with 6% of a comparable group with minimal lesion nephrotic syndrome. No significant differences were found in the initial mean serum albumin, cholesterol, triglyceride and creatinine levels in FSGS-TB compared with children with glomerulosclerosis but without TB (FSGS-nonTB). The mean serum levels of C4, IgA and IgM were increased by 30%, 25% and 23%, respectively in children with FSGS-TB compared with FSGS-nonTB. Initial estimated creatinine clearance was similar in the two groups, but after a mean follow-up of 2.4 years, the mean estimated creatinine clearance of children with FSGS-TB was significantly reduced by 46% from the initial value, but remained stable in the FSGS-nonTB group. FSGS-TB children also had significantly increased requirements for renal replacement therapy compared with children with FSGS-nonTB. We conclude that TB infection is commonly associated with FSGS in black South African children; this may have deleterious effects on renal function.

Glomerular injury in end-stage liver disease--role of circulating IgG and IgM immune complexes.

The relationship of IgG- and IgM-bound circulating immune complexes and immune dysfunction to glomerular injury was evaluated in 15 children with end-stage liver disease (ESLD) awaiting liver transplantation. Compared with age-matched controls, children with ESLD had significantly (P < 0.01) increased serum IgG, IgA, and IgM levels, as well as IgG- and IgM-bound circulating immune complexes. Furthermore, they showed a significant (P < 0.05) depression of C3 and C4 levels compared with controls. Hematuria occurred in 66% of children with ESLD, and the urinary protein/creatinine ratio was also significantly (P < 0.01) increased compared with controls (4.65 +/- 2.56 vs. 0.16 +/- 0.04 mg/mg). Light microscopy of renal biopsy tissue obtained from 6 children with ESLD at the time of transplantation demonstrated mesangial proliferation and expansion with basement membrane splitting. This was associated with subendothelial deposits on electron-microscopic examination, compatible with a diagnosis of membranoproliferative glomerulonephritis. By immunofluorescence, deposition of IgG, IgA, and IgM occurred in various combinations with co-deposition of complement fragments. We conclude that membranoproliferative glomerulonephritis is a common finding in children with ESLD, probably due to entrapment of circulating IgG- and IgM-bound immune complexes.

Enhancement of renal and hepatic glutathione metabolism by dimethylthiourea.

Dimethylthiourea (DMTU), a free radical scavenger, was administered to rats to study its effect on renal and hepatic glutathione metabolism, since it is a potential sulfhydryl donor. Six hours following DMTU, renal GSH content was significantly (P < 0.05) increased (10%), and was increased further after 24 h (28%) (P < 0.001). Hepatic GSH content was also significantly (P < 0.001) elevated at 6 and 24 h (5 and 33%, respectively). Seven days of daily DMTU therapy significantly (P < 0.001) increased renal and hepatic GSH content by 36 and 54%, respectively, which was associated with a significant (P < 0.001) increase in the renal activities of glutathione peroxidase (GP) by 38%, glutathione transferase (GT) by 92%, and glutathione reductase (GR) by 19% (P < 0.05). Significantly increased activities of hepatic GP by 84% (P < 0.01) and GT by 101% (P < 0.001) also occurred in DMTU-treated rats after 7 days of continuous therapy. From these data, we conclude that DMTU stimulates renal and hepatic GSH metabolism, which may be important in mediating DMTU's protective effect against free radical-induced tissue injury.

Glutathione monoethyl ester moderates mercuric chloride-induced acute renal failure.

Glutathione (GSH)-dependent reactions are an important cellular defense against ischemic or oxidative injury, although their role in toxin-induced renal cellular injury is less clear. Because of the known sulfhydryl reactivity of mercury (M), we hypothesized that GSH could modify mercuric chloride (MC)-induced acute renal failure (ARF). Therefore, we evaluated the effects of glutathione monoethyl ester (GE), which produces high intrarenal levels of GSH, on the nephrotoxicity of MC. GE treatment in normal rats did not alter their creatinine clearance (CCr), fractional sodium (CNa/CCr) or lysozyme (CLy/CCr) excretion, but histologically resulted in prominent proximal tubular vacuolization. GE pretreatment in rats with MC-induced ARF resulted in partial preservation of their CCr, CNa/CCr and CLy/CCr. Renal histology also demonstrated a reduction in tubular necrosis. M content in the renal cortex 3 following MC was lower in the MC + GE group, but levels were higher in the liver and inner stripe/inner medulla as compared to animals receiving MC alone. No differences were seen in the outer stripe at 3 h or in any of the tissues 24 h following MC injection. Thus, GE moderated MC-induced ARF, likely by providing a large intracellular sulfhydryl pool and thereby reducing M reactivity with endogenous cellular proteins and enzymes.

Role of glutathione metabolism in the reduction of proteinuria by dimethylthiourea in adriamycin nephrosis.

Glutathione (GSH) metabolism, a tissue detoxification pathway, was evaluated in rats with adriamycin nephrosis (AN) treated with dimethylthiourea (DMTU), a free radical scavenger. After 7 days of DMTU, a significant reduction in proteinuria occurred as compared to AN controls (62.4 +/- 13.3 vs. 155.0 +/- 24.0 mg/24 h). A significant increase in renal cortical GSH content as well as glutathione peroxidase (GP) and transferase (GT) activities occurred in DMTU-treated rats as compared to controls. Glutathione monoethyl ester (GME) administration alone reduced proteinuria by 21% in AN, which was not significant despite a large increase in the renal GSH content, however, GP and GT activities were not increased by GME. We conclude that DMTU ameliorates glomerular injury in AN by stimulating GSH metabolism.

Amelioration of glomerular injury in doxorubicin hydrochloride nephrosis by dimethylthiourea.

The hydroxyl radical scavengers dimethylthiourea (DMTU), sodium benzoate, and dimethylsulfoxide (DMSO) were administered to rats before doxorubicin hydrochloride (ADR) (5 mg/kg, IV) to probe the role of free radicals in mediating proteinuria in doxorubicin hydrochloride nephrosis (AN). Because ADR stimulates free radical production, the role of renal glutathione was also evaluated; glutathione metabolism is involved in tissue detoxification processes. DMTU administration to rats with AN caused a significant (p less than 0.01) reduction in their proteinuria after 7 days (52.84 +/- 13.21 mg/24 hours) when they were compared with ADR controls (155.81 +/- 20.16 mg/24 hours). In similar fashion, their urine albumin excretion was also significantly reduced when compared with that of ADR controls (11.13 +/- 2.75 mg/24 hours vs 32.08 +/- 4.14 mg/24 hours; p less than 0.01). DMTU-treated rats also had significantly (p less than 0.001) reduced urinary protein and albumin excretion at 14 days when compared with rats that received ADR alone. The urinary excretion of lysozyme and N-acetyl-glucosaminidase, markers of renal tubular injury, were significantly increased after 7 or 14 days in rats with AN, despite DMTU treatment. Creatinine clearance was significantly reduced (p less than 0.05) in rats receiving ADR alone (0.223 +/- 0.011 ml/min/100 gm) when compared with that in normal controls (0.331 +/- 0.027 ml/min/100 gm) or DMTU-treated rats (0.289 +/- 0.035 ml/min/100 gm). Unlike DMTU, neither sodium benzoate nor DMSO reduced proteinuria in rats with AN.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal tubular protein handling in experimental renal disease.

Competitive inhibition of renal tubular transport occurs between low- and high-molecular-weight proteins following intravenous infusion, but this relationship is less clear following de novo glomerular or renal tubular injury. The present study evaluated renal lysozyme and albumin handling following renal tubular injury induced by both low- and high-dose mercuric chloride (0.5 and 2.0 mg/kg) and maleic acid (50 and 400 mg/kg), and following glomerular injury induced by puromycin aminonucleoside (5 mg/100 g) or Adriamycin (5 mg/kg). Subtle renal tubular injury induced only mild isolated albuminuria, while severe tubular injury caused dramatic lysozymuria and moderate albuminuria. However, increased filtration of albumin in these models of glomerular injury did not inhibit lysozyme transport.

Management of severe hypertension in childhood Takayasu's arteritis.

Six children presented with severe hypertension caused by Takayasu's arteritis (TA), of whom four had bilateral renal artery narrowing and two coarctation syndrome. Two presented with hypertensive encephalopathy and four with congestive cardiac failure. All had a strongly positive skin reactions to purified protein derivative of mycobacterium tuberculosis. Bilateral renal arterial bypass grafts performed in two children resulted in prolonged normalization of their blood pressures, but the grafts clotted 12-18 months later. Primary renal autotransplantation was unsuccessful in two children, one with bilateral renal arterial narrowing and iliac vessel involvement and one with a long coarctation. Secondary renal autotransplantation was successful in a third child with localized aortitis. A successful aortic patch graft was performed in one child with coarctation of the aorta. Angiotensin-converting-enzyme inhibitors should be used with caution in treating the hypertension caused by TA, since bilateral renal arterial narrowing is common and their administration may result in renal insufficiency. The long-term prognosis is guarded in severely hypertensive children with extensive vascular disease due to TA.

The pattern of congenital renal anomalies associated with neural tube defects.

It has been suggested that there may be a consistent pattern of congenital renal abnormalities related to a particular sensory level in patients with spina bifida. In assessing 163 spina bifida patients by reviewing intravenous pyelograms (without knowledge of clinical details) and correlating with the level of sensory loss (without knowledge of radiological findings), the prevalence of renal abnormalities was similar, but a consistent pattern was not confirmed.

Autosomal recessive polycystic kidney disease. Evidence for high frequency of the gene in the Afrikaans-speaking population.

Polycystic kidney disease was investigated in 28 families in which at least one member attended the paediatric nephrology clinic at a Johannesburg or Pretoria hospital. Twenty-five (89.3%) of the families had autosomal recessive polycystic kidney disease (ARPKD), and of these a significantly larger number than would have been expected (92%) were Afrikaans-speaking. There was a consanguineous marriage in the ancestry of 2 patients but 6 of the families (26%) had ancestors with one surname in common and 7 of the families (28%) had their origin in the western Transvaal. A point prevalence for ARPKD of 1:26,000 was estimated for the Afrikaans population (based on the age cohort 0 - 19 years) and the carrier rate for the gene was 1:83; on the basis of the live-birth rate for ARPKD of 1:11,000 the carrier rate is 1:53. These findings suggest that ARPKD may be unusually frequent in the Afrikaans-speaking population. A founder effect is probably responsible.

Autosomal dominant inheritance of small kidneys.

We report herein bilateral small kidneys found in a mother and her two sons. This was associated with slowly progressive chronic renal failure. None of the patients had any of the associated clinical manifestations of recognized syndromes in which there is autosomal dominant inheritance of bilateral small kidneys (e.g., branchio-oto-renal syndrome). Nor did they have the clinical symptoms commonly associated with medullary cystic kidney-juvenile nephronophthisis. However, there were some manifestations that have been reported in familial hypoplastic kidneys with glomerular cysts. Without wanting to claim that this is a "new" syndrome, we are, however, unaware of any reports describing a similar kindred. The importance of this report stems mainly from the fact that a woman with mild to moderate stable chronic renal failure associated with, or caused by, bilateral small dysplastic kidneys gave birth to two sons with the same problem.

Mutations for the autosomal recessive and autosomal dominant forms of polycystic kidney disease are not allelic.

The autosomal dominant form of polycystic kidney disease (ADPKD) has been linked to the alpha-globin gene locus on 16p. Linkage studies between the autosomal recessive type (ARPKD) and the 3' HVR of the alpha-globin gene cluster showed that the ARPKD and ADPKD are not allelic.

Biochemical and serological characteristics of children with membranous nephropathy due to hepatitis B virus infection: correlation with hepatitis B e antigen, hepatitis B DNA and hepatitis D.

Fourteen children with biopsy-proven membranous nephropathy associated with hepatitis B virus (HBV-MN) were evaluated biochemically and serologically and compared to 45 children with idiopathic nephrotic syndrome (INS). The mean ages of the two groups were similar (4.9 +/- 1.6 vs. 4.6 +/- 2.6 years). Serum albumin levels were similar in both groups, but serum cholesterol was significantly reduced in children with HBV-MN compared to INS. Serum C3 was also significantly depressed in children with HBV-MN compared to INS, but no differences in C4 levels were noted. Serum alanine transaminase as well as aspartate transaminase concentrations were significantly elevated in children with HBV-MN compared to those with INS, suggesting the presence of chronic hepatitis in children with HBV-MN. Hepatitis B surface and e antigens were present in serum of all children with HBV-MN, but only 54% had circulating HBV-DNA particles demonstrable in their serum. Serum C3 levels were higher in children with HBV-MN and circulating HBV-DNA, compared to those without circulating HBV-DNA. No other serological or biochemical differences occurred between these two groups. Glomerular deposition of IgG and C3 occurred in 91% of children with HBV-MN; but IgM deposition appeared to occur more frequently and with greater intensity in those children positive for circulating HBV-DNA. Antibody to delta antigen was negative in all children with HBV-MN. We conclude that biochemical and serological differences can be identified between HBV-MN and INS.(ABSTRACT TRUNCATED AT 250 WORDS)

Amelioration of murine lupus nephritis by dimethylsulfoxide.

Dimethylsulfoxide was given to NZB/W F1 female mice from age 10 weeks to see if proteinuria and glomerular injury could be reduced. Twenty mice were randomly assigned to saline or DMSO treatment groups and the following studies were done: urine protein determination, serum concentrations of creatinine, IgG, C3, and albumin; and ANA titers. Kidney tissue were studied by light, immunofluorescent and electron microscopy. DMSO-treated mice had significant reductions in protein excretion at 5 and 6.5 months of age; in urine protein/creatinine ratio at 6.5, 7, and; 7.5 months; in serum C3 at 7.5 months; and in serum creatinine concentration. There were no significant differences among serum IgG, nor among the ANA titers. Histopathologic studies revealed nearly normal kidneys in 5/6 DMSO-treated mice whereas 4/8 controls had severe mixed membranous and membranoproliferative glomerulonephritis. Ultrastructural studies revealed mesangial, subendothelial, and subepithelial deposits and membranous transformation of the glomerular capillary wall. DMSO therefore appears capable of ameliorating glomerular injury in NZB/W F1 mice.

Penicillin resistant pneumococcal peritonitis in nephrotic syndrome.

Two infants with nephrotic syndrome who developed penicillin resistant pneumococcal peritonitis while receiving penicillin chemoprophylaxis are reported and the problems associated with prophylaxis against pneumococcal infection discussed. It is suggested that penicillin prophylaxis may be hazardous in an environment in which penicillin resistant pneumococci are prevalent.

Colchicine reduces proteinuria in passive Heymann nephritis.

Colchicine was given to rats in the heterologous phase of passive Heymann nephritis to see whether this drug could reduce proteinuria. Treatment with 0.06 mg/day for 14 days caused significant reductions in proteinuria and albuminuria. Administration of dimethyl sulfoxide (DMSO) alone or in combination with colchicine also reduced protein and albumin excretion. In a long-term experiment, rats treated with colchicine had significantly less proteinuria. After stopping therapy, urine protein excretion was similar to controls. No differences in glomerular C3 and IgG deposition were found between treated and control rats 24 h, 3,7 and 14 days after immunization. Depressed serum C3 levels were measured at 24 h in colchicine-treated rats. No difference in serum-circulating immune complexes was detected between the two groups. Concurrent administration of indomethacin and colchicine to rats with passive Heymann nephritis (PHN) partially reversed the reduction in proteinuria and albuminuria seen in rats treated with colchicine alone. The G.F.R, however, was significantly reduced in colchicine-treated rats as well as in rats treated with colchicine and indomethacin. Serum cholesterol and triglyceride levels were significantly lower in colchicine-treated rats than in controls. Serum cholesterol concentrations in rats given both colchicine and indomethacin were similar to control values. These findings suggest that colchicine reduces urine protein and albumin excretion, and hyperlipidemia in PHN. The finding that indomethacin partially blocks the effects of colchicine suggests that renal prostaglandin stimulation by colchicine may have been involved in the reduction in proteinuria.

Interactions of dimethyl sulfoxide and nonsteroidal anti-inflammatory agents in passive Heymann's nephritis.

The effect of treatment with indomethacin on the ability of dimethyl sulfoxide (DMSO) to reduce proteinuria in rats with passive Heymann's nephritis (PHN) was studied. PHN rats treated with DMSO alone excreted significantly less protein by day 14 than PHN rats treated with buffer or with indomethacin alone. Rats treated with DMSO excreted 19 +/- 6.0 mg protein/24 hr, and those treated with DMSO and indomethacin excreted 161 +/- 27.4 mg protein/24 hr (P less than 0.001). Rats treated with DMSO alone had significantly higher serum albumin and significantly lower serum cholesterol and triglyceride concentrations than those given the two drugs together. Glomerular deposits of C3 were reduced in DMSO-treated rats, but serum C3 concentrations and rat antirabbit serum antibody titers were similar in the two groups. When a higher dose of indomethacin (5 mg/kg) plus DMSO was used, protein excretion was significantly reduced. Rats treated with DMSO and acetylsalicylic acid (ASA) (37 mg/kg/day) or DMSO and meclofenamate (5 mg/kg/day) did not have a significant reduction in protein excretion compared with untreated controls. High-dosage indomethacin alone did not reduce proteinuria. Low doses of nonsteroidal anti-inflammatory agents therefore appear to block the effect of DMSO on proteinuria. This was in marked contrast to the finding of reduction of proteinuria induced by larger doses of indomethacin (5 mg/kg) plus DMSO. DMSO did not reduce proteinuria in rats with nephrosis induced by puromycin of aminonucleoside.