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.

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.

Severe neutropenia in children after renal transplantation: incidence, course, and treatment with granulocyte colony-stimulating factor.

BACKGROUND: Infections are an important cause of morbidity and mortality in solid organ transplant recipients. Neutrophils play a crucial role in the initial host defense against bacterial pathogens. Neutropenia is not uncommon after renal transplantation in adults; however, there are scarce published data in children. We conducted a historical cohort study to evaluate the incidence, clinical course, and management of severe neutropenia after renal transplantation in children. METHODS: In a single-center study, we collected clinical and laboratory data on all children (<20 years) who underwent renal transplantation from January 2005 to March 2014. All post-transplantation blood counts were reviewed; the lowest absolute neutrophil count was recorded and correlated with clinical information and other laboratory findings. RESULTS: Of the 72 patients studied, 46 (64%) had at least one episode of neutropenia [absolute neutrophil count (ANC) <1500/µl] during the study period, 16 of whom (22%) had severe neutropenia (ANC < 500/µl), 2-11 months (median, 3.5) after renal transplantation. Work-up for viral infection or malignancy was performed. Initial management included dose decrease and subsequent discontinuation of antimetabolite, stopping co-trimoxazole and valganciclovir. Bone marrow aspiration in four children revealed normal marrow cellularity in all cases, with myelocyte maturational arrest in two. Eight children (11%) were treated with granulocyte colony-stimulating factor (G-CSF) (5 mcg/kg/day) 1-4 doses (median, 2), with excellent response in all and no adverse effects. Eight children presented with fever during severe neutropenia, and were treated with empiric antibiotics. Mycophenolate/azathioprine were resumed in all patients unless contraindicated (pre-existing BK viremia -1, PTLD -1). Recurrence of neutropenia was seen in five patients, only one of whom required further treatment with G-CSF. Graft function was preserved during and after resolution of neutropenia. Post-transplant neutropenia in children is common, and mostly occurs in the first few months. Its etiology is probably primarily a result of the combination of immunosuppressive agents and prophylactic treatment of infections in the early post-transplant period. CONCLUSIONS: Decreasing immunosuppressive or antimicrobial medications carries the risk of acute rejection or infection. Off-label treatment with G-CSF may present a safe and effective alternative.

Vitamin A deficiency associated with urinary retinol binding protein wasting in Dent's disease.

BACKGROUND: Three patients with Dent's disease presented with complaints of impaired night vision or xerophthalmia and were found to have severely decreased serum retinol concentrations. Retinol, bound to its carrier retinol-binding protein (RBP), is filtered at the glomerulus and reabsorbed at the proximal tubule. We hypothesized that urinary loss of retinol-RBP complex is responsible for decreased serum retinol. OBJECTIVE AND METHODS: The study aim was to investigate vitamin A status and RBP in serum and urine of patients with genetically confirmed Dent's disease. RESULTS: Eight patients were studied, three boys had clinical vitamin A deficiency, three had asymptomatic deficiency, and two young men with Dent's disease and impaired renal function had normal retinol values. Serum RBP concentrations were low in patients with vitamin A deficiency and were correlated with vitamin A levels. Urinary RBP concentrations were increased in all patients (2,000-fold), regardless of vitamin A status. This was in contrast to patients with glomerular proteinuria who had only mildly increased urinary RBP with normal serum RBP and vitamin A, and patients with cystinosis with impaired renal function who had massive urinary RBP losses but without a decrease in serum RBP or vitamin A levels. Treatment with vitamin A supplements in patients with retinol deficiency resulted in rapid resolution of ocular symptoms and an increase in serum retinol concentrations. CONCLUSIONS: Vitamin A deficiency is common in patients with Dent's disease and preserved renal function. We therefore recommend screening these patients for retinol deficiency and treating them before visual symptoms develop.

Dent's disease manifesting as focal glomerulosclerosis: Is it the tip of the iceberg?

Dent's disease is an X-linked proximal tubulopathy. It often manifests in childhood with symptoms of Fanconi syndrome and low-molecular-weight proteinuria. We describe four boys from three unrelated families whose only presenting symptoms of Dent's disease were nephrotic-range proteinuria and histological findings of focal segmental and/or global glomerulosclerosis. In all families, a causal mutation in the CLCN5 gene, encoding a voltage-gated chloride transporter and chloride-proton exchanger, was identified. All three mutations are pathogenic: two are novel (p.Asp727fs and p.Trp122X), and one is a recurrent mutation, p.R648X. Given the atypical phenotype of these patients with Dent's disease, it is possible that this clinical entity is markedly underdiagnosed and that our report represents only the tip of the iceberg. The diagnosis of Dent's disease should be considered in all patients with nephrotic-range proteinuria without hypoalbuminemia or edema. Establishing the diagnosis of Dent's disease will prevent the administration of unnecessary immunosuppressive medications with their undesirable side effects.

Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor.

The hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. We investigated 21 HDR probands and 14 patients with isolated hypoparathyroidism for GATA3 abnormalities. Thirteen different heterozygous germline mutations were identified in patients with HDR. These consisted of three nonsense mutations, six frameshifting deletions, two frameshifting insertions, one missense (Leu348Arg) mutation and one acceptor splice site mutation. The splice site mutation was demonstrated to cause a pre-mRNA processing abnormality leading to the use of an alternative acceptor site 8 bp downstream of the normal site, resulting in a frameshift and prematurely terminated protein. Electrophoretic mobility shift assays (EMSAs) revealed three classes of GATA3 mutations: those that lead to a loss of DNA binding which represent over 90% of all mutations, and involved a loss of the carboxy-terminal zinc finger; those that resulted in a reduced DNA-binding affinity; and those (e.g. Leu348Arg) that did not alter DNA binding or the affinity but likely altered the conformational change that occurs during binding in the DNA major groove as predicted by a three-dimensional modeling. These results elucidate further the molecular mechanisms underlying the altered functions of mutants of this zinc finger transcription factor and their role in causing this developmental anomaly. No mutations were identified in patients with isolated hypoparathyroidism, thereby indicating that GATA3 abnormalities are more likely to result in two or more of the phenotypic features of the HDR syndrome and not in one, such as isolated hypoparathyroidism.

Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23.

UNLABELLED: Two hyperphosphatemic patients with mutations in GALNT3 showed low intact FGF23 levels with marked increase of processed C-terminal fragments. FGF23 protein has three O-linked glycans and FGF23 with incomplete glycosylation is susceptible to processing. Silencing GALNT3 resulted in enhanced processing of FGF23. Decreased function of FGF23 by enhanced processing is the cause of hyperphosphatemia in patients with GALNT3 mutation. INTRODUCTION: Hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive entity manifesting as severe hyperphosphatemia associated with episodic bone pain and radiological findings of cortical hyperostosis and periosteal reaction. Persistent hyperphosphatemia is not counterbalanced by PTH or 1,25-dihydroxyvitamin D, posing a mirror image of hypophosphatemic states attributed to increased fibroblast growth factor (FGF)23 activity. MATERIALS AND METHODS: We describe two children with HHS who were found to be homozygous for a mutation in GALNT3 encoding a peptide involved in mucin-type O-glycosylation (ppGaNTase-T3). FGF23 levels were evaluated by two ELISAs and Western blotting. FGF23 protein was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Effect of silencing GALNT3 was evaluated using siRNA in cells transfected with expression vector for FGF23. RESULTS: Both patients had low levels of the full-length FGF23 with markedly augmented amounts of the inactive fragments. Biologically active FGF23 has three O-linked glycans. FGF23 with only one or two O-linked glycans is processed into inactive fragments. Decreasing the expression of the GALNT3 gene by RNA interference resulted in enhanced processing of FGF23. CONCLUSIONS: The primary defect in HHS is impairment of glycosylation of FGF23 resulting from mutations in GALNT3 and leading to augmented processing of FGF23. These changes in FGF23 abolish its phosphaturic effect and lead to severe persistent hyperphosphatemia. This study provides the pathogenetic mechanism of the first mucin-type O-glycosylation defect identified.

Risk factors for cardiovascular disease in children and young adults after renal transplantation.

Despite good outcomes in pediatric renal transplantation, life expectancy is reduced, mostly as a result of accelerated atherosclerosis. A comprehensive evaluation of cardiac status and risk factors for cardiovascular disease was performed in 60 patients after renal transplantation (age 3 to 29 yr; mean 15.8). Posttransplantation diabetes was diagnosed in 7%. Half of the patients did not engage in any physical activity, and this was associated with increased body mass index. Uncontrolled hypertension was found in 13% of patient, and 53% were on antihypertensive medications. BP index was associated with left ventricular mass index (LVMI). Dyslipidemia was relatively uncommon, with hypercholesterolemia found in 15% and elevated LDL cholesterol found in 10% of patients. Hyperhomocysteinemia was frequent (58%); in most patients, it was not due to folate or B(12) deficiency. Lipid and homocysteine abnormalities were associated with cyclosporine therapy. Echocardiography demonstrated normal LVMI in 93% of patients, although LVMI was higher than in healthy control subjects. Cardiac troponin I was normal in all patients, but N-terminal pro-brain natriuretic peptide was elevated in 35% and was associated with LVMI and renal function. Although present cardiac status is relatively normal in pediatric renal transplantation patients, cardiac risk factors are common, and strategies to prevent cardiovascular disease need to be developed.

Mutated podocin manifesting as CMV-associated congenital nephrotic syndrome.

We report a girl with congenital nephrotic syndrome (CNS) associated with cytomegalovirus (CMV) infection and histological findings on renal biopsy that suggested a causal relationship between the two. She was subsequently found to be homozygous for a nonsense mutation in the NPHS2 gene encoding podocin (R138X), which is the true cause of her NS. Based on review of the literature and our findings in this patient, we propose that the clinical entity known as CMV causing CNS may not exist.

Mutations in NPHS2 encoding podocin are a prevalent cause of steroid-resistant nephrotic syndrome among Israeli-Arab children.

Steroid-resistant nephrotic syndrome (SRNS) represents a heterogeneous group of kidney disorders that are often resistant to other immunosuppressive agents and tend to progress to end-stage renal failure. Mutations in the gene NPHS2 that encode a protein named podocin have recently been found in a recessive form of SRNS. Ten children from two inbred families of Israeli-Arab descent presented with SRNS. Renal histologic findings were of diffuse mesangial proliferation. Six patients reached end-stage renal failure, but nephrotic syndrome did not recur after renal transplantation. Mutation analysis of NPHS2 revealed that they were homozygous for the C412T mutation (R138X). Eighteen children were subsequently analyzed with SRNS due to biopsy-proven focal segmental glomerulosclerosis (FSGS) from unrelated families of Israeli-Arab descent. Analysis disclosed six additional patients (33%) bearing the same mutation in a homozygous pattern. Three of them had no affected relatives, although they came from large families. Taken together, of the 27 patients tested (familial and nonfamilial), 15 patients (55%) were homozygous for the mutation (R138X). They all shared the same haplotype and were homozygous for the A1023G polymorphism, thus pointing to a possible founder effect. Thirteen children of Israeli-Jewish origin with SRNS and biopsy-proven FSGS and 15 children of both ethnic groups with steroid-responsive FSGS were tested, and none was found to have mutations in NPHS2. The results of this study demonstrate that mutations in NPHS2 are a common cause of SRNS in Israeli-Arab children. Mutations in NPHS2 may cause SRNS in nonfamilial cases. The interethnic differences in the occurrence of NPHS2 mutations may explain, in part, the previous observation that Arab patients with FSGS in Israel have a worse prognosis as compared with Jewish patients, despite similar presenting symptoms and medical management. Identifying the causing mutation will enable clinicians to avoid unnecessary immunosuppressive therapeutic trials in newly diagnosed patients and to provide prenatal diagnosis to families at risk.