Pediatric Nephrology最新文献

Background: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder with dysregulated glyoxylate metabolism in the liver. Oxalate over-production leads to renal stones, progressive kidney damage and renal failure, with potentially life-threatening systemic oxalosis. Nedosiran is a synthetic RNA interference therapy, designed to reduce hepatic lactate dehydrogenase (LDH) to decrease oxalate burden in PH.

Methods: Currently, in the PHYOX8 study (NCT05001269), pediatric participants (2-11 years) with PH1 (N = 15) and estimated glomerular filtration rate (eGFR) ≥ 30mL/min/1.73m² received nedosiran once monthly for 6 months.

Results: Urinary oxalate:creatinine (Uox:Ucr) levels reduced by 64% on average. Mean Uox:Ucr reduction was 52% at day 60 and ˃60% at day 180. At one or more study visits, 93.3% (N = 14) of participants reached Uox:Ucr < 1.5 × upper limit of normal (ULN), and 53.3% (N = 8) reached ≤ 1.0 × ULN. Median percent change in plasma oxalate (12.0 µmol/L at baseline) to day 180 was -39.23% (n = 10). Average number of kidney stones per participant remained stable, whilst a 10.1% average decrease in summed surface area was observed. Median percent change from baseline in eGFR was 2.5%, indicating preservation of renal function.

Conclusions: Nedosiran was well tolerated, with only 3 participants experiencing at least one serious adverse event, none considered treatment-related. The incidence of injection site reactions was 6.7% (1/15 participants). In conclusion, nedosiran treatment led to a significant and sustained reduction of Uox levels in children with PH1. These findings support nedosiran treatment in pediatric patients to reduce Uox and shows promise for limiting PH1-related complications.

Background: Changes in cardiac function and structure as well as their association with the cardiac autonomic nervous system remain incompletely characterized in children with stage 5 chronic kidney disease (CKD) receiving hemodialysis (HD).

Methods: A prospective observational cohort study was conducted on 40 Egyptian children with CKD on regular HD compared to 40 age- and sex-matched healthy children. All participants underwent thorough clinical examination, laboratory investigations, 24-h Holter monitoring, and 2D/4D echocardiographic study (conventional and advanced modalities). Participants were followed for mortality and morbidity over 36 months.

Results: Following HD sessions, CKD children showed significant reductions of left and right ventricular (LV/RV) systolic function by 2D and 4D echocardiography compared to controls. HD children had significant impairment of heart rate variability parameters (evaluated by time and frequency domains). LV/RV global longitudinal shortening (GLS) as well as tricuspid annular plane systolic excursion were closely correlated with different Holter parameters, including frequency domain parameters (including low frequency, high frequency, and LF/HF ratio), time domain parameters including percentage of differences > 50 ms between consecutive normal RR intervals (pNN50), and root-mean-square of the difference between successive normal intervals (rMSSD). Over a follow-up of 34.5 ± 16.8 months, 10 (25%) patients died. Reduced LV/RV-GLS and decreased rMSSD values were independently associated with higher mortality among HD children.

Conclusions: LV and RV myocardial deformation (either 2D or 4D) primarily decreased in HD children. Altered time and frequency domain indices revealed cardiac autonomic dysfunction, evidenced by increased sympathetic activity and decreased vagal activity. Reduced LV/RV-GLS and decreased rMSSD values were independently associated with higher mortality among HD children.

Background: Inadequate treatment of acute rejection (AR) in pediatric kidney transplant recipients (KTR) can contribute to early allograft failure. Serum creatinine is an insensitive marker of allograft function, especially in the pediatric population, and may not detect ongoing rejection after treatment. We evaluated the utility of follow-up biopsies to detect persistent inflammation and future episodes of rejection.

Methods: We performed a single-center retrospective review to identify pediatric KTR with biopsy-proven rejection and a subsequent follow-up biopsy, noting type of AR, Banff scores, serum creatinine, and presence of donor specific antibodies (DSA). Outcomes included resolution of AR, change in eGFR, DSA, persistent microvascular inflammation (MVI) and future episodes of AR.

Results: Twelve cases of cellular (TCMR), 9 antibody-mediated (AMR), and 8 mixed cases of AR were identified among 23 KTR. Resolution was noted in 75% with TCMR, significantly higher than AMR (22%) or mixed rejection (13%), p < 0.01. Those without resolution of AR on follow-up biopsy were more likely to have ongoing episodes of AR or graft loss (p = 0.02). Persistence of DSA and MVI was associated with lack of AR resolution (p = 0.01 and p = 0.001, respectively). Those with persistent MVI on follow-up biopsy had higher probability of future AR events or graft loss, p = 0.003.

Conclusion: Follow-up biopsies to assess response to AR treatment revealed that most cases of TCMR were successfully treated but that AMR and mixed rejection portend a component of chronicity and more complicated course. Identification of persistent subclinical inflammation predicts future rejection episodes, has adverse effects on graft longevity, and can inform the need for additional treatment. We advocate for implementation of a follow-up biopsy protocol and future study of non-invasive biomarkers paired with protocol biopsies.

Wernicke's encephalopathy (WE) is a severe neurological condition caused by the deficiency of thiamine, which is a vitamin B1 molecule. Herein, we present the case of a 3-year-old girl with steroid-resistant nephrotic syndrome (SRNS) who did not achieve remission despite steroid pulse therapy (MPT) and rituximab. She had frequent vomiting and decreased oral intake on the 61st day. High-calorie total parenteral nutrition was initiated on the 86th day, and levothyroxine was administered for suspected hypothyroidism. On the 88th day, she experienced altered consciousness with ocular deviation and abnormal electroencephalography findings, raising suspicion of WE. Following thiamine supplementation, recurrence of symptoms and neurological sequelae were not observed. Following 10 courses of MPT, rituximab, and mycophenolate mofetil, the patient achieved incomplete remission from SRNS. Monitoring levels of water-soluble vitamins in prolonged cases of nephrotic syndrome, such as SRNS, is critical to prevent WE and irreversible neurological damage.

Renovascular hypertension is the second leading cause of hypertension. Twenty-seven genes have been attributed to monogenic renovascular hypertension at present. We present a 15-year-old boy with facial dysmorphism, thick skin and renovascular hypertension with a novel gain-of-function variant in SMAD4 gene suggesting Myhre syndrome. Hypertension was controlled with three anti-hypertensive agents and vascular intervention is planned. It is characterized by a multisystem connective tissue disorder associated with progressive fibrosis of skin, cardiovascular, musculoskeletal, gastrointestinal and respiratory systems. This case highlights the need for recognizing syndromic features in children with renovascular hypertension.

Background: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a notably common complication in pediatrics, with an incidence rate ranging from 15 to 64%. This rate is significantly higher than that observed in adults. Currently, there is a lack of substantial evidence regarding the association between intraoperative blood pressure variability (BPV) during cardiac surgery with cardiopulmonary bypass (CPB) and the development of AKI in pediatric patients.

Methods: This retrospective observational study encompassed children aged 0-7 years undergoing cardiac surgery with CPB. Intraoperative BPV was calculated using coefficients of variation (CVs) and the area under the curve (AUC). Univariate and multivariate analyses were employed to identify risk factors associated with CSA-AKI.

Results: Among 570 patients (median age 1 year) reviewed, 36.1% developed CSA-AKI (68.9% risk stage, 22.8% injury stage, and 8.3% failure stage). After adjusting for other variables, male gender (OR = 2.044, 95% CI 1.297-3.222, P = 0.002), congenital heart surgery risk assessment grade (RACHS-1) classification ≥ 3 (OR = 0.510, 95% CI 0.307-0.846, P = 0.009), longer CPB time (OR = 1.022, 95% CI 1.007-1.037, P = 0.004) and higher peak value of intraoperative vasoactive inotropic score (VIS) (OR = 1.072, 95% CI 1.026-1.119, P = 0.002) were identified as independent risk factors for CSA-AKI. ± 30% AUCm was different in univariate analysis (P = 0.014), however, not statistically different in multifactor analysis (P = 0.610).

Conclusion: Greater BPV, specifically MAP variations exceeding 30% AUC during CPB, may be a potential risk factor for CSA-AKI in pediatric patients. Further large sample clinical studies are warranted to analyze the correlation between BPV and CSA-AKI.

Autosomal recessive proximal renal tubular acidosis (AR-pRTA) with ocular abnormalities is a rare syndrome caused by variants in the SLC4A4 gene, which encodes Na/HCO3 cotransporter (NBCe1). The syndrome primarily affects the kidneys, but also causes extra-renal manifestations. Pancreatic type NBCe1 is located at the basolateral membrane of the pancreatic ductal cells and together with CFTR chloride channel, it is involved in bicarbonate secretion. In vitro models have demonstrated that mutations in the pancreatic type NBCe1 lead to a reduction in pancreatic bicarbonate secretion. Although elevated amylase levels have been observed in some cases, there is no evidence of symptomatic pancreas involvement in children with AR-pRTA. This report presents the case of a seven-year-old girl with AR-pRTA and exocrine pancreatic insufficiency. This novel presentation with a novel mutation in SLC4A4 expands the extra-renal involvement in this rare disease. We recommend that these children be screened for exocrine pancreatic insufficiency.

Background: We investigated factors associated with post-transplant growth in pediatric kidney transplant (KTx) recipients with a focus on plasma bicarbonate (HCO3^-) and estimated the effect of alkali treatment on growth.

Methods: In this study of the CERTAIN Registry, data were collected up to 5 years post-transplant. Generalized Additive Mixed Models were applied to assess the association between post-transplant growth and covariates. A trial-emulation analysis was performed to estimate the causal effect of alkali supplementation on growth.

Results: We report on 2147 primary KTx recipients with a median age at KTx of 10.2 (IQR 5.1;14.3) years. No statistically significant association was found between growth and HCO3^- (p = 0.21), but the shape of the estimated conditional association showed a decreasing estimated growth with increasing HCO3^-. Glucocorticoid treatment and allograft rejection showed an inverse association with growth. Living donor KTx, glomerulopathy, recombinant growth hormone use, low height z-score at KTx, younger age, and higher eGFR were positively associated with growth. The trial-emulation analysis included patients at 30 days and 3, 6, and 9 months post-transplant with HCO3^-  < 22 mmol/L and no prior alkaline treatment. Alkaline treatment was initiated in 194, 93, 47, and 25 patients, respectively. After adjustment for confounders, there was no significant difference in growth at 1-year post-transplant in treated and untreated patients.

Conclusions: We found no association between HCO3^- and growth nor evidence of improved growth after treatment of metabolic acidosis. Living donor KTx was positively associated with post-transplant growth, while there was an inverse association with allograft rejection.

Background: Primary hyperoxaluria type 1 (PH 1) is a rare genetic condition due to mutations in the AGXT gene. This leads to an overproduction of oxalate in the liver. Hyperoxaluria often causes kidney stones, nephrocalcinosis, and chronic kidney disease. Lumasiran is a recently approved drug that reduces the hepatic oxalate production by mRNA interference.

Methods: In this multicenter study, we evaluated the response to lumasiran treatment in PH 1 patients (n = 8) with a median age of 10.9 years (range 1.2-17.9 years), including two patients on hemodialysis. We retrospectively analyzed the reduction of urinary and plasma oxalate levels as well as changes in kidney stone events, nephrocalcinosis, and kidney function.

Results: In patients without kidney failure, the median reduction of urinary oxalate was 64% (range 10-80%) and 71% (61-86%) at 6 and 12 months, respectively. However, only one patient reached urinary oxalate levels within the age-specific normal range. Two patients did not respond to lumasiran and treatment was stopped. In one of the two patients on hemodialysis, the frequency of sessions could be reduced. The only notable side effects were injection site reactions.

Conclusion: There was a variable response to lumasiran in PH 1. Despite a reduction of hyperoxaluria in many patients with PH 1, only one patient reached normal values and 2 of 8 patients did not respond. Regular monitoring of urinary oxalate values and registry data collection seems mandatory to monitor the efficacy and the long-term outcome of PH 1 treated with lumasiran.

The integrity of the filtration barrier of the kidney relies on the proper composition of podocyte interdigitating foot processes. Their architecture is supported by a complex actin-cytoskeleton. Following podocyte stress or injury, podocytes encounter structural changes, including rearrangement of the actin network and subsequent effacement of the foot processes. Immunosuppressive drugs, which are currently used as treatment in proteinuric kidney diseases, have been shown to exert not only immune-mediated effects. This review will focus on the direct effects of glucocorticoids, cyclosporine A, tacrolimus, mycophenolate mofetil, and rituximab on podocytes by regulation of Ca²⁺ ion channels and consecutive downstream signaling which prevent cytoskeletal rearrangements and ultimately proteinuria. In addition, the efficacy of these drugs in genetic nephrotic syndrome will be discussed.