Search

Background Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients. Methods To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children’s Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD. Results By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients. Conclusions Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.

Nephrolithiasis is a prevalent condition with a high morbidity. Although dozens of monogenic causes have been identified, the fraction of single-gene disease has not been well studied. To determine the percentage of cases that can be molecularly explained by mutations in 1 of 30 known kidney stone genes, we conducted a high-throughput mutation analysis in a cohort of consecutively recruited patients from typical kidney stone clinics. The cohort comprised 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis ( n =256) or isolated nephrocalcinosis ( n =16). We detected 50 likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases; 20 of 50 detected mutations were novel (40%). The cystinuria gene SLC7A9 ( n =19) was most frequently mutated. The percentage of monogenic cases was notably high in both the adult (11.4%) and pediatric cohorts (20.8%). Recessive causes were more frequent among children, whereas dominant disease occurred more abundantly in adults. Our study provides an in-depth analysis of monogenic causes of kidney stone disease. We suggest that knowledge of the molecular cause of nephrolithiasis and nephrocalcinosis may have practical implications and might facilitate personalized treatment.

Thirty-four children were entered into a pilot trial of calcineurin inhibitor avoidance after living-donor kidney transplantation, the CN-01 study. Patients were treated with anti-CD25 mAb, prednisone, mycophenolate mofetil, and sirolimus. Twenty patients were maintained on the protocol for up to 3 yr of follow-up. One enrolled patient did not receive the transplant because of a donor problem, eight terminated because of one or more rejection episodes, four terminated because of adverse events, and one was lost to follow-up. Two grafts were lost, one as a result of chronic rejection and the other as a result of posttransplantation lymphoproliferative disorder. There were no deaths. The 6- and 12-mo acute rejection rates were 21.8 and 31.5%, respectively. GFR were stable throughout the course of the study, with a slight downward trend by 6 mo after transplantation followed by a slight upward trend to a mean of 70 ml/min thereafter. Early surveillance graft biopsies frequently showed focal interstitial mononuclear cellular infiltrates without overt vasculitis or tubulitis, but these infiltrates disappeared without treatment. Anti-HLA class I and II antibodies were detected in three patients before transplantation, and all three had acute rejections, including the two patients who lost their grafts. De novo anti-HLA Ab production occurred in only one patient after transplantation. There were two episodes of Epstein Barr virus-related posttransplantation lymphoproliferative disorder, one of which developed after the patient had been terminated from the study. It is concluded that calcineurin inhibitor-free immunosuppression can be safe and effective in pediatric living-donor renal transplantation. However, further modifications that are designed to lessen early rejection rates and decrease complications should be tested before this approach is used routinely.

SRL is an mTOR inhibitor that provides several advantages over CNI immunosuppressive protocols. mTOR inhibitors such as SRL have been shown to result in less renal and gastrointestinal toxicity, and beneficial effects on countering vascular proliferation in comparison with 4 CNI such as cyclosporine and tacrolimus. Complications of SRL include hyperlipidemia that often requires co-therapy with lipid-lowering agents, and transient thrombocytopenia. Current SRL use in children is based mostly on extrapolation of PK data in adult transplant recipients and single dose PK data in children on hemodialysis. One study of adult transplant recipients showed that the SRL T1/2 is 62 ± 16 h (1). Another study of single dose SRL in 16 stable, adult renal transplant recipients showed that the elimination T1/2 ranged from 43.8 to 86.5 h, with a mean of 56.9 h (2). A single dose PK study in uremic children on hemodialysis showed similar T1/2 values (70.5 ± 40 h in children and 55.3 ± 18 h in adolescents) (3). However, these data do not reflect steady state SRL PK in stable, pediatric renal transplant recipients. Previously, young children were reported to have poor short and long-term graft survival. Proposed reasons for this poor survival included an hypothesized heightened immune response, especially in infants (4, 5). However, other causes were likely more important. Children are known to have higher rates of drug metabolism, particularly with respect to key cytochrome enzymes compared with adults (6–12). Faster drug metabolism is very likely the reason why cyclosporine T1/2 is notoriously shorter in children compared with adults. One study determined that cyclosporine T1/2 was 9.3 h in children, compared with 16–27 h in adults (13). Therefore, it is possible that lack of pediatric-specific PK information previously led to insufficient provision of these drugs to children. Thus, suboptimal immunosuppression, rather than an inherent immune hyper-responsiveness, may have been the cause of higher rejection rates previously seen in young children. Improved age-specific dosing, therefore, may have been instrumental in the recently observed improved outcomes in children (14, 15). We have initiated an experimental protocol of IL-2r antibody induction, prednisone, MMF and SRL in pediatric renal transplant recipients, including SRL PK studies at 1 and 3 months after transplantation. The goal of this study is to assess SRL PK in children on a CNI-free protocol, and to determine whether these pediatric renal transplant recipients require different doses or dosing schedules of SRL.