Allograft outcomes of treated children with kidney transplant who developed plasma cell-rich acute rejection (PCAR): A single center's experience.

INTRODUCTION: PCAR is a rare form of ACR that may compromise renal allografts. This review evaluates the outcomes of a protocol used to treat PCAR (Study group), and compares these outcomes with a matched cohort with ACR (Control group). METHODS: A retrospective analysis of 138 of pRTRs who underwent renal allograft biopsies between January 2008 and November 2016. RESULTS: Seven biopsies revealed in situ hybridization of EBER-negative PCAR (5%). Three Study group pRTRs lost their grafts within 3 months after rejection (43%). None of the Control group pRTRs lost their graft during this period. At the time of rejection, eGFR was different between the Control and Study groups (27.0 ± 19.9 mL/min per m2 vs 40.0 ± 10.6 mL/min/1.73 m2 , respectively; P < 0.05). Among Study group pRTRs with functioning allografts (n = 4), treatment resulted in an increase in eGFR from nadir levels (27.0 ± 19.9 vs 55.6 ± 18.3 mL/min/1.73 m2 , P < 0.05). In the Study group, complications included neutropenia, BK and EBV viremia, and infusion-related hypotension and hypertension. SUMMARY: (a) Graft loss in Study group while remaining high (43%) was lower than that reported in the published pediatric literature. (b) Our protocol was associated with improvement in eGFR in all surviving pRTRs within the Study group. (c) No life-threatening complications or malignancy were reported during the observation period.

Renal-Limited "Lupus-Like" Nephritis: How Much of a Lupus?

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by development of autoantibodies to nuclear and cytoplasmic antigens. A small subset of SLE patients who had the typical clinical features of SLE was reported to show persistently negative antinuclear antibody tests. Our report describes a 5-year-old male who presented with histopathological findings suggestive of lupus nephritis with no clinical signs or symptoms of SLE and negative autoantibodies. He was treated with corticosteroids, mycophenolate mofetil, and monthly intravenous cyclophosphamide. During the 2-year follow-up period, the proteinuria resolved and kidney function improved with continued negative autoantibody workup. This case presents a category of renal-limited "lupus-like" glomerulonephritis which can be challenging to treat and carries a poor prognosis.

Management of sensitized pediatric patients prior to renal transplantation.

BACKGROUND: Data on renal allograft outcome in sensitized children are scarce. We report the clinical courses of four children who received desensitization therapy prior to renal transplantation in our institution. METHODS: Between 2009 and 2011, four pediatric patients with stage 5 chronic kidney disease received desensitization therapy due to: (1) positive donor-specific antibodies (DSA) and/or crossmatches with potential living donors, (2) more than three positive crossmatches with deceased donors or (3) high calculated panel-reactive antibody of >80 %. Desensitization with rituximab, intravenous immunoglobulin and bortezomib was performed in all patients. Induction therapy included combinations of plasmapheresis and/or alemtuzumab or anti-thymocyte globulin. Standard post-transplant medications included tacrolimus, mycophenolate mofetil and prednisolone. RESULTS: Post-transplant screening revealed DSA in three patients. Biopsy showed no evidence of rejection at 1 month in two patients, one of whom developed chronic active antibody-mediated rejection 4.5 years later. One patient developed borderline acute cellular rejection at 1 month, but the serum creatinine level was stable and DSA disappeared without treatment 1 month later, with stable long-term allograft function at 3 years. Estimated or measured glomerular filtration rate of the patients ranged between 30 and 75 ml/min/1.73 m(2) after 1 to 4.5 years. CONCLUSIONS: The four sensitized patients reported here who received desensitization therapy had successful renal transplants with a low risk of immediate post-transplant rejection. Overall, long-term allograft functions and complications from immunosuppression were encouraging.

Growth in children with chronic kidney disease: a report from the Chronic Kidney Disease in Children Study.

BACKGROUND: Growth failure is common among children with chronic kidney disease (CKD). We examined the relationship of growth parameters with glomerular filtration rate (GFR), CKD diagnosis, sex and laboratory results in children with CKD. METHODS: Baseline data from 799 children (median age 11.0 years, median GFR 49.9 mL/min/1.73 m(2)) participating in the Chronic Kidney Disease in Children Study were examined. Growth was quantified by age-sex-specific height, weight, body mass index (BMI-age), and height-age-sex-specific BMI (BMI-height-age) standard deviation scores (SDS). RESULTS: Median height and weight SDS were -0.55 [interquartile range (IQR) -1.35 to 0.19] and 0.03 (IQR -0.82 to 0.97), respectively. Girls with non-glomerular CKD were the shortest (median height SDS -0.83; IQR -1.62 to -0.02). Compared to those with a serum bicarbonate (CO2) level of ≥ 22 mEq/L, children with CO2 of <18 mEq/L had a height SDS that was on average 0.67 lower [95 % confidence interval (CI) -0.31 to -1.03]. Only 23 % of children with a height SDS of ≤-1.88 were prescribed growth hormone therapy. Forty-six percent of children with glomerular CKD were overweight or obese (BMI-height-age ≥ 85th percentile). CONCLUSIONS: Growth outcomes in a contemporary cohort of children with CKD remain suboptimal. Interventions targeting metabolic acidosis and overcoming barriers to recombinant human growth hormone usage may improve growth in this population.

Validation of the CKiD formulae to estimate GFR in children post renal transplant.

BACKGROUND: The Chronic Kidney Disease in Children (CKiD) study reported new formulae to estimate glomerular filtration rate (eGFR). The study reported here aimed to assess the accuracy of these formulae in estimating levels and changes in GFR in pediatric renal transplant recipients and generate a new formula in our cohort. METHODS: Two hundred and fifty-two studies of plasma disappearance of (125)I-iothalamate (CIO) were used to measure GFR in 155 renal transplant recipients. The CKiD bedside formula (CKiD-BS) was compared with CIO. A mixed logistic regression model was fit to evaluate the performance of estimating change in posttransplant CIO using CKiD-BS. We used mixed-effects linear regression to fit a multiplicative model of CIO. The CKiD cystatin-C-based formula (CKiD-Cys) was also used for comparison in 32 additional transplant recipients. Comparisons were made using Bland-Altman plots. RESULTS: CKiD-BS underestimates CIO by 20 % for GFR >25 ml/min per 1.73 m(2). Percentage change in CKiD-BS performed reasonably well in estimating 15 % change of CIO beginning 6 months posttransplant [area under the curve (AUC) = 0.791)] The multiplicative constant in the CKiD-BS was recalibrated [R-Bedside = 0.461 × ht(cm)/SCr).]A GFR model [GFR-M) = 10.73 × [(ht(cm)]0.51/(SCr)0.90 × (BUN)0.23] has higher specificity but similar sensitivity for CIO compared with R-Bedside. CKiD-Cys overestimates CIO by 10 ml/min per 1.73 m(2) across a broad range of GFR. CONCLUSIONS: In our cohort, the CKiD-BS underestimates CIO; however, changes in CKiD-BS can be used to estimate changes in CIO. CKiD-Cys overestimates CIO and is not accurate in estimating CIO.

Acute antibody-mediated rejection in pediatric kidney transplants: a single center experience.

aAMR is a potentially devastating complication of kidney transplantation. The incidence of aAMR in children, while thought to be rare, is not well defined, and there is a paucity of data on treatment regimens in children. We retrospectively reviewed the outcomes of our pediatric patients that were treated for aAMR between 2007 and 2009. Three adolescent Hispanic males were found to have aAMR. All three received deceased donor transplants, and all three verbalized non-adherence. Treatment consisted of rituximab, solumedrol, PE, and IVIgG in one patient, and PE, IVIgG, and bortezomib in two patients. The only side effect of therapy noted was mild hypotension with rituximab that resolved after decreasing the infusion rate. There were no reported infections two yr after treatment, and all of the viral monitoring in these patients remained negative.

Highlights for the management of a child with hypertension.

Over the past several decades, childhood hypertension has undergone a considerable conceptual change, as hypertension is a predictor of future development of cardiovascular disease in adults. Childhood hypertension has distinctive features that distinguish it from hypertension in adults. Pediatric hypertension is often secondary. It is widely believed that therapeutic intervention at an early age favorably modifies the long-term outcome of hypertension. Despite its significance as a cause for morbidity, childhood hypertension is underdiagnosed and less studied with many basic issues remaining contentious.

Intraventricular rituximab and systemic chemotherapy for treatment of central nervous system post-transplant lymphoproliferative disorder after kidney transplantation.

PTLD of the CNS is a rare complication of solid organ transplantation, and there are only case reports/series available in the literature. Current literature suggests that CNS PTLD carries a worse prognosis than PTLD outside the CNS, and most are of B-cell lineage, predominantly monomorphic, and are associated with EBV infection. Because this disorder is so rare, there is no standard chemotherapy for pediatric patients with CNS PTLD and reported therapies for EBV-associated CNS PTLD are heterogeneous with mixed results. Since outcomes of CNS PTLD are historically poor, we attempted to develop a novel therapeutic treatment regimen. Based on a review of the literature and with the help of a multidisciplinary team, we created a regimen of chemotherapy that included dexamethasone and high-dose methotrexate in addition to intravenous and intraventricular Rituximab in two pediatric patients. The intraventricular chemotherapy succeeded in shrinking the tumor in both of our patients; however, as shown in the second case, the clinical outcome depends on the location of the tumor. Systemic and intraventricular therapies hold promise in the management of EBV-associated CNS PTLD; however the rarity of this entity prevents the development of well-designed studies necessary for the establishment of an evidence-based treatment standard.

Inosine monophosphate dehydrogenase (IMPDH) activity as a pharmacodynamic biomarker of mycophenolic acid effects in pediatric kidney transplant recipients.

Monitoring inosine monophosphate dehydrogenase (IMPDH) activity as a biomarker of mycophenolic acid (MPA)-induced immunosuppression may serve as a novel approach in pharmacokinetics (PK)/pharmacodynamics (PD)-guided therapy. The authors prospectively studied MPA pharmacokinetics and IMPDH inhibition in 28 pediatric de novo kidney transplant recipients. Pretransplant IMPDH activity and full PK/PD profiles were obtained at 3 different occasions: 1 to 3 days, 4 to 9 days, and approximately 6 months after transplant. Large intra- and interpatient variability was noted in MPA pharmacokinetics and exposure and IMPDH inhibition. MPA exposure (AUC(0-12 h)) was low early posttransplant and increased over time and stabilized at months 3 to 6. Mean pretransplant IMPDH activity (6.4 ± 4.6 nmol/h/mg protein) was lower than previously reported in adults. In most of the patients, IMPDH enzyme activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory E(max) model (EC(50) = 0.97 mg/L). This study suggests the importance of early PK/PD monitoring to improve drug exposure. Because IMPDH inhibition is well correlated to MPA concentration, pretransplant IMPDH activity may serve as an early marker to guide the initial level of MPA exposure required in a pediatric population.

Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review.

Focal segmental glomerulosclerosis is a major cause of chronic kidney disease requiring transplantation in children. Recurrence rate in the renal allograft transplantation is as high as 50%. Recurrence of FSGS is associated with renal dysfunction and early graft loss. To date, there is no established therapy for recurrent FSGS after renal transplant. We have reviewed the current English literature in order to summarize current practices with emphasis on graft outcome. We conclude that despite multiple approaches to the post transplant management of recurrent FSGS, none have been shown to be consistently beneficial. Currently, pheresis combined with high dose anti-calcineurin with or without rituximab seems to be the most promising. Further controlled studies are needed to define the optimal therapeutic regimens to treat recurrent of FSGS.

Strategies of treatment of pediatric hypertension.

Over the past two decades the attitudes of pediatric health care providers towards childhood hypertension, as a predictor of future development of hypertension in adults have undergone considerable conceptual change. Childhood hypertension has unique features that differentiate it from hypertension in adults. It is widely accepted that pediatric hypertension carries an increased risk for future cardiovascular morbidity and mortality. There is also a prevalent belief that therapeutic intervention at an early age may favorably modify the long-term outcome of hypertension. Despite its importance, childhood hypertension is understudied and several basic questions remain controversial. This article addresses several issues pertinent to the treatment of hypertension during childhood and discusses some of the newer pharmacological agents used in children.

Pediatric end stage renal disease health-related quality of life differs by modality: a PedsQL ESRD analysis.

We previously validated the 34-item PedsQL 3.0 End Stage Renal Disease (ESRD) Module designed to measure pediatric ESRD-specific health-related quality of life (HRQOL) in children and adolescents receiving maintenance dialysis or with a renal transplant. The study reported here was undertaken to assess for potential HRQOL differences between ESRD modality in children with ESRD and their parents using the PedsQL 3.0 ESRD Module. Parents of patients with a renal transplant reported a significantly higher HRQOL for their children than parents of pediatric patients receiving dialysis on all ESRD Module Scales except the Perceived Physical Appearance Scale, with the majority of the effect sizes in the medium range. Pediatric renal transplant patients self-reported comparable HRQOL to pediatric patients receiving dialysis across the ESRD Module Scales, with the exception of the Family and Peer Interaction Scale, in which pediatric renal transplant patients self-reported significantly higher HRQOL than pediatric patients receiving dialysis. Our cross-sectional data suggest that parents of children with ESRD observe a positive impact from renal transplantation on the majority of HRQOL domains compared to dialysis, whereas children self-report generally non-significant small effect size differences in favor of renal transplantation. These findings suggest that the PedsQL ESRD 3.0 Module may be used to identify ESRD- and modality-specific challenges that impact pediatric patient HRQOL.

The effect of rhGH on height velocity and BMI in children with CKD: a report of the NAPRTCS registry.

The aim of this investigation was to evaluate the impact of recombinant human growth hormone (rhGH) therapy on height velocity (HV), estimated glomerular filtration rate (eGFR) and body mass index (BMI) in a large cohort of children with chronic kidney disease (CKD). We reviewed longitudinal data from patients enrolled in the chronic renal insufficiency registry of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS). Of the 7189 patients enrolled in the registry, 827 (11.5%) received rhGH. A total of 787 children with CKD previously rhGH naïve who received rhGH for 1-4 years (median 1.5 years) were paired with 787 control patients, and over 100 of the case-controls were followed for 4 years. The control group was matched for age, gender, height and length of time in the NAPRTCS registry. Height velocity was also compared to the general U.S. population. The eGFR of the treated group (37.5 ml/min per 1.73 m(2)) was significantly less than that of the control group (42.3 ml/min per 1.73 m(2); p < 0.001). The rhGH-treated group had a significantly greater HV standard deviation score (SDS) than the control group (p < 0.01) at each 6-months post-rhGH treatment initiation point for 2.5 years (p < 0.007). Among 220 pairs at 2 years, the height SDS of the rhGH group was 0.56 SDS higher than that of the control group (p < 0.05). Treatment with rhGH had no significant impact on the BMI or eGFR. As demonstrated in smaller cohorts, rhGH usage is associated with improved HV in children with CKD. In contrast, rhGH does not appear to have any impact on BMI or kidney function in this population of patients.

Successful split liver-kidney transplant for factor H associated hemolytic uremic syndrome.

BACKGROUND AND OBJECTIVES: A male infant with a family history of thrombotic microangiopathy developed atypical hemolytic uremic syndrome (aHUS). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Case report. RESULTS: Genetic analysis demonstrated a heterozygous mutation (S1191L) of CFH, the gene coding complement factor H (CFH). The child suffered many episodes of HUS, each treated with plasma exchange. In time, despite initiation of a prophylactic regimen of plasma exchange, his renal function declined significantly. At the age of 4 yr he received a (split liver) combined liver-kidney transplant (LKT) with preoperative plasma exchange and enoxaparin anticoagulation. Initial function of both grafts was excellent and is maintained for nearly 2 yr. CONCLUSIONS: This report adds to the small but growing number of individuals in whom LKT has provided a favorable outcome for aHUS associated with CFH mutation, expands the technique of using a split liver graft, and describes the unique histologic features of subclinical liver disease in HUS.

Respiratory syncytial virus prophylaxis: a survey of pediatric solid organ transplant centers.

RSV can cause respiratory illness after SOT, yet preventive recommendations are lacking for this population. To ascertain current preventive practices against RSV disease in pediatric SOT candidates and recipients, a survey was developed. The survey was mailed to 108 SOT programs in the United States (liver, 42; heart, 28; lung, 11; intestinal, 25; and heart-lung, 2). Results were tabulated and analyzed using standard methods. Sixty-two percent (67/108) of surveys were completed. Forty-nine percent (33/67) of programs reported using RSV prophylaxis; palivizumab was used at 97% (32/33) of centers with 26 giving palivizumab to candidates and 27 to recipients. Prophylaxis was provided to infants aged 0-12 months by 27/29 (93%) of responding centers; 23/29 of centers extended its use to infants aged 0-24 months. Three centers gave prophylaxis to children between ages two and four yr and two centers for those over four yr. RSV prophylactic strategies, and in particular the use of palivizumab, are employed by almost 50% of responding pediatric SOT centers. Strategies varied at centers based on age and organ type. Data on RSV hospitalization and outcome are needed to refine approaches to RSV immunoprophylaxis in these high-risk patients.

Low bone mineral density in spinal muscular atrophy.

BACKGROUND AND PURPOSE: Pathological fractures are common in pediatric neuromuscular disorders. Dual-energy x-ray absorptiometry has become the most accepted technique for the measurement of bone mineral density (BMD) in adults and children. Limited data are available on BMD in pediatric neuromuscular diseases except Duchenne muscular dystrophy. METHODS: We retrospectively analyzed the results of all dual-energy x-ray absorptiometry scans done in a period of 23 months at a tertiary care pediatric neuromuscular center. BMD was performed on spine region L1-4. Osteopenia was classified as mild if the Z scores were between 0 and -1.5, moderate if Z scores were between -1.5 and -2.5, and severe if Z scores were > -2.5 standard deviation scores. RESULTS: Eighty-four dual-energy x-ray absorptiometry scans were performed on 79 patients between the ages of 4 months and 18 years with the mean age of 8 years. Z scores were used to compare their BMDs. BMD was lowest in patients with spinal muscular atrophy (SMA) with Z score of -2.25 +/- 0.31 standard deviation scores. The Z score for patients with Duchenne muscular dystrophy was -1.72 +/- 0.1. The BMD in nonambulatory patients with SMA was significantly decreased compared with ambulatory patients with SMA (P < 0.05). CONCLUSIONS: We conclude that osteopenia is common in children with neuromuscular disorders. Patients with SMA have the lowest BMD.