Effect of nitric oxide inhibition on kidney function in experimental renovascular hypertension.

We examined the effect of acute systemic blockade of nitric oxide (NO) synthesis on blood pressure and renal function in rats with angiotensin II dependent two-kidney, one-clip Goldblatt hypertension. Hypertensive animals had significantly higher blood pressures, plasma NO metabolite concentrations and urinary NO metabolite excretion rates than control rats. Intravenous administration of N(G)-nitro-L-arginine methylester (L-NAME) (10 mg/kg) increased mean arterial pressure in both hypertensive and control animals with the magnitude of increase being greater in hypertensive than control rats (32 +/- 3 vs. 20 +/- 2 mmHg, p < 0.05). L-NAME did not affect glomerular filtration rates of normal and clipped kidneys but significantly decreased non-clipped kidney glomerular filtration rate (1.1 +/- 0.1 vs. 0.7 +/- 0.1 ml/min per g kidney wt, p < 0.05). Blood flow to normal and non-clipped kidneys fell in response to L-NAME. Percent reduction in renal blood flow produced by L-NAME was significantly greater in non-clipped than normal kidneys (38 +/- 3 vs. 24 +/- 2%, p < 0.05). In contrast, clipped kidney blood flow increased after L-NAME (3.3 +/- 0.2 vs. 4.0 +/- 0.2 ml/min per g kidney wt, p < 0.05). An identical improvement in clipped kidney blood flow occurred when arterial pressure was raised with aortic constriction indicating that the systemic pressor effect of L-NAME was responsible for this finding. These results indicate that NO plays an important role in systemic and non-clipped kidney hemodynamics in renovascular hypertension. Because NO has little influence on stenotic kidney function, the stimulus for increased NO system activity in this disease appears to be vascular shear stress rather than elevated circulating or intrarenal angiotensin II concentrations.

Oxybutynin does not affect cyclosporin blood levels.

Cyclosporin is an important immunosuppressive medication used to prevent organ rejection. Drug interactions that alter its blood levels can cause serious problems with toxicity or transplant rejection. Current evidence indicates that both cyclosporin and oxybutynin, which is used to treat bladder dysfunction, are metabolized by the cytochrome P450 3A enzyme system, raising the possibility of an adverse interaction between these medications. However, a study of two children receiving cyclosporin with and without oxybutynin revealed no significant changes in trough blood cyclosporin concentrations.

Toxicity of ifosfamide and its metabolite chloroacetaldehyde in cultured renal tubule cells.

Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite chloroacetaldehyde may contribute to this nephrotoxicity. The present study examined the effects of ifosfamide and chloroacetaldehyde on rabbit proximal renal tubule cells in primary culture. The ability of the uroprotectant medication sodium 2-mercaptoethanesulfonate (mesna) to prevent chloroacetaldehyde-induced renal cell injury was also assessed. Chloroacetaldehyde (12.5-150 microM) produced dose-dependent declines in neutral red dye uptake, ATP levels, glutathione content, and cell growth. Coadministration of mesna prevented chloroacetaldehyde toxicity while pretreatment of cells with the glutathione-depleting agent buthionine sulfoximine enhanced the toxicity of chloroacetaldehyde. Ifosfamide (1000-10,000 microM) toxicity was detected only at concentrations of 4000 microM or greater. Analysis of media collected from ifosfamide-treated cell cultures revealed the presence of several ifosfamide metabolites, demonstrating that renal proximal tubule cells are capable of biotransforming this chemotherapeutic agent. This primary renal cell culture system should prove useful in studying the cause and prevention of ifosfamide nephrotoxicity.

Contemporary incidence of morbidity related to vesicoureteral reflux.

OBJECTIVES: The association among vesicoureteral reflux (VUR), renal scarring, and reflux nephropathy is well established. Screening programs for children who present with urinary tract infection (UTI) and their siblings, along with medical and surgical management, have been promoted by pediatric medical and urologic specialists in Buffalo and the surrounding community for more than two decades. Has this comprehensive and costly effort resulted in a decrease in VUR-related morbidity and should it be continued? METHODS: The records of all active patients who presented from 1982 through 1997 to this region's single pediatric nephrology referral center were reviewed. One hundred twenty-two children and adolescents (73 boys, 49 girls) were identified with hypertension (HTN), renal insufficiency (RI), and end-stage renal disease (ESRD) requiring dialysis or transplantation. RESULTS: There were 70 patients (57%) with HTN, 19 (16%) with RI, and 33 (27%) with ESRD. Reflux nephropathy was the underlying cause in 6 patients (5%)-3 with HTN and 3 with ESRD. The etiologies of morbidity in the remaining patients were medical renal disease, 61 (50%); idiopathic, 17 (14%); obstructive uropathy, 14 (11%); primary congenital renal hypoplasia, 12 (10%); and vascular, 12 (10%). Of the 6 patients with VUR-related morbidity, 4 were boys (3 with ESRD, 1 with HTN) and 2 were girls (with HTN). Five children presented in the 1980s and 1 in the 1990s. Only 1 patient had a history of UTI, and she presented early in the series in 1982 at 5 years of age. Ages of presentation were infancy (2 boys), early childhood (1 boy, 1 girl), and adolescence (1 boy, 1 girl). Reasons for presentation were failure to thrive (n = 2), voiding dysfunction without UTI (n = 1), muscle cramps (n = 1), UTI (n = 1), and HTN (n = 1). Reflux grade ranged from I to V, but 4 patients had grade III or less. CONCLUSIONS: Awareness of VUR-related morbidity has led to more widespread diagnosis and treatment, which appears to have resulted in a dramatic decrease in the numbers of affected patients in this community. The diagnosis and treatment of VUR has altered the epidemiology of HTN and renal failure in children and young adults.

High mutation detection rate in the COL4A5 collagen gene in suspected Alport syndrome using PCR and direct DNA sequencing.

Approximately 85% of patients with Alport syndrome (hereditary nephritis) have been estimated to have mutations in the X chromosomal COL4A5 collagen gene; the remaining cases are autosomal with mutations in the COL4A3 or COL4A4 genes located on chromosome 2. In the present work, the promoter sequence and previously unknown intron sequences flanking exons 2 and 37 of COL4A5 were determined. Furthermore, intron sequences flanking the other 49 exons were expanded from 35 to 190 to facilitate mutation analysis of the gene. Using this information, all 51 exons and the promoter region were PCR-amplified and sequenced from DNA of 50 randomly chosen patients with suspected Alport syndrome. Mutations were found in 41 patients, giving a mutation detection rate of 82%. Retrospective analysis of clinical data revealed that two of the cases might be autosomal. Although it could not be determined whether the remaining seven cases (14%) were autosomal or X chromosome-linked, it is likely that some of them were autosomal. It is concluded that PCR amplification and direct DNA sequencing of the promoter and exons is currently the best procedure to detect mutations in COL4A5 in Alport syndrome.

Special topics in pediatric hypertension.

This review emphasizes four major areas of pediatric hypertension. Because hypertension is the most common reason student athletes fail the sports pre-participation examinations, we have attempted to provide a rationale approach to the decision process to permit a hypertensive child to partake in leisure and competitive sports. Without question, obesity is a major reason for referral for hypertension to a pediatric nephrologist. The work-up should be directed to diet control and an exercise program to achieve sustained weight reduction. Hypertension associated with chronic renal failure and renal disease secondary to insulin-dependent diabetes mellitus is a major problem in pediatric and adult nephrology. With adequate control of systemic blood pressure, progressive decline in renal function may be delayed. By understanding these common areas of associated pediatric hypertension, a more systematic approach to the evaluation and treatment can be achieved.

Effect of nitric oxide inhibition on blood pressure and renal function in TGR(mRen2)27 rats.

We examined the effect of acute systemic blockade of nitric oxide synthesis on blood pressure and renal function in the monogenetically hypertensive TGR(mRen2)27 rat strain. Untreated conscious transgenic rats had significantly (p < 0.01) higher systolic blood pressures (185 +/- 9 versus 130 +/- 5 mm Hg) and urinary albumin excretion (32 +/- 5 versus 6 +/- 2 mg/day) than did control animals without evidence of renal insufficiency. Plasma and urinary nitric oxide metabolite levels did not differ between transgenic and control rats. i.v. administration of NG-nitro-L-arginine methyl ester (10 mg/kg) to both groups caused similar elevations in systemic blood pressure (transgenic 25 +/- 3 versus control 24 +/- 3 mm Hg). NG-Nitro-L-arginine methyl ester induced reductions in whole kidney (1.4 +/- 0.2 versus 0.7 +/- 0.1 mL/min), and single nephron (23 +/- 3 versus 11 +/- 2 nL/min) glomerular filtration rates were significantly (p < 0.05) larger in transgenic than in control rats. This greater loss of GFR in transgenic animals was caused by a larger reduction in glomerular ultrafiltration coefficient (1.8 +/- 0.2 versus 1.1 +/- 0.1 nL x min[-1] x mmHg[-1], p < 0.05), a larger increase in afferent arteriole resistance (3.4 +/- 0.2 versus 1.4 +/- 0.1 dyne x s x cm[-5], p < 0.05), and a subsequently smaller rise in glomerular transcapillary pressure (10 +/- 1 versus 5 +/- 1 mmHg, p < 0.05). These results indicate that the renal microvasculature and glomerular hydraulic conductivity or surface area of transgenic rats are more sensitive to nitric oxide inhibition and are consistent with an important role for nitric oxide in TGR(mRen2)27 kidney function.

Screening dipstick urinalysis: a time to change.

OBJECTIVE: This study attempted to determine the minimal cost of screening dipstick urinalyses in a hypothetical cohort of 2000 asymptomatic pediatric patients in a primary care setting. METHODOLOGY: The minimal cost utilizing a private practitioner in an urban or suburban group pediatric setting was calculated. Costs were determined by using current charges for supplies ordered to perform tests in the office, charges for tests performed by a commercial laboratory, and the cost of an initial evaluation by a pediatric nephrologist. Data from published studies were also utilized. RESULTS: Nine percent (179/2000) of patients were calculated to have an initial abnormal urinalysis. Upon retesting only 1.5% (29/2000) of patients were calculated to have a persistent abnormality. The calculated rate of a false positive/transient abnormality for all patients in the hypothetical cohort of 2000 asymptomatic pediatric patients was 84% (150/179). The calculated minimal cost for the outpatient evaluation of 2000 asymptomatic pediatric patients by dipstick urinalyses ranged between $5022 to $6475. The range depends on whether 50% versus 100% of patients with a repeat abnormal dipstick urinalysis were referred to a pediatric nephrologist for further evaluation. The calculated cost was $1290 to initially screen all 2000 patients with a dipstick urinalysis or 65 cents per patient. The calculated cost to evaluate the 29 patients with any persistent abnormality on repeat dipstick urinalysis was $3732 to $5185 or $129 to $179 per patient. This is the calculated cost for a single screening of 2000 asymptomatic pediatric patients. The calculated cost for four multiple screening urinalyses as currently recommended is $20 088 to $25 900. Additionally, these are only minimal initial calculated costs. Costs of any renal imagining or function studies ordered by the pediatric nephrologist or the pediatrician pursuing a further evaluation on his/her own were not included. CONCLUSION: Multiple screening dipstick urinalyses in asymptomatic pediatric patients are costly and should be discontinued. In their place, we propose that a single screening dipstick urinalysis be obtained at school entry age, between 5 and 6 years old, in all asymptomatic children. The sample should be a first morning void.

Enalapril and renal function in hypertensive rats transgenic for mouse renin gene.

We examined the effect of long-term enalapril treatment on renal function and histology in the monogenetically hypertensive TGR(mRen2)27 rat strain. Untreated transgenic rats had significantly (P<.01) higher blood pressures than treated transgenic and control animals throughout the study. Urinary nitric oxide metabolite excretion was significantly lower in young transgenic rats and rose with enalapril, suggesting abnormal TGR nitric oxide production and its correction by enalapril. Converting enzyme inhibition produced preferential preglomerular vasodilatation and increased renal blood flow (6.5 +/- 0.5 versus 9.0 +/- 0.7 mL/min per gram kidney weight, P<.05) without altering whole-kidney and single-nephron glomerular filtration rates in TGR(mRen2)27. Glomerular capillary pressure fell modestly in treated transgenic animals (54 +/- 1 versus 50 +/- 1 mm Hg, P<.05). These hemodynamic changes were associated with reductions in albuminuria (59 +/- 6 versus 9 +/- 2 mg/d, P<.01) and glomerulosclerosis in TGR. However, urinary albumin excretion (15 +/- 3 versus 3 +/- 1 mg/d, P<.05) and glomerulosclerosis also declined in treated control animals in the absence of significant alterations in glomerular hemodynamics. The mechanism of the beneficial effect of enalapril on the TGR(mRen2)27 kidney is unclear but could involve either control of hypertension or suppression of the intrarenal renin-angiotensin system.

Renal clearance of ifosfamide.

Nephrotoxicity is an important clinical side effect of the chemotherapeutic agent ifosfamide. This medication is activated by the hepatic cytochrome P450 system with potentially toxic metabolites produced through both ring hydroxylation and chloroethyl side chain oxidation pathways. Using an isolated perfused rat kidney preparation, we examined the possibility that renal metabolism of ifosfamide also occurs. Renal function before and after addition of ifosfamide to perfusate was not significantly different. After addition of ifosfamike to the perfusate, the metabolites N2-dechloroethylifosfamide, N3-dechloroethylifosfamide, and isophasphoramide mustard were recovered from urine and renal venous effluent. These results provide the first demonstration of ifosfamide metabolism by the kidney and suggest the possibility that intrarenal metabolism may contribute to nephrotoxicity.

Toxic nephropathies.

A variety of medications can adversely affect the kidney. Awareness of these potential nephrotoxic effects is crucial to prevention of serious sequelae. This review discusses renal injury caused by the chemotherapeutic agent ifosfamide, the problem of analgesic nephropathy, and the newly identified complication of trimethoprim-induced hyperkalemia. In addition, recent information about the classic nephrotoxins (cisplatin, amphotericin B, and aminoglycosides) is presented.

Enalapril and pressure-diuresis in hypertensive rats transgenic for mouse renin gene.

The recent development of a transgenic rat strain bearing the mouse ren-2 renin gene [TGR(mRen2)27] has provided a new monogenetic model of hypertension. Other hypertensive rat strains are characterized by a blunted pressure-diuresis-natriuresis response such that higher renal perfusion pressures are required to excrete normal amounts of water and sodium. Dysfunction of the renin-angiotensin and nitric oxide systems may cause in this abnormality. This study examined the effect of enalapril on the pressure-natriuresis response and urinary nitric oxide metabolite excretion in 6-month-old TGR(mRen2)27 rats. The slope of the line relating renal perfusion pressure and urine flow rate in TGR (0.08+/-0.01 microl x min(-1) x g kidney weight(-1) mm Hg[-1]) was significantly lower than that in control rats (0.15+/-0.01 microl x min(-1) x g kidney weight(-1) mm Hg[-1]). Pressure-natriuresis responses were also shifted to higher pressure levels in TGR. Treatment with enalapril for 3 months lowered the mean arterial pressure from 94+/-2 to 84+/-4 mm Hg in control rats and from 146+/-3 to 89+/-3 mm Hg in TGR. The slopes of lines relating renal perfusion pressure and urine flow rate as well as sodium excretion were significantly increased by enalapril in control and transgenic animals. Urinary nitric oxide metabolite excretion rose similarly with increasing renal perfusion pressure in both control and TGR rats and was not affected by enalapril. These results confirm that older TGR rats have a blunted pressure-diuresis-natriuresis response that can be corrected by inhibition of the renin-angiotensin system and suggest that their production of nitric oxide is normal.

Ifosfamide metabolite chloroacetaldehyde causes renal dysfunction in vivo.

Renal injury is a common side-effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite chloroacetaldehyde may be responsible for this nephrotoxicity. The present study examined the effect of increasing amounts of intrarenally infused chloroacetaldehyde on kidney function, glutathione content and malondialdehyde formation. The ability of the uroprotectant medication sodium 2-mercaptoethanesulfonate (mesna) to prevent chloroacetaldehyde-induced renal injury was also assessed. Intrarenal chloroacetaldehyde infusion caused dose-dependent declines in glomerular filtration rate and p-aminohippuric acid clearance and increases in urine flow rate, sodium, glucose and protein excretion. These abnormalities were associated with progressive kidney glutathione depletion and malondialdehyde accumulation. Mesna infusion did not affect renal function but did cause a significant fall in kidney glutathione content. Simultaneous administration of chloroacetaldehyde and mesna only partially corrected renal functional abnormalities and prevented malondialdehyde accumulation but not glutathione depletion. These results show that the ifosfamide metabolite chloroacetaldehyde causes kidney dysfunction, glutathione depletion and lipid peroxidation in vivo. Mesna provides limited protection against chloroacetaldehyde nephrotoxicity, potentially explaining its inability to completely prevent ifosfamide-related renal injury in clinical practice.

Hypertensive encephalopathy and reversible magnetic resonance imaging changes in a renal transplant patient.

An 18-year-old renal transplant patient presented with sudden onset of seizures almost 2 years after she received the graft. Diagnostic work-up was unrevealing except for magnetic resonance imaging abnormalities of the brain that resolved spontaneously 4 weeks later. In this brief report, we discuss the etiology of the seizures and neurological abnormalities in renal transplant patients in light of the findings of our patient.

Prolonged hypocomplementemia in poststreptococcal acute glomerulonephritis.

Complement levels conventionally return to normal in eight weeks in patients with poststreptococcal acute glomerulonephritis (PSAGN). The objective of this study was to determine the significance of prolonged hypocomplementemia (> 8 weeks) in this group of patients. Between April 1993 and January 1995, 20 patients were followed prospectively for a mean of 6 months (range 3-20 months after the episode of PSAGN. Serum C3 concentrations were measured at diagnosis and at regular intervals. Five patients (26%) had prolonged hypocomplementemia. Percutaneous renal biopsies were performed in three patients which revealed findings consistent with the clinical diagnosis of PSAGN. All of these patients showed gradual improvement of their symptoms; some have persistent microscopic hematuria without proteinuria. Kidney function is normal in all despite hypocomplementemia. We conclude that hypocomplementemia (> 8 weeks) with resolving features of acute glomerulonephritis does not exclude the diagnosis of PSAGN, and a renal biopsy may be deferred if there is clinical improvement.

Spectrum of glomerulocystic kidneys: a case report and review of the literature.

An 8-year-old boy developed end-stage renal disease 7 years after the in utero diagnosis of bilateral cystic kidneys. There was no history of cystic renal disease in the family. Initial ultrasonographic screening of the parents failed to reveal cysts in the kidneys. Pathological evaluation of the kidney biopsy findings was consistent with the glomerulocystic kidney disease. He had bilateral nephrectomies in preparation for a living related renal transplant at 7 years of age. At that time, a repeated renal ultrasound examination of the mother showed bilateral cystic kidneys. Pathological evaluation of the nephrectomy specimens confirmed the diagnosis of autosomal dominant polycystic kidney disease. In this report, a discussion of the differential diagnosis of glomerular cysts and the relationship of glomerulocystic kidney disease and autosomal dominant polycystic kidney disease is provided.

Nephrotoxicity of ifosfamide in rats.

Renal proximal tubule cell injury is an important side effect of the chemotherapeutic agent ifosfamide in humans. We investigated the effect of this medication on kidney function in rats. Animals received either 40 or 80 mg kg(-1) ifosfamide intraperitoneally daily for 3 days every 3 weeks for a total of four treatment courses. Ifosfamide-treated rats had significantly lower body weight and hematocrit than sterile water-treated control rats. Animals receiving 40 mg kg(-1) ifosfamide developed isolated phosphaturia after their fourth and final treatment course. Rats receiving 80 mg kg(-1) ifosfamide had low-grade glucosuria, phosphaturia and proteinuria throughout the study. Urine flow rate, creatinine clearance, urinary sodium and potassium excretion and kidney glutathione and malondialdehyde content were not affected by ifosfamide at either dose. These findings indicate that ifosfamide produces abnormalities in rat renal function resembling subclinical Fanconi syndrome.

Single nephron hemodynamics in spontaneously hypertensive rats.

This study was designed to determine whether glomerular hypertension develops as a function of age in the spontaneously hypertensive rat (SHR). Male SHR and age-matched Wistar-Kyoto (WKY) normotensive controls were divided into three groups for measurements of whole kidney and single nephron hemodynamics at 5, 10, and 15 months of age. As reported previously, SHR developed significant proteinuria which was predominantly an albuminuria, after 5 months of age. There were no differences in whole kidney or single nephron glomerular filtration rates between SHR and WKY. Afferent glomerular capillary hydraulic pressure (PGC) was slightly increased in SHR compared with WKY at 10 months of age. At 15 months of age, PGC in SHR was significantly lower than WKY. Our studies indicate that increased capillary pressure is not a major factor in the development and progression of renal injury in the spontaneously hypertensive rat.