Nivolumab-associated IgA Nephropathy in a Child With Malignant Melanoma.

Immune checkpoint inhibitors are humanized antibodies that inhibit downregulatory receptors on T cells, enhancing the antitumor activity of these cells. However, they have been associated with a wide range of systemic immune-related adverse events, including renal toxicities, among others. Most renal immune-related adverse events are acute interstitial nephritis causing acute kidney injury. Recently, immune checkpoint inhibitors-associated glomerular diseases, including IgA nephropathy, have been reported in adults. Most of the adult cases with glomerular involvement had also concomitant acute interstitial nephritis and acute kidney injury. We present the first pediatric case of IgA nephropathy without acute kidney injury during nivolumab treatment.

Causes and management of urinary system problems in children on long-term home invasive mechanical ventilation.

Many ventilator-dependent children have comorbid conditions including urinary tract disorders. We aimed to present a focused review of the literature describing the causes and management of urinary system problems in children with long-term home mechanical ventilation. We performed a literature search in PubMed/MEDLINE, Scopus, and Web of Science with keywords "children," "home mechanical ventilation," "urinary system," "urinary tract," "neurogenic bladder," "clean intermittent catheterization," "urinary tract infection," "urolithiasis," and "acute kidney injury." We included original articles, reviews, guidelines, and case reports published in English. Ventilator-dependent children may have neurogenic bladder/bowel dysfunction which renders them prone to urinary tract infection, high bladder pressure, vesicoureteral reflux, hydronephrosis, and renal dysfunction. These children require bladder catheterization, medications affecting parasympathetic/sympathetic nervous systems, or surgical procedures to prevent urinary infections, and to maintain continence and renal functions. However, bladder catheterization or surgical procedures like augmentation cystoplasty may also be complicated with urinary infections, urolithiasis, or urethral strictures. Urolithiasis frequency is also increased due to immobilization-related hypercalciuria, hypocitraturia caused by antiepileptic drugs, urinary stasis, and urinary infections. On the other hand, mechanical ventilation can impair renal function by reduction of cardiac output, redistribution of intrarenal blood flow and stimulation of sympathetic and hormonal pathways. Children requiring long-term invasive home mechanical ventilation may have other comorbid conditions, including urinary system diseases, which become manifest as these patients are being kept alive due to the advances in ventilation strategies. These children must be carefully observed for urological complications and managed accordingly to prevent kidney injury.

Complement gene mutations in children with C3 glomerulopathy: do they affect the response to mycophenolate mofetil?

BACKGROUND: C3 glomerulopathy (C3G) is a complement-mediated disease. Although genetic studies are not required for diagnosis, they are valuable for treatment planning and prognosis prediction. The aim of this study is to investigate the clinical phenotypes, kidney survival, and response to mycophenolate mofetil (MMF) treatment in pediatric C3G patients with and without mutations in complement-related genes. METHODS: Sixty pediatric C3G patients were included, divided into two groups based on complement-related gene mutations. Demographic and clinical-pathological findings, treatment modalities, and outcome data were compared, and Kaplan-Meier analysis was performed for kidney survival. RESULTS: Out of the 60 patients, 17 had mutations. The most common mutation was in the CFH gene (47%). The mean age at diagnosis was higher in the group with mutation (12.9 ± 3.6 vs. 11.2 ± 4.1 years, p = 0.039). While the patients without mutation most frequently presented with nephritic syndrome (44.2%), the mutation group was most likely to have asymptomatic urinary abnormalities (47.1%, p = 0.043). Serum parameters and histopathological characteristics were similar, but hypoalbuminemia was more common in patients without mutation. During 45-month follow-up,10 patients progressed to chronic kidney disease stage 5 (CKD5), with 4 having genetic mutation. The time to develop CKD5 was longer in the mutation group but not significant. MMF treatment had no effect on progression in either group. CONCLUSIONS: This study is the largest pediatric C3G study examining the relationship between genotype and phenotype. We showed that the mutation group often presented with asymptomatic urinary abnormalities, was diagnosed relatively late but was not different from the without mutation group in terms of MMF treatment response and kidney survival.

The outcomes of renin-angiotensin-aldosterone system inhibition and immunosuppressive therapy in children with X-linked Alport syndrome.

BACKGROUND: Alport syndrome (AS) is characterized by progressive kidney disease. There is increasing evidence that renin-angiotensin-aldosterone system (RAAS) inhibition delays chronic kidney disease (CKD) while the effectiveness of immunosuppressive (IS) therapy in AS is still uncertain. In this study, we aimed to analyze the outcomes of pediatric patients with X-linked AS (XLAS) who received RAAS inhibitors and IS therapy. METHODS: Seventy-four children with XLAS were included in this multicenter study. Demographic features, clinical and laboratory data, treatments, histopathological examinations, and genetic analyses were analyzed retrospectively. RESULTS: Among 74 children, 52 (70.2%) received RAAS inhibitors, 11 (14.9%) received RAAS inhibitors and IS, and 11 (14.9%) were followed up without treatment. During follow-up, glomerular filtration rate (GFR) decreased < 60 ml/min/1.73 m2 in 7 (9.5%) of 74 patients (M/F=6/1). In male patients with XLAS, kidney survival was not different between RAAS and RAAS+IS groups (p=0.42). The rate of progression to CKD was significantly higher in patients with nephrotic range proteinuria and nephrotic syndrome (NS), respectively (p=0.006, p=0.05). The median age at the onset of RAAS inhibitors was significantly higher in male patients who progressed to CKD (13.9 vs 8.1 years, p=0.003). CONCLUSIONS: RAAS inhibitors have beneficial effects on proteinuria and early initiation of therapy may delay the progression to CKD in children with XLAS. There was no significant difference between the RAAS and RAAS+IS groups in kidney survival. AS patients presenting with NS or nephrotic range proteinuria should be followed up more carefully considering the risk of early progression to CKD.

The role of height and weight growth in spontaneous resolution of vesicoureteral reflux.

BACKGROUND: The aim of this study was to investigate the role of height and weight growth in the resolution of primary vesicoureteral reflux (VUR). METHODS: We retrospectively evaluated the data of 74 males and 135 females who were diagnosed with primary VUR. According to the vesicoureteral reflux resolution, patients were divided into two groups. Patients with complete or partial resolution of VUR were included in Group 1 and patients with no resolution of VUR were included in Group 2. Patients were evaluated for weight Z-score, height Z-score and body mass index at the diagnosis and in the follow-up. In addition, age, sex, grade of reflux and laterality were recorded. RESULTS: There were no significant differences between the two groups, according to height Z-score, weight Z-score and body mass index at the diagnosis, in the follow-up and also annual changes of these parameters. In addition, the same parameters did not significantly differ in Groups 1 and 2, between the initial and final evaluations. However, when we evaluate the patients older than 12 months old, weight Z-scores were significantly higher at the final evaluation than at the diagnosis, in Group 1. This significant difference was not detected in Group 2 at the same age. CONCLUSIONS: Although we could not detect the hectic pace of height growth as being important in the prediction of long-term outcomes of VUR, weight growth should be considered to predict the resolution of VUR.

Late onset Bartter syndrome: Bartter syndrome type 2 presenting with isolated nephrocalcinosis and high parathyroid hormone levels mimicking primary hyperparathyroidism.

OBJECTIVES: Nephrocalcinosis is associated with conditions that cause hypercalcemia and the increased urinary excretion of calcium, phosphate, and/or oxalate. A monogenic etiology is found in almost 30% of childhood-onset nephrocalcinosis which is also a common manifestation of primary hyperparathyroidism. We discuss a child with nephrocalcinosis and features mimicking primary hyperparathyroidism. CASE PRESENTATION: A 7-year-old girl presented with nephrocalcinosis. Hypercalciuria, hyperphosphaturia, mild hypercalcemia, hypophosphatemia and elevated parathyroid hormone levels along with normal serum creatinine and absence of hypokalemic alkalosis suggested primary hyperparathyroidism. However, she was ultimately diagnosed with Bartter syndrome type 2 based on the presence of homozygous pathogenic variation in KCNJ1gene. CONCLUSIONS: This is the second reported case of late-onset Bartter syndrome type 2 without hypokalemic alkalosis. Patients with Bartter syndrome may present with high parathyroid hormone levels and hypercalcemia in addition to hypercalciuria. Thus, the present case suggests that the KCNJ1 gene should be included in genetic analysis even in older children with isolated nephrocalcinosis.

Comparison of clinical, pathological and long-term renal outcomes of children with Henoch-Schonlein purpura nephritis and IgA nephropathy.

PURPOSE: To compare clinical, pathological, and long-term renal outcomes of children with Henoch-Schonlein purpura nephritis (HSPN) and IgA nephropathy (IgAN). METHODS: The medical records of patients diagnosed as HSPN and IgAN during childhood were evaluated retrospectively. HSPN and IgAN groups were compared in terms of gender, age, upper respiratory infection history, blood pressure; presence of nephrotic and/or nephritic syndrome; hemoglobin level, leukocyte count, C-reactive protein (CRP), serum albumin (sAlb), creatinine, complement 3 (sC3), complement 4 (sC4) and immunoglobulin A (sIgA) levels; estimated glomerular filtration rate (eGFR) and proteinuria levels; and renal pathology findings at the onset of disease; total follow-up time; and blood pressure, eGFR and proteinuria levels at the last visit. RESULTS: Fifty-four patients were enrolled in the study [38 (70%) HSPN and 16 (30%) IgAN]. The median follow-up time was 60.5 and 72.0 months in HSPN and IgAN groups, respectively (p > 0.05). The HSPN and IgAN groups were also not different in terms of gender, age at the onset; leukocyte count, eGFR, sC3-sC4-sIgA levels; and the presence of endocapillary, extracapillary and mesangial proliferation, tubular atrophy, interstitial fibrosis and IgA, IgM, C3 accumulation in renal tissue. Upper respiratory tract infection history was more common in children with IgAN (8/16 vs 8/38, p = 0.045). sAlb (3.96 ± 0.58 vs 4.40 ± 0.46 g/dL, p = 0.005), hemoglobin (12.1 ± 1.3 vs 13.3 ± 1.2 g/dL, p = 0.004,) and the incidence of mesangial IgG deposition (15/38 vs 11/16, p = 0.049) were lower, while CRP (16.3 ± 7.2 vs 7.8 ± 4.4 mg/L, p = 0.002) and proteinuria (72.1 ± 92.4 vs 34.2 ± 37.9 mg/m2/24 h, p = 0.041) was higher in HSPN group at the onset of disease. Proteinuria and eGFR were similar between the two groups at last visit. CONCLUSION: Children with HSPN and IgAN have little clinical and histological differences in our population. The most prominent difference at presentation with nephritis was higher proteinuria in HSPN probably associated with inflammation due to systemic vasculitis. Long-term renal outcome was good in both HSPN and IgAN.

Assessments of left ventricular systolic and diastolic functions with tissue Doppler imaging and myocardial performance index in children with chronic kidney disease.

BACKGROUND: This study aimed to document early left ventricular (LV) dysfunction in chronic kidney disease (CKD) using methods such as tissue Doppler imaging and the myocardial performance index (MPI). METHODS: A total of 40 patients diagnosed with CKD (mean age, 10.1 ± 4.1 years) and 40 sex- and age-matched healthy controls (mean age, 9.6 ± 4.3 years) were examined. In the patient group, 20 patients had early stage (Stage 2-3) CKD and 20 patients had late-stage (stage 4-5) CKD, and 18 patients had hypertension. RESULTS: The pulmonary artery systolic pressure (PAPs) and LV mass index (LVMI) were significantly higher in the patient group (P < 0.05). The LV septal and lateral margins of the mitral annulus E'/A' ratio, E/E' ratio and MPI results were significantly different between the groups (P < 0.05). The MPI scores were higher in late-stage CKD than in early stage CKD (P < 0.05). The E'/A' ratio was lower and the MPI was higher in the hypertensive CKD group compared with the normotensive CKD group (P < 0.05). The E/E' ratio was correlated positively with the LVMI, and the PAPs, and negatively with glomerular filtration rate, S' value, E'/A' ratio. The MPI was correlated positively with blood pressure, LVMI, PAPs, and the S value, and negatively with the E'/A' ratio. CONCLUSIONS: The E'/A' ratio, the E/E' ratio, and the isovolumetric relaxation time measured by tissue Doppler imaging is highly accurate and easily applicable for detecting diastolic LV function, and the MPI is suitable for detecting both systolic and diastolic LV dysfunction. Their routine use may be useful in evaluating LV functions in children with CKD.

Clinical predictive value of the urine leukocyte esterase test positivity in childhood.

BACKGROUND: False negative or positive results may occur in the urine dipstick test for leukocyte esterase (LE), which is used to determine urinary tract infection (UTI). We aimed to investigate the clinical importance of the presence or absence of pyuria in urine sediment for diagnosing UTI in the presence of positive LE in dipstick analysis. METHODS: Patients admitted to the pediatric nephrology outpatient clinic with positive urine LE tests were divided into two groups: those without pyuria (Group 1) and those with pyuria (Group 2) in their urine sediment. Hospital files of the patients were evaluated retrospectively for demographic variables, lower or upper UTI symptoms, physical examination for phimosis and vulvovaginitis, urinalysis for LE and nitrite tests, urine sediment microscopy, urine culture, complete blood count and C-reactive protein. Both groups were compared for the significant growth of pathogenic bacteria in urine cultures along with clinical and laboratory parameters. RESULTS: Among 578 children giving samples for urinalysis, there were 287 cases with positive LE tests. Groups 1 and 2 included 123 and 164 cases, respectively. The proportion of girls was higher in Group 1 and vulvovaginitis rate was higher among the girls in Group 1. Girls with vulvovaginitis were mostly prepubertal. Upper UTI symptoms, significant pathogen growth rate, and elevated acute phase response were more common in Group 2. In addition, the phimosis rate was more common among the boys in Group 1 with false positive LE test. CONCLUSIONS: Children with positive LE tests without pyuria are mostly prepubertal girls and there is a high rate of vulvovaginitis in these girls. Unnecessary tests and treatments for UTI may be avoided with detailed history and physical examination in prepubertal girls who have a false positive LE test. We also found, for the first time, that a false positive LE test is significantly associated with phimosis in boys.

IL-1ß blockade in periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: case-based review.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome and familial Mediterranean fever (FMF) are considered as inflammasome disorders associated with uncontrolled interleukin (IL)-1ß production. Anti-IL1 agents are used in colchicine-resistant cases of FMF. Increase in pro-inflammatory mediators even between febrile attacks in PFAPA suggests that anti-IL1 treatment might be beneficial in these patients. We describe a child presenting with recurrent, self-limited febrile attacks at 1 year of age who was diagnosed as FMF being heterozygous for M694 V mutation. Her clinical findings were only controlled by the addition of canakinumab (2 mg/kg/8 week) to colchicine treatment. However, she developed typical PFAPA attacks during this treatment at 3 years of age. We conducted a literature search focusing on English articles with keywords including PFAPA, anakinra, canakinumab, and rilonacept. Five children and one adult patient with PFAPA were found and evaluated. Anakinra was reported to abort PFAPA attacks in children, while the adult patient first responded and then became resistant to anakinra. Canakinumab was effective in preventing febrile attacks in this patient. Failure of canakinumab to prevent PFAPA attacks in our case may arise from the differences in the pathophysiology of PFAPA and FMF. Thus, further experience with higher doses or shorter intervals of canakinumab is needed in children with PFAPA.

Evaluation of left ventricular systolic functions in two-dimensional speckle-tracking echocardiography in children with chronic renal failure.

BACKGROUND AND AIM: Chronic kidney disease may lead to left ventricular dysfunction. Early detection of cardiovascular disease in children with chronic kidney disease is essential to prevent cardiovascular morbidity and mortality in early adulthood. This study aimed to document the dysfunction using methods such as two-dimensional speckle-tracking echocardiography in the early stage. METHODS: A total of 34 patients diagnosed with chronic kidney disease (mean age ± standard deviation, 10.5 ± 4.1 years) and 37 sex- and age-matched (mean age 9.8 ± 4.2 years) healthy controls were studied. The results of the two groups were compared along with those of the published studies. RESULTS: The echocardiography measurements had no significant difference in the end-diastolic and end-systolic diameter values of left ventricular, ejection fraction, shortening fraction, mitral E value, mitral A value, and E/A ratio between the groups. Pulmonary artery systolic and diastolic pressure and left ventricular mass index were significantly higher in the patient group (p < 0.01). The longitudinal global strain values in the apical four-chamber, three-chamber, and two-chamber views and the total global strain values were significantly lower in the patients (p < 0.01). The circumferential global strain values in the apical, mid, basal, and total global strain were lower in the patient group, but this difference was statistically significant in the apical global and total global strain values (p < 0.05). CONCLUSIONS: Speckle-tracking echocardiography might help identify subclinical left ventricular dysfunction in patients with chronic kidney disease with unremarkable conventional echocardiography.

Predictors of poor kidney outcome in children with C3 glomerulopathy.

BACKGROUND: C3 glomerulopathy (C3G) is characterized by heterogeneous clinical presentation, outcome, and predominant C3 accumulation in glomeruli without significant IgG. There is scarce outcome data regarding childhood C3G. We describe clinical and pathological features, treatment and outcomes, and risk factors for progression to chronic kidney disease stage 5 (CKD5) in the largest pediatric series with biopsy-proven C3G. METHODS: Sixty pediatric patients with C3G from 21 referral centers in Turkey were included in this retrospective study. Patients were categorized according to CKD stage at last visit as CKD5 or non-CKD5. Demographic data, clinicopathologic findings, treatment, and outcome data were compared and possible risk factors for CKD5 progression determined using Cox proportional hazards model. RESULTS: Mean age at diagnosis was 10.6 ± 3.0 years and follow-up time 48.3 ± 36.3 months. Almost half the patients had gross hematuria and hypertension at diagnosis. Nephritic-nephrotic syndrome was the commonest presenting feature (41.6%) and 1/5 of patients presented with nephrotic syndrome. Membranoproliferative glomerulonephritis was the leading injury pattern, while 40 patients had only C3 staining. Patients with DDD had significantly lower baseline serum albumin compared with C3GN. Eighteen patients received eculizumab. Clinical remission was achieved in 68.3%. At last follow-up, 10 patients (16.6%) developed CKD5: they had lower baseline eGFR and albumin and higher frequency of nephrotic syndrome and dialysis requirement than non-CKD5 patients. Lower serum albumin and eGFR at diagnosis were independent predictors for CKD5 development. CONCLUSIONS: Children with C3G who have impaired kidney function and hypoalbuminemia at diagnosis should be carefully monitored for risk of progression to CKD5. Graphical abstract.

Rituximab-induced serum sickness and anaphylaxis in a child with nephrotic syndrome.

BACKGROUND: Rituximab is effective for treatment of children with refractory nephrotic syndrome (NS). However, the drug may cause serum sickness characterized by fever, rash, and arthralgia 10-14 days after primary antigen exposure or within a few days after secondary antigen exposure. Rituximab may also lead to anaphylaxis. It is important to recognize rituximab-induced serum sickness (RISS) clinically, as it may mimic various infectious or vasculitic diseases. CASE: A six-year-old male with NS treated with rituximab presented with diffuse arthralgia and myalgia eight days after the first dose. He developed an urticarial rash and arthralgia one week after the second dose, while he had swelling of lips and periorbital regions, choking sensation and erythematous rash in whole body within minutes after the third dose of rituximab. The first two reactions resemble typical serum sickness whereas the third reaction seem to be an anaphylaxis/anaphylactoid reaction. CONCLUSIONS: Although rituximab-induced serum sickness is typically self-limited, further infusions of rituximab should be avoided as it may provoke more severe symptoms. Most of the previous reported cases of RISS are patients with autoimmune or hematologic disorders. We present the first pediatric case with membranous nephropathy and RISS. The patient also developed anaphylactoid reaction during the third rituximab infusion.

Obesity is associated with severe clinical course in children with Henoch-Schonlein purpura.

BACKGROUND: We aimed to evaluate the role of obesity on the clinical course and response to treatment in patients with Henoch-Schonlein purpura (HSP). METHODS: Data charts of children with HSP followed in a tertiary hospital between 2000 and 2018 were reviewed retrospectively. Persistent purpura was defined as skin involvement persisting for ≥ 30 days. Mild nephropathy was defined as the presence of microscopical hematuria and/or non-nephrotic proteinuria, while severe nephropathy as nephrotic proteinuria, nephritic syndrome, and/or kidney insufficiency. Obese and non-obese patients were compared for demographic, clinical, and laboratory parameters. RESULTS: There were 199 patients (M/F, 104/95; median (IQR) presenting age 7.1 (5.0-9.2) years; follow-up period 17.5 (6-50) months). Obese patients (n = 35 (17.6%)) had significantly higher rate of persistent purpura (46% vs 21%), severe renal involvement (58% vs 31%), high-grade renal histopathological lesions (83% vs 39%), hypertension (29% vs 9%), and increased erythrocyte sedimentation rate (79% vs 56%). Obese patients also showed delayed improvement of cutaneous (25 vs 14 days), articular (12.5 vs 10.0 days), and kidney (280 vs 57 days) symptoms. Obese children used steroids for significantly longer period of time (236 vs 40 days). Furthermore, need for immunosuppressive medications were higher in obese patients (40% vs 9%). CONCLUSIONS: Obese children with HSP had higher erythrocyte sedimentation rate, hypertension, and severe renal involvement; showed delayed improvement of skin, joint, and kidney findings; and need more immunosuppressive medications and a longer period of steroid treatment. These findings may be associated with the effect of adipose tissue on inflammation.

Characteristics of infant urolithiasis: A single center experience in western Turkey.

INTRODUCTION: Urolithiasis (UL) in infancy has different incidence, etiology, presentation and course compared to UL in childhood and in adults. We evaluated the clinical, radiological, metabolic factors and course of infant UL in western Turkey. METHODS: Medical records of the infants between 1 and 12 months of age with a diagnosis of UL were reviewed retrospectively for gender, gestational age, age at diagnosis, presenting symptoms, past medical history, parental consanguinity, family history of UL, urinary tract abnormalities, urinary tract infections, localization-size-number of stones, course of stones, treatment modality of UL (medical vs surgical) and follow up duration. Patients were grouped as those who did not require surgical intervention (Group 1) and those who underwent any kind of stone surgery (Group 2). Both groups were compared for the study parameters. RESULTS: There were 80 infants (48 males) with a mean age of 6.0 ± 2.9 months at diagnosis. Mean follow-up duration was 29.7 ± 23.1 months. Two thirds of the patients presented with symptoms/signs not directly related to urinary system. Predisposing factors included metabolic abnormalities in 24 (30%) patients and urinary tract malformations in 9 (11%) patients. Group 1 (n = 58) and Group 2 (n = 22) were not different with respect to the study parameters except for the larger stone size and higher rate of hyperuricosuria in Group 2. Stone size of 4.5 mm has a 72.7% sensitivity and 74.1% specificity for predicting surgical intervention. Infants treated medically and those followed by hydration only did not differ for regression rate of stones and for requirement for surgical intervention. However, metabolic abnormalities were significantly higher in medically treated infants. CONCLUSION: Every infant with urolithiasis should be evaluated for risk factors. Modification of such predisposing factors when possible may mitigate the notably high recurrence rate of UL in children. Increased awareness of infant UL may allow for earlier detection, improved evaluation and follow up, and may thereby decrease the morbidity of the disease.