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A careful history, thorough physical exam and limited diagnostic studies often point the way to the cause and successful treatment of this distressing disorder. [ABSTRACT FROM AUTHOR]

Unlabelled: Calcineurin inhibitor-associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients., Methods: This open-label, randomized, multinational study evaluated the effect of planned transition from tacrolimus to sirolimus on kidney function in renal allograft recipients. Patients received tacrolimus-based immunosuppression and then were randomized 3 to 5 months posttransplantation to transition to sirolimus or continue tacrolimus. The primary end point was percentage of patients with 5 mL/min per 1.73 m(2) or greater improvement in estimated glomerular filtration rate from randomization to month 24., Results: The on-therapy population included 195 patients (sirolimus, 86; tacrolimus, 109). No between-group difference was noted in percentage of patients with 5 mL/min per 1.73 m(2) or greater estimated glomerular filtration rate improvement (sirolimus, 34%; tacrolimus, 42%; P = 0.239) at month 24. Sirolimus patients had higher rates of biopsy-confirmed acute rejection (8% vs 2%; P = 0.02), treatment discontinuation attributed to adverse events (21% vs 3%; P < 0.001), and lower rates of squamous cell carcinoma of the skin (0% vs 5%; P = 0.012)., Conclusions: Our findings suggest that renal function improvement at 24 months is similar for patients with early conversion to sirolimus after kidney transplantation versus those remaining on tacrolimus.

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., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). During the clinical development programme, increases in mean serum creatinine (SCr) of approximately 0.07 mg/dL and 0.08 mg/dL were observed which plateaued early. This study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib relative to placebo in patients with active RA., Methods: This was a randomised, placebo-controlled, Phase 1 study (NCT01484561). Patients were aged ≥18 years with active RA. Patients were randomised 2:1 to oral tofacitinib 10 mg twice daily (BID) in Period 1 then placebo BID in Period 2 (tofacitinib → placebo); or oral placebo BID in both Periods (placebo → placebo). Change in mGFR was evaluated by iohexol serum clearance at four time points (run-in, pre-dose in Period 1, Period 1 end, and Period 2 end). The primary endpoint was the change in mGFR from baseline to Period 1 end. Secondary endpoints included: change in mGFR at other time points; change in estimated GFR (eGFR; Cockcroft-Gault equation) and SCr; efficacy; and safety., Results: 148 patients were randomised to tofacitinib → placebo (N = 97) or placebo → placebo (N = 51). Baseline characteristics were similar between groups. A reduction of 8% (90% confidence interval [CI]: 2%, 14%) from baseline in adjusted geometric mean mGFR was observed during tofacitinib treatment in Period 1 vs placebo. During Period 2, mean mGFR returned towards baseline during placebo treatment, and there was no difference between the two treatment groups at the end of the study--ratio (tofacitinib → placebo/placebo → placebo) of adjusted geometric mean fold change of mGFR was 1.04 (90% CI: 0.97, 1.11). Post-hoc analyses, focussed on mGFR variability in placebo → placebo patients, were consistent with this conclusion. At study end, similar results were observed for eGFR and SCr. Clinical efficacy and safety were consistent with prior studies., Conclusion: Increases in mean SCr and decreases in eGFR in tofacitinib-treated patients with RA may occur in parallel with decreases in mean mGFR; mGFR returned towards baseline after tofacitinib discontinuation, with no significant difference vs placebo, even after post-hoc analyses. Safety monitoring will continue in ongoing and future clinical studies and routine pharmacovigilance., Trial Registration: Clinicaltrials.gov NCT01484561. Registered 30 November 2011.

Background: Despite a decreased incidence of acute rejection and early renal allograft loss due to calcineurin inhibitors (CNIs) in transplant recipients, nephrotoxicity associated with long-term CNI use remains an important issue. This study evaluated whether a CNI-free regimen, including sirolimus, mycophenolate mofetil, corticosteroids, and anti-interleukin-2 receptor antibody induction, results in improved long-term renal function., Methods: This open-label, randomized, parallel group, comparative study in primary de novo renal transplant recipients was planned for 48 months but terminated early because of high acute rejection rates in the sirolimus arm., Results: Enrollment was stopped after ≈12 months, with 475 transplanted patients randomized (2:1) to sirolimus (n=314) or cyclosporine A (CsA) treatment (n=161). Mean length of follow-up after transplantation was 190 days; this article focuses on available data through 6 months. Mean±SD on-therapy Nankivell-calculated glomerular filtration rate was not significantly different between the sirolimus (69.1±18.7 mL/min) and CsA (66.0±15.2 mL/min) treatment groups. Occurrence and length of delayed graft function was not significantly different between groups. Patients in the sirolimus group experienced numerically lower survival rates (96.9% vs. 99.4%; P=0.14), with nine deaths reported with sirolimus and one with CsA; higher rates of biopsy-confirmed acute rejection (21.4% vs. 6.1%; P<0.001); and higher rates of discontinuations due to adverse events (17.4% vs. 6.8%; P=0.001)., Conclusion: A sirolimus-based, CNI-free immunosuppressive regimen, when used with mycophenolate mofetil, corticosteroids, and anti-interleukin-2 receptor antibody induction, was associated with high rates of biopsy-confirmed acute rejection compared with CsA-based immunosuppression and is not recommended.

Background: Methylnaltrexone, a selective peripheral acting mu-opioid receptor antagonist, alleviates the constipating effects of opioids without affecting centrally mediated analgesia., Objectives: To assess the effect of subcutaneous (SC) methylnaltrexone injection on patient-reported constipation symptoms and pain scores., Methods: A total of 469 subjects on opioids for chronic non-malignant pain with opioid-induced constipation were randomized to methylnaltrexone SC with once daily (QD) or every other day (QOD) dosing or placebo for 4 weeks. Constipation symptoms and pain were assessed using the patient assessment of constipation-symptoms (PAC-SYM) questionnaire and a 11-point scale, respectively, at baseline, Day 14 and Day 28. Change from baseline in PAC-SYM and pain scores were compared between methylnaltrexone and placebo arms at Day 28 using analysis of covariance, with treatment group as factor and baseline score as covariate., Results: A majority of patients were women (60%), average age was 49 years old, and back pain (60%) was the primary pain condition. At Day 28, the methylnaltrexone SC QD group showed a significant improvement over placebo for rectal symptoms (-0.56 vs. -0.30; P < 0.05), stool symptoms (-0.76 vs. -0.43; P < 0.001) and global scores (-0.62 vs. -0.37; P < 0.001). Improvement in stool symptoms (-0.69 vs.-0.43; P < 0.05) and the global scores (-0.52 vs. -0.37; P < 0.05) were significantly greater than placebo in the methylnaltrexone QOD group. Differences in change from baseline in abdominal symptoms and pain scores between the methylnaltrexone SC QD or QOD dosing arms and placebo were not significant., Conclusion: The results of our study indicate significant improvement in constipation symptoms with methylnaltrexone QD or QOD dosing compared to placebo without a significant effect on pain scores., (Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: The efficacy and safety of sirolimus (SRL) plus tacrolimus (TAC) versus SRL plus cyclosporine (CsA) were compared in high-risk renal allograft recipients., Methods: Evaluable patients (448) were randomly assigned (1:1) before transplant to receive SRL+TAC or SRL+CsA with corticosteroids. Eligible patients were black and/or repeat transplant recipients, and/or those with high titer of panel-reactive antibodies., Results: Demographics were similar between groups. Both treatments demonstrated equivalent efficacy of the composite endpoint at 12 months with efficacy failure rates of 21.9% vs. 23.2% (SRL+TAC vs. SRL+CsA, respectively, 95% CI -10.0 to 7.1, P=0.737). Biopsy-confirmed acute rejection rate (13.8% vs. 17.4%) and graft survival rate (89.7% vs. 90.2%) were similar (SRL+TAC vs. SRL+CsA, respectively). In evaluable patients (received at least 1 dose of study drug), renal function (calculated Nankivell glomerular filtration rate) was not superior in SRL+TAC versus SRL+CsA (54.5 vs. 52.6 mL/min, P=0.466); however, in on-therapy patients, glomerular filtration rate was significantly higher in SRL+TAC at most time points. At 12 months, there were no significant differences in rates of death, discontinuation because of adverse events, hypercholesterolemia, hyperlipemia, or proteinuria. Diarrhea and herpes simplex infections occurred significantly more often in SRL+TAC patients. Hypertension, cardiomegaly, increased creatinine, overdose (primarily calcineurin inhibitor toxicity), acne, urinary tract disorders, lymphocele, and ovarian cysts occurred significantly more often in SRL+CsA patients., Conclusions: This study demonstrated that SRL-based therapy was efficacious in high-risk renal allograft recipients in the first year after transplant, providing equivalent efficacy with CsA or TAC, similar graft survival, low biopsy-confirmed acute rejection rates, excellent renal function, and an acceptable safety profile.

The practicing urologist commonly sees children with lower-urinary tract dysfunction who wet or have recurrent urinary tract infections. This article identifies the proposed etiologies of such behavior in children in whom there are no anatomic or neuropathic causes, outlines the approach to evaluating affected children, and describes a stepwise,interdisciplinary approach to treatment.

Objective: To develop and evaluate a parent-completed questionnaire for use by clinicians as part of routine care to assess the burden of diurnal and nocturnal enuresis on children and their families., Methods: The questionnaire consisted of items that measure the impact on the child and his/her parent, the child's coping ability and commitment to treatment, previous treatment success, family frustration and overall cohesion, and parental attitudes about enuresis and its treatment. Questionnaires (n = 208) were completed by parents during the child's scheduled office visit for enuresis at 5 specialty clinics across the United States. Traditional criteria were used to assess reliability and validity of the questionnaire, including analysis of variance., Results: Success rates provide evidence that many of the items in the child scale (79%) and all items in the parent scale (100%) met stringent criteria. alpha values were.62 and.77, respectively. Statistically significant differences were observed for the scales across responses on all but 1 global item, the majority of parental attitude items, whether the child urinated at bedtime, and the number of pads used. These findings suggest that the child's coping ability and commitment and the family's overall cohesion and frustration with the problem influence parental perceptions about the impact of enuresis on the child and the family., Conclusions: Findings about the performance of the new measure were satisfactory and suggest that, after further refinement, it should prove as a useful tool for clinicians treating enuresis in children.

Voiding dysfunction leads to daytime wetting, night-time wetting, and recurrent urinary tract infection (UTI). Our interdisciplinary center has been committed to treating children with dysfunctional voiding since 1992. We describe the long-term follow-up of a large cohort of children using our approach to treatment. We reviewed the records of 199 children with symptoms of voiding dysfunction seen between March 1992 and December 1993. We contacted 98 parents and 51 patients by phone at least 6.5 years after initial presentation and asked about current symptoms, effective strategies, and satisfaction of care. Of the initial group of contacted parents, 81 (83%) were female with a median age of 7.8 years. Patients were followed in the clinic for a mean time of 1.6 years and a median of three visits. Of the 90 patients with daytime wetting, 82 (91%) reported complete resolution with a median time of resolution of 2.9 years. Parents felt that maturation was the most important factor leading to improvement. Of the patients that were directly contacted (41 females, 10 males, median age 15.2 years), all were dry and 86% denied any sense of urgency; 86% of parents and 87% of patients were highly satisfied with their care. Almost every child improved within 5 years of the initial evaluation. Only small fractions are still wet, are infected, or have urgency. Maturation seems to be the most important factor leading to improvement. Most parents and patients are satisfied with this form of treatment.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Cytomegalovirus (CMV), the most significant infectious cause of morbidity following renal transplantation, may be a greater problem for children than for adults due to their relative lack of experience with this virus. Therefore, we prospectively gave Gammagard as prophylaxis to CMV-negative children who received CMV-positive allografts and compared the results to our experience with similar high-risk recipients transplanted prior to our use of intravenous immunoglobulin G (IvIgG). Symptomatic CMV disease developed in 17% of the IvIgG recipients as compared with 71% of the untreated patients (p = 0.01). The CMV infections that did occur in IvIgG recipients developed significantly later than in untreated children (median time of onset after transplantation 2.60 vs. 1.35 months; p < 0.05) and generally were less severe, although 1 IvIgG recipient died despite prophylaxis. IvIgG administration did not affect the frequency of rejection or graft or patient survival. We conclude that IvIgG administration to high-risk pediatric renal transplant recipients may protect against posttransplantation CMV disease and may lessen the severity of infections that do develop in patients who receive it.

Viral infections such as influenza are an important cause of morbidity following organ transplantation. We evaluated the immunogenicity of a commercially available influenza vaccine in pediatric renal transplant recipients in a two-phase, prospective study. In phase one, 47 transplant patients and seven control subjects with bronchopulmonary dysplasia received influenza vaccine. Sera were collected at the time of vaccination and 6 wk later. In phase two, sera from 18 transplant recipients and 47 healthy adults who had received the same vaccine were collected 6-12 months after vaccination. Antibody titers to the A/Taiwan/1/86 antigen were measured with hemagglutination inhibition assay in both phases of the study. Vaccine was well tolerated in all subjects. No vaccinated patient required hospitalization for complications of influenza infection. Vaccination did not increase the frequency of acute allograft rejection. In phase one, 43 patients (91%) and 5 controls (71%) either seroconverted (developed a fourfold or greater rise in titer), or developed post-vaccination titers > or = 1:160 (p = NS). Among the transplant recipients, non-seroconverters had a higher pre-vaccination geometric mean antibody titer (GMT) than those who seroconverted. Seroconversion developed independently of whether patients received double or triple immunosuppression. In phase two, post-vaccination GMT were similar for patients and control subjects at 11.5 and 8 months post-vaccination, respectively. In our study, influenza vaccination produced equivalent humoral immunity in transplant recipients and normal subjects. Routine influenza vaccination should be performed annually in this high-risk population.

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.

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.

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.

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.

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.

The records of 14 boys with posterior urethral valves who had renal failure and subsequently underwent renal transplantation were reviewed to determine the postoperative incidence of urinary tract infection relative to that of 29 male transplant children without valves, who served as controls. There were no significant differences between the posterior urethral valve patients and controls with regard to age, donor source, immunosuppression, followup after transplantation or mean calculated creatinine clearance. Vesicoureteral reflux was found in 1 child with posterior urethral valves and 3 of the children in the control group (p not significant). A total of 15 urinary tract infections occurred in 5 children (36%) with posterior urethral valves, for a rate of 1 per 30 patient-months of followup, and 6 urinary tract infections occurred in 2 controls (7%), for a rate of 1 per 216 patient-months of followup (p < 0.05). However, only 1 of 26 controls (4%) without vesicoureteral reflux had urinary tract infection, for a rate 1 per 1,144 patient-months (p < 0.01). Conversely, the rate of urinary tract infections in controls with vesicoureteral reflux was similar to that of children with posterior urethral valves. Of the 5 children with posterior urethral valves 4 had the initial urinary tract infection within 2 months of transplantation and 10 of 15 episodes occurred within the first 4 months. Antimicrobial prophylaxis did not appear to decrease the rate of infection in children with posterior urethral valves. A history of posterior urethral valves increases the frequency of urinary tract infection after renal transplantation but the usefulness of antimicrobial prophylaxis and the relationship to long-term graft function remain to be determined. Urinary tract infection rarely develops in other transplanted boys without vesicoureteral reflux.

A child with congenital nephrotic syndrome underwent renal transplantation, was treated for acute rejection, and then developed nephrotic syndrome and renal failure. He was felt to have minimal change disease on allograft biopsy, but failed to respond to therapy with corticosteroids. Cyclophosphamide was substituted for cyclosporine and rapidly induced a complete remission of his nephrotic syndrome. We feel that this case not only represents an important example of a useful therapeutic approach to the child with congenital nephrotic syndrome who develops nephrotic syndrome post transplantation, and also raises questions concerning the pathogenesis of congenital nephrotic syndrome.

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.

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.

A 3.5-year-old boy presented with end-stage renal disease and bilateral nephrocalcinosis. Renal biopsy demonstrated marked parenchymal calcium oxalate deposition and a diagnosis of primary hyperoxaluria (PH) was made. Following 2 years of hemodialysis he received two renal allografts which were lost at 7 and 11 months, respectively, due to biopsy-proven recurrent oxalosis. Combined liver-kidney transplantation was then performed, after which renal and hepatic function initially stabilized. The patient died on the 28th postoperative day, of infectious complications and progressive respiratory insufficiency. However, comparisons between the patterns of urinary oxalate excretion noted after the isolated renal and liver-kidney transplants indicated that, following the latter, successful biochemical correction of the enzyme defect responsible for type 1 PH had occurred.

OKT3 has become one of the more effective antirejection therapies for patients receiving kidney transplants. However, its usefulness is diminished or blocked by the development of antimouse/anti-OKT3 antibodies. We evaluated 17 children receiving OKT3 for steroid-resistant acute rejection for the development and persistence of antibodies after therapy. OKT3 was successful in reversing acute rejection in 14 of 17 patients. Eight children developed antimouse antibodies, 7 at a low titer (1:100). The retesting of all children 6 months later showed no detectable antibodies. Children develop anti-OKT3 antibodies at a rate similar to adults and with time lose detectable levels which may have significance if a subsequent course of OKT3 is needed.

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.