Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase.

Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase. These chimaeric genes are specific for GRA and explain the biochemistry, physiology and genetics of this form of hypertension. Sites of crossing over range from intron 2 to intron 4. Most mutations have arisen independently from either sister or non-sister chromatid exchange between these genes, which are only 45 kilobases apart. The possibility of a susceptibility allele for GRA of Irish origin is suggested. These findings indicate the utility of a direct genetic test for this disorder.

Serum creatinine, height, and weight do not predict glomerular filtration rate in children with IDDM.

OBJECTIVE: To assess the validity of two equations: K x height/serum creatinine (KL/Cr; K = 0.55 for females 1-18 yr of age and 0.7 for males 12-18 yr of age) and (140 - age) x weight/72 x creatinine (x0.85 for women; Cockroft-Gault) in estimating glomerular filtration rate in children and adolescents with IDDM. RESEARCH DESIGN AND METHODS: From the records of the Children's Hospital Diabetes Clinic, we selected 70 patients with GFR determined by 99mTc-labeled DTPA plasma clearance, stable renal function, and simultaneous measurements of height, weight, blood pressure, HbA1c, and plasma creatinine. We compared DTPA-GFR with estimated GFR from KL/Cr and Cockroft-Gault equations for three groups: all patients, patients with DTPA-GFR < or = 140 ml.min-1 x 1.73 m-2, and patients with DTPA-GFR > 140 ml.min-1 x 1.73 m-2. RESULTS: For all patients, mean values for DTPA-GFR = 147 (95% confidence interval, 139-155), for KL/Cr = 118 (110-125), and for Cockroft-Gault = 84 ml.min-1 x 1.73 m-2 (78-90). For patients with DTPA-GFR < or = 140, DTPA-GFR = 123 (117-128), KL/Cr = 110 (100-119), and Cockroft-Gault = 92 (82-102). For patients with DTPA-GFR > 140, DTPA-GFR = 167 (158-177), KL/Cr = 125 (114-136), and Cockroft-Gault = 77 (71-84). Linear regression analysis showed significant (P < 0.05) relationships for KL/Cr only in patients with DTPA-GFR < or = 140 (r = 0.29), for Cockroft-Gault in all patients (r = -0.46), and for patients with DTPA-GFR < or = 140 (r = -0.31). Determination of a revised K for use in KL/Cr from individual calculations of K (DTPA-GFR x Cr/L) yielded an average value of 0.70 (SD = 0.11). With the use of K = 0.7, the mean KL/Cr value for patients with DTPA-GFR < or = 140 ml.min-1 x 1.73 m-2 was 125 +/- 27 (95% confidence interval, 115-135), compared with a DTPA-GFR value of 123 +/- 14 (95% confidence interval, 117-128). CONCLUSIONS: KL/Cr and Cockroft-Gault do not accurately estimate DTPA plasma clearance. We recommend the use of K equal to 0.70 when estimating GFR in children and adolescents with IDDM and DTPA-GFR < or = 140 using KL/Cr and do not recommend the use of the KL/Cr (for patients with DTPA-GFR > 140) or the Cockroft-Gault equation in this population.

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.

Enalapril and renal injury in spontaneously hypertensive rats.

Rats of the spontaneously hypertensive strain develop kidney damage that resembles the nephropathy seen in some cases of human essential hypertension. Previous studies with a triple drug antihypertensive regimen indicated that proteinuria and glomerular histopathology in spontaneously hypertensive rats might develop despite long-term effective control of systemic blood pressure. To investigate further the relation between hypertension and kidney disease, a group of spontaneously hypertensive rats were treated with enalapril at 15 weeks of age. Blood pressure, protein excretion, and kidney function were measured in those rats at regular intervals during the next year and a half and were compared with untreated spontaneously hypertensive rats and the normotensive Wistar-Kyoto parent strain. Kidney tissue samples from all three groups, collected at autopsy, were stained by immunohistochemical and conventional methods to assess the relative severity and nature of kidney damage. Although enalapril therapy was completely effective in controlling the blood pressure of spontaneously hypertensive rats, it only postponed the onset of kidney disease. Enalapril-treated spontaneously hypertensive rats eventually exhibited albuminuria as severe as that found in hypertensive rats. Kidney vessel pathology was completely prevented with enalapril, but the abnormal accumulation of mononuclear cells in tubulointerstitial and periglomerular sites was the same as in untreated spontaneously hypertensive rats. We have concluded that elevated protein excretion in rats of the spontaneously hypertensive rat strain is not a secondary consequence of systemic hypertension. Structural abnormalities of renal vessels also do not appear to contribute significantly to the pathogenesis of albuminuria in spontaneously hypertensive rats. Other explanations must be sought to account for the close link between spontaneous hypertension and kidney damage in this animal model. The clear dissociation of kidney disease from systemic hypertension exhibited by spontaneously hypertensive rats may also be relevant for human disease.

Decreased urinary excretion of nitric oxide in acute rejection episodes in pediatric renal allograft recipients.

Acute renal allograft rejection continues to have a negative effect on graft survival despite a better understanding of the molecular basis of renal allograft rejection. Nitric oxide (NO) has important biological functions in cell defense and injury and some evidence exists that it may act as an immunomodulator in allograft transplantation. To determine if NO has any role in acute renal allograft rejection in pediatric patients, acute rejection episodes in pediatric renal transplant recipients were evaluated. Four out of eleven patients who received a renal allograft in 1995 at Children's Kidney Center at The Children's Hospital of Buffalo had eight episodes of acute rejection. One patient received a living-related and three received cadaveric grafts. Stable metabolites of NO (NO-2 + NO-3 = NOx) were measured in the serum and urine samples of the patients daily. Serum levels of NO did not change significantly during acute rejection episodes. Urinary NOx levels decreased by 73+/-9% of the baseline values during episodes of acute rejection: mean +/-SE urinary nitric oxide/creatinine ratio (NOx/Cr) of 0.17+/-0.05 at baseline vs. 0.05+/-0.01 during rejection (P=0.02). Successful treatment of acute rejection by administration of high dose i.v. steroids or OKT-3 induced acute rises in the urinary NO levels to baseline values: NO/Cr = 0.17+/-0.04 (mean +/-SE). We conclude that urinary NO excretion decreases significantly during acute renal allograft rejection and that NOx concentration in the urine increases in response to successful antirejection therapy.

Safety of kidney biopsy in pediatric transplantation: a report of the Controlled Clinical Trials in Pediatric Transplantation Trial of Induction Therapy Study Group.

BACKGROUND: Historically, young children undergoing renal transplantation have lower allograft survival than adults, and potential causes of this are being addressed by the North American Pediatric Renal Transplant Cooperative Study through the National Institutes of Health-sponsored study Cooperative Clinical Trials in Pediatric Transplantation. Included in this study is evaluation of surveillance renal biopsies (SB) and clinically indicated biopsies (CB). Few data exist in children to identify the risk involved with renal transplant biopsies. METHODS: Questionnaires were mailed to 21 participating centers asking for descriptions of adverse events associated with kidney biopsies, with choices limited to none, gross hematuria, perinephric hematoma, and other. Further clinical details were obtained from review of medical records of all patients with reported adverse events. Data were collected from 19 centers on 126 patients. RESULTS: Eighty-six patients had undergone 212 biopsies (75 SB and 137 CB). Nine biopsy-related adverse events were reported (4.2%): three SB (4.0%) and six CB (4.4%). Gross hematuria was reported in six patients (2.8%): two SB (2.7%) and four CB (2.9%). A perinephric hematoma was reported in one patient. Two patients with intraperitoneal kidneys developed significant bleeding after biopsy and required transfusions and surgical exploration. No patient lost kidney function or required nephrectomy after biopsy. No difference was noted in adverse events between SB at day 5 or 12 versus CB. CONCLUSION: Evaluation of transplanted kidney tissue may provide important information for the care of the transplantation patient. This analysis suggests that transplanted kidney biopsies can be performed with minimal risks in pediatric patients.

Computed axial tomographic scanning of the thigh: an alternative method of nutritional assessment in pediatrics.

In this study we compared the findings of computed axial tomographic (CT) scanning of the thigh with the findings of arm anthropometry and urinary creatinine determinations to assess nutrition in children with inflammatory bowel disease receiving total parenteral nutrition. All 14 children received our standard solution for total parenteral nutrition as well as prednisone and sulfasalazine (Azulfidine) therapy. All patients were assessed by arm anthropometry, 24-hour urine collections for creatinine clearance, and CT scanning of the thigh during total parenteral nutrition. Arm muscle and fat area were estimated by anthropometry, and those in the thigh were estimated by CT scanning. Our results show the total muscle area from the CT scan can predict muscle mass calculated from the urinary creatinine excretion rates. In addition, there is a close correlation between the thigh muscle area as measured by CT scanning and the muscle area calculated from urinary creatinine excretion rates. In addition, the comparison of thigh muscle area and thigh fat area to the midarm muscle area and midarm fat area, respectively, showed that the thigh is a better predictor of muscle than fat in the midarm. We conclude that the total thigh muscle area is a better predictor of muscle mass as compared to the midarm muscle area. In addition, the CT scan cut at the level of the thigh in children and adolescents with inflammatory bowel disease can provide valuable information about the thigh compartment and analyses of different cross-sectional areas of the thigh.

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.

Renal growth characteristics in children born with multicystic dysplastic kidneys.

OBJECTIVES: To report on the growth characteristics of the affected and contralateral kidneys in children born with multicystic dysplastic kidneys (MCDKs). METHODS: Thirty-three patients were enrolled from 1970 to 1995: 23 were initially managed nonoperatively (mean follow-up 3.39 years), and 10 underwent nephrectomy. Patients underwent radionuclide renal imaging and contrast voiding cystography. Serial ultrasonography was used to obtain measurements of the affected and contralateral kidneys. Blood pressure measurements and serum creatinine levels were available in some patients. RESULTS: Among the 23 nonoperative patients, the affected MCDK involuted in 4 patients during a mean follow-up of 4.5 years at a rate of 1.02 cm/yr (24% annually); 7 kidneys decreased in size at a mean rate of 0.38 cm/yr (5.8% annually); 6 grew at a mean rate of 1.16 cm/yr (9.9% annually); 1 kidney did not change in size; and 5 children were lost to follow-up. The mean size of the contralateral kidneys at birth was 5.3 cm, 2 standard deviations larger than normal. Over time, this relative hypertrophy was maintained at a growth rate of 0.89 cm/yr (18.5% annually). Two patients who had undergone nephrectomy also had serial postoperative ultrasonic renal measurements, and contralateral growth was 0.61 cm/yr (12.16% annually). All but 1 patient had normal blood pressure measurements and serum creatinine levels. CONCLUSIONS: Most MCDKs involute or decrease in size over time, although this may take many years. Contralateral hypertrophy is seen at birth and is maintained during childhood growth, regardless of whether the affected kidney is removed. There is no associated hypertension or malignancy when the dysplastic kidney is left in place.

Urinary tract infections in childhood: definition, pathogenesis, diagnosis, and management.

Urinary tract infections in childhood are defined as significant bacterial growth in urine obtained by bladder catheterization, suprapubic aspiration, or several clean-voided specimens. In infants and young children they may be easily overlooked because of nonspecific symptoms. This leads to an underestimation of their true prevalence. The severity of these infections is a function of the balance between the various host defense mechanisms and the virulence of the microorganism. The assessment of symptomatic infants and children requires a complete radiographic evaluation (renal ultrasound and voiding cystourethrogram), because of the high frequency of anatomic abnormalities, particularly vesicoureteral reflux. The major issues in the management of children with uncomplicated lower urinary tract infections are whether a single dose or short course of therapy is as efficacious as the conventional 7-10 days, and whether asymptomatic bacteriuria requires treatment.

Endogenous creatinine clearance in the rat: strain variation.

The clearance of endogenous creatinine was examined in five strains of rats (Wistar, Wistar Kyoto, Spontaneously Hypertensive Rats, Biobreeding/Worcester diabetic prone and diabetic resistant rats). Creatinine clearance was compared with inulin clearance as the standard. Conditions for clearance measurements were also varied (anesthesia with constant infusion, overnight collection of urine, fed vs. unfed state, single-injection technique). The clearance of creatinine adequately reflects the glomerular filtration rate in three strains (Wistar, Wistar-Kyoto and the Spontaneously Hypertensive Rat). In the two strains of the Biobreeding/Worcester rat creatinine clearance is consistently lower than the inulin clearance. When creatinine clearance is measured from an overnight collection of urine with food withheld it is always lower than when food is present. This clearance should always be validated by comparison with inulin clearance measured simultaneously or under comparable conditions. The ease with which endogenous creatinine clearance can be measured makes it a reasonable method when large numbers of repeated determinations of glomerular filtration rate are required.

Dietary cholesterol supplementation in the spontaneously diabetic rat.

Dietary cholesterol supplementation was used to increase serum cholesterol concentration in diabetic and non-diabetic rats. With the use of numerous dietary formulations, extremely elevated serum cholesterol concentrations and gastrointestinal intolerance were found. We conclude that there are unacceptable side effects with a vast number of exogenous cholesterol supplemented diets which preclude standard and long-term usage.

Renal effects of atrial natriuretic factor in domestic fowl.

The renal hemodynamic and tubular effects of ANF were investigated using the Sperber technique in chickens. This technique takes advantage of the unique portal circulation of the avian kidney and permits direct access to the renal peritubular space independent of renal arterial blood flow and glomerular filtration. Infusion of ANF into the avian renal portal system increased urine flow rate and sodium excretion by as much as 300% and 100%, respectively. These changes occurred in the absence of significant alterations in glomerular filtration rate or renal plasma flow. There was no significant difference in urine flow, sodium excretion or glomerular filtration rate between the ANF-infused kidney and the contralateral, non-infused kidney. We conclude that the diuretic and natriuretic effects of ANF do not depend on changes in glomerular filtration rate and that the site of action of ANF is the renal medulla.

Hematuria in children and adolescents with insulin-dependent diabetes mellitus.

Hematuria is not described as a common finding in diabetic nephropathy, and may suggest nondiabetic renal disease. We reviewed the records of 59 children and adolescents with insulin-dependent diabetes mellitus referred to the Children's Kidney Center from 1983 to 1992. Fifty-two patients had clinical and/or biopsy evidence of diabetic nephropathy; 18/52 (35%) had microscopic hematuria at the time of referral. Patients with hematuria on presentation were referred for: hypertension (61%), proteinuria (61%), and decreased glomerular filtration rate (GFR) (11%). For patients without hematuria on presentation, reasons for referral included hypertension (79%), proteinuria (56%), and decreased GFR (3%). When comparing patients with and without hematuria, those with hematuria had a significantly longer duration of diabetes (12.8 +/- 3.1 versus 10.8 +/- 3.7 years, p < 0.05). The groups did not differ significantly with regard to age (18.3 +/- 1.8 versus 17.1 +/- 2.9 years), height (162.2 +/- 10.4 versus 159.3 +/- 11.3 cm), weight (63.9 +/- 10.9 versus 59.4 +/- 14.8 kg), systolic blood pressure (137.2 +/- 11.9 versus 133.2 +/- 13.2 mm Hg), diastolic blood pressure (85.6 +/- 7.6 versus 83.9 +/- 13.4 mm Hg), serum creatinine (1.0 +/- 0.18 versus 1.0 +/- 0.43 mg/dL), blood urea nitrogen (15 +/- 5 versus 13 +/- 4 mg/dL), glomerular filtration rate (117 +/- 34 versus 117 +/- 46 mL/min/1.73 m2), 24-h urine protein (2311 +/- 3862 versus 570 +/- 476 mg/day), or microalbuminuria (75 +/- 41 versus 34 +/- 35 micrograms/min). We detected a significant association between retinopathy and microscopic hematuria (sensitivity 47%, specificity 82%, p < 0.05), but no association between labstix proteinuria or sex and hematuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of parenteral nutrition on whole body and extremity composition in children and adolescents with active inflammatory bowel disease.

The effect of parenteral nutrition (PN), combined with corticosteroid therapy, on body composition was evaluated in 22 pediatric patients with active and complicated inflammatory bowel disease (IBD). The patients were divided into two groups according to the duration of PN. Group A consisted of 14 patients who received PN for an average of 43 days (short term) whereas eight patients received PN for an average of 104 days (long term); group B. Nutritional assessments were performed before and following the PN periods. In addition, a follow-up assessment was performed 50 days after the cessation of PN for group A. Serial evaluations included; weight, height, disease activity score, arm anthropometry, subscapular skinfold (SSSF) thickness, 24-hr urinary creatinine, and computed tomography (CT) scan of the thigh. Following PN with a glucose-fat mixture used as a nonprotein energy source, there were significant (p less than 0.05) increases in weight, SSSF, and muscle mass (MM) in both groups. Disease activity declined in both groups and height increased in group B and at the follow-up assessment for group A. Considering extremity composition, both groups exhibited increases in midarm muscle area, midarm fat area, thigh muscle area, and thigh fat area. However, a differential distribution of incremental change was observed depending on the duration of PN. Fat deposition predominated in both the upper and lower extremities for group A. Group B patients, however, although showing a predominance of fat accumulation in the upper extremities, gained muscle and fat components equally in the lower extremities.(ABSTRACT TRUNCATED AT 250 WORDS)

A proposed method for the noninvasive evaluation of renal asymmetry in a living-related donor candidate.

This report proposes an adjunctive technique for the evaluation of asymmetry of renal size and function of undetermined etiology, discovered during the assessment of two living-related donor candidates. The method utilizes the observation of renal functional reserve measurement as demonstrated by oral protein loading in patients with normal and diseased kidneys. Renal function was measured as timed Ccr and estimation of differential GFR by technetium-99m diethylenetriaminepentaacetic acid (99mTcDTPA) scintigraphy. A comparison of renal function before and after protein loading in two such patients demonstrated the anticipated increase in GFR. No change in differential GFR as determined by renal scan in one patient was interpreted as supportive evidence for bilaterally normal parenchymal function. Follow-up of both donors shows continued normal renal function.

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.

Fluid needs in acute renal failure.

Derangements of fluid, electrolyte, and acid-base homeostasis are an inevitable part of acute renal failure. Understanding the pathophysiology of these disorders is essential to treating and preventing potentially life-threatening complications. Appropriate nutritional support is also an important part of management in childhood acute renal failure.

Hematuria. An integrated medical and surgical approach.

The need to perform a detailed work-up of microscopic hematuria is based on the following set of questions: Does the history or physical examination findings suggest systemic or renal disease? Is the patient able to acidify and concentrate urine? Is proteinuria present? Do other family members have hematuria or other renal problems? Does the microscopic analysis show casts, crystals, or WBCs? Are the RBCs eumorphic or dysmorphic? Using this scheme of questions, most children do not require laboratory tests or radiographic studies. In the case of gross or macroscopic hematuria, the initial evaluation may require only a urine culture, urine calcium-to-creatinine ratio, and renal and bladder sonography or a very detailed evaluation for renal parenchymal disease, stones, tumors, or anatomic abnormalities. In these instances, consultation with a pediatric nephrologist, urologist, or both is necessary.

Degenerated intramural pericytes ('ghost cells') in the retinal capillaries of diabetic rats.

One of the earliest histopathological signs of diabetic retinopathy is a selective loss of intramural pericytes from retinal capillaries. In the present study, the retinal vessels of rats with streptozotocin-induced diabetes (STZ Wistar) and rats with genetically-induced insulin dependent diabetes mellitus (BB Wistar) and non-insulin dependent diabetes mellitus (SHR/N-corpulent) were examined after 6 to 8 months duration for diabetes-related retinal microangiopathies. The SHR/N-corpulent (cp) rats were fed a 54% sucrose diet, whereas the STZ Wistar and BB Wistar rats were fed laboratory chow for 32 to 36 weeks. In all the diabetic rats, the retinal capillaries in enzyme-digested flat mounts exhibited an increase in periodic-acid-Schiff (PAS) staining and loss of pericytes compared to their respective euglycemic controls. Pericyte "ghosts", like those defined in human diabetes as intramural pockets lacking normal cell contents, were documented by high resolution micrographs in all the diabetic rats. Endothelial cell proliferation, capillary dilation, and varicose loop formation were noted in some of the diabetic rats. Hence, similar capillary lesions were found in very different groups of diabetic rats. The findings suggest that a chronic high tissue concentration of glucose is the underlying factor which triggers pathogenesis in the pericyte. Hyperglycemia-induced activation of endogenous aldose reductase of the polyol pathway is probably the initial insult, but other factors such as advanced glycosylation products may affect the final outcome.