Kidney transplantation in children and adolescents with C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis: a real-world study within the CERTAIN research network.

BACKGROUND: Complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40-50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the transplanted kidney. However, there is a lack of published data on clinical outcomes in the pediatric population following transplantation. METHODS: In this multicenter longitudinal cohort study of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, we compared the post-transplant outcomes of pediatric patients with C3G (n = 17) or IC-MPGN (n = 3) with a matched case-control group (n = 20). RESULTS: Eleven of 20 children (55%) with C3G or IC-MPGN experienced a recurrence within 5 years post-transplant. Patients with C3G or IC-MPGN had a 5-year graft survival of 61.4%, which was significantly (P = 0.029) lower than the 5-year graft survival of 90% in controls; five patients with C3G or IC-MPGN lost their graft due to recurrence during this observation period. Both the 1-year (20%) and the 5-year (42%) rates of biopsy-proven acute rejection episodes were comparable between patients and controls. Complement-targeted therapy with eculizumab, either as prophylaxis or treatment, did not appear to be effective. CONCLUSIONS: These data in pediatric patients with C3G or IC-MPGN show a high risk of post-transplant disease recurrence (55%) and a significantly lower 5-year graft survival compared to matched controls with other primary kidney diseases. These data underscore the need for post-transplant patients for effective and specific therapies that target the underlying disease mechanism.

Urine soluble TLR4 levels may contribute to predict urinary tract infection in children: the UTILISE Study.

BACKGROUND: One of the most common bacterial infections in childhood is urinary tract infection (UTI). Toll-like receptors (TLRs) contribute to immune response against UTI recognizing specific pathogenic agents. Our aim was to determine whether soluble TLR4 (sTLR4), soluble TLR5 (sTLR5) and interleukin 8 (IL-8) can be used as biomarkers to diagnose UTI. We also aimed to reveal the relationship between urine Heat Shock Protein 70 (uHSP70) and those biomarkers investigated in this study. METHODS: A total of 802 children from 37 centers participated in the study. The participants (n = 282) who did not meet the inclusion criteria were excluded from the study. The remaining 520 children, including 191 patients with UTI, 178 patients with non-UTI infections, 50 children with contaminated urine samples, 26 participants with asymptomatic bacteriuria and 75 healthy controls were included in the study. Urine and serum levels of sTLR4, sTLR5 and IL-8 were measured at presentation in all patients and after antibiotic treatment in patients with UTI. RESULTS: Urine sTLR4 was higher in the UTI group than in the other groups. UTI may be predicted using 1.28 ng/mL as cut-off for urine sTLR4 with 68% sensitivity and 65% specificity (AUC = 0.682). In the UTI group, urine sTLR4 levels were significantly higher in pyelonephritis than in cystitis (p < 0.0001). Post-treatment urine sTLR4 levels in the UTI group were significantly lower than pre-treatment values (p < 0.0001). CONCLUSIONS: Urine sTLR4 may be used as a useful biomarker in predicting UTI and subsequent pyelonephritis in children with UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Different approaches among physicians to treat pediatric stone disease: a survey-based study. / Distintos enfoques adoptados por los médicos para tratar la nefrolitiasis en pediatría: estudio basado en una encuesta.

INTRODUCTION: Pediatricians, surgeons and subspecialties as pediatric urology and nephrology are involved in the diagnosis and treatment of pediatric renal stone disease (RSD). The aim of this study was to determine diagnostic and treatment approaches, of different disciplines, and to assess differences in their routine diagnostic and treatment protocols. POPULATION AND METHODS: A questionnaire was designed and administered to the participants of the RSD sessions in national congresses of all disciplines in 2017 to evaluate the diagnostic and treatment routines of specialties (surgeons and pediatricians) and subspecialties (pediatric nephrologists and pediatric urologists) for RSD. RESULTS: A total, of 324 questionnaires were analyzed, from 88 pediatricians (27 %), 121 urologists (37 %), 23 pediatric surgeons (7 %), 54 pediatric nephrologists (17 %), and 38 pediatric urologists (12 %). Both groups agreed on the necessity of metabolic evaluation. For distal ureter stones that were ≥ 6 mm; surgeons preferred ureteroscopy (URS), pediatricians preferred shock wave lithotripsy (SWL) (p < 0.001) and subspecialties preferred URS for the treatment (p = 0.636). For lower calix stones less than 1 cm surgeons and subspecialists preferred SWL, while pediatricians preferred hydration (p < 0.001, p = 0.371). For the stone between 1.1 and 2 cm, surgeons preferred intrarenal surgery (RIRS) and SWL, pediatricians preferred SWL (p = 0.001). For larger stones, surgeons and subspecialists preferred percutaneous nephrolithotomy (PCNL), and pediatricians preferred SWL (p = 0.458 p = 0.001). Pediatric urologist chose low-dose computerized tomography as a diagnostic radiologic evaluation (p = 0.029). CONCLUSION: There are differences between the disciplines who take an active role in diagnosis and treatment of RSD.

Introducción. Los pediatras, cirujanos y subespecialistas, como urólogos y nefrólogos pediátricos, participan en el diagnóstico y tratamiento de la nefrolitiasis pediátrica. El objetivo fue determinar los enfoques de distintas disciplinas y evaluar las diferencias en sus protocolos de diagnóstico y tratamiento habituales. Población y métodos. Cuestionario administrado a participantes de sesiones sobre nefrolitiasis en congresos nacionales en 2017 para evaluar las rutinas de diagnóstico y tratamiento de la nefrolitiasis entre distintas especialidades (cirujanos y pediatras) y subespecialidades (nefrólogos pediátricos y urólogos pediátricos). Resultados. Se analizaron 324 cuestionarios de 88 pediatras, 121 urólogos, 23 cirujanos pediátricos, 54 nefrólogos pediátricos y 38 urólogos pediátricos. Ambos grupos coincidieron en la necesidad de una evaluación metabólica. Para los cálculos ureterales distales ≥6 mm, los cirujanos preferían una ureteroscopía; los pediatras, una litotricia por ondas de choque (LOC) (p < 0,001); y los subespecialistas, una ureteroscopía (p = 0,636). Para los cálculos en la parte inferior de los cálices renales < 1 cm, los cirujanos y los subespecialistas preferían la LOC y los pediatras, la hidratación (p < 0,001; p = 0,371). Para los cálculos de entre 1,1 cm y 2 cm, los cirujanos preferían la cirugía retrógrada intrarrenal (CRIR) y la LOC, y los pediatras, la LOC (p = 0,001). Para los cálculos más grandes, los cirujanos y subespecialistas preferían la nefrolitotomía percutánea (NLP) y los pediatras, la LOC (p = 0,458; p = 0,001). Conclusión. Existen diferencias entre las disciplinas que participan activamente en el diagnóstico y tratamiento de la nefrolitiasis.

Does Voiding Cystourethrogram Exclude Posterior Urethral Valves in Late Presenting Cases?

INTRODUCTION: Delayed presentation of posterior urethral valves (PUVs) is a rare condition. Presentation and diagnosis of the patients with late PUVs are challenging. Voiding cystourethrogram (VCUG) is mainly practiced. In this study, we aimed to evaluate the children with late-presented PUVs, and the reliability of VCUG in this group. MATERIALS AND METHODS: Between January 2003 and December 2017 records of patients who were diagnosed with late-presented PUVs were analyzed. Delayed presentation of PUV was defined as patients who were diagnosed and treated after infancy. Cases were examined in terms of age at diagnosis, presenting symptoms, urinalysis, urinary ultrasound, urodynamic studies, VCUG, and dimercaptosuccinic acid scintigraphy findings. Postoperative follow-up conditions were also assessed. RESULTS: Seventeen boys were diagnosed with late-presented PUVs (mean age was 7.35 years). The most common symptoms at presentation were frequency (58.8%), day and nighttime incontinence (47%), and febrile urinary infection (41%). PUV was noted by VCUG in 10 patients alone. The classical sign of dilated posterior urethra was detected in 9 patients. The 10th patient had posterior urethral irregularity. Urethra could not be evaluated due to unsuccessful voiding in one patient. Six patients had normally appearing urethra on VCUG. Reflux was detected in nine (52.9%) patients. CONCLUSION: Late-presented PUVs may be missed on VCUG. Whether a PUV might be present is crucial in boys with a history of recurrent urinary infection, persistent reflux, and repetitive daytime incontinence. Based on our results, we conclude that cystoscopic examination should be preferred for those cases to diagnose PUVs regardless of VCUG results.

Urinary biomarkers in the early detection and follow-up of tubular injury in childhood urolithiasis.

BACKGROUND: To investigate relationships among urinary biomarkers [kidney injury molecule-1 (KIM-1), N-acetyl-ß-glucosaminidase (NAG)], neutrophil gelatinase-associated lipocalin (NGAL) levels and renal tubular injury in childhood urolithiasis. METHODS: Seventy children [36 girls, mean age: 7.3 ± 5.0 years (0.5-18.2)] with urolithiasis/microlithiasis and 42 controls [18 girls, mean age: 8.5 ± 3.8 years (0.9-16.2)] were included in this multicenter, controlled, prospective cohort study. Patients were evaluated three times in 6-month intervals (0, 6 and 12th months). Anthropometric data, urinary symptoms, family history and diagnostic studies were recorded. Urine samples were analyzed for metabolic risk factors (urinary calcium, uric acid, oxalate, citrate, cystine, magnesium, and creatinine excretion), and the urinary KIM-1, NAG, and NGAL levels were measured. RESULTS: Stones were mostly located in the upper urinary system (82.9%), and six patients (8.6%) had hydronephrosis. Thirty patients (42.9%) had several metabolic risk factors, and the most common metabolic risk factor was hypocitraturia (22.9%). Urinary KIM-1/Cr, NAG/Cr and NGAL/Cr ratios were not significantly different between patients and controls. Furthermore, no significant changes in their excretion were shown during follow-up. Notably, the urinary KIM-1/Cr, NAG/Cr, and NGAL/Cr levels were significantly higher in children under 2 years of age (p = 0.011, p = 0.006, and 0.015, respectively). NAG/Cr and NGAL/Cr ratios were significantly increased in patients with hydronephrosis (n = 6, p = 0.031 and 0.023, respectively). CONCLUSIONS: The results of this study suggest that none of the aforementioned urinary biomarkers (KIM-1, NAG and NGAL levels) may be useful for the early detection and/or follow-up of renal tubular injury and/or dysfunction in childhood urolithiasis.

Comparison of recombinant human erythropoietin and darbepoetin alpha in children.

BACKGROUND: The aim was to compare the clinical efficacy of recombinant human erythropoietin (rHuEPO) and darbepoetin alpha (DA) in the treatment of anemia in children with chronic kidney disease (CKD). METHOD: Thirty-four (13 female, 21 male) CKD patients were enrolled in the study. Mean age was 11.42 ± 4.05 years. Nine patients were on hemodialysis, 18 were on peritoneal dialysis and seven patients were in CKD stage 4. RESULTS: Seventeen patients received rHuEPO and the remaining 17 patients received DA. Hemoglobin (Hb) was not significantly different between the two groups during monthly follow up and at the end of 6 months (P > 0.05), but there was a significant increase within each group at the end of 6 months (P = 0.01 for rHuEPO; P = 0.02 for DA). Hb was not different between the patients on and not on dialysis in both groups at the end of the study (P > 0.05). The efficacy of the s.c. and i.v. routes was similar within each group (P > 0.05). Systolic hypertension was observed in only one patient in the DA group, no other adverse effect was observed in either groups. CONCLUSION: DA is a reasonable alternative to rHuEPO in the treatment of anemia in pediatric CKD patients, due to its clinical efficacy, convenience of use, patient compliance and tolerability.

Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome.

BACKGROUND: Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCepsilon1) have been recently described in patients with early onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported. METHOD: In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, mutational analysis was performed in a worldwide cohort of 139 patients (95 familial cases belonging to 68 families and 44 sporadic cases) with steroid resistant NS presenting at a median age of 23.0 months (range 0-373). RESULTS: Homozygous or compound heterozygous mutations were identified in 33% (8/24) of DMS cases. PLCE1 mutations were found in 8% (6/78) of FSGS cases without NPHS2 mutations. Nine were novel mutations. No clear genotype-phenotype correlation was observed, with either truncating or missense mutations detected in both DMS and FSGS, and leading to a similar renal evolution. Surprisingly, three unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families. CONCLUSION: PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although additional variants in 19 candidate genes (16 other PLC genes, BRAF,IQGAP1 and NPHS1) were not identified, it is speculated that other modifier genes or environmental factors may play a role in the renal phenotype variability observed in individuals bearing PLCE1 mutations. This observation needs to be considered in the genetic counselling offered to patients.

EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria.

OBJECTIVES: To validate the previously proposed classification criteria for Henoch-Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA). METHODS: Step 1: retrospective/prospective web-data collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis

[A case of brown tumor mimicking fibrous dysplasia in a patient with chronic renal failure]. / Kronik böbrek yetersizligi olan bir hastada fibröz displaziye benzeyen kahverengi (brown) tümör.

Renal osteodystrophy is one of the major causes of morbidity in patients receiving long-term dialysis treatment for renal failure and after transplantation. Its clinical implications include high-turnover bone disease, low-turnover bone disease, osteomalacia, osteosclerosis, and osteoporosis. A 13-year-old boy who had been on dialysis treatment for renal failure was admitted with a pathologic supracondylar femur fracture after a minor trauma. Radiological studies showed cystic lesions in the femoral supracondyle, left acetabular roof, and right proximal and distal tibia. Based on radiologic appearances of the lesions and on histopathologic findings of the lesion excised from the right distal tibia, brown tumor and fibrous dysplasia were considered in the differential diagnosis. Initially, serum parathyroid hormone level was slightly increased and calcium level was normal, but during follow-up, serum parathyroid hormone level increased significantly, enabling the diagnosis of brown tumor.

Is paraoxonase 192 gene polymorphism a risk factor for membranoproliferative glomerulonephritis in children?

We investigated the effects of paraoxonase (PON1) 192 polymorphism on serum PON1 activity and the impact of phenotypic expression on the risk and prognosis of Turkish children with membranoproliferative glomerulonephritis (MPGN). Eighteen children with biopsy-proven Type I MPGN (10 boys, 8 girls) and age-matched 53 healthy controls were included in the study. PCR (polymerase chain reaction), RFLP (restriction fragment length polymorphism) and agarose gel electrophoresis techniques were used to determine the PON1 192 genotype. PON1 activity was measured by spectrophotometric assay of p-nitrophenol production following addition of paraoxon. We found that PON1 192 genotype distribution (AA, AB, BB) in MPGN patients were 61.1%, 22.3%, 16.6% and 15.1%, 35.8%, 49.1% in controls, respectively. The frequency of AA genotypes was significantly higher in the MPGN group (0.611) compared with the healthy controls (0.151) (p < 0.001). Although the serum PON1 activity was lower in MPGN patients (103.3 +/- 55.2 U/l) than the healthy controls (130.9 +/- 71.2 U/mol), the difference was not statistically significant (p = 0.0563). In the genotypes of patients and controls classified according to PON1 A/B polymorphism; serum PON1 activities were significantly increased (p < 0.001, ANOVA) in the order of PON1 AA, AB and BB in both MPGN patients (82.4, 91.7 and 173.6 U/l) and healthy controls (85.9, 119.9 and 193.1 U/l), respectively. There was a significant relationship between the poor prognosis and having AA genotype and low PON1 activity. Of the 8 patients with poor prognosis, 7 had genotype AA and the remaining one was AB heterozygote. Our results suggest that homozygosity for the A allele might have an important role on the risk for developing MPGN and may also be associated with the poor prognosis of disease. In conclusion, we suggest that the PON1 activities are affected by PON1 genetic variability in Turkish patients with MPGN.

Crescentic glomerulonephritis in a child with infective endocarditis.

Renal manifestations associated with infective endocarditis (IE) may present with different clinical patterns, and the most common renal histopathological finding is diffuse proliferative and exudative type of glomerulonephritis, leading to hematuria and/or proteinuria. Renal failure due to crescentic glomerulonephritis (CGN) in children with IE is a very rare condition. We report here a 6-year-old boy, who had a history of cardiac surgery for pulmonary atresia and ventricular septal defect, presenting with the clinical findings of IE and hematuria associated with renal failure due to CGN. He was treated with a combination of intravenous (IV) methylprednisolone pulses and appropriate antibiotics, but also received one dose of IV cyclophosphamide. Complete serological, biochemical, and clinical improvement was achieved after 2 months of follow-up. Antibiotic therapy is the essential part of the treatment of IE-associated glomerulonephritis; however, this case also highlights the importance of aggressive immunosuppressive therapy to suppress the immunological process related with infection in this life-threatening condition leading to renal failure.

Brain calcification due to secondary hyperparathyroidism in a child with chronic renal failure.

Secondary hyperparathyroidism (SHPT) has been better treated over the last decades, but the rate of metastatic calcifications, which were rarely seen before, was significantly increased in dialysis patients. The presence of uncontrolled SHPT, disorders of calcium (Ca) and phosphorus homeostasis and the common usage of large doses of vitamin D and Ca- containing phosphate binders may all contribute to the metastatic calcifications of soft tissues and vasculature leading to some life-threatening complications. Although the metastatic lung, heart, kidney, intestinal wall, skin, eye and soft tissue calcifications have been commonly reported in adults and also in children undergoing dialysis, the central nervous system calcification is a very rare condition. We report here a pediatric hemodialysis patient who presented with severe neurological findings due to the metastatic brain calcification secondary to his uncontrolled hyperparathyroidism.

Central nervous system vasculitis secondary to parvovirus B19 infection in a pediatric renal transplant patient.

Central nervous system (CNS) vasculitis secondary to chronic parvovirus B19 (B19) infection presenting with recurrent neurological findings is a very rare disorder during childhood. Here we report a 12-year-old boy with a renal transplant who had chronic B19 infection with skin eruptions and recurrent episodes of encephalopathy with focal neurological deficits. B19 DNA was detected in blood, bone marrow, and skin biopsy specimens. Repeat cranial magnetic resonance (MR) imaging during each episode of encephalopathy showed variable focal findings, and MR angiography revealed vasculitic changes with narrowing of the cerebral arteries. We hypothesized that the CNS vasculitis might be associated with the chronic B19 infection. At the time of his fourth presentation with the same clinical findings, we administered intravenous immunoglobulin (IVIG) (1 g/kg per day, 2 consecutive days), which we continued for 6 months, at monthly intervals. IVIG therapy resulted in remission and has been effective not only for the clearance of B19, but also for the improvement of clinical and radiological findings of CNS vasculitis. We suggest that chronic B19 infection should be considered in immunocompromised patients with suspected CNS vasculitis. IVIG should be considered as a part of the treatment.

Pyelolithotomy in a patient with Glanzmann thrombasthenia and antiglycoprotein IIb/IIIa antibodies: the shortest possible duration of treatment with recombinant activated factor VII and platelet transfusions.

Transfusion of platelet concentrates remains the first-line therapy for Glanzmann thrombasthenia in case of bleeding or preparation for surgery. However, development of antibodies to platelet glycoprotein (Gp) IIb/IIIa complex or human leukocyte antigens (HLA) is frequent and the main cause of platelet refractoriness. Recombinant activated factor VII (rFVIIa) is a potent alternative for patients with Glanzmann thrombasthenia with anti-platelet antibodies. We describe a case of Glanzmann thrombasthenia with alloantibodies to platelet Gp IIb/IIIa complex who underwent a successful pyelolithotomy operation under the coverage of recombinant activated factor VIIa and platelet transfusions.