Is anuria prior to pediatric renal transplantation associated with poor allograft outcomes?

INTRODUCTION: Anuria from end-stage renal disease leads to a defunctionalized bladder and may pose technical challenges at the time of renal transplantation. Anuria's effect on bladder function after renal transplantation is considered to be minimal in adults, although a paucity of evidence is available in children. The purpose of this study was to examine the effects of anuria prior to pediatric renal transplantation for ESRD due to medical renal disease on allograft outcome. METHODS: We performed a retrospective review of pediatric patients who underwent renal transplantation for medical renal disease at our institution between 2005 and 2016. Demographics and clinical data were assessed. We also compared GFR at 1 year post-transplant for medical renal patients with history of anuria and those without. RESULTS: Twenty-one patients fulfilled our inclusion criteria with median duration of anuria was 10 months. Preoperative VCUG was available in five patients and their bladder capacity was 29% of expected bladder capacity for age (range 8%-41%). Anticholinergic therapy was prescribed in six patients (28%) for a mean duration of 5 months (range 1-16 months). Comparison of GFR at 1 year post-transplant in anuria group and those without anuria showed no difference (69 vs 75 mL/min, P = 0.37). No correlation was observed between duration of anuria and post-transplant GFR. CONCLUSION: The majority of children in our pretransplant anuria cohort did not develop bladder dysfunction after renal transplantation. No difference was observed between GFR at 1 year when comparing anuric to non-anuric transplant recipients of medical renal disease etiology.

Chronic Kidney Disease Stage Progression in Patients Undergoing Repair of Persistent Cloaca.

PURPOSE: Children born with persistent cloaca undergo complex pelvic reconstruction early in life. Long-term risks of bladder dysfunction and chronic kidney disease are well described. We report upper urinary tract outcomes and the risk of chronic kidney disease stage progression in this patient population. MATERIALS AND METHODS: We retrospectively studied a cohort of patients undergoing posterior sagittal anorecto-vagino-urethroplasty at a single institution from 2006 to 2013. Inclusion criteria consisted of complete urological care at our institution. Chronic kidney disease stage was calculated from cystatin C or nuclear medicine glomerular filtration rate. RESULTS: A total of 44 patients met inclusion criteria. Of the patients 12 had undergone vesicostomy or ureterostomy. A total of 19 patients had hydronephrosis, 19 had vesicoureteral reflux and 15 had a tethered spinal cord. Median length of the common channel was 3.5 cm. Median age at posterior sagittal anorecto-vagino-urethroplasty was 7.3 months. Median followup was 5.3 years. A total of 30 patients had neurogenic bladder, of whom 27 required clean intermittent catheterization and 3 had undergone vesicostomy. Of the patients 38 had stage I or II, 5 had stage III and 1 had stage IV chronic kidney disease. During followup no patient with initial stage I to III chronic kidney disease had stage progression. The patient with stage IV chronic kidney disease had a renal allograft placed at age 34 months before needing dialysis. CONCLUSIONS: Early outcomes in patients with stage I to III chronic kidney disease demonstrate that renal function can be maintained despite a high rate of lower urinary tract dysfunction. Aggressive bladder management may help prevent progressive renal injury in this population.

Epididymitis in patients with anorectal malformations: a cause for urologic concern.

INTRODUCTION: Epididymitis in patients with anorectal malformation (ARM) represents a unique problem because unlike the general population, an underlying urinary tract problem is frequently identified. We review our experience with epididymitis in ARM population with an emphasis on examining urologic outcomes. MATERIALS AND METHODS: We performed a retrospective review of male patients with ARM cared for from 1980 to 2010. Clinical and pathologic variables recorded included age at presentation, recurrence, associated urologic anomalies, incidence of ureteral fusion with mesonephric ductal structures, glomerular filtration rate and urodynamic parameters. RESULTS: Twenty-six patients were identified with documented episodes of epididymitis. Renal injury was noted in five patients (19%), all of whom were diagnosed with neurogenic bladder (NGB) several years after anorectoplasty. NGB was found in ten patients (38%) in our series. Ectopic insertion of ureter into a mesonephric ductal structure was discovered in five patients (19%). Twelve patients (46%) had recurrent episodes of epididymitis, with seven of these patients (58%) being diagnosed with NGB. Two patients in the pubertal group presented with a history of epididymitis and complained of ejaculatory pain. CONCLUSION: Epididymitis in a patient with ARM warrants a comprehensive urologic investigation, particularly in recurrent episodes. Attempts at surgical intervention (e.g. vasectomy) should be avoided until functional assessment of the urinary tract has occurred. Failure to recognize this association may lead to potentially avoidable complications and morbidity. Long term urological follow up of these patients is warranted to identify at risk patients and minimize renal deterioration.

Reoperative Anorectal Procedures in Patients with Anorectal Malformations - Is Bladder Function Affected?

BACKGROUND: Anorectal malformations (ARM) are associated with neurogenic bladder. The traditional surgical ARM repair is a posterior sagittal anorectoplasty (PSARP), which is believed to have a minimal effect on bladder dynamics. However, little is known about the effects of reoperative PSARP (rPSARP) on bladder function. We hypothesized that a high rate of bladder dysfunction existed in this cohort. METHODS: We performed a retrospective review of ARM patients undergoing rPSARP at a single institution from 2008 to 2015. Only patients with Urology follow-up were included in our analysis. Data was collected regarding original level of ARM, coexisting spinal anomalies and indications for reoperation. We assessed urodynamic variables and bladder management (voiding, CIC or diverted) before and after rPSARP. RESULTS: A total of 172 patients were identified, of which 85 met inclusion criteria with a median follow-up of 23.9 months (IQR, 5.9-43.8 months). Thirty-six patients had spinal cord anomalies. Indications for rPSARP included mislocation (n = 42), posterior urethral diverticulum (PUD; n = 16), stricture (n = 19) and rectal prolapse (n = 8). Within 1 year following rPSARP, 11 patients (12.9%) had a negative change in bladder management, defined as need for beginning intermittent catheterization or undergoing urinary diversion, which increased to 16 patients (18.8%) at last follow-up. Postoperative bladder management changed in rPSARP patients with mislocation (p < 0.0001) and stricture (p 0.005) but not for rectal prolapse (p 0.143). CONCLUSIONS: Patients who undergo rPSARP warrant especially close attention for bladder dysfunction as we observed a negative postoperative change in bladder management in 18.8% of our series. LEVEL OF EVIDENCE: Level IV.

Neutralizing Antibody Validation Testing and Reporting Harmonization.

Evolving immunogenicity assay performance expectations and a lack of harmonized neutralizing antibody validation testing and reporting tools have resulted in significant time spent by health authorities and sponsors on resolving filing queries. A team of experts within the American Association of Pharmaceutical Scientists' Therapeutic Product Immunogenicity Community across industry and the Food and Drug Administration addressed challenges unique to cell-based and non-cell-based neutralizing antibody assays. Harmonization of validation expectations and data reporting will facilitate filings to health authorities and are described in this manuscript. This team provides validation testing and reporting strategies and tools for the following assessments: (1) format selection; (2) cut point; (3) assay acceptance criteria; (4) control precision; (5) sensitivity including positive control selection and performance tracking; (6) negative control selection; (7) selectivity/specificity including matrix interference, hemolysis, lipemia, bilirubin, concomitant medications, and structurally similar analytes; (8) drug tolerance; (9) target tolerance; (10) sample stability; and (11) assay robustness.

Recommendations on ELISpot assay validation by the GCC.

Gene therapy, cell therapy and vaccine research have led to an increased need to perform cellular immunity testing in a regulated environment to ensure the safety and efficacy of these treatments. The most common method for the measurement of cellular immunity has been Enzyme-Linked Immunospot assays. However, there is a lack of regulatory guidance available discussing the recommendations for developing and validating these types of assays. Hence, the Global CRO Council has issued this white paper to provide a consensus on the different validation parameters required to support Enzyme-Linked Immunospot assays and a harmonized and consistent approach to Enzyme-Linked Immunospot validation among contract research organizations.

Low incidence of urinary tract infections following renal transplantation in children with bladder augmentation.

PURPOSE: Children with end-stage renal disease and bladder dysfunction may require augmentation cystoplasty before kidney transplantation. Previous reports have suggested unacceptable urinary tract infection rates in these immunosuppressed patients. We reviewed our experience in this population. MATERIALS AND METHODS: We retrospectively studied patients undergoing augmentation cystoplasty and subsequent renal transplantation by a single surgeon between 1989 and 2007. This cohort was compared with a control group on clean intermittent catheterization who had undergone transplantation without augmentation. Patient demographics, etiology of renal failure, surgical details, surgical/allograft outcomes and occurrence of urinary tract infection were analyzed. RESULTS: The augmented group included 17 patients with a median age at reconstruction of 6.4 years. Stomach was used in 15 patients and colon in 2. Median time between reconstruction and transplantation was 1.2 years. Median followup after transplantation was 7.7 years. The control group included 17 patients with a median age at transplantation of 10.9 years. Median followup in the controls was 6.1 years. All ureteral reimplantations were antirefluxing. Patients on clean intermittent catheterization were maintained on oral antibiotic suppression and/or gentamicin bladder irrigations. In the augmented group 35 episodes of urinary tract infection were noted, and the number of documented infections per patient-year of followup was 0.22, compared to 32 episodes of urinary tract infection and 0.28 infections per patient-year of followup in the controls. No allograft was lost to infectious complications. CONCLUSIONS: In our series there was no increase in urinary tract infection rate following renal transplantation in patients with augmented bladders compared to controls. This finding may be due to the use of gastric augmentation, antirefluxing reimplantation and gentamicin irrigations.

Outcomes according to channel type for continent catheterizable channels in patients undergoing simultaneous urinary and fecal reconstruction.

INTRODUCTION: When creating a continent catheterizable channel (CCC) the choice of bowel segment used as the conduit should be tempered with the morbidity associated with it. The split-appendix technique allows the creation of both a urinary and fecal CCC without the need for a bowel anastomosis. However, there is concern that by splitting the appendix there is compromise to its blood supply and may affect outcomes. We aim to compare what affect the bowel segment used for urinary and fecal CCCs has on perioperative and long-term outcomes in patients undergoing simultaneous urinary and fecal reconstruction. METHODS: A retrospective review was performed analyzing all patients that underwent simultaneous continent catheterizable urinary and fecal CCC between the years 2010-2016. Patient demographics, channel characteristics, perioperative complications and clinical success rate were analyzed. RESULTS: A total of 106 patients were identified that had simultaneous fecal and urinary CCC created at time of reconstruction. For urinary CCC, there were 64 patients (60.4%) that underwent a split-appendix technique, 27 patients (25.4%) underwent a Monti, and 15 patients (14.2%) had the appendix used only for the urinary channel. Those patients undergoing a split-appendix technique had median operative time of 447 min compared to 619 min when a Monti channel was created. The median length of hospital stay was 9 days for the split-appendix technique compared to 12 and 13 day median hospital stay when the appendix was used only for the urinary channel or a Monti was created, respectively. There was no difference seen in revision free survival of the channel following surgery of any of the channels with median follow-up of 44.5 months. However, there were more subfascial revisions of urinary CCC in those that underwent a Monti (5 patients, 18.5%) compared to other bowel segments (0 patients). CONCLUSIONS: Utilizing a split-appendix approach for creation of urinary and fecal CCCs does not affect 30-day complications or long-term revision rates compared to other established techniques. This technique minimizes the potential surgical morbidity of a bowel anastomosis and provide shorter operative times, when feasible, at time of simultaneous creation of fecal and urinary CCC.

Progression of renal insufficiency in children and adolescents with neuropathic bladder is not accelerated by lower urinary tract reconstruction.

PURPOSE: Children with chronic renal insufficiency and neuropathic bladder resistant to medical management may require lower urinary tract reconstruction before renal transplantation. A low pressure urinary reservoir optimizes the chance of graft survival and may slow native kidney death. We evaluated whether the renal deterioration rate is affected by augmentation cystoplasty. MATERIALS AND METHODS: We performed a retrospective cohort study in children who presented to our institution with chronic renal insufficiency and neuropathic bladders from 2005 to 2009. Chronic renal insufficiency was defined as a glomerular filtration rate of less than 60 ml per minute. As a surrogate for renal function change, we used the inverse creatinine trend with respect to time to determine the progression rate of renal insufficiency before and after augmentation. RESULTS: A total of 11 patients with a mean glomerular filtration rate of 34 ml per minute per 1.73 m(2), mean bladder capacity 168 ml and mean compliance 3.5 ml/cm H(2)O met study inclusion criteria. Bladder augmentation or replacement was done at a mean age of 9.7 years with a resultant mean capacity of 486 ml and compliance of 14.7 ml/cm H(2)O. Mean followup was 4 years before and 1.9 years after augmentation. There was no statistically significant difference between the preoperative and postoperative slopes of inverse creatinine in 8 of 11 patients (73%). Two of the 3 patients (18%) with different preoperative and postoperative slopes had improving renal function after surgery. There was no statistically significant difference in slopes across all patients. CONCLUSIONS: In our series bladder augmentation did not appear to hasten progression to end stage renal disease in patients with severe chronic renal insufficiency and neuropathic bladder.

Need for botulinum toxin injection and bladder augmentation after isolated bladder outlet procedure in pediatric patients with myelomeningocele.

INTRODUCTION: In patients with neurogenic bladder outlet incompetence, a bladder outlet procedure (BOP) may be required to achieve urinary continence. However, when performed in isolation, a BOP can be associated with bladder deterioration and upper-tract injury. In the event of bladder deterioration, additional procedures such as bladder augmentation (BA) or botulinum toxin injection (BTI) may be pursued. OBJECTIVE: The aim of this study was to assess long-term outcomes after isolated BOP in a pediatric myelomeningocele (MMC) population, including the need for additional surgical intervention in the form of BTI or BA. MATERIALS AND METHODS: A retrospective cohort study was performed for patients with MMC who underwent an isolated BOP between 2004 and 2017. Primary outcomes included the need for postoperative BTI or BA. Secondary outcomes included the association between preoperative urodynamic parameters and need for BTI or BA. RESULTS: BTI or BA was performed in 18 of 36 (50%) patients at a median of 17.8 months (IQR 11.2-29.3) after an isolated BOP. A median of 1 (IQR 1-3) BTI was performed in 11 (30.6%) patients. BA was performed in 9 (25%) patients, including 2 patients who previously underwent BTI. Patients who did not undergo BTI or BA after BOP had a slightly increased percentage estimated bladder capacity at the end of follow-up (107% versus 95%, p=0.42). By contrast, patients who underwent BTI or BA had a post-BOP percentage estimated bladder capacity that decreased from 112 to 70% (p < 0.001), increased maximum detrusor leak point pressure from 43 to 67 cm H2O (p = 0.01), and higher rate of de novo upper-tract changes. Unfortunately, no preoperative clinical, radiographic, or urodynamic factors predicted the need for BTI or BA. DISCUSSION: On time-to-event analysis, the risk of BTI or BA was 53% at 5 years in our cohort. Risk of these procedures was highest in the first two years after BOP. 9 of 11 (82%) patients who underwent BTI had improvement in bladder dynamics and BA was not pursued. These findings suggest that BTI provides a less-morbid alternative to BA in patients with MMC and de novo adverse bladder storage changes after an isolated BOP. CONCLUSION: The need for BTI or BA after an isolated BOP is significant in patients with MMC. BTI offers a less-invasive alternative to BA in this population.

Clinical urologic and urodynamic outcomes in patients with anorectal malformation and absent vagina after vaginal replacement.

INTRODUCTION AND OBJECTIVES: Anorectal malformations (ARMs) represent a complex spectrum of anorectal and genitourinary anomalies and a paucity of evidence is available on long-term urologic outcomes in all ARM subtypes. It was our subjective bias from being a referral center for ARM patients that the subtype of rectovestibular fistula and absent vagina had higher risk of renal and bladder abnormalities than typical rectovestibular fistula patients. Therefore, to confirm or refute our clinical suspicions, the purpose of this study was to review this specific cohort of ARM patients and describe both the clinical urological and urodynamic outcomes. METHODS: A retrospective cohort study was performed for 120 patients who were treated for ARM and vaginal replacement at our institution between 1991 and 2017. Fifteen patients with rectovestibular fistula and absent vagina were included in our review. Demographic and clinical data were abstracted from their medical records, including urodynamic findings, need for clean intermittent catheterization (CIC), urinary continence, and renal function. RESULTS: Vaginal replacement surgery was undertaken concomitantly with ARM repair in 10 of the 15 patients (67%). One patient was lost to follow up, and mean follow up postoperatively was 39 months. In all but one patient, rectum or colon was used as the substrate for vaginal replacement. Of the 15 patients, 13 had continence data available. A total of 10 patients (77%) were able to achieve social continence. Overall six patients used CIC to manage their bladder and 40% of continent patients used CIC. Urinary continence outcomes in patients who had partial vaginal replacement compared to those with total vaginal replacement did not reveal a clinically significant difference. Continence was achieved in 3/4 patients (75%) with a history of tethered cord compared to 7/9 patients (78%) without a history of tethered cord release. Urodynamics were performed postoperatively in 7 of the 157 patients (47%). Uninhibited detrusor contractions (UDCs) were present in 3 out of 7 patients, and a cystometric capacity greater than expected was noted in 4 patients. Additionally, 2 patients had end filling detrusor pressure greater than 40 cm H2O. GFR data were available for 13 of the 15 patients and (85%) were classified as chronic kidney disease (CKD) stage I or not having any significant loss of renal function. CONCLUSIONS: In this cohort of rectovestibular fistula and absent vagina, 77% reported achieving urinary continence. However CIC was employed in 40% of the patients which is higher than prior published noncloaca female ARM patient population. Urodynamic abnormalities were noted when performed and led to change in bladder management. Renal function measured with GFR was normal in 85%. Patients with rectovestibular fistula and absent vagina benefit from urologic screening given higher rates of lower urinary tract dysfunction that can require CIC to protect the upper urinary tract and achieve urinary continence. TYPE OF STUDY: Case series. LEVEL OF EVIDENCE: Level IV.

Risk factors for urinary tract infection after dextranomer/hyaluronic acid endoscopic injection.

PURPOSE: Endoscopic injection of dextranomer/hyaluronic acid is an option for primary vesicoureteral reflux. Few groups have assessed the rate of urinary tract infection after dextranomer/hyaluronic acid injection. We reviewed our experience with dextranomer/hyaluronic acid injection, and determined the incidence of and risk factors for postoperative urinary tract infection. MATERIALS AND METHODS: A retrospective cohort study was performed of all children with primary vesicoureteral reflux treated with dextranomer/hyaluronic acid from 2002 to 2007 at a single institution. Patient demographics and clinical outcomes were abstracted from the medical record. Risk factors for postoperative urinary tract infection, including female gender, preoperative vesicoureteral reflux grade, recurrent urinary tract infection, bladder dysfunction, nephropathy and persistent vesicoureteral reflux after surgery, were analyzed in a multivariate logistic regression model. RESULTS: We treated 311 children, of whom 87% were female and 13% were male (464 renal units), during the study period. Mode of presentation was urinary tract infection in 85% of cases. Mean followup was 2.6 years. Postoperatively urinary tract infection developed in 40 patients (13%) and febrile urinary tract infection developed in 11 (3.5%). Of patients with urinary tract infection 26 had initially negative postoperative voiding cystourethrogram, of whom 16 underwent repeat voiding cystourethrogram and 9 showed recurrent vesicoureteral reflux. Five of these 9 patients had clinical pyelonephritis. Of assessed risk factors only preoperative recurrent urinary tract infection (OR 2.2, p = 0.03) and bladder dysfunction (OR 3.3, p = 0.001) were independent predictors of post-injection urinary tract infection. CONCLUSIONS: In our series urinary tract infection after dextranomer/hyaluronic acid injection was rare. Patients with recurrent urinary tract infections and bladder dysfunction preoperatively are at increased risk for urinary tract infection after treatment. Patients with febrile urinary tract infection after dextranomer/hyaluronic acid injection are at high risk for recurrent vesicoureteral reflux.

Long-term outcomes of the neobladder in pediatric continent urinary reconstruction.

PURPOSE: In rare instances when native bladder tissue is either unsuitable or unavailable a continent neobladder may be an option for pediatric lower urinary tract reconstruction. We report our long-term outcomes and experience in this challenging patient population. MATERIALS AND METHODS: A retrospective cohort study was performed of all patients who underwent creation of a neobladder at 2 pediatric institutions. Patient demographics, surgical details and clinical outcomes were abstracted from the medical records. RESULTS: A total of 26 patients were identified with a median age of 8.9 years at surgery. Median followup was 8.0 years. Most procedures used a composite of gastric and ileal tissue. All patients were continent of urine and had a stable upper urinary tract. Median bladder capacity was 400 ml. Postoperative complications included reservoir stones (8 patients), febrile urinary tract infection (8), metabolic acidosis (6), small bowel obstruction (4), bladder perforation (4) and pelvic lymphocele (1). Five patients had difficulty with catheterization due to stomal stenosis. Gross hematuria with clots developed in 1 patient with anuria who had a gastroileal neobladder and was awaiting renal transplantation. No other patient with a gastric component had the hematuria-dysuria syndrome. Five patients had end stage renal disease and subsequently underwent successful renal transplantation. No upper urinary tract deterioration was observed, and no malignant transformation has occurred. CONCLUSIONS: Creation of a continent neobladder is a reconstruction option in children when bladder augmentation is not feasible. However, complication rates are not insignificant, underscoring the need for careful long-term followup.

12th GCC Closed Forum: critical reagents; oligonucleotides; CoA; method transfer; HRMS; flow cytometry; regulatory findings; stability and immunogenicity.

The 12th GCC Closed Forum was held in Philadelphia, PA, USA, on 9 April 2018. Representatives from international bioanalytical Contract Research Organizations were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The issues discussed at the meeting included: critical reagents; oligonucleotides; certificates of analysis; method transfer; high resolution mass spectrometry; flow cytometry; recent regulatory findings and case studies involving stability and nonclinical immunogenicity. Conclusions and consensus from discussions of these topics are included in this article.

Recommendations for classification of commercial LBA kits for biomarkers in drug development from the GCC for bioanalysis.

Over the last decade, the use of biomarker data has become integral to drug development. Biomarkers are not only utilized for internal decision-making by sponsors; they are increasingly utilized to make critical decisions for drug safety and efficacy. As the regulatory agencies are routinely making decisions based on biomarker data, there has been significant scrutiny on the validation of biomarker methods. Contract research organizations regularly use commercially available immunoassay kits to validate biomarker methods. However, adaptation of such kits in a regulated environment presents significant challenges and was one of the key topics discussed during the 12th Global Contract Research Organization Council for Bioanalysis (GCC) meeting. This White Paper reports the GCC members' opinion on the challenges facing the industry and the GCC recommendations on the classification of commercial kits that can be a win-win for commercial kit vendors and end users.

Risk factors for end stage renal disease in children with posterior urethral valves.

PURPOSE: Obstructive uropathy secondary to posterior urethral valves is an important cause of end stage renal disease in children. Early diagnosis and intervention to decrease bladder pressure and stabilize the upper urinary tract are important to delay or prevent the progression of renal insufficiency. We analyzed the records of patients with posterior urethral valves to determine risk factors that might be predictive of ultimate renal failure. MATERIALS AND METHODS: A retrospective cohort study was performed of children presenting to our institution with a diagnosis of posterior urethral valves from 1975 to 2005. Patient demographics, clinical background, laboratory and radiographic data, and renal outcomes were abstracted from the medical record. Potential risk factors were analyzed, such as high grade vesicoureteral reflux at diagnosis, nadir serum creatinine greater than 1.0 mg/dl, urinary tract infection and severe bladder dysfunction requiring clean intermittent catheterization. Risk factors were analyzed by univariate analysis with Fisher's exact test. Those achieving significance were placed in a multivariate logistic regression model and an OR was generated. RESULTS: A total of 142 patients were identified, of whom half presented in the neonatal period. Of the patients 119 had sufficient records for evaluation and mean followup was 7.2 years. A total of 15 patients progressed to end stage renal disease. The mean interval from diagnosis to end stage renal disease was 8.1 years. Of these patients 93% initially presented with vesicoureteral reflux and 87% ultimately required clean intermittent catheterization. Increased nadir creatinine was seen in 80% of cases. Multivariate analysis revealed that increased nadir creatinine and bladder dysfunction were independent risk factors for end stage renal disease (OR 71 and 8.9, respectively). Vesicoureteral reflux was also associated with an increased risk of end stage renal disease (OR 2.0), although this was not statistically significant. Urinary tract infections were not associated with end stage renal disease. CONCLUSIONS: Patients with posterior urethral valves and severe bladder dysfunction in whom nadir creatinine remains increased are at risk for upper urinary tract deterioration, requiring renal replacement therapy. It is unclear whether high grade vesicoureteral reflux at diagnosis may also be a poor prognostic sign. Further analysis is necessary to evaluate the effects of early aggressive bladder management on renal outcomes.

Urinary metabolic evaluations in solitary and recurrent stone forming children.

PURPOSE: We have previously reported a high rate of urinary metabolic abnormalities in stone forming children compared to normal controls. At our institution a 24-hour urine evaluation is initiated after the first stone episode in children, to measure stone risk indices. The purpose of this study was to determine which children are at the greatest risk for recurrent stone formation. MATERIALS AND METHODS: A retrospective cohort study was performed to assess urinary metabolic profiles in children with urolithiasis. In all patients 24-hour urine collections were performed and evaluated elsewhere. Urine chemistry assessments such as calcium and citrate were adjusted for creatinine and weight. Calcium oxalate supersaturation was measured. Patients were stratified as solitary or recurrent stone formers based on review of the medical record. Univariate analysis between means was performed with a 2-tailed t test. RESULTS: A total of 148 samples from 88 solitary stone formers and 84 samples from 51 recurrent stone formers were evaluated. Age and gender were well matched between the 2 groups. Timed urinary calcium levels referenced to creatinine and citrate were significantly higher in patients with recurrent stones. Supersaturation levels of calcium oxalate were higher in recurrent stone formers but did not reach statistical significance. CONCLUSIONS: There are significant differences in 24-hour urinary calcium levels between solitary and recurrent calcium stone forming children. A patient with increased urinary calcium indices on a 24-hour specimen may benefit from more aggressive initial dietary and pharmacological treatment to prevent stone recurrence.

Urological issues in pediatric renal transplantation.

PURPOSE OF REVIEW: The pediatric patient with end-stage renal disease provides a great opportunity for the involvement of the pediatric urologist because of the high incidence of associated urologic anomalies. RECENT FINDINGS: Renal transplant remains the procedure of choice in the child with end-stage renal disease. The durability of survival of the graft is impacted by successful management of the genitourinary tract. SUMMARY: Preoperative, intraoperative, and postoperative evaluation is critical for the child with associated urologic disease and end-stage renal disease. Early and appropriate management may stabilize renal function and prolong the time to transplant. Due to the relatively long life expectancy of children compared with adults with end-stage renal disease, appropriate management may be of benefit to avoid the morbidity associated with renal replacement therapy. In certain children, the appropriate management and reconstruction of the genitourinary tract may allow for a planned and preemptive renal transplant, thus avoiding dialysis.

11th GCC Closed Forum: cumulative stability; matrix stability; immunogenicity assays; laboratory manuals; biosimilars; chiral methods; hybrid LBA/LCMS assays; fit-for-purpose validation; China Food and Drug Administration bioanalytical method validation.

The 11th Global CRO Council Closed Forum was held in Universal City, CA, USA on 3 April 2017. Representatives from international CRO members offering bioanalytical services were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The second CRO-Pharma Scientific Interchange Meeting was held on 7 April 2017, which included Pharma representatives' sharing perspectives on the topics discussed earlier in the week with the CRO members. The issues discussed at the meetings included cumulative stability evaluations, matrix stability evaluations, the 2016 US FDA Immunogenicity Guidance and recent and unexpected FDA Form 483s on immunogenicity assays, the bioanalytical laboratory's role in writing PK sample collection instructions, biosimilars, CRO perspectives on the use of chiral versus achiral methods, hybrid LBA/LCMS assays, applications of fit-for-purpose validation and, at the Global CRO Council Closed Forum only, the status and trend of current regulated bioanalytical practice in China under CFDA's new BMV policy. Conclusions from discussions of these topics at both meetings are included in this report.

Comparison of the Pharmacokinetics of Ketorolac Tromethamine After Continuous Subcutaneous Infusion and Repeat Intramuscular Bolus Injections in Healthy Adult Subjects.

Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug that exhibits analgesic activity with no sedative or anxiolytic properties. Twelve healthy male subjects were enrolled in a study to receive either of 2 treatments over 2 periods in an open-label, randomized, 2-way crossover design: (A) 120 mg of ketorolac tromethamine administered as a continuous subcutaneous infusion over a 24-hour period; or (B) an identical total daily dose administered as 4 intramuscular bolus injections of 30 mg each given every 6 hours (current labeled treatment regimen). The pharmacokinetic and safety profiles were evaluated for both treatments. Both modes of administration have similar values for area under the curve (AUC) and half-life (t1/2 ), suggesting that continuous subcutaneous infusion and repeated intramuscular bolus injections have similar bioavailability. The peak plasma concentration (Cmax ) was 40% lower when ketorolac was administered as a continuous subcutaneous infusion compared with repeat intramuscular bolus injections. The concentration at steady-state (Css ) for continuous subcutaneous infusion was between the Cmax and Ctrough values obtained following the 4 intramuscular injections. Both treatment arms were well tolerated.