Effect of Ramipril on Urinary Protein Excretion in Maintenance Renal Transplant Patients Converted to Sirolimus.

This prospective, randomized, double-blind, placebo-controlled study evaluated the effects of ramipril on urinary protein excretion in renal transplant patients treated with sirolimus following conversion from a calcineurin inhibitor. Patients received ramipril or placebo for up to 6 weeks before conversion and 52 weeks thereafter. Doses were increased if patients developed proteinuria (urinary protein/creatinine ratio ≥0.5); losartan was given as rescue therapy for persistent proteinuria. The primary end point was time to losartan initiation. Of 295 patients randomized, 264 met the criteria for sirolimus conversion (ramipril, 138; placebo, 126). At 52 weeks, the cumulative rate of losartan initiation was significantly lower with ramipril (6.2%) versus placebo (23.2%) (p < 0.001). No significant differences were observed between ramipril and placebo for change in glomerular filtration rate from baseline (p = 0.148) or in the number of patients with biopsy-confirmed acute rejection (13 vs. 5, respectively; p = 0.073). One patient in the placebo group died due to cerebrovascular accident. Treatment-emergent adverse events were consistent with the known safety profile of sirolimus and were not potentiated by ramipril co-administration. Ramipril was effective in reducing the incidence of proteinuria for up to 1 year following conversion to sirolimus in maintenance renal transplant patients.

Interaction between tacrolimus and chloramphenicol in a renal transplant recipient.

BACKGROUND: The metabolism of tacrolimus is influenced by several medications when they are given concurrently. We report the interaction between tacrolimus and chloramphenicol in a renal transplant recipient. METHODS: An adolescent with vancomycin-resistant Enterococcus was given standard doses of chloramphenicol. Tacrolimus trough levels increased, and the dose was adjusted to maintain the target trough level. Pharmacokinetic studies were obtained during chloramphenicol administration and 14 days after its discontinuation. RESULTS: Toxic levels of tacrolimus were seen on the second day of chloramphenicol administration, requiring an 83% reduction in the tacrolimus dose. The dose-adjusted area under the curve value for tacrolimus was 7.5-fold greater while the patient was on chloramphenicol. These data are consistent with inhibition of tacrolimus clearance by chloramphenicol CONCLUSIONS: Chloramphenicol interferes with tacrolimus metabolism. Careful monitoring of tacrolimus trough levels during concomitant chloramphenicol therapy is recommended to avoid toxicity.

Effect of recipient's race on pediatric renal allograft survival: a single-center study.

One hundred twenty-seven children (83 males, 44 females, 86 white, 41 nonwhite; mean age 12.1 years) who received 160 renal transplants between 1980 and 1989 were retrospectively studied. Variables such as age, sex, primary diagnosis, type, HLA-DR mismatching, and repeated transplants were compared between races and found not to be significant. However, HLA-A and -B cadaveric-graft mismatching, which was equivalent between whites and nonwhites prior to 1985 (pre-cyclosporine A era), has significantly favored whites (49% with 0 to 2 HLA-A and -B mismatch vs 16% in nonwhites) since 1985 (P less than .05), and a significantly higher proportion of nonwhite patients (59%) were receiving medical assistance (P less than .0001). Graft survival was evaluated with significantly poorer results in nonwhites as compared to whites (P less than .05). Although no difference was found between white and nonwhite cadaveric-graft survival before 1985, nonwhites had significantly worse graft survival since 1985 (72% vs 59% for 1 year and 61% vs 24% for 3 years in whites and nonwhites, respectively; P less than .05). Subpopulations such as nonwhite adolescents, nonwhite females, nonwhites with repeated transplants, and all low socioeconomic patients were identified as high-risk children with poor long-term survival. It is concluded that secondary to poorer matching since 1985 there has been decreased graft survival in nonwhites despite cyclosporine A. Attempts to improve matching and attention to high-risk groups are needed for equivalent survival.

Effectiveness of treatments for nocturnal enuresis in a heterogeneous population.

The objective of this study was to determine the effectiveness of various treatments for nocturnal enuresis in a large, diverse population of children. A retrospective cohort review of patients with nocturnal enuresis was undertaken. All patients selected treatment after a single visit that included a history, examination, and demonstration of treatments. Families were contacted 1 year later to determine what treatment they chose and whether their child still wet. Families primarily chose an alarm (31%), followed by desmopressin acetate (22%) and oxybutynin (9%). Some preferred no treatment (23%). Fifty-six percent of patients using the alarm were completely dry compared to 18% using desmopressin acetate (p<0.0001), 16% using oxybutynin, and 28% receiving no treatment. In a heterogeneous population 1 year after a single visit, children whose parents chose the nocturnal enuresis alarm were most likely to be completely dry.

Identification and management of urinary tract infection in the preschool child.

Urinary tract infections commonly occur in preschool children and can be associated with significant morbidity if they are not identified quickly and treated appropriately. Vesicoureteral reflux is found in a larger proportion of these patients. Recognizing and treating risk factors such as dysfunctional voiding may aid in the resolution of vesicoureteral reflux and reduce the recurrence of urinary tract infections.

Vesicoureteral reflux and reflux nephropathy in children.

Vesicoureteral reflux is seen in up to one half of all children with urinary tract infections and reflux nephropathy is potentially the leading reversible cause of end-stage renal disease in children and adults. Recent studies still leave some doubt to the pathogenesis of reflux nephropathy. In 1992, the International Reflux Study in Children published data on the 5-year follow-up of children with high-grade reflux showing no clear advantage toward either surgical or medical management (although new surgical techniques may prove beneficial). A need to identify children with dysfunctional voiding exists. Appropriate, preferably noninvasive, studies should be employed to identify children at risk including those with antenatally diagnosed hydronephrosis and siblings of children with documented reflux.

Rhabdomyolysis and acute renal failure in a child with influenza A infection.

A 13-year-old previously healthy girl developed rhabdomyolysis and acute renal failure during influenza A infection. The patient recovered renal function completely with supportive therapy. This complication has been described in adult patients, but progression to acute renal failure in this context has not been reported previously in children. This diagnosis should be considered in the differential diagnosis of a pediatric patient presenting with acute renal failure and viral symptomatology.

Management of patients with hemolytic uremic syndrome demonstrating severe azotemia but not anuria.

There are no specific indications for dialysis in a patient with typical hemolytic uremic syndrome (D + HUS) who does not have anuria, hyperkalemia, volume overload, or severe acidemia. We managed five patients with D + HUS, aged 1.5-14 years, without dialysis despite marked azotemia, because they were not anuric and because they had none of the acid-base, fluid, or electrolyte perturbations that may have been indications for dialysis. Each had markedly elevated blood urea nitrogen (range 137-234 mg/dl) and serum creatinine concentrations (range 5.4-15.4 mg/dl). None was anuric and one was oliguric for 4 days. There were no complications and each recovered. We have reviewed the published literature on the use of dialysis in patients with D + HUS and have not found any guidelines that relate to the management of similar cases. It is our view that management of D + HUS patients without dialysis is appropriate when the patient is passing urine and the acid-base, serum electrolyte concentrations and fluid balances can be managed without dialysis.

Increased prevalence of urinary symptoms and voiding dysfunction in Williams syndrome.

Thirteen of 41 patients (32%) with Williams syndrome in a multidisciplinary clinic were noted to have genitourinary symptoms. The predominant features were increased urinary frequency and daytime wetting. Four patients had bladder diverticula and uninhibited detrusor contractions as demonstrated on urodynamic studies. We speculate that there may be an association between increased detrusor pressure, an abnormal bladder matrix, and the presence of diverticula. Early detection of urinary dysfunction through clinical symptoms and appropriate urodynamic studies, with institution of bladder training and anticholinergic medication can improve the patients' voiding patterns, both medically and socially.

An analysis of the approach to management of childhood nephrotic syndrome by pediatric nephrologists.

The value of a renal biopsy for a child with frequently relapsing corticosteroid-responsive or corticosteroid-dependent nephrotic syndrome is unresolved. This was the subject of two independent surveys done by North American pediatric nephrologists. In one study, 59% of the respondents indicated that they would nearly always perform a biopsy prior to starting cytotoxic therapy, while 23% would do so rarely. Less experienced pediatric nephrologists were more inclined to recommend a biopsy (P < 0.05). The indications for a renal biopsy were to provide prognostic information and to make decisions concerning further therapy. In the second survey, 33% of pediatric nephrologists said they would perform a renal biopsy in children with frequent relapses, while 91% would recommend a biopsy in children with corticosteroid resistance (P < 0.001). Once a biopsy was performed, therapy was based on the histopathologic findings regardless of the previous clinical response to corticosteroids. At this time, there is no standard approach to the evaluation and management of children with frequently relapsing, corticosteroid-dependent nephrotic syndrome. Some physicians rely on their clinical acumen, whereas others depend on the histopathologic findings.

Behavioral characteristics of children with daytime wetting.

PURPOSE: We hypothesized in this descriptive investigation that children with daytime wetting demonstrate unique emotional/behavioral patterns, independent of gender and age, compared to children with nocturnal wetting. MATERIALS AND METHODS: Two groups of children 5 to 17 years old with day wetting and urinary tract infections in the absence of organic etiology were recruited for study. There were 488 children in group 1 and 418 in group 2. Group 1 was given a short set of behavioral questions and group 2 was evaluated for behavioral characteristics with a revised and longer set of questions. Also in group 2 children with nocturnal wetting only were recruited as a comparison group. A subgroup of 58 children was randomly selected from group 2 and administered 2 standardized questionnaires. RESULTS: Children with day wetting and urinary tract infection had a significantly higher rate of constipation (35%) than those with day wetting and no infection (25%, p <0.02). Parents of group 1 children reported the level of frustration and anger to be similar whether the children had urinary tract infection or not. Parents also reported that only 3.8% of children had significant learning or school problems. Parents of group 2 did not report any differences between nighttime and daytime wetting with respect to positive outlook, organizational skills or willingness to talk. Differences were noted, with daytime wetters perceived as more stubborn (p <0.0001), secretive (p <0.0001), refusing to follow parental requests (p <0.002) and constipation (p <0.0003). Of the subsample group the incidence of verified attention deficit/hyperactivity disorder was highest in children with daytime wetting and no infection (21%), and nighttime wetting (22%) compared to 0% in daytime wetting and infection. The Child Behavioral Checklist results on this sample suggested that 35% of the children with daytime wetting and no infection earned significant T scores of mixed or externalizing symptoms, while the nocturnal enuresis group demonstrated 16% significant T scores, primarily externalizing. All females with the daytime wetting and infection showed significant T scores within the internalizing domain. The Child Behavioral Checklist defines externalizing behaviors as aggressive and acting out behaviors, while internalizing behaviors include withdrawn and anxious/depressed behaviors. Mixed behaviors on this questionnaire include social, attention and thought problems. CONCLUSIONS: These data suggest that a minority of children with daytime wetting and infection tend to show an internalizing style of problems (11%) and constipation, while those with daytime wetting and no infection show a more mixed style of psychological problem (35%). In contrast, the nighttime wetting group tends to show externalizing problems (16%). Based on a subsample of the data children with daytime wetting and no infection, and nighttime wetting showed a significantly incidence of verified attention deficit/hyperactivity disorder compared to the general population. According to parent perceptions, stubbornness and secretiveness seem to describe a style that the children with daytime wetting exhibit that is not present in those with nighttime wetting. There is a possible role of uncontrol and over control psychological styles to the development and treatment of daytime wetting as well as the relationship of these styles to treatment outcome. Further research is needed to clarify the psychological style of children with daytime wetting to customized treatment protocols.

The efficacy and safety of oral desmopressin in children with primary nocturnal enuresis.

PURPOSE: We confirmed findings that oral desmopressin safely decreases the number of wet nights in children with enuresis and identified doses at which acceptable responses can be obtained. MATERIALS AND METHODS: We evaluated the safety and efficacy of oral desmopressin in a double-blind, placebo controlled, parallel group, randomized, multicenter trial of 193 children 6 to 16 years old with documented primary nocturnal enuresis. The study was conducted in 2 phases: 1) a 2-week dose ranging phase in which children received desmopressin (0.2, 0.4 or 0.6 mg.) or placebo at bedtime and 2) an 8-week dose titration phase that followed a 2-week placebo washout. Patients received 0.2 mg. desmopressin or placebo for the first 2 weeks and then the dose was increased in 0.2 mg. increments at 2-week intervals until the patient was completely dry or was receiving 0.6 mg. Patients were instructed to limit fluid intake. Mean decrease from baseline in the number of wet nights, percentage of responding patients and safety were assessed at 2-week intervals. RESULTS: There was a statistically significant linear response to oral desmopressin at doses from 0.2 to 0.6 mg. during the dose ranging phase (p < or =0.05). The decrease in wet nights after 2 weeks of treatment with desmopressin was 27%, 30% and 40% at 0.2, 0.4 and 0.6 mg. doses, respectively, compared to 10% with placebo. All doses were statistically significantly different from placebo (p < or =0.05). During the dose titration phase all placebo treated and 87% of desmopressin treated patients were receiving the maximum dose of 3 tablets nightly because they had not been completely dry in the previous 2 weeks. Nevertheless, 44% of desmopressin treated patients had achieved at least a 50% reduction from baseline in the number of wet nights per 2 weeks at the lower doses of 0.2 and 0.4 mg. Most adverse events (rhinitis, pharyngitis, headache and increased cough) were mild to moderate in severity, unrelated to treatment and resolved before the study was completed. CONCLUSIONS: Oral desmopressin administered at bedtime to children with primary nocturnal enuresis was significantly better than placebo for decreasing episodes of bed-wetting (p <0.05). A linear dose-response relationship was observed (p <0.05). An acceptable response to treatment (50% or greater reduction from baseline in wet nights per 2 weeks) was seen at all doses of desmopressin. Oral desmopressin, up to 0.6 mg. for 8 weeks, was well tolerated.

Response to measles-mumps-rubella vaccine in children on dialysis.

Ten children receiving maintenance dialysis were immunized with the standard dose of measles-mumps-rubella vaccine between 15 and 33 months of age. Immune responses to vaccination were determined using commercially available enzyme-linked immunosorbent assays for measles, mumps, and rubella viruses. Eight children responded to measles vaccine, 5 to mumps vaccine, 8 to rubella vaccine, and only 3 children to all three vaccines, compared with a seroconversion rate of over 90% to all three vaccines in healthy children (P less than 0.0001). We contend that the relatively poor immunocompetence of our dialysis patients explains their less than optimal vaccine response and suggest that children vaccinated while undergoing dialysis be tested to confirm serological evidence of immunity.

Predicting the response to cytotoxic therapy for childhood nephrotic syndrome: superiority of response to corticosteroid therapy over histopathologic patterns.

To determine the utility of steroid response in classifying childhood nephrotic syndrome, we reviewed 119 biopsies in 92 children aged 1 to 16 years who had been followed for a mean of 7.2 years. Steroid responses were classified as steroid resistant, steroid dependent, and frequent relapser as defined by the International Study of Kidney Disease in Children. Biopsy specimens were classified as showing focal glomerulosclerosis (FSGS) in 39 children, as showing lipoid nephrosis in 28, and as questionable in another 25 with either focal global sclerosis, IgM nephropathy, or mesangial prominence and tubular changes. A strong agreement (p less than 0.01) was found between children whose FSGS was steroid resistant and children whose lipoid nephrosis resulted in frequent relapses. The length of the remission after therapy with chlorambucil or cyclophosphamide was determined in 84 children. A significantly shorter length of remission after cytotoxic drug therapy (p less than 0.05) was identified for patients with FSGS versus those with lipoid nephrosis; this difference became more significant for steroid-resistant patients in comparison with those who were steroid dependent or were frequent relapsers (p less than 0.005). Among all steroid-resistant patients, those with FSGS had shorter remissions than patients with other histologic changes (p less than 0.001). The data suggest that patterns of response to corticosteroid therapy correlate with the histologic abnormality. Thus steroid-sensitive patients need not undergo renal biopsy before receiving cytotoxic drugs. Steroid-resistant patients would benefit from a biopsy, because the findings tend to predict the outcome.

Comprehensive management of dysfunctional voiding.

OBJECTIVE: Dysfunctional voiding is a major problem leading to daytime-wetting and recurrent urinary tract infection (UTI). Our center is devoted to treating children with dysfunctional voiding. We offer a multidisciplinary approach with a pediatric nephrologist, nurse practitioners, and a psychologist. This article is the first to describe the efficacy of this approach on a large population of American children. PATIENTS: Between 1992 and 1995, 366 children with symptoms of voiding dysfunction were referred for urodynamic studies. Criteria were based on the child's age, symptoms, and failure to respond to empirical therapy. Females made up 77% of the population, and the mean age at referral was 8.5 years (range, 4 to 18 years). Day-wetting occurred in 312 (89%), night-wetting in 278 (79%), recurrent UTI in 218 (60%), and vesicoureteral reflux (VUR) in 48 (20%) of those undergoing voiding cystourethrography. RESULTS: A minimum of 6 months' follow-up data (mean, 22 months) is available on 280 children (77% studied). Urge syndrome was the predominant urodynamic finding in 52%, followed by bladder sphincter dysfunction in 25%. Treatment consisted of antibiotic prophylaxis (59%), anticholinergic medication (49%), biofeedback (25%), and psychological counseling (15%). Of the 222 children with daytime-wetting (45%), 100 are cured (off all medication, no wetting) and 82 (37%) are improved (on medication or >50% reduction in symptoms). Improvement or cure was seen in 69% of children with night-wetting. Of the 199 children with UTI, 127 (64%) never developed another infection. Vesicoureteral reflux resolved in 16 of 30 (53%) children undergoing repeat voiding cystourethrography. CONCLUSION: Our comprehensive approach demonstrates a favorable outcome that promises to reduce the medical and psychological morbidity seen in patients with voiding dysfunction.

Biofeedback methodology: does it matter how we teach children how to relax the pelvic floor during voiding?

PURPOSE: Biofeedback is a noninvasive treatment that has been documented to be helpful for children with daytime wetting and/or urinary tract infection secondary to voiding dysfunction. We wish to determine the effectiveness of biofeedback in a large population of children presenting with voiding dysfunction, and evaluate differences between 2 different methods with regard to resolution of symptoms, improvement of objective measurements and patient satisfaction. MATERIALS AND METHODS: The charts of 102 consecutive patients treated with biofeedback were reviewed. Of the patients 21 were asked to void 4 to 8 times in 6 hours seated in front of a uroflow device while receiving coaching by a staff member (method 1), 56 were taught pelvic floor relaxation techniques in front of a computer monitor that displayed electromyogram readings for 45 to 90 minutes (method 2), and both methods were used in 25. Outcome variables were obtained through chart review and telephone contact, and included resolution of symptoms, elimination of urinary tract infection, character of voiding curve, post-void residual, decrease in relaxation score and parental satisfaction. RESULTS: Females comprised 79% of the population and median age at first treatment was 7.7 years (range 4.3 to 15.4 y). Daytime wetting was seen in 84% and recurrent urinary tract infection in 66% of patients. Among children with daytime wetting there was 100% success or improvement with method 1, 91% with method 2 and 80% with both methods (p not significant). Among those with urinary tract infection, 25% had subsequent infection with method 1, 25% with method 2 and 31% with both methods (p not significant). Normalization of the flow curve was seen in 94% with method 1, 67% with method 2 and 30% with both methods. Patients using both methods had a significantly greater post-void residual compared to patients using method 1 (0 versus 33%, p = 0.003). Relaxation scores decreased a median of 6.5% in with method 2 and 20% with both methods. After a median followup of 1.8 years 98% of parents expressed satisfaction with biofeedback with more than 80% indicating a high degree of satisfaction. CONCLUSIONS: Reduction of daytime wetting and urinary tract infection can be achieved regardless of the type of biofeedback used. Although symptoms improved, patients using a shorter but more intensive approach aimed at teaching control of the pelvic floor musculature were more likely to demonstrate persistent post-void residuals and abnormal flow curves. A considerable degree of enthusiasm was reported using both of these non-invasive forms of treatment.

Adverse neurologic events associated with rebound hypertension after using short-acting nifedipine in childhood hypertension.

INTRODUCTION: Short-acting nifedipine (SA-NIF) is widely prescribed for acute hypertension (HTN) in children despite reports of ischemic complications in adults. We describe two children with neurologic events caused by rebound hypertension following SA-NIF use. CASES: Patient 1 is a 7-year-old with acute nephritis and blood pressure (BP) of 185/130. She received SA-NIF which decreased BP to 114/79. When BP rebounded to 160/103, she developed severe cortical visual impairment. Head CT demonstrated edema and petechial hemorrhages in the watershed region. Patient 2 is a 10-year-old renal transplant recipient who received SA-NIF for a BP of 155/98, which resulted in a prompt decrease to 114/74. Two hours later he developed aphasia and right-sided neglect. His BP increased to 168/88 and he developed partial complex seizures. Brain MRI showed high signal intensity in the watershed areas with early gadolinium enhancement. DISCUSSION: The temporal association of the neurologic events with the rebound increase in BP suggests a possible role for the SA-NIF, consistent with its pharmacokinetic profile. Although the adult literature has focused on the unpredictable decline in BP after SA-NIF treatment, these cases suggest that rapid increases in BP following the maximal SA-NIF effect may be associated with impaired cerebral autoregulation and encephalopathy in children. These cases underscore the need for frequent blood pressure determinations and therapy to prevent rebound hypertension.

The long-term outcome of posterior urethral valves treated with primary valve ablation and observation.

PURPOSE: We believe that primary valve ablation with observation is the preferred management for posterior urethral valves. However, debate continues as to the role of high diversion. We examined the long-term outcome of a large series of patients treated with primary valve ablation, and compared it to the outcome of high diversion and vesicostomy. MATERIALS AND METHODS: We reviewed the records of 100 patients treated with primary valve ablation (74%), vesicostomy (13%) or high diversion (9%) before 1985. Median followup was 11.2 years. RESULTS: Overall 13% of our patients had end stage renal disease by age 15 years. Three patients initially treated with valve ablation and 3 initially treated with vesicostomy later underwent high diversion but none benefited from the secondary procedure. Four patients initially treated with valve ablation subsequently underwent vesicostomy but only 1 benefited. Bladder storage capacity was well preserved. Diurnal urinary continence developed in 46% of patients at age 10 years and only 1 remained incontinent after age 20 years. One patient with diversion who awaits transplantation had a small contracted bladder. Recent urodynamic studies in 10 cases of delayed urinary continence have not shown decreased bladder compliance or capacity. Kaplan-Meier analysis of outcomes of the different treatments indicated no statistical difference in patient age at end stage renal disease development. However, comparing the number of surgical procedures in the different treatment groups revealed a significant increase in the amount of surgery in infants with diversion. Our results were equivalent to those of the best published series, many of which strongly advocate high diversion. CONCLUSIONS: By avoiding diversion in most cases bladder function is preserved and the need for bladder augmentation is decreased.

Increased urinary transforming growth factor-beta(1) excretion in children with posterior urethral valves.

OBJECTIVES: Patients with posterior urethral valves (PUV) are at significant risk for progression to end-stage renal disease, despite early correction of the obstruction. Experimental models of urinary obstruction demonstrate increased renal expression of the profibrotic inflammatory mediator, transforming growth factor-beta(1) (TGF-beta(1)). Urinary TGF-beta(1) excretion is elevated in certain glomerular diseases, but has not been well studied in patients with obstructive lesions. The objective of this study was to examine urinary TGF-beta(1) excretion in children with PUV. METHODS: Fourteen patients with PUV, aged 3.2 to 14.5 years, with estimated glomerular filtration rates (GFRs) of 12.8 to 139 mL/min/1.73 m(2) were enrolled. Sixteen normal subjects (9 male, 7 female), aged 4.3 to 20.5 years, served as controls. Total urinary TGF-beta(1) concentration was assayed by enzyme-linked immunoabsorbent assay, and expressed as a ratio to urinary creatinine concentration. RESULTS: Urinary TGF-beta(1) excretion was significantly greater in patients with PUV (range 0 to 0.063, median 0.019 ng/mg urine creatinine) compared with that of healthy controls (range 0 to 0.022, median 0.005 ng/mg urine creatinine) (P <0.01). There was no correlation between urinary TGF-beta(1) excretion and estimated GFR, past urinary diversion surgery, or bladder wall thickening. Among healthy controls, urinary TGF-beta(1) was not correlated with age or gender. CONCLUSIONS: Results from this study suggest that TGF-beta(1) may contribute to progressive renal insufficiency in patients with PUV. Further studies are indicated to determine if agents that affect TGF-beta(1) expression, such as angiotensin-converting enzyme inhibitors, can slow the progression of renal disease in PUV.