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Assessment of the true impact of therapeutic interventions is a challenge in the absence of universal, standardized definitions for clinical trial endpoints in children with kidney diseases. Steroid-resistant nephrotic syndrome (SRNS) is a difficult kidney disease to treat, with unremitting disease progressing to kidney failure. Currently, available therapies result in suboptimal cure rates. Clinical trials with innovative, targeted treatments will likely be conducted for this disease in the foreseeable future. An international consortium of the IPNA Best Practices and Standards Committee and the Pediatric Nephrology Expert Group of the conect4children (c4c) network developed through consensus, standardized, internationally acceptable definitions for trial outcomes for SRNS. The endpoint definitions were formulated for use with urine protein to creatinine ratios and estimated glomerular filtration rates. Definitions of complete remission, partial remission, non-remission of disease, reduction in proteinuria, kidney disease progression, kidney failure, and composite kidney outcome were refined using an iterative process until a consensus was achieved., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Nephronophthisis (NPHP) is an autosomal recessive disorder with a subset of patients presenting with extrarenal manifestations such as retinal degeneration, cerebella ataxia, liver fibrosis, skeletal abnormalities, cardiac malformations, and lung bronchiectasis. However, the involvement of other organ systems has also been documented. Extrarenal manifestations occur in approximately 10-20% of patients. In developed countries, it has been reported as one of the most common causes of monogenic chronic kidney failure (CKF) during the first three decades of life, with more than 25 genes associated with this condition. The current treatment options for managing NPHP include supportive care, management of complications, and kidney replacement therapy when necessary. The index patient is a 10-year-old Caucasian female who presented with recurrent attacks of abdominal pain. Her elder sister, TN, who was 17 years old, was diagnosed with CKF and noted to have persistently elevated liver enzymes (gamma-glutamyl transferase, alanine, and aspartate transaminases). Following genetic testing, her elder sister was shown to have Nephronophthisis Type 3, and a liver biopsy showed early fibrotic changes. Subsequent genetic testing confirmed the index patient as having NPHP Type 3. A kidney biopsy showed focal sclerosed glomeruli with patchy areas of tubular atrophy and related tubulointerstitial changes in keeping with NPHP. We present the first confirmatory case of NPHP from South Africa based on histopathology and genetic testing in a 10-year-old Caucasian female who presented with recurrent attacks of abdominal pain, whose elder sister also presented with CKF and early liver fibrosis, confirmed on biopsy and genetic testing., Conclusion: In low-middle-income countries, genetic testing should be undertaken whenever possible to confirm the diagnosis of NPHP, especially in those with a suggestive biopsy or if there is CKF of unknown aetiology with or without extra-renal manifestations., (© 2024. The Author(s).)

Background. Africa has the highest rate of HIV infection, and HIV-associated nephropathy (HIVAN) is one of the most frequent kidney diseases observed in children. HIVAN in children usually presents as a form of nephrotic syndrome, predominantly focal segmental glomerulosclerosis (FSGS) on histopathology, that often leads to chronic kidney failure. Objective. This study determined the urinary concentrations of ß-2-microglobulin (ß2M) and cystatin C proteins in children with HIVAN and primary FSGS. Methods. The study group comprised 34 children; 14 with HIVAN and 20 with primary FSGS. The control groups were 20 HIV-positive and 20 HIV-negative children with no kidney disease. Urine samples collected from these 74 children were stored at -80°C. Bio-Plex technology was used to analyse the urinary protein concentration of cystatin C and ß2M. Results. A significant increase in urinary ß2M levels was observed in the HIVAN group compared with the HIV-negative group (p=0.0240). No other statistically significant differences in urinary ß2M concentrations were noted across the study groups. Urinary cystatin C levels were significantly increased in primary FSGS children compared with both HIV-negative (p=0.0041) and HIV-positive controls (p=0.0256). Urinary cystatin C displayed a significant increase in the primary FSGS compared with the HIVAN group (p=0.0150). No significant differences in urinary cystatin C levels were noted in the HIVAN group compared with the HIV-negative and HIV-positive control groups. Conclusion. Urinary cystatin C has promising prognostic value to predict primary FSGS from HIVAN. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease-2019 (COVID-19) has been challenging for patients and medical staff. Radical changes have been needed to prevent disruptions in patient care and medical education. Methods: A web-based survey was sent to European Society for Pediatric Nephrology (ESPN) members via the ESPN mailing list to evaluate the effects of the COVID-19 pandemic on delivery of pediatric nephrology (PN) care and educational activities. There were ten questions with subheadings. Results: Seventy-six centers from 24 countries completed the survey. The time period was between the beginning of the pandemic and May 30, 2020. The number of patients admitted in PN wards and outpatient clinics were significantly decreased (2.2 and 4.5 times, respectively). Telemedicine tools, electronic prescriptions, online applications for off-label drugs, and remote access to laboratory/imaging results were used in almost half of the centers. Despite staff training and protective measures, 33% of centers reported COVID-19 infected staff, and 29% infected patients. Difficulties in receiving pharmaceuticals were reported in 25% of centers. Sixty percent of centers suspended living-related kidney transplantation, and one-third deceased-donor kidney transplantation. Hands-on education was suspended in 91% of medical schools, and face-to-face teaching was replaced by online systems in 85%. Multidisciplinary training in PN was affected in 54% of the centers. Conclusions: This survey showed a sharp decline in patient admissions and a significant decrease in kidney transplantation. Telemedicine and online teaching became essential tools, requiring integration into the current system. The prolonged and fluctuating course of the pandemic may pose additional challenges necessitating urgent and rational solutions. [ABSTRACT FROM AUTHOR]

Background: CKF is an overwhelming illness, especially in children. Kidney transplantation is considered the definitive management of CKF. It has substantial benefits, including increased patient survival, improved skeletal growth, social adjustment, neuropsychological development, and better quality of life compared to chronic dialysis., Methods: This is a retrospective, clinical, observational study in 13 children ≤16 years old who underwent kidney transplantation at IALCH in KwaZulu-Natal, South Africa, from May 2015 to December 2019., Results: Over 4 years and 7 months, 13 kidney transplants were performed; 7 (53.8%) were males, and 6 (46.2%) were females. Eleven (84.6%) were Black African and 2 (15.4%) Indian children. The mean age ± (SD) of transplantation was 10.1 ± 2.8 years (range 5.8-15.8). Eight (61.5%) children were from a rural setting. The mean ± (SD) duration of follow-up was 29.5 ± 15.9 months. All kidney transplants done were from live related donors; 8 (61.5%) were parents of the recipients. None were pre-emptive transplants. Graft loss occurred in 2 (15.4%) children with 100% patient survival. Two (15.4%) children developed acute rejection., Conclusions: The commissioning of transplant services in KwaZulu-Natal, South Africa, has improved access to this modality of treatment, particularly in our Black African patients. The significant limitations we experienced were a shortage of cadaveric donors and resource limitations with no dedicated transplant unit for pediatric patients together with staffing constraints. Enhancing patient and healthcare personal education will hopefully overcome cultural and religious barriers to organ donation., (© 2021 Wiley Periodicals LLC.)

Background: Chronic kidney disease (CKD) is a globally significant non-communicable disorder. CKD prevalence varies between countries and within a country. We compared the prevalence rates of CKD in South Africa with sub-Saharan Africa, Africa, and globally., Methods: We registered a systematic review with the International Prospective Register of Systematic Reviews for prevalence studies reporting CKD stages III-V from 2013 to 2021. The analysis sought to explain any significant differences in prevalence rates. The R statistical package was used for data analysis. Comparisons included measures of effect size due to the large sample sizes analysed. We also compared sex differences in prevalence rates, common aetiologies, and type of study methodologies employed., Results: Eight studies were analysed, with two from each region. The matched prevalence rates of CKD between the various regions and South Africa showed significant differences, except for one comparison between South Africa and an African study [p = 0.09 (95% CI - 0.04-0.01)]. Both sub-Saharan African studies had a higher prevalence than South Africa. One study in Africa had a higher prevalence, while the other had a lower prevalence, whilst one Global study had a higher prevalence, and the other had a lower prevalence compared to South Africa. The statistical differences analysed using the Cramer's V test were substantially less than 0.1. Thus, differences in comparisons were largely due to differences in sample sizes rather than actual differences., Conclusion: Variable prevalence rates between regions included disparities in sample size, definitions of CKD, lack of chronicity testing and heterogeneous laboratory estimations of eGFR. Improved consistency and enhanced methods for diagnosing and comparing CKD prevalence are essential., (© 2023. The Author(s).)

Idiopathic nephrotic syndrome is the most frequent pediatric glomerular disease, affecting from 1.15 to 16.9 per 100,000 children per year globally. It is characterized by massive proteinuria, hypoalbuminemia, and/or concomitant edema. Approximately 85-90% of patients attain complete remission of proteinuria within 4-6 weeks of treatment with glucocorticoids, and therefore, have steroid-sensitive nephrotic syndrome (SSNS). Among those patients who are steroid sensitive, 70-80% will have at least one relapse during follow-up, and up to 50% of these patients will experience frequent relapses or become dependent on glucocorticoids to maintain remission. The dose and duration of steroid treatment to prolong time between relapses remains a subject of much debate, and patients continue to experience a high prevalence of steroid-related morbidity. Various steroid-sparing immunosuppressive drugs have been used in clinical practice; however, there is marked practice variation in the selection of these drugs and timing of their introduction during the course of the disease. Therefore, international evidence-based clinical practice recommendations (CPRs) are needed to guide clinical practice and reduce practice variation. The International Pediatric Nephrology Association (IPNA) convened a team of experts including pediatric nephrologists, an adult nephrologist, and a patient representative to develop comprehensive CPRs on the diagnosis and management of SSNS in children. After performing a systematic literature review on 12 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, recommendations were formulated and formally graded at several virtual consensus meetings. New definitions for treatment outcomes to help guide change of therapy and recommendations for important research questions are given., (© 2022. The Author(s).)

Background: Multisystem inflammatory syndrome in children (MIS-C) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been infrequently described in Africa., Objective: To describe the clinical characteristics, outcomes and associations of severe disease in children hospitalized with MIS-C in KwaZulu-Natal., Methods: Retrospective multicenter study of children (0-13 years) who met the Centers for Disease Control and Prevention criteria for MIS-C. Children with shock were compared with children without shock to determine the characteristics of severe MIS-C., Results: Twenty-nine children with MIS-C were identified, the mean age was 55 (SD ±45) months, 25 (86%) were Black-African, and 8 (28%) had pre-existing comorbidities. The predominant presenting symptoms included fever 29 (100%), gastrointestinal symptoms 25 (83%), skin rash 19 (65%), and shock 17 (59%). Children with shock had significantly increased CRP (P = 0.01), ferritin (P < 0.001), troponin-T (P = 0.02), B-type natriuretic peptide (BNP) (P = 0.01), and lower platelets (P = 0.01). Acute kidney injury (P = 0.01), cardiac involvement (P = 0.02), and altered levels of consciousness (P = 0.03) were more common in children with shock. The median length of hospital stay was 11 (IQR 7-19) days, with a mortality of 20.6%. Children who did not survive had significantly higher ferritin levels 1593 (IQR 1069-1650) ng/mL versus 540 (IQR 181-1156) ng/mL; P = 0.03) and significantly more required mechanical ventilation (OR 18; confidence interval 1.7-191.5; P = 0.005)., Conclusions: Hospitalized children with MIS-C in KwaZulu-Natal had more aggressive disease and higher mortality than children in better-resourced settings. Markedly elevated biomarkers and critical organ involvement were associated with severe disease. Risk factors for poor outcomes include higher ferritin levels and the need for mechanical ventilation., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

There is a paucity of data identifying genetic mutations that account for the high rate of steroid-resistant nephrotic syndrome (SRNS) in a South African paediatric population. The aim was to identify causal mutations in genes implicated in SRNS within a South African paediatric population. We enrolled 118 children with primary nephrotic syndrome (NS), 70 SRNS and 48 steroid-sensitive NS. All children with SRNS underwent kidney biopsy. We first genotyped the NPHS2 gene for the p.V260E variant in all NS cases (n = 118) and controls (n = 219). To further identify additional variants, we performed whole-exome sequencing and interrogated ten genes (NPHS1, NPHS2, WT1, LAMB2, ACTN4, TRPC6, INF2, CD2AP, PLCE1, MYO1E) implicated in SRNS with histopathological features of focal segmental glomerulosclerosis (FSGS) in 56 SRNS cases and 29 controls; we also performed exome sequencing on two patients carrying the NPHS2 p.V260E mutation as positive controls. The overall detection rate of causal and putative pathogenic mutations in children with SRNS was 27/70 (39%): 15 (21%) carried the NPHS2 p.V260E causal mutation in the homozygous state, and 12 (17%) SRNS cases carried a putative pathogenic mutation in the heterozygous state in genes (INF2 (n = 8), CD2AP (n = 3) and TRPC6 (n = 1)) known to have autosomal dominant inheritance mode. NPHS2 p.V260E homozygosity was specifically associated with biopsy-proven FSGS, accounting for 24% of children of Black ethnicity (15 of 63) with steroid-resistant FSGS. No causal or putative pathogenic mutations were identified in NPHS1, WT1, LAMB2, PLCE1, MYO1E and ACTN4. We report four novel variants in INF2, PLCE1, ACTN4 and TRPC6.   Conclusion: We report putative missense variants predicted to be pathogenic in INF2, CD2AP and TRPC6 among steroid-resistant-FSGS children. However, the NPHS2 p.V260E mutation is a prevalent cause of steroid-resistant FSGS among Black South African children occurring in 24% of children with SRNS. Screening all Black African children presenting with NS for NPHS2 p.V260E will provide a precision diagnosis of steroid-resistant FSGS and inform clinical management. What is Known: • Limited data is available on the genetic disparity of SNRS in a South African paediatric setting. • The high rate of steroid resistance in Black South African children with FSGS compared to other racial groups is partially explained by the founder variant NPHS2 p.V260E. What is New: • We report putative missense variants predicted to be pathogenic in INF2, CD2AP and TRPC6 among steroid-resistant FSGS children. • NPHS2 p.V260E mutation remains a prevalent cause of steroid-resistant FSGS among Black South African children, demonstrating precision diagnostic utility., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background. Hypertension (HPT) is often underdiagnosed in children, although significant morbidity and mortality arises from hypertensive target organ damage and hypertensive crises. Objectives. To determine the prevalence, complications and causes of severe HPT in children =12 years old at a central hospital. Methods. Hospital records of children =12 years old with severe HPT (stage 2 and higher) from 2005 to 2014 were reviewed. Demographics, nutritional status, causes, HIV status, presence of target organ damage and treatment were analysed. Results. Of 821 children admitted to the paediatric nephrology unit, 152 (18.5%) children had severe HPT, with a mean age of 6.3 years; 86 (57%) were boys. A total of 28 (19%) were HIV-positive, and 19 (68%) were treatment naive. Kidney disease accounted for 82% of cases, 46 (30%) having steroid-resistant nephrotic syndrome, 22 (14%) HIV-associated nephropathy, 19 (13%) glomerulonephritis, 21 (14%) congenital urinary tract abnormalities and 17 (11%) other renal causes. Renovascular causes accounted for 12 (8%) cases. Of these 12, 7 (58%) had left ventricular hypertrophy (LVH), compared with 10/125 (8%) who had other forms of kidney disease (p<0.023). Hypertensive crises occurred in 28 (18%) patients, and were significantly more common in children with HPT secondary to renovascular causes than renal causes (p=0.001). Conclusion. Renal diseases were the most common cause of severe HPT in children. Hypertensive crises, retinopathy and LVH are common in renovascular HPT. [ABSTRACT FROM AUTHOR]

Background. HIV-associated nephropathy (HIVAN) in sub-Saharan Africa remains a significant cause of morbidity and mortality in children. Early detection of kidney injury is essential for injury-specific interventions that may avert permanent kidney damage and delay progression of kidney injury. Kidney biopsy is presently the gold standard for diagnosis of related kidney disease; however, it is pervasive with attendant complications, and may not be representative owing to sampling error. Serum creatinine is an insensitive and non-specific marker for the diagnosis of various kidney diseases, particularly in HIV-infected patients, who usually have varying degrees of muscle wasting. Therefore, a non-invasive approach using additional biomarkers for early detection of HIV-related kidney diseases, particularly HIV-associated nephropathy (HIVAN), is urgently needed. Objective. To determine the urinary concentrations of kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18) and glutathione-Stransferase- p (GST-p) in children with idiopathic focal segmental glomerulosclerosis (FSGS) and HIVAN. Methods. The study group comprised 34 children: 13 with HIVAN and 21 with idiopathic FSGS. The control groups were 19 HIV-positive and 16 HIV-negative children with no kidney disease. Urine samples collected from these 69 children were stored at -80°C. Urinary concentrations of KIM-1, IL-18 and GST-p were quantified using Bio-Plex assay. Results. A significant increase in urinary KIM-1 levels was observed in the HIVAN group compared with the HIV-positive (p=0.0039) and HIV-negative (p=0.0438) control groups. There was no significant increase in KIM-1 levels on comparison of the idiopathic FSGS group with the control groups (HIV-positive and HIV-negative children) (p=0.0737 and p=0.1757, respectively). No statistically significant differences were noted in urinary IL-18 and GST-p levels across all study groups. Conclusion. Urinary KIM-1 levels are significantly elevated in children with HIVAN and may be a useful biomarker to detect kidney disease in HIV-1-infected children. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Impact of coronavirus disease‑2019 on pediatric nephrology practice and education: an ESPN survey."

Background: The outcome and response of idiopathic nephrotic syndrome (NS) to steroids have been linked to race., Objectives: To determine the age of presentation, sex, race, histopathology, kidney function and disease status at the last hospital visit and correlate these with steroid response in Indian and black African children with idiopathic NS., Methods: This is a retrospective review of 231 children aged 1 - 14 years, who were seen at Inkosi Albert Luthuli Central Hospital, Durban, South Africa (SA) from 2003 to 2018., Results: The mean (standard deviation (SD)) age of presentation was 6.2 (3.4) years, with the majority of children (n=107; 46.3%) presenting at an early age (1 - 3 years) with a mean (SD) follow-up of 3.0 (2.4) years. One-hundred and twenty-one (52.4%) were males and 110 (47.6%) were females, with a male/female ratio of 1.1:1. There were 166 (71.9%) black African and 65 (28.1%) Indian children. The latter presented at a younger age than black African children (p&lt;0.001). Seventy-six (32.9%) children were steroid sensitive (SS) and 155 (67.1%) were steroid resistant (SR). Black African children were more likely to be SR (odds ratio (OR) 2.0; p=0.02; 95% confidence interval (CI) 1.1 - 3.7). A kidney biopsy was performed in 209 (90.5%) children. Minimal change disease (MCD) was observed in 32 (13.9%) children and 162 (70.1%) had focal segmental glomerulosclerosis (FSGS). Black African children were slightly more likely to have FSGS; this, however, did not reach statistical significance (122/166 (73.5%) v. 40/65 (61.5%); OR 1.73; p=0.08; 95% CI 0.94 - 3.18). On comparing disease status at last hospital visit by race, 49/65 (75.4%) Indian and 94/166 (56.6%) black African children were in remission. At last hospital visit, black African children were less likely to be in remission than Indian children (OR 0.47; p=0.02; 95% CI 0.2 - 0.9), while 15/65 (23.1%) Indian and 47/166 (28.3%) black African children had relapsed, with no significant difference between the two groups. One (1.5%) Indian child and 25 (15.1%) black African children had end-stage kidney disease (ESKD) (OR 9.27; p=0.03; 95% CI 1.2 - 70.4) ‒ the majority had FSGS. Sixteen (61.5%) received renal replacement therapy., Conclusions: Our study shows a rising incidence of FSGS, with the majority of patients having SRNS, particularly black African children. This highlights the need for alternative efficacious therapy in the management of this disease. Also, a higher percentage of black African children with both MCD and FSGS were SS on histopathological examination, which was in keeping with reports from other regions in SA. There are still major challenges for the inclusion of all children into a chronic dialysis and transplant programme.

The epidemiological landscape of nephrotic syndrome (NS) in South Africa has changed drastically in the New Millennium. Although the pattern of disease in the 3 main non-Black racial groups (White, Indian, and Mixed race) mirror that seen in Western countries, Black African children show a pattern of disease that is at variance with these 3 racial groups. The incidence of infectious diseases, particularly hepatitis B virus associated nephropathy has sharply declined to being almost extinct in Black children in the New Millennium whereas HIV-related nephropathy surfaced. However, following the widespread use of anti-retroviral therapy, its incidence has also decreased dramatically. Focal segmental glomerulosclerosis (FSGS), which was once uncommon, has, in the New Millennium, emerged as one of the most challenging forms of NS across all racial groups, particularly in Black children. Although the introduction of calcineurin inhibitors, mycophenolate mofetil and monoclonal antibodies (e.g., rituximab) has improved the outcome of children with FSGS, the reponse in Black children is less than optimal, with those having single gene mutations being universally unresponsive to all forms of immunosuppression.

Background: In a resource-limited setting, acute peritoneal dialysis (APD) is the modality of choice as a form of renal replacement therapy in children with acute kidney injury (AKI). However, there is a high risk of peritonitis that causes significant morbidity and mortality. Data on PD and peritonitis in developing countries are scarce. The purpose of this retrospective study was to determine the prevalence of APD-related peritonitis at a central referral hospital in KwaZulu-Natal, South Africa., Methods: A retrospective study from January 2010 until December 2014 was done at Inkosi Albert Luthuli Central Hospital (IALCH). All children under the age of 13 years with AKI requiring APD were included in the study., Results: Forty children were included in the study. Age ranged from 0.2 years to 12.25 years; 25 (62.5%) were male and 15 (37.5%) female. Twenty-seven (67.5%) were admitted to the intensive care unit (ICU) and 13 (32.5%) to the pediatric high care ward. Septicemia with multi-organ dysfunction was the was the main cause of AKI requiring APD in 18 (45%) children followed by poststreptococcal glomerulonephritis in 8 (20%). Acute PD was complicated by culture-proven peritonitis in 19 (47.5%) children of whom 16 (84.2%) had a single organism cultured while in 3, (15.7%) there was a mixed culture. The total number of organisms cultured was 24: 8 (33.3%) were gram-positive organisms, 12 (50%) gram-negative organisms, and 4 (16.67%) fungal. The Paediatric Index of Mortality (PIM) 2 Score risk of mortality was 99.4% for patients admitted to ICU. Mortality rate was 65%, and 14 (53%) of the children who demised had peritonitis., Conclusion: This study showed an inordinately high complication rate of peritonitis, mostly secondary to gram-negative organisms, of children undergoing APD in a central referral hospital. The use of surgically placed, tunneled catheters, meticulous attention to aseptic techniques and judicious use of antimicrobials is highly recommended in reducing the incidence of peritonitis in children undergoing APD., (Copyright © 2018 International Society for Peritoneal Dialysis.)

Introduction: In South Africa (SA), steroid-resistant nephrotic syndrome (SRNS) is more frequent in black than in Indian children., Methods: Seeking a genetic basis for this disparity, we enrolled 33 Indian and 31 black children with steroid-sensitive nephrotic syndrome (SSNS) and SRNS from KwaZulu-Natal, SA; SRNS children underwent kidney biopsy. We sequenced NPHS2 and genotyped APOL1 in 15 SSNS and 64 SRNS unrelated patients and 104 controls and replicated results in 18 black patients with steroid-resistant focal segmental glomerulosclerosis (SR-FSGS). Known FSGS genes (n = 21) were sequenced in a subset of patients., Results: Homozygosity for NPHS2 V260E was found in 8 of 30 black children with SRNS (27%); all 260E/E carriers had SR-FSGS. Combining SR-FSGS patients from the 2 groups, 14 of 42 (33%) were homozygous for V260E. One black control was heterozygous for V260E; no Indian patients or controls were carriers. Haplotype analysis indicated that homozygosity for V260E was not explained by cryptic consanguinity. Children with NPHS2 260E/E developed SRNS at earlier age than noncarriers (34 vs. 78 months, P  = 0.01), and none achieved partial or complete remission (0% vs. 47%, P  = 0.002). APOL1 variants did not associate with NS. Sequencing FSGS genes identified a CD2AP predicted pathogenic variant in the heterozygous state in 1 Indian case with SR-FSGS., Conclusion: NPHS2 260E/E was present in one-third of black FSGS patients, was absent in black controls and Indian patients, and affected patients were unresponsive to therapy. Genotyping V260E in black children from South Africa with NS will identify a substantial group with SR-FSGS, potentially sparing these children biopsy and ineffective steroid treatment.

Hypertension in childhood leads to hypertension in adult life, the strongest risk factor being obesity. This study determined the prevalence of primary hypertension and its risk factors in Grade XII learners in KwaZulu-Natal, South Africa, from March 2016 to June 2017. Weight, height, body mass index (BMI), random finger prick cholesterol and glucose, and spot urine for an albumin : creatinine ratio were measured. An average of three separate blood pressure readings taken was at least 5 minutes apart. Five hundred and sixty-four learners had weight, height, and BMI; 536 had random blood glucose; and 545 had cholesterol and random spot urine albumin : creatinine ratios measured. Prehypertension was detected in 168 (29.7%) and hypertension in 77 (13.7%) of learners. Ninety (15.9%) were overweight and 75 (13,3%) were obese. Hypercholesterolaemia was present in 58 (10.8%) and a high spot random urine albumin : creatinine ratio in 5 (1.0%). None had a high blood glucose level. Both prehypertension and hypertension in all learners showed a significant increase with increasing BMI. Six (1.0%) learners had metabolic syndrome. Female learners in other racial groups (defined as Indian, mixed race, and White learners), overweight, and obese learners showed significantly higher rates of hypercholesterolaemia. We showed overweight and obesity as risk factors for prehypertension and hypertension. This presages the need for an appropriate diet and adequate exercise in a child's school career.

Background The use of serum creatinine equations for estimating glomerular filtration rate is well known in adults and children. We evaluated the revised Schwartz creatinine-based estimated glomerular filtration rate prediction equation in Black African children in KwaZulu-Natal, South Africa. Methods Review of medical records of all Black African patients aged 2-18 years old who have had glomerular filtration rate determined by intravenous Technetium-99 m-diethylene-triamine-pentaacetate, for the period 1 January 2010 to 31 December 2014 at the Inkosi Albert Luthuli Central Hospital, Durban, South Africa was performed. Estimated glomerular filtration rate result obtained using the revised Schwartz equation was compared to Technetium-99 m-diethylene-triamine-pentaacetate plasma clearance measured glomerular filtration rate. Accuracy of the estimated glomerular filtration rate equations within 10% (P 10 ) and 30% (P 30 ) of the measured glomerular filtration rate, sensitivity and specificity for predicting glomerular filtration rate < 60 mL/min/1.73 m 2 and < 30 mL/min/1.73 m 2 was determined. Results Results from 148 African children between 2 and 18 years old were analysed. P 10 and P 30 values were 16 and 49%, respectively. Sensitivity of 92.9% (95% CI: 80.5-85), specificity of 95.3 (95% CI: 89.3-98.5) and AUC of 0.96 (95% CI 0.92-0.99) were obtained for measured estimated glomerular filtration rate < 60 mL/min/1.73 m 2 . Sensitivity of 88.2% (95% CI: 63.6-98.5), specificity of 90.8 (95% CI: 84.5-95.2) and area under the curve of 0.93 (95% CI 0.88-0.96) were obtained for measured estimated glomerular filtration rate < 30 mL/min/1.73 m 2 . Conclusions The revised Schwartz equation did not meet the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines of 90% of estimated glomerular filtration rate results within 30% of measured glomerular filtration rate.

Background: Despite adverse events associated with the long-term use of immunosuppressants, their long-term discontinuation remains challenging in children with idiopathic nephrotic syndrome. Relapse and resumption of immunosuppressants after discontinuation and associated risk factors were analyzed., Methods: This single-center retrospective cohort study included children with frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS) or steroid-resistant nephrotic syndrome (SRNS) who initiated immunosuppressant treatment between 2010 and 2020. Patients treated with immunosuppressants for less than two years, those with genetic SRNS, and those with continuation of immunosuppressants were excluded., Results: Sixty-eight patients with FRNS/SDNS or SRNS discontinued immunosuppressants. Discontinuation of immunosuppressants was more frequently tried in patients with less relapse on initial immunosuppressants and less rituximab administration. Of 68 patients who discontinued immunosuppressants, 45 (66%) relapsed and 31 (46%) resumed immunosuppressants with a median follow-up of 39.8 months (IQR 24.6-71.2 months) after discontinuation. The relapse-free survival rates were 40.0%, 35.3%, and 35.3% in 1, 2, and 3 years from discontinuation of immunosuppressants, respectively. Relapse on initial immunosuppressants (HR 2.038, 95%CI 1.006-4.128, P = 0.048) and the relapse-free interval before discontinuation of immunosuppressants (HR 0.971, 95%CI 0.944-0.998, P = 0.037) were significant risk factors associated with relapse after the discontinuation of immunosuppressants, adjusting for sex, age at immunosuppressant treatment initiation, SRNS, and rituximab use., Conclusions: Long-term discontinuation of immunosuppressants can be feasible in patients without a relapse on initial immunosuppressants, those with longer relapse-free interval before discontinuation of immunosuppressants, and those without a relapse for one year after discontinuation of immunosuppressants., Trial Registration: Not applicable., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Targeted sequencing of discrete gene sets is a cost effective strategy to screen subjects for monogenic forms of disease. One method to achieve this pairs microfluidic PCR with next generation sequencing. The PCR step of this pipeline creates challenges in accurate variant calling. This includes that most reads targeting a specific exon are duplicates that have been amplified from the PCR step. To reduce false positive variant calls from these experiments, previous studies have used threshold-based filtering of alternative allele depth ratio and manual inspection of the alignments. However even after manual inspection and filtering, many variants fail to be validated via Sanger sequencing. To improve the accuracy of variant calling from these experiments, we are challenged to design a variant filtering strategy that sufficiently models microfluidic PCR-specific issues., Results: We developed an open source variant filtering pipeline, targeted sequencing support vector machine ("tarSVM"), that uses a Support Vector Machine (SVM) and a new score the normalized allele dosage test to identify high quality variants from microfluidic PCR data. tarSVM maximizes training knowledge by selecting variants that are likely true and likely false variants by incorporating knowledge from the 1000 Genomes and the Exome Aggregation Consortium projects. tarSVM improves on previous approaches by synthesizing variant features from the Genome Analysis Toolkit and allele dosage information. We compared the accuracy of tarSVM versus existing variant quality filtering strategies on two cohorts (n = 474 and n = 1152), and validated our method on a third cohort (n = 75). In the first cohort, our method achieved 84.5 % accuracy of predicting whether or not a variant would be validated with Sanger sequencing versus 78.8 % for the second most accurate method. In the second cohort, our method had an accuracy of 73.3 %, versus 61.5 % for the second best method. Finally, our method had a false discovery rate of 5 % for the validation cohort., Conclusions: tarSVM increases the accuracy of variant calling when using microfluidic PCR based targeted sequencing approaches. This results in higher confidence downstream analyses, and ultimately reduces the costs Sanger validation. Our approach is less labor intensive than existing approaches, and is available as an open source pipeline for read trimming, aligning, variant calling, and variant quality filtering on GitHub at https://github.com/christopher-gillies/TargetSpecificGATKSequencingPipeline .

CD2-associated protein (CD2AP) was identified as a genetic risk factor for late-onset Alzheimer’s disease (LOAD). However, it is unclear how CD2AP contributes to LOAD synaptic dysfunction underlying AD memory deficits. We have shown that loss of CD2AP function increases β-amyloid (Aβ) endocytic production, but it is unknown whether it contributes to synapse dysfunction. As CD2AP is an actin-binding protein, it may also function in F-actin-rich dendritic spines, which are the excitatory postsynaptic compartments. Here, we demonstrate that CD2AP colocalizes with F-actin in dendritic spines of primary mouse cortical neurons of both sexes. Cell-autonomous depletion of CD2AP specifically reduces spine density and volume, resulting in a functional decrease in synapse formation and neuronal network activity. Postsynaptic reexpression of CD2AP, but not blocking Aβ production, is sufficient to rescue spine density. CD2AP overexpression increases spine density, volume, and synapse formation, while a rare LOAD CD2AP mutation induces aberrant F-actin spine-like protrusions without functional synapses. CD2AP controls postsynaptic actin turnover, with the LOAD mutation in CD2AP decreasing F-actin dynamicity. Our data support that CD2AP risk variants could contribute to LOAD synapse dysfunction by disrupting spine formation and growth by deregulating actin dynamics. [ABSTRACT FROM AUTHOR]

Introduction: Young people living with HIV (YPLHIV) are at increased risk of developing chronic kidney disease (CKD) which is associated with high mortality and morbidity. Early diagnosis is important to halt progression. We aimed to estimate the prevalence and factors associated with CKD among YPLHIV in Kampala, Uganda, and to compare serum creatinine and cystatin C for early diagnosis of CKD in this population. Methods: A cross-sectional study with YPLHIV aged 10 to 24 years was conducted in seven HIV clinics. Participants provided a urine and blood sample to measure urinary albumin, proteinuria, serum creatinine and cystatin C levels at baseline and after three months. The estimated glomerular filtration rate (eGFR) was calculated using CKDEPI 2021, Cockroft-Gault and bedside Schwartz equations using creatinine or cystatin C. The albumin creatinine ratio (ACR) and proteinuria were measured. CKD was defined as either eGFR < 60 ml/min/1.73m2 or < 90 ml/min/1.73m2 or ACR above 30 mg/g on two separate occasions. Univariable and multivariable logistic regression were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for factors associated with CKD. Results: A total of 500 participants were enrolled. Most were female (56%; n = 280) and aged 10 to 17 years (66.9%; n = 335). CKD prevalence ranged from 0 to 23% depending on the criteria, equation and biomarker used. Cystatin C-based equations estimated higher prevalence of CKD compared to creatinine-based ones. Prevalence of ACR above 30 mg/g was 10.1% and of proteinuria 29%. Factors independently associated with CKD were age (aOR = 1.42; 95% CI:1.30–1.51) and male sex (aOR = 3.02; 95% CI:1.68–5.43). Conclusion: CKD prevalence among YPLHIV varied substantially depending on definitions used and the current definition would likely lead to missed cases of CKD among YPLHIV. Estimating equations should be validated against measured GFR in YPLHIV and the optimal definition of CKD in this vulnerable population should be revised to optimise detection and opportunities for reducing disease progression. Clinical trial number: Not applicable. [ABSTRACT FROM AUTHOR]

Minimal Change Disease (MCD) is a predominant cause of idiopathic nephrotic syndrome in the pediatric population, yet presents significant clinical challenges due to its frequent relapses and steroid resistance. Despite its relatively benign histological appearance, MCD is characterized by severe proteinuria, hypoalbuminemia, and edema, which may affect patient outcomes. Current treatment strategies primarily rely on corticosteroids, which are effective in inducing remission but are associated with high relapse rates, steroid resistance, and numerous long-term side effects, underscoring the need for more targeted and effective therapeutic approaches. This narrative review synthesizes current knowledge on the pathophysiological mechanisms underlying MCD, focusing on the following three critical areas: podocyte dysfunction, immune dysregulation, and genetic susceptibility. Podocyte dysfunction, particularly involving alterations in nephrin, plays a central role in the breakdown of the glomerular filtration barrier, leading to the characteristic proteinuria observed in MCD. Immune dysregulation, including the presence of autoantibodies against nephrin and other podocyte components, exacerbates podocyte injury and contributes to disease progression, suggesting an autoimmune component to the disease. Genetic factors, particularly mutations in the NPHS1 and NPHS2 genes, have been identified as significant contributors to disease susceptibility, influencing the variability in treatment response and overall disease severity. Understanding these mechanisms is crucial for developing targeted therapies that address the underlying causes of MCD rather than merely managing its symptoms. This review highlights the need for further research into these pathophysiological processes to pave the way for more personalized and effective treatment strategies, ultimately improving patient outcomes and reducing reliance on corticosteroids. [ABSTRACT FROM AUTHOR]

Background: Globally, the prevalence of chronic kidney disease (CKD) is increasing among young people living with HIV (YPLHIV), with inconsistent estimates. Aggregated data on the prevalence of CKD are needed in sub-Saharan Africa (SSA) to inform strategies for early diagnosis and management. We conducted a systematic review and meta-analysis to estimate the pooled prevalence of CKD among YPLHIV in SSA. Methods: We searched Medline/PubMed, EMBASE, African Index Medicus, and African Journals Online for articles reporting the prevalence of CKD among YPLHIV in SSA using predefined search strategies up to 15th January 2024. The reference lists of identified articles were checked for additional eligible studies. The eligibility criteria were studies among YPLHIV aged 10–24 years reporting CKD prevalence defined by either glomerular filtration rate (GFR), albumin-to-creatinine ratio (ACR) or proteinuria. We used a narrative synthesis to report differences between the included studies. The DerSimonian-Laird random effects model was used to pool the CKD prevalence, and heterogeneity was assessed using the Cochrane Q-test and I-squared values. We assessed the risk of bias in each article using the Joanna Briggs Institute checklist and publication bias in a funnel plot and Egger's test. Results: Of 802 retrieved articles, 15 fulfilled the eligibility criteria and were included in the meta-analysis. Of these, 12 (80%) were cross-sectional studies that used estimated GFR to diagnose CKD. Only one study followed the standard definition of CKD. The pooled CKD prevalence from 15 studies was 12% (95% CI 6.0–19.5%), ranging from 0.8% to 53.1% according to the definition used, with a high degree of heterogeneity (I2 = 97.7%, p<0.001). The included studies were of moderate quality, with no evidence of publication bias. Sensitivity analysis showed that the findings were robust to the methodological and analytic approach. Conclusion: CKD prevalence among YPLHIV is moderately high and highly heterogeneous across SSA. The standard definition of CKD should be used to enable estimation of CKD prevalence in different studies and settings. HIV programs enrolling YPLHIV should routinely screen for CKD to ensure early diagnosis and management. Trial registration: PROSPERO registration number: CRD42022347588. [ABSTRACT FROM AUTHOR]

Background: Idiopathic membranous nephropathy (IMN) is a rare form of childhood nephropathy. To date there are no standardized protocols of management for this condition in children. The aim of this study is to report on 4 children with IMN who were treated with mycophenolate mofetil (MMF)., Methods: MMF was given in combination with low dose steroids and angiotensin converting enzyme antagonists in a dose of 1,200 mg/m2 body surface area in two divided doses for a minimum of 6 months., Results: All children had histopathological findings in keeping with Stage III membranous nephropathy. At the last hospital visit, 3 children had achieved a > 50% reduction of proteinuria with preservation of renal function. One patient who failed to respond progressed to Stage III chronic kidney disease. None of the children who were treated with MMF experienced any major side effects of the drug., Conclusions: MMF, administered over a limited period, served as a safe and effective immunosuppressive agent in the treatment of this condition, in conjunction with low dose steroids and angiotensin converting enzyme inhibitors. Large multicenter randomized studies of children with IMN are necessary to assess the efficacy and long term safety of MMF.

Introduction: Involvement of the kidney in children and adolescents with perinatal (HIV-1) infection can occur at any stage during the child's life with diverse diagnoses, ranging from acute kidney injury, childhood urinary tract infections (UTIs), electrolyte imbalances and drug-induced nephrotoxicity, to diseases of the glomerulus. The latter include various immune-mediated chronic kidney diseases (CKD) and HIV-associated nephropathy (HIVAN)., Discussion: The introduction of highly active anti-retroviral therapy (HAART) has dramatically reduced the incidence of HIVAN, once the commonest form of CKD in children of African descent living with HIV, and also altered its prognosis from eventual progression to end-stage kidney disease to one that is compatible with long-term survival. The impact of HAART on the outcome of other forms of kidney diseases seen in this population has not been as impressive. Increasingly important is nephrotoxicity secondary to the prolonged use of anti-retroviral agents, and the occurrence of co-morbid kidney disease unrelated to HIV infection or its treatment. Improved understanding of the molecular pathogenesis and genetics of kidney diseases associated with HIV will result in better screening, prevention and treatment efforts, as HIV specialists and nephrologists coordinate clinical care of these patients. Both haemodialysis (HD) and peritoneal dialysis (PD) are effective as renal replacement therapy in HIV-infected patients with end-stage kidney disease, with PD being preferred in resource-limited settings. Kidney transplantation, once contraindicated in this population, has now become the most effective renal replacement therapy, provided rigorous criteria are met. Given the attendant morbidity and mortality in HIV-infected children and adolescents with kidney disease, routine screening for kidney disease is recommended where resources permit., Conclusions: This review focuses on the pathogenesis and genetics, clinical presentation and management of kidney disease in children and adolescents with perinatal HIV-1 infection.

Background: Despite the burden of human immunodeficiency virus (HIV) disease in Southern Africa, there have been few reports of HIV-related nephropathy in children. This study outlines the spectrum of HIV-1-related kidney diseases of children in KwaZulu-Natal, South Africa., Methods: A review of the clinical presentation, laboratory and histopathological findings of children diagnosed with HIV-related nephropathy., Results: Forty-nine out of 71 children (1-16 years old) with HIV-1 related nephropathy underwent kidney biopsy. The most common histopathological finding was focal segmental glomerulosclerosis (FSGS), which was present in 32 (65.3%) children; 13 (26.5%) having collapsing glomerulopathy and 19 (38.8%) classic FSGS. The majority of patients showed haematological (86.4%) and electrolyte abnormalities (69.4%). Renal impairment was present in 41% of patients on initial presentation. However, end-stage kidney disease was present in only 4% of these patients. All patients were treated with highly active anti-retroviral therapy (HAART), the majority (79.6%) showed decreased proteinuria with 38.8% having complete remission., Conclusions: This study, one of the largest series of children reported from Africa, demonstrates that nephrotic syndrome due to HIV-associated nephropathy (HIVAN) is the commonest presentation of HIV-related nephropathy in childhood. Highly active anti-retroviral therapy in combination with angiotensin-converting enzyme antagonists is highly effective in decreasing proteinuria and preserving renal function.

Pediatric cryptococcosis has been documented in various organs, but pediatric renal cryptococcosis (RC) remains undocumented to date. The authors report RC in 2 children with AIDS, 7 and 9 years of age, with proteinuria. Both patients, on antiretroviral therapy (ARV) for 28 (patient 1) and 54 (patient 2) weeks each, had secured viral immunosuppression, but immune restoration was realized by patient 1 only. Cryptococcal immune reconstitution inflammatory syndrome (IRIS) was diagnosed on the renal biopsy from patient 1 based on the clinicopathological profile and the presence of segmental glomerular and an interstitial lymphoplasmacytic and granulomatous reaction to Cryptococcus neoformans, with a predominance of capsule-deficient fungal forms. The renal biopsy from patient 2 demonstrated typical HIV-associated nephropathy with focal intratubular and interstitial C neoformans yeasts. Pediatric AIDS-associated renal disease must be expanded to include RC and cryptococcal IRIS, and the kidney must be included as a potential sentinel site of IRIS.

Background: A causal relationship exists between HBV infection and membranous nephropathy. The association is especially close in Black children in sub-Saharan Africa. Interferon-alpha2b is commonly used to treat this condition, but is effective in only 30-40% of patients. The reason for the poor response is unknown. The objective of this study was to determine if mutations in the surface gene of HBV isolated from Black children with HBV-associated membranous nephropathy before, during and after interferon treatment, have any effect on treatment response and vice versa., Methods: HBV DNA was extracted from a responder, a reverter and a non-responder before and after initiation of 16 weeks of interferon-alpha2b treatment. The preS1/preS2/S region was amplified, cloned and sequenced., Results: The preS2 region was the most variable in the reverter and the non-responder, and the S region was the most variable in the non-responder. Phylogenetic analysis showed that the viral population dynamics between the responder and the reverter/non-responder strains differed as a result of mutations in the surface gene., Conclusions: The presence of mutations in the S region of HBV could be used as predictive markers to differentiate interferon-alpha2b responders from non-responders provided that detailed analysis of further genomes confirms our findings.

HIV infection remains one of the leading causes of morbidity and mortality worldwide, especially in children living in resource-limited settings. Although the World Health Organization (WHO) recently recommended antiretroviral therapy (ART) initiation upon diagnosis regardless of the number of CD4, ART access remains limited, especially in children living in sub-Saharan Africa (SSA). HIV-infected children who do not receive appropriate ART are at increased risk of developing HIV-associated nephropathy (HIVAN). Although due to genetic susceptibility, SSA is recognized to be the epicenter of HIVAN, limited information is available regarding the burden of HIVAN in children living in Africa. The present review discusses the information available to date on the prevalence, pathogenesis, risk factors, diagnosis, and management of HIVAN in children, focusing on related challenges in a resource-limited setting., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)