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.

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.

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.

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.

Ifosfamide metabolite chloroacetaldehyde causes Fanconi syndrome in the perfused rat kidney.

Renal proximal tubule dysfunction has been reported in patients treated with the chemotherapeutic agent ifosfamide. The present study investigated whether ifosfamide or its metabolites acrolein and chloroacetaldehyde would impair function in the isolated perfused rat kidney. Renal function was monitored before and after these chemicals were added to a modified Krebs-Ringer-bicarbonate perfusion medium containing 6.6 g/dl albumin and a mixture of substrates. No functional changes were observed when ifosfamide (470 microM) or acrolein (470 microM) was added to the perfusate. Addition of chloroacetaldehyde (210 microM) resulted in significant decreases in the fractional reabsorption of sodium (from 92 to 32%), glucose (from 97 to 46%), inorganic phosphate (from 88 to 22%), and inorganic sulfate (from 94 to 86%). There were no changes in glomerular filtration rate. PAH clearance also significantly decreased from 4.1 to 0.7 ml/min per gram of kidney weight, indicating impairment of proximal tubule organic acid secretion. This impairment was associated with a significant decline in the extraction ratio for PAH, suggesting abnormal PAH uptake at the basolateral membrane. These results show that chloroacetaldehyde causes generalized renal proximal tubule dysfunction and that it may be the ifosfamide metabolite responsible for nephrotoxic side effects.

Renal function in hypertensive rats transgenic for mouse renin gene.

The recent development of a transgenic rat strain carrying the mouse ren-2 renin gene [TGR(mRen2)27] has provided a new model of hypertension characterized by suppressed plasma renin levels and marked hyperproreninemia. In this long-term study, we examined the kidney function of these animals. Transgenic rats had significantly (P < 0.01) higher blood pressures than control animals at 2, 4, and 8 mo of age. However, the severity of their hypertension diminished over time (225 +/- 8 mmHg at age 2 mo vs. 169 +/- 5 mmHg at age 8 mo, P < 0.001), indicating age-dependent transgene regulation. Whole kidney and single-nephron blood flows and glomerular filtration rates did not differ between control and TGR(mRen2)27 animals studied with micropuncture techniques at 4 and 8 mo of age. Preglomerular vasoconstriction was responsible for this normal autoregulatory response. Elevated preglomerular vascular resistance of transgenic rats prevented transmission of systemic hypertension to glomeruli at 4 but not 8 mo of age leading to increased glomerular capillary pressures in these older animals (53 +/- 1 vs. 48 +/- 1 mmHg, P < 0.05). Pathological albuminuria appeared as early as 2 mo of age but did not increase over the subsequent 6 mo of follow-up. The incidence of glomerulosclerosis, assessed at 4 and 8 mo of age, was greater in TGR(mRen2)27 than control animals (6.6 +/- 1.4% vs. 0.9 +/- 0.3%, P = 0.01) but did not differ between 4- and 8-mo-old transgenic rats. Glomerular ultrafiltration coefficients were significantly elevated (P < 0.05) in transgenic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic value of sonography in childhood nephrotic syndrome.

This retrospective case review of 43 children with primary nephrotic syndrome was designed to evaluate the relationship among renal ultrasound findings at presentation, subsequent corticosteroid responsiveness and histological diagnoses. Fifty-one percent of patients had abnormal sonograms; nephromegaly was present in 42% and increased renal echogenicity in 35%. There was no relationship between nephromegaly and either response to corticosteroids or specific glomerular lesions causing nephrosis. Although the presence of echogenic kidneys did not denote a particular type of renal disease, it was significantly more frequent in corticosteroid-resistant than in corticosteroid-responsive patients (62% vs. 18%, P < 0.05). We conclude that increased renal echogenicity at time of presentation is a possible indicator of corticosteroid resistance in children with primary nephrotic syndrome.

Type III posterior urethral valves: presentation and management.

The clinical and radiographic presentation of infants with type III posterior urethral valves help to distinguish them from patients with the more common type I valves. The diaphragmatic valvular obstruction may make catheterization impossible. Percutaneous cystography can confirm the diagnosis and allow for short-term decompression. The presence of smooth-walled bladders with narrow posterior urethras is unique to type III valves but is not always present. Type III valves present within a spectrum of clinical severity; however, the majority involve significant renal impairment. The prognosis for survival and renal function appears poorer for patients with type III valves than for those with type I valves.