Inherited kidney diseases are among the leading causes of kidney failure in children, resulting in increased mortality, high healthcare costs and need for organ transplantation. Next-generation ...sequencing technologies can help in the diagnosis of rare monogenic conditions, allowing for optimized medical management and therapeutic choices.
Clinical exome sequencing (CES) was performed on a cohort of 191 pediatric patients from a single institution, followed by Sanger sequencing to confirm identified variants and for family segregation studies.
All patients had a clinical diagnosis of kidney disease: the main disease categories were glomerular diseases (32.5%), ciliopathies (20.4%), CAKUT (17.8%), nephrolithiasis (11.5%) and tubular disease (10.5%). 7.3% of patients presented with other conditions. A conclusive genetic test, based on CES and Sanger validation, was obtained in 37.1% of patients. The highest detection rate was obtained for ciliopathies (74.4%), followed by nephrolithiasis (45.5%), tubular diseases (45%), while most glomerular diseases and CAKUT remained undiagnosed.
Results indicate that genetic testing consistently used in the diagnostic workflow of children with chronic kidney disease can (i) confirm clinical diagnosis, (ii) provide early diagnosis in the case of inherited conditions, (iii) find the genetic cause of previously unrecognized diseases and (iv) tailor transplantation programs.
Background and objectives Children with multi-drug resistant idiopathic nephrotic syndrome (MDR-INS) usually progress to end-stage kidney disease with a consistent risk of disease recurrence after ...transplantation. New therapeutic options are needed for these patients. Mesenchymal stromal cells (MSCs) are multipotential non-hematopoietic cells with several immunomodulatory properties and growing clinical applications. Cord blood-derived MSC have peculiar anti-inflammatory and immunosuppressive properties. We aimed at assessing safety and efficacy of cord-blood-derived MSCs (CB-MSCs) in children with MDR-INS. Design, setting, participants Prospective, open-label, single arm phase I-II pilot study. Pediatric patients with MDR-INS, resistant to at least two lines of therapy, were enrolled. Allogenic CB-MSCs were administered intravenously on days 0, 14, and 21 at a dose of 1.5 x 10.sup.6 cells/kg. Patients were followed for at least 12 months. The primary outcomes were safety and toxicity. The secondary outcome was remission at 12 months evaluated by urinary protein/urinary creatinine ratio (uPr/uCr). Circulating regulatory T cells (Tregs) were monitored. Results Eleven pediatric patients with MDR-INS (10 females, median age 13 years) resistant to a median of 3 previous lines of therapy were enrolled. All patients completed the CB-MSC infusion schedule. No patient experienced any infusion-related adverse event or toxicity. Nine patients were assessable for efficacy. At the 12 months follow-up after the treatment, the median uPr/uCr did not change significantly from baseline (8.13 vs. 9.07; p = 0.98), while 3 patients were in partial or complete remission. A lower baseline uPr/uCr was a predictor of remission (2.55 vs. 8.74; p = 0.0238). Tregs count was not associated with CB-MSCs therapy. Conclusions CB-MSCs are safe and may have a role in the immunosuppressive therapy of pediatric patients with MDR-INS. This preliminary experience paves the way toward further phase II studies addressing MSC efficacy in immune-mediated kidney diseases. Keywords: Idiopathic nephrotic syndrome, Mesenchymal stromal cells, Multi-drug resistant nephrotic syndrome, Children, Advanced therapy medical products, Cord-blood-derived mesenchymal stromal cells
Abstract
Background and Aims
Severe primary hyperoxaluria type 1 (PH1) with rapid onset nephrocalcinosis and renal function loss in early infancy required so far combined liver and kidney transplant. ...RNA interfering drugs are the new challenge for these children. Here we present the first case of a newborn affected by PH1 treated with RNA-interfering Lumasiran 6 hours after birth.
Method
Diagnosis of PH1 (homozygous mutation AGXT c.731T>C9 p.Ile244Thr) was done at 11 weeks of pregnancy on chorionic villus due to family history. Parents are first cousins, both heterozygous carriers of the mutation. Their first child is homozygous, affected by PH1, in dialysis for massive nephrocalcinosis since two months of life, kidney-liver transplanted at 14 months, with multiple comorbidities, severe retinal oxalate deposition, early ischemic stroke and post-transplant lympho-proliferative disease. Mother blood Oxalate, Glycolate and Urinary Oxalate during pregnancy proved normal (3 umol/L and 4 umol/L; 35 umol/mmol). Fetal morphology at ultrasound was normal, showing a male fetus large for gestational age, due to gestational diabetes, and polyhydramnios. At 37w cesarean section was performed. Birth weight 4120 g; Length 49.9 cm (99° centile for gestational age). Apgar score 9/9. Cord blood and amniotic fluid were obtained for Oxalate dosage and Sanger sequencing for diagnosis confirmation. Umbilical central venous line and bladder catheter were placed for immediate start of infusions and serial sampling.
Results
PH1 was confirmed due to Homozygous mutation AGXT c.731T>C9 p.(Ile244Thr). Oxalate on cord blood was 15 umol/L (nv <10), on amniotic fluid 55 umol/L (nv 19-71), on first urine 401 umol/mmolCr (nv < 300 umol/mmolCr). Blood Oxalate at 6h of life rose to 32 umol/L, Glycolate to 107 umol/L and urinary Oxalate to 573 umol/mmolCr. Serum Creatinin was normal (0.3 mg/dl). At 6 hours of life the child was treated with Glycolate Oxidase RNAi Lumasiran at the dose 6 mg/kg subcutaneously, in combination with Pyridoxin 10 mg/kg/day. Hyperhydration (240 ml/kg/day) was maintained iv for 16 days in combination with oral water and potassium citrate (500 mg in 500 ml/day) above breast feeding. Blood Oxalate was serially assessed every 48 hrs showing a peak level of 108 umol/l (nv <10) at day 6, higher than the supersaturation level of 60 umol/L, then a gradual decline (65-56-62 umol/L at 10-20-30 days respectively). Lumasiran 6 mg/kd was repeated at 30 and 60 days according to schedule, then at 3 mg/kg every month. After the second dose of Lumasiran a steeper decline of blood Oxalate was observed (31-17 umol/L at 45-60 days respectively) reaching the upper normal limit of 12 umol/L after three doses, at 80 days. Urinary Oxalate in spite of Lumasiran early start rose until a maximum of 4173 umol/mmolCr (nv for age <300 umol/mmolCr) at 13 days and gradually declined to 765 umol/mmolCr at 80 days, after three doses. Blood and urine Glycolate initially paralleled Oxalate then increased after each Lumasiran dose. Renal ultrasound normal at birth, showed only minimal hyperechogenic spots during the first 2 months, then mild bilateral hyperechogenic papillary deposits without signs of nephrocalcinosis/stones. Renal function at 3 months of life is normal (serum Creatinine 0.2 mg/dl); child growth on the higher centiles (7 kg), with no adverse events.
Conclusion
Blood and urine Oxalate serial analysis in a severe case of PH1 treated immediately after birth show that Glycolate Oxidase inhibition has a latency of at least 15 days, even when no previous deposits are present. In these days extremely high level of urine and blood Oxalate, far higher than supersaturation level, are reached, in spite of normal renal function, hyperhydration, B6 and citrate supplementation. This case confirms that familiar severe forms of PH1 should be treated immediately after birth with Lumasiran in combination with aggressive supportive therapy to avoid irreversible nephrocalcinosis and renal failure. Prenatal treatment of these cases might be considered in future.
Background Bone alterations in young renal transplant recipients were investigated in several studies with conflicting results. Quantitative ultrasound of the phalanges is a recently developed ...noninvasive procedure to assess skeletal status. Study Design Cross-sectional study at a single transplant center with values compared with previously studied healthy controls. Settings & Participants 40 children and young adult recipients of renal grafts (15 females, 25 males; age, 20.0 ± 8.4 years) studied 7.1 ± 3.8 years after kidney transplantation. Predictor Clinical, biochemical, and therapeutic features, including calcium, phosphate, and intact parathormone levels; and cumulative dosages of glucocorticoids and cyclosporine administered since transplantation. Outcome & Measurement Phalangeal quantitative ultrasound, including amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT), mainly dependent on mineral density and cortical thickness, respectively. Age- and sex-matched healthy controls were used to provide age-related z scores; sex- and height-matched healthy subjects, to provide z scores related to statural age. Results Mean z scores of AD-SoS and BTT were −0.05 ± 1.59 and −0.54 ± 1.17, respectively ( P > 0.05 and P < 0.001, respectively). Multivariate analysis showed that AD-SoS z score was associated significantly with body mass index, intact parathormone level, cumulative glucocorticoids administered in the first posttransplantation year, and cyclosporine administered since transplantation (model r2 = 0.79; P < 0.001); BTT z score was associated significantly with glucocorticoid dosage in the first posttransplantation year and age (model r2 = 0.55; P < 0.001). Limitations Absence of other measures of bone structure and longitudinal measures and comparison to a noncurrent control group. Conclusions Children and young adults may have decreased cortical thickness with maintained overall mineral density after renal transplantation. The findings of phalangeal quantitative ultrasound parallel observations using other imaging techniques. Phalangeal quantitative ultrasound may be a useful method to assess bone alternations after renal transplantation.
Unavailability of the iliac-caval system due to thrombosis or aberrant anatomy may preclude kidney transplantation (KT) in small infants, exposing them to the complications of long-term dialysis. A ...tailored approach may enable KT also in these difficult patients.
We report the cases of 2 pediatric patients with a history of long-term hemodialysis, a previously failed KT, pending exhaustion of vascular accesses for dialysis, and unsuitability of the iliac-caval axis as a site for KT. Both patients were successfully managed by using splenic vessels as a source of arterial inflow or venous drainage during KT. Notably, one patient also had a previous liver transplant.
Both kidney grafts showed primary function. Posttransplant courses were uneventful, and no rejection episode was observed. At 64- and 10-mo follow-ups, both children had optimal renal function and excellent quality of life.
When the iliac-caval system is unavailable, kidney graft implantation on splenic vessels represents a safe and effective option for pediatric KT.
Corticosteroid-related toxicity in children with steroid-sensitive nephrotic syndrome is primarily related to the cumulative dose of prednisone. To optimize treatment of relapses, we conducted the ...PROPINE study, a multicentric, open-label, randomized, superiority trial. Seventy-eight relapsing children aged 3-17 years who had not received steroid-sparing medications during the previous 12 months were randomized to receive, from day five after remission, either 18 doses of 40 mg/m2 of prednisone on alternate days (short arm), or the same cumulative dose tapered over double the time (long arm). Patients were monitored with an ad-hoc smartphone application, allowing daily reporting. The primary outcome was the six-month relapse rate at which time, 23/40 and 16/38 patients had relapsed in the long and short arms, respectively (no significant difference). Additionally, 40/78 patients were also enrolled in a secondary crossover study and were allocated to the opposite arm. Altogether, at six months, the relapse rate was 32/40 and 28/40 in the long and short arms, respectively (no significant difference). A post-hoc analysis excluding 30 patients treated with low-dose prednisone maintenance therapy failed to show significant differences between the two arms. No differences in adverse events, blood pressure and weight gain were observed. Thus, our data do not support the prescription of prolonged tapering schedules for relapses of steroid-sensitive nephrotic syndrome in children.
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Background:
Factors predictive of renal outcome were investigated in 219 cases of biopsy-proven Henoch-Schönlein purpura nephritis (HSPN); 83 children and 136 adults enrolled in a national study were ...followed up for up to 27 years (median, 4.5 years).
Methods:
The criterion for defining disease progression was time elapsed until doubling of baseline creatinine level and until dialysis therapy. Age, sex, data at onset (renal function, proteinuria, hematuria, hypertension, and crescents), and data during follow-up (proteinuria and therapy) were tested as covariates.
Results:
Multivariate Cox regression analysis indicated the following parameters as independent prognostic predictors: age (adults versus children, relative risk, 3.57; 95% confidence interval, 1.18 to 10.79;
P = 0.024 for creatinine level doubling; relative risk, 14.89; 95% confidence interval, 1.72 to 129.07;
P = 0.014 for dialysis therapy), sex (females versus males, relative risk, 5.71; 95% confidence interval, 1.67 to 19.55;
P = 0.006 for creatinine level doubling; relative risk, 26.03; 95% confidence interval, 2.64 to 256.73;
P = 0.005 for dialysis therapy), and mean proteinuria during follow-up (for each 1 g/d of protein increase, relative risk, 1.77; 95% confidence interval, 1.35 to 2.32;
P < 0.001 for creatinine level doubling; relative risk, 1.73; 95% confidence interval, 1.18 to 2.52;
P = 0.005 for dialysis therapy). Information for mean proteinuria levels during follow-up increased the sensitivity at logistic regression to 62.5%, with dialysis therapy as the end point. No data detected at diagnosis, including renal function impairment, proteinuria, hypertension, and crescentic nephritis (involving >50% of glomeruli in only 2.6%), were significantly related to functional decline at multivariate Cox.
Conclusion:
This analysis indicates that, even more than when decreased renal function, severe proteinuria, hypertension, or crescents are present at onset, the risk for progression of HSPN (greater in adults and females) was associated with increasing mean proteinuria levels during follow-up.
Although chronic peritoneal dialysis (CPD) is considered the replacement therapy of choice for infants with end-stage renal failure, many questions persist about treatment risks and outcomes.
We ...present data on 84 infants who started CPD at <1 year of age; these patients represent 12% of the total population of the Italian Registry of Paediatric Chronic Dialysis. We analysed patient records from all children consecutively treated with CPD between 1995 and 2007 in Italy. Growth data analysis was performed only in infants with complete auxological parameters at 0, 6 and 12 months of follow-up.
Median age at the start of CPD was 6.9 months, weight was 6.1 kg and length 63.6 cm. In one-half of the study population diagnosis leading to renal failure was congenital nephrouropathy. Twenty-eight per cent of the children had at least one pre-existing comorbidity. The mean height standard deviation score was -1.65 at the start of CPD, -1.82 after 12 months and -1.53 after 24 months. Catch-up growth was documented in 50% of patients during dialysis. A positive correlation was observed between longitudinal growth and both exchange volume (R(2) = 0.36) and dialysis session length (R(2) = 0.35), while a negative association was found with the number of peritonitis cases (P = 0.003). Peritonitis incidence was 1:20.7 episode:CPD-months (1:28.3 in the older children from the same registry) and was significantly higher in children with oligoanuria (1:15.5 episode:CPD-months) compared to infants with residual renal function (1:37.4 episode:CPD-months). Catheter survival rate was 70% at 12 months and 51% at 24 months. Catheter-related complications were similar in infants and older children (1:20.5 versus 1:19.8 episode:CPD-months), while clinical complications were more frequent in children under 1 year of age (1:18.3 versus 1:25.2 episode:CPD-months; P < 0.05). During the follow-up period, 33 patients were transplanted (39.3%), 18 were shifted to haemodialysis (21.4%) and 8 died (9.5%). The mortality rate was 4-fold greater than in older children (2.3%).
Our data confirm that infants on CPD represent a high-risk group; however, our experience demonstrated that growth was acceptable and a large portion was successfully transplanted. Increased efforts should be aimed at optimizing dialysis efficiency and preventing peritonitis. The higher mortality rate in infants was largely caused by comorbidities.
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