ABSTRACT
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.
Subject(s)
Kidney Diseases, Cystic , Humans , Female , Child , Kidney Diseases, Cystic/genetics , Kidney Diseases, Cystic/diagnosis , Kidney Diseases, Cystic/congenital , South Africa , AdolescentABSTRACT
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.
Subject(s)
Nephrology , Nephrotic Syndrome , Child , Humans , Nephrotic Syndrome/diagnosis , Nephrotic Syndrome/drug therapy , Nephrotic Syndrome/epidemiology , Glucocorticoids/therapeutic use , Immunosuppressive Agents/adverse effects , Proteinuria/drug therapy , Steroids/adverse effects , RecurrenceABSTRACT
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.
Subject(s)
Renal Insufficiency, Chronic , Female , Humans , Male , Prevalence , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/epidemiology , South Africa/epidemiologyABSTRACT
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.
Subject(s)
Glomerulosclerosis, Focal Segmental , Nephrotic Syndrome , Child , DNA Mutational Analysis , Glomerulosclerosis, Focal Segmental/diagnosis , Glomerulosclerosis, Focal Segmental/genetics , Humans , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mutation , Nephrotic Syndrome/diagnosis , Nephrotic Syndrome/drug therapy , Nephrotic Syndrome/genetics , South Africa , Steroids/therapeutic use , TRPC6 Cation Channel/geneticsABSTRACT
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.
Subject(s)
Kidney Failure, Chronic/surgery , Kidney Transplantation , Adolescent , Child , Child, Preschool , Female , Follow-Up Studies , Graft Rejection/epidemiology , Graft Survival , Health Services Accessibility , Humans , Kidney Transplantation/statistics & numerical data , Male , Retrospective Studies , South Africa , Tissue Donors/supply & distribution , Treatment OutcomeABSTRACT
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 .
Subject(s)
Alleles , High-Throughput Nucleotide Sequencing/methods , Microfluidics , Software , Support Vector Machine , Data Accuracy , Humans , Polymerase Chain Reaction , Sequence Analysis, DNA/methodsABSTRACT
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.
Subject(s)
Glomerulonephritis, Membranous/drug therapy , Immunosuppressive Agents/therapeutic use , Mycophenolic Acid/analogs & derivatives , Adrenal Cortex Hormones/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Child , Child, Preschool , Drug Therapy, Combination , Female , Glomerular Filtration Rate , Humans , Male , Mycophenolic Acid/therapeutic useABSTRACT
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.
Subject(s)
COVID-19 , United States , Child , Humans , Middle Aged , COVID-19/complications , COVID-19/epidemiology , SARS-CoV-2 , South Africa/epidemiologyABSTRACT
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.
Subject(s)
AIDS-Associated Nephropathy/physiopathology , AIDS-Associated Nephropathy/complications , AIDS-Associated Nephropathy/pathology , Adolescent , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiretroviral Therapy, Highly Active , Blotting, Western , Child , Child, Preschool , Enzyme-Linked Immunosorbent Assay , Female , Glomerulosclerosis, Focal Segmental/etiology , Glomerulosclerosis, Focal Segmental/pathology , Growth Disorders/etiology , HIV Infections/epidemiology , HIV Seropositivity , Humans , Infant , Kidney/pathology , Kidney Failure, Chronic/etiology , Kidney Failure, Chronic/pathology , Kidney Function Tests , Male , Nephrotic Syndrome/etiology , Proteinuria/drug therapy , Proteinuria/etiology , South Africa/epidemiology , Viral LoadABSTRACT
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.
ABSTRACT
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.
Subject(s)
Acute Kidney Injury/diagnosis , Acute Kidney Injury/therapy , Peritoneal Dialysis/adverse effects , Peritonitis/etiology , Peritonitis/mortality , Acute Kidney Injury/mortality , Adolescent , Anti-Bacterial Agents/therapeutic use , Child , Child, Preschool , Cohort Studies , Developing Countries , Female , Follow-Up Studies , Hospital Mortality/trends , Humans , Infant , Intensive Care Units , Male , Peritoneal Dialysis/methods , Peritonitis/drug therapy , Peritonitis/physiopathology , Poverty , Retrospective Studies , Risk Assessment , Severity of Illness Index , South Africa , Tertiary Care Centers , Treatment OutcomeABSTRACT
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% (P10) and 30% (P30) of the measured glomerular filtration rate, sensitivity and specificity for predicting glomerular filtration rate < 60 mL/min/1.73 m2 and < 30 mL/min/1.73 m2 was determined. Results Results from 148 African children between 2 and 18 years old were analysed. P10 and P30 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 m2. 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 m2. 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.
Subject(s)
Black People , Creatinine/urine , Glomerular Filtration Rate , Kidney Function Tests/standards , Adolescent , Area Under Curve , Child , Child, Preschool , Female , Humans , Limit of Detection , Male , South AfricaABSTRACT
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.
ABSTRACT
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.
ABSTRACT
BACKGROUND: The use of tacrolimus in steroid-resistant (SR) focal segmental glomerulosclerosis (FSGS) has been reported in single and small series case reports. AIM: To determine the efficacy of tacrolimus in the management of SR FSGS in children. STUDY DESIGN: This was a prospective study of 20 children with SR FSGS treated with tacrolimus (0.2-0.4 mg/kg/day in two divided doses over 12 h adjusted to a trough level between 7 and 15 ng/ml) for 12 months in combination with low-dose steroids. Other therapies included angiotensin-converting enzyme inhibitors, folic acid, multivitamins and lipid-lowering agents. RESULTS: The mean age at study entry was 11.1 years (range 5.6-16.8). The mean duration of nephrotic syndrome before initiation of tacrolimus therapy was 4.7 years (range 2.1-7.6). At the end of the treatment period, 8 (40%) children were in complete remission, 9 (45%) were in partial remission, and 3 (15%) failed to respond. The average follow-up period following cessation of tacrolimus treatment was 27.5 months (range 13.7-43.7). At last hospital follow-up, 5 (25%) children were in complete remission, 10 (50%) in partial remission, and 2 (10%) in relapse. Three children died from dialysis-related complications following cessation of tacrolimus treatment. Adverse events included sepsis (2), nausea (2), diarrhea (2), anemia (4) and worsening of hypertension (4). CONCLUSION: Tacrolimus is a safe and effective treatment for SR FSGS. However, like cyclosporine, some children tend to relapse following cessation of treatment.
Subject(s)
Glomerulosclerosis, Focal Segmental/drug therapy , Immunosuppressive Agents/therapeutic use , Tacrolimus/therapeutic use , Adolescent , Child , Female , Humans , Immunosuppressive Agents/adverse effects , Male , Steroids/therapeutic use , Tacrolimus/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: The hepatitis B virus (HBV) vaccine has resulted in a decline in the incidence of HBV carriage and hepatocellular carcinoma in southeast Asia. Vaccine efficacy in Africa has not been adequately assessed. OBJECTIVE: To report on the impact of HBV vaccination in South Africa on HBV-associated membranous nephropathy (MN) over 6 years. METHODS: King Edward VIII Hospital in Durban is the only tertiary referral center for the province of KwaZulu-Natal for children with renal diseases. The HBV vaccine was introduced into the South African Expanded Programme on Immunisation on April 1, 1995; vaccine coverage rates between April 1, 1995, and December 31, 2001, for children for the first, second, and third doses were 85.4%, 78.2%, and 62.0%, respectively. Hepatitis B virus status was determined using a radioimmunoassay (January 1, 1984-March 31, 1991) or an enzyme-linked immunosorbent assay. Membranous nephropathy was confirmed by the results of a renal biopsy. The hospital average annual incidence of HBV-associated MN was compared before and after vaccination and according to age groups. RESULTS: Between January 31, 1984, and December 31, 2001, there were 119 children with HBV-associated MN; their mean age was 7 years (range, 1-14 years), and 101 (84.9%) were males. The average annual rate ratio per 105 child population was 0.25. The overall incidence rate ratio showed a significant decrease from January 1, 2000, to December 31, 2001, compared with the preimmunization period (January 1, 1984-December 31, 1994) (incidence rate ratio, 0.12; 95% confidence interval, 0.03-0.50). Children from birth to the age of 4 years experienced no disease after 1998. Children aged 5 to 10 years showed a significant decrease in 2000-2001 compared with the prevaccination years (incidence rate ratio, 0.19; 95% confidence interval, 0.05-0.80). CONCLUSION: The HBV vaccine, even at low coverage for the full South African Expanded Programme on Immunisation schedule, reduced the hospital incidence of HBV-associated MN over 6 years.
Subject(s)
Glomerulonephritis, Membranous/therapy , Glomerulonephritis, Membranous/virology , Hepatitis B Vaccines/therapeutic use , Hepatitis B virus , Adolescent , Age Factors , Child , Child Welfare , Child, Preschool , Female , Glomerulonephritis, Membranous/epidemiology , Hepatitis B Vaccines/immunology , Hepatitis B virus/immunology , Humans , Immunization/trends , Incidence , Infant , Infant Welfare , Infant, Newborn , Male , Patient Admission/trends , South Africa/epidemiology , Survival Analysis , Treatment OutcomeABSTRACT
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.
Subject(s)
HIV Infections/complications , Kidney Diseases/epidemiology , Adolescent , Anti-HIV Agents/adverse effects , Anti-HIV Agents/therapeutic use , Child , HIV Infections/virology , HIV-1/isolation & purification , Humans , Kidney Diseases/etiology , Kidney Diseases/pathology , Kidney Diseases/therapyABSTRACT
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.
Subject(s)
AIDS-Related Opportunistic Infections/microbiology , Acquired Immunodeficiency Syndrome/microbiology , Cryptococcosis/diagnosis , Kidney Diseases/microbiology , AIDS-Related Opportunistic Infections/complications , Acquired Immunodeficiency Syndrome/complications , Acquired Immunodeficiency Syndrome/drug therapy , Antiretroviral Therapy, Highly Active , Child , Cryptococcosis/complications , Cryptococcosis/microbiology , Cryptococcus neoformans , Female , Humans , Kidney Diseases/complications , Male , Proteinuria/complications , Proteinuria/microbiologyABSTRACT
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.