Acute glomerulonephritis with concurrent suspected bacterial pneumonia - is it the tip of the iceberg?

BACKGROUND: Post infectious glomerulonephritis is the most common glomerulopathy in children, occurring several weeks after nephritogenic streptococcal throat or skin infection. Reports of acute glomerulonephritis (AGN) occurring during active bacterial pneumonia in children are rare. The aim of this study was to evaluate the incidence of AGN concurrent with bacterial pneumonia in children. METHODS: We reviewed records of all children admitted with a diagnosis of pneumonia to the pediatric department in a single tertiary medical center between January 2015 and April 2023. Patients with bacterial pneumonia and concurrent glomerulonephritis were included. RESULTS: Eleven (0.98%) of 1,123 patients with bacterial pneumonia had concurrent AGN. All were males with a median age of 2.7 years (range 1-13). Mean time from bacterial pneumonia onset to acute glomerulonephritis symptoms was 2.7 ± 1.5 days. Five (45%) patients had evidence of pneumococcal infection. Hypertension was found in 10 (91%) patients. Mean trough eGFR was 43.5 ± 21.4 ml/min/1.73 m2 (range 11-73). Ten patients (91%) had low C3 levels. Median urinary protein-to-creatinine ratio was 2.5 mg/mg (IQR 2.15-14.75). All patients fully recovered. Microscopic hematuria was the last finding to normalize after a median of 29.5 days (IQR 17.25-38). CONCLUSION: AGN during bacterial pneumonia may be more frequent than previously recognized. Kidney prognosis was excellent in all patients. Prospective studies are needed to evaluate the impact of this condition.

Metabolic alkalosis in infants treated with peritoneal dialysis.

BACKGROUND: Acid-base balance is maintained by kidney excretion of titratable acids and bicarbonate reabsorption. Metabolic alkalosis is uncommon in dialysis-treated patients. The aim of this retrospective study was to assess the rate of metabolic alkalosis in pediatric patients treated with peritoneal dialysis. METHODS: Medical records of children treated with peritoneal dialysis in Shaare Zedek Medical Center from January 2000 to June 2021 were reviewed and compared with young adults currently treated with peritoneal dialysis. Demographic, clinical, and peritoneal dialysis characteristics were extracted from the medical records. RESULTS: Thirty chronic peritoneal dialysis patients were included in our study, seven under 2 years, 13 between 2 and 18 years, and 10 adults. 90.3% of the measurements in infants showed metabolic alkalosis compared to 32.3% in the 2-18-year group and none in the adult group. Higher size-adjusted daily exchange volume, lack of urine output, and high lactate-containing dialysate were associated with metabolic alkalosis. Alkalosis was not explained by vomiting, diuretic therapy, or carbonate-containing medications. High transport membrane, low dietary protein, and malnutrition, all previously reported explanations for metabolic alkalosis, were not found in our study. CONCLUSIONS: Metabolic alkalosis is common in infants treated with peritoneal dialysis as opposed to older children and adults. High lactate-containing dialysate is a possible explanation. Higher size-adjusted daily dialysate exchange volume, which may reflect higher bicarbonate absorption, is another independent predictor of alkalosis. Acid-base status should be closely followed in infants, and using a dialysis solution with lower bicarbonate or lactate level should be considered. A higher resolution version of the graphical abstract is available as Supplementary Information.

First-week urine beta-2 microglobulin levels in term healthy neonates.

BACKGROUND: Beta-2 microglobulin (ß2mG) is a low-molecular-weight protein that is almost exclusively eliminated through the kidneys. It is freely filtered in the glomeruli and almost completely reabsorbed and degraded in the proximal tubules. Normal urinary ß2mG levels are very low (between 0.04 and 0.22 mg/L). No reference values are known in infants and young children. METHODS: Urinary ß2mG levels were measured in 103 healthy term neonates during the first week of life by nephelometric technology. RESULTS: The average level of urinary ß2mG was 0.65 mg/L (95% confidence interval between 0 and 10.8 mg/L). There was a minor difference between male and female neonates but it did not reach statistical significance. There was no effect of the gestational week, birth weight, or weight loss in the first week of life, on urinary ß2mG levels. CONCLUSIONS: First-week urinary ß2mG levels in healthy term infants were higher than adult levels. Incomplete maturation of kidney tubules in neonates could be a possible explanation. These can now be used in clinical practice and further studies that assess the degree of proximal tubular function in health and disease. Graphical abstract.

Long-term complications of systemic oxalosis in children-a retrospective single-center cohort study.

BACKGROUND: Systemic oxalosis is a severe complication seen in primary hyperoxaluria type I patients with kidney failure. Deposition of insoluble calcium oxalate crystals in multiple organs leads to significant morbidity and mortality. METHODS: We describe a retrospective cohort of 11 patients with systemic oxalosis treated at our dialysis unit from 1982 to 1998 (group 1) and 2007-2019 (group 2). Clinical and demographic data were collected from medical records. Imaging studies were only available for patients in group 2 (n = 5). RESULTS: Median age at dialysis initiation was 6.1 months (IQR 4-21.6), 64% were male. Dialysis modality was mostly peritoneal dialysis in group 1 and daily hemodialysis in group 2. Bone disease was the first manifestation of systemic oxalosis, starting with the appearance of sclerotic bands (mean 166 days, range 1-235), followed by pathological fractures in long bones (mean 200.4 days, range 173-235 days). Advanced disease was characterized by vertebral fractures with resulting kyphosis, worsening splenomegaly, and adynamic bone disease. Two patients developed pulmonary hypertension, 4 and 8 months prior to their death. Four of 11 patients developed hypothyroidism 0-60 months after dialysis initiation. Only one patient survived after a successful liver-kidney transplantation. Four patients died after liver or liver-kidney transplantation. CONCLUSIONS: This is the first comprehensive description of the natural history of pediatric systemic oxalosis. We hope that our findings will provide basis for a quantitative severity score in future, larger studies.

Eosinophilia in a peritoneal dialysis patient: Answers.

Icodextrin is a starch-derived glucose polymer used in peritoneal dialysis dialysate to treat volume overload by increasing ultrafiltration in patients with end-stage renal disease. Reported adverse reactions to icodextrin are mild and rare and mainly consist of skin rash that resolves spontaneously after discontinuation of treatment. We describe a young patient with extreme eosinophilia that appeared with the use of icodextrin, disappeared after its discontinuation, and reappeared after a rechallenge with the drug. The eosinophilia was not associated with peritonitis, was asymptomatic, and fully resolved after discontinuation of the drug. Severe eosinophilia can potentially cause tissue damage in several organs, which would indicate that blood eosinophil count is recommended in routine complete blood counts while icodextrin peritoneal dialysis is being administered.

Associations Between Prematurity, Birthweight, and Adolescence Blood Pressure in a Nationwide Cohort.

Introduction: Prematurity is associated with incomplete nephrogenesis and an increased incidence of acute kidney injury, that may increase the risk of future kidney disease, including hypertension, proteinuria and reduced glomerular filtration rate. The aim of this study was to evaluate the risk of hypertension or proteinuria in adolescents born prematurely or small for gestational age, in a nationwide cohort. Methods: The study cohort included potential recruits examined in the Israel Defense Forces (IDF) medical facilities, between November 2005 and October 2018. Clinical and anthropometric data, including blood pressure (BP) measurement, were retrieved from the IDF medical files. Adolescents born between January 1993 and December 2000 had additional data on gestational age at birth, retrieved from the Israeli Ministry of Health database. Results: The study cohort included 513,802 participants, aged 17.3 ± 0.9 years, of whom 48,994 had gestational age data. Adolescents born as very preterm, as extremely preterm infants, those born with very low birthweight (VLBW), or with extremely low birthweight (ELBW) had higher incidence of hypertensive-range BP (55%, 47%, 19% and 12%, respectively). No significant association between birthweight (BW) adjusted to gestational age and hypertension was observed. Within the overweight and obese adolescents, those born with VLBW and ELBW, had further increased hypertensive-range BP rate. Proteinuria was diagnosed in 0.33% of the study cohort, with no significant difference between BW or gestational age categories. Conclusion: Adolescents born with VLBW or as significant preterm were associated with high BP and should be monitored for hypertension development and its potential complications.

Diagnostic Utility of Exome Sequencing Among Israeli Children With Kidney Failure.

Introduction: Genetic etiologies are estimated to account for a large portion of chronic kidney diseases (CKD) in children. However, data are lacking regarding the true prevalence of monogenic etiologies stemming from an unselected population screen of children with advanced CKD. Methods: We conducted a national multicenter prospective study of all Israeli pediatric dialysis units to provide comprehensive "real-world" evidence for the genetic basis of childhood kidney failure in Israel. We performed exome sequencing and assessed the genetic diagnostic yield. Results: Between 2019 and 2022, we recruited approximately 88% (n = 79) of the children on dialysis from all 6 Israeli pediatric dialysis units. We identified genetic etiologies in 36 of 79 (45%) participants. The most common subgroup of diagnostic variants was in congenital anomalies of the kidney and urinary tract causing genes (e.g., EYA1, HNF1B, PAX2, COL4A1, and NFIA) which together explain 28% of all monogenic etiologies. This was followed by mutations in genes causing renal cystic ciliopathies (e.g., NPHP1, NPHP4, PKHD1, and BBS9), steroid-resistant nephrotic syndrome (e.g., LAGE3, NPHS1, NPHS2, LMX1B, and SMARCAL1) and tubulopathies (e.g., CTNS and AQP2). The genetic diagnostic yield was higher among Arabs compared to Jewish individuals (55% vs. 29%) and in children from consanguineous compared to nonconsanguineous families (63% vs. 29%). In 5 participants (14%) with genetic diagnoses, the molecular diagnosis did not correspond with the pre-exome diagnosis. Genetic diagnosis has a potential influence on clinical management in 27 of 36 participants (75%). Conclusion: Exome sequencing in an unbiased Israeli nationwide dialysis-treated kidney failure pediatric cohort resulted in a genetic diagnostic yield of 45% and can often affect clinical decision making.

COVID-19 in children and young adults with kidney disease: risk factors, clinical features and serological response.

BACKGROUND: Chronic kidney disease (CKD) and kidney transplantation in adults are well-recognized risk factors for coronavirus disease 2019 (COVID-19) associated morbidity and mortality. Data on the toll of the pandemic on children and young adults with kidney disease is scarce. The aim of this study was to assess the incidence and severity of COVID-19, as well as the serological response, in this population. METHODS: Study population included all patients with CKD stage 3-5, glomerular disease treated with immunosuppression and kidney transplant recipients followed-up at a tertiary medical center, between 1.12.2020 and 15.2.2021. Data collected included PCR testing, symptoms, exposure, and socio-demographic data. Anti-SARS-CoV-2 antibodies were tested. RESULTS: A total of 197 children and 63 young adults were included, 57% were Jewish, 43% were Arab. PCR-confirmed COVID-19 incidence was 20.8%, 37% of cases were asymptomatic, three patients were hospitalized for observation, and the remainder had mild symptoms. Kidney function remained stable without treatment modification. Risk factors for infection included exposure at home (OR 15.4, 95% CI 6.9-34.2) and number of household members (OR 1.45, 95% CI 1.21-1.73). Anti-SARS-CoV-2 antibodies were detected in 61% of cases and were not associated with COVID-19 severity or immunosuppressive therapy. Three patients who did not develop antibodies had a mild recurrent infection. CONCLUSIONS: Unlike COVID-19 in adult patients with kidney disease, in our cohort of children and young adults, COVID-19 incidence was similar to the general population and all cases were mild. It may be unnecessary to impose severe restrictions on this patient population during the pandemic.

Early puberty in end stage renal failure and renal transplant recipients.

Background Delayed puberty and hypogonadism are common in children with chronic kidney disease and in renal transplant recipients, but precocious puberty has rarely been reported in these populations. We describe six girls with precocious and/or early-onset, rapidly progressive puberty before and following renal transplantation. Methods Of 112 children under the age of 18 years (67 boys, 45 girls) who received renal transplants between 2010 and 2018, six girls presented with precocious or rapidly progressive early puberty at ages 6-7/12, 7-2/12, 7-4/12, 8, 8-8/12 and 8-11/12 years. Clinical evaluation included measurements of height, weight, body mass index (BMI), Tanner staging and bone age assessment. Gonadotropin responses to intravenous gonadotropin releasing hormone (GnRH) or intramuscular triptorelin acetate were determined. Results Tanner breast stage 3 was noted at 2-6 years following renal transplantation in five girls, four with preserved kidney function. One girl began puberty before renal transplantation. Peak luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels were 6.5, 20.2, 7.83, 19.1, 9 and 2.2 mIU/mL and 13, 8.3, 8.01, 7.5, 8.1 and 7.7 mIU/mL, respectively. Treatment with an intramuscular slow-release formulation of triptorelin acetate every 4 weeks slowed progression of breast development. Conclusions Although delayed puberty is more common in children with renal disease, precocious puberty can also be seen. Evaluation of growth and puberty by a pediatric endocrinologist should be part of the routine care for all children following kidney transplantation.

Central venous catheter-related venous thrombosis in children with end-stage renal disease undergoing hemodialysis.

Despite the high rate of central venous catheter (CVC)-related venous thromboembolic (VTE) complications and long-term sequelae, CVCs remain a vital component of patient care in children with complex underlying diseases. In this review, we focus on CVC-related VTE in children with end-stage renal disease (ESRD) undergoing hemodialysis, a population in whom the provision of renal replacement therapy is a lifelong undertaking. Occlusion of the CVC and thrombosis underlie most instances of access malfunction and failure in children on chronic hemodialysis. Frequent CVC replacements are required, resulting in increased risk of central vein thrombosis and stenosis, precluding adequate hemodialysis in years to come. As recurrent CVC malfunction may constitute the sole sign of CVC-related VTE, a high index of suspicion is required for its investigation and the consequent institution of anticoagulation treatment, attempting to salvage the CVC and minimize recurrent line exchanges and venous cannulations and their sequelae. Hemodialysis access planning should take into account potentially modifiable prothrombotic risk factors in order to preserve vascular access. Effective strategies for maintenance of catheter patency and survival are needed for the conservation of future hemodialysis access. Further investigation aiming for identification of predictors of CVC-related VTE in children undergoing hemodialysis will aid in the design and application of much needed multicenter prospective studies examining the benefit and the safety of thromboprophylaxis.

Translation inhibition corrects aberrant localization of mutant alanine-glyoxylate aminotransferase: possible therapeutic approach for hyperoxaluria.

Primary hyperoxaluria type 1 is a severe kidney stone disease caused by abnormalities of the peroxisomal alanine-glyoxylate aminotransferase (AGT). The most frequent mutation G170R results in aberrant mitochondrial localization of the active enzyme. To evaluate the population of peroxisome-localized AGT, we developed a quantitative Glow-AGT assay based on the self-assembly split-GFP approach and used it to identify drugs that can correct mislocalization of the mutant protein. In line with previous reports, the Glow-AGT assay showed that mitochondrial transport inhibitors DECA and monensin increased peroxisomal localization of the mutant. Here, we demonstrate that prolonged treatment with the translation elongation inhibitor emetine, a medicinal alkaloid used in treatment of amoebiasis, corrected G170R-AGT mislocalization. Furthermore, emetine reduced the augmented oxalate level in culture media of patient-derived hepatocytes bearing the G170R mutation. A distinct translation inhibitor GC7 had a similar effect on the mutant Glow-AGT relocalization indicating that mild translation inhibition is a promising therapeutic approach for primary hyperoxaluria type 1 caused by AGT misfolding/mistargeting. KEY MESSAGES: • There is no effective conservative treatment to decrease oxalate production in PH1 patients. • Chemical chaperones rescue mislocalization of mutant AGT and reduce oxalate levels. • We have developed an assay for precise monitoring of the peroxisomal AGT. • Inhibition of translation by emetine reroutes the mutant protein to peroxisome. • Mild translation inhibition is a promising cure for conformational disorders.