Primary nephrotic syndrome in the new millennium in KwaZulu-Natal, South Africa.

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<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.

Basic fibroblast growth factors as a biomarker of focal segmental glomerulosclerosis in HIV-positive and HIV-negative children

Background. HIV infection can lead to the development of HIV-associated nephropathy (HIVAN) with the majority of patients progressing to end-stage kidney disease. Previous studies have recognised basic fibroblast growth factor (bFGF) as a biomarker for HIVAN, since significant levels of bFGF low-affinity receptors have been found in the kidneys of HIV-infected children.Objective. To assess the association between bFGF and kidney disease in the development of focal segmental glomerulosclerosis (FSGS) in HIV-positive and negative children.Methods. The study group consisted of 31 children; HIVAN (n=11) and idiopathic FSGS (n=20). The control group consisted of both HIV-positive (n=20) and HIV-negative (n=20) children with no kidney disease. Serum samples from all patients in both the study and control groups were analysed for bFGF.Results. The concentration of bFGF was higher, in comparison with idiopathic FSGS children, in HIVAN children (p=0.0167). There was also a significant elevation of serum bFGF levels in children with HIVAN when compared with HIV-positive (p=0.0288) and HIV-negative (p=0.0043) control groups.Conclusion. This study demonstrated statistically significant differences between bFGF levels in children with HIVAN and a control group, although it failed to distinguish significant differences in bFGF levels between HIVAN and idiopathic FSGS children

Severe hypertension in children at a central referral hospital in KwaZulu-Natal Province, South Africa

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

Arthritis in association with human immunodeficiency virus infection in Black African children: causal or coincidental?

OBJECTIVES: To compare human immunodeficiency virus (HIV)-infected and HIV-uninfected children with arthritis of unknown origin to determine whether the association between HIV infection and arthritis is causal or coincidental. METHOD: Retrospective review of 132 children with arthritis who were tested for HIV infection. RESULTS: Thirty-five (27%) of the children were HIV infected and the male to female ratio was 2.5:1 (P = 0.02). Arthritis was the presenting feature of HIV infection in 78% of these children. The remaining 97 (73%) were diagnosed as having juvenile idiopathic arthritis. 'Spondyloarthropathy-like' features were found in 34% of HIV-infected children compared with 5% of uninfected children. CONCLUSION: The high prevalence of HIV infection in 27% of children, the predominance of males and the increased prevalence of 'spondyloarthropathy-like' features, supports a causal relationship between HIV infection and arthritis.

Human immunodeficiency virus and urinary tract infections in children.

This was a retrospective study of HIV-infected children aged 0-12 years attending the King Edward VIII Hospital in Durban, South Africa over a 5-year period (January 1996 to December 2001) with culture-proven urinary tract infection (UTI). UTI was defined as the presence of a single bacterial growth of >10(5) colony-forming units/ml in a clean-catch, mid-stream urine sample or >10(3) organisms/ml in a catheter or suprapubic aspirate of urine. HIV/AIDS was diagnosed in accordance with World Health Organization and/or Centers for Disease Control criteria. Comparison between HIV-positive and HIV-negative children with UTI was done using the chi2 and Wilcoxon rank sum tests. Of the 55 children recruited into the study, 29 (52.1%) were HIV-positive and 26 (47.3%) HIV-negative. Escherichia coli was isolated in 50 (87.2%) children. Clinical presentation, aetiological agents, response to therapy and renal function were similar in both groups. This study showed no significant impact of HIV/AIDS on the presentation of UTI in children.

Re-evaluating criteria for peritoneal dialysis in "classical" (D+) hemolytic uremic syndrome.

BACKGROUND: Indications for peritoneal dialysis in children with post-dysenteric hemolytic uremic syndrome (D+ HUS) have not been thoroughly evaluated. Although early institution of dialysis may reduce mortality, the procedure has attendant complications. AIM: To determine whether the use of more stringent criteria for instituting dialysis had a better outcome to that of using conventional criteria. METHOD: Following an outbreak of Shigella dysenteriae type 1 D+ HUS in KwaZulu/Natal during June 1994 to October 1995, we compared the renal outcome and mortality between two periods: before May 1995 (69 children) when conventional criteria for dialysis were employed and after May 1995 (70 children) when more stringent criteria for dialysis were applied. RESULTS: The mean age of presentation was 35 months, 79 (56.8%) were males. Both groups were comparable except for gut perforation, which was more frequent before May 1995, and hypertension and severe disease, which were more frequent after May 1995. Seventy patients underwent dialysis, 36 (52.2%) before May 1995. There were no significant differences in renal outcome or death following discharge from hospital in both groups. Overall mortality was 20.1%, 15 (53.6%) of the 28 children that demised presented before May 1995. OUTCOME: Accordingly, although children with more severe disease and a higher frequency of hypertension presented after May 1995, there were no significant differences in morbidity or mortality in those using stringent criteria for dialysis, compared to those in whom conventional criteria were used. CONCLUSION: We showed that several children, who would previously have been dialyzed, may be managed conservatively, without an increase in mortality or morbidity.

Focal segmental glomerulosclerosis in children from KwaZulu/Natal, South Africa.

AIM: The aim of this paper was to describe the clinical course, histological grading, response to therapies and complications of nephrotic children with focal segmental glomerulosclerosis (FSGS) in Durban, South Africa. METHODS: The demographic data, response to drug therapy, complications, renal function and disease status at the last hospital visit were recorded in children diagnosed as FSGS on histology. Biopsies were graded according to the degree of glomerulosclerosis and interstitial involvement. RESULTS: Seventy-five children, 32 Indian and 43 Black were studied. FSGS as a proportion of all children seen with nephrotic syndrome, has risen between 1970 to 1995 from 1.8% to 20% in Indian children and 5% to 28% in Black children. Of those children followed for two years or more, the two racial groups were similar with respect to age at presentation, gender, histological grading, hypertension, renal outcome and response to therapies except for cushingoid features (p < 0.7), alopecia (p < 0.003) and respiratory tract infections (p < 0.001) which occurred more frequently in Indian children. Forty-three children were followed for between 2-16 years: 14 (10 Indian and 4 Black (p < 0.5)) (29%) had grade 1 changes, 24(13 Indian, 11 Black (p < 0.98)) (56%) had grade 2 changes, 3 (Indian (p < 0.26)) (7%) had grade 3 changes and 2 (Black (p < 0.17)) grade 4 changes. Over this period 27 (63%) had normal renal function, 6 (14%) died, 4 (9%) developed impaired renal function, 6 (14%) chronic renal insufficiency and 6 (14%) end-stage renal disease. Three of the latter were transplanted. At the last hospital visit, Indian children had remitted more often (p < 0.6) and Black children suffered relapse more frequently (p < 0.03). Two children had spontaneous disease remission, and 5 had sustained remission following a course of prednisolone and/or cyclophosphamide. CONCLUSION: This, one of the largest studies of FSGS in children, shows a marked rise in this condition and some differences between Indian and Black children. The outcome in Black children was not as poor as anticipated.

Characterization of proteinuria in asymptomatic family members and household contacts of children with hepatitis B virus-associated membranous nephropathy.

The biosocial background in which the hepatitis B virus (HBV) carrier state with membranous nephropathy (MN) develops was studied by evaluating HBV carriage and proteinuria among 195 family members and household contacts of 31 index HBV carrier children with MN. Unrelated individuals from the communities of these index cases who were negative for HBV served as controls (n = 123). HBV was determined by using third-generation enzyme-linked immunosorbent assay, slot-blot hybridization, and nested polymerase chain reaction. Patterns of proteinuria were determined by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis; immunoglobulin G and haptoglobulin were suggestive of MN. Seventy-two members (36.9%) of the study group (n = 195) were HBV carriers; 21 of these carriers (29.2%) had proteinuria. Twenty-eight members (41.2%) of the study group who were HBV negative (n = 68) and 26.8% of the controls showed proteinuria. This lack of association between HBV carriage and proteinuria remained when controlled for sex and family relationship. HBV was not protective against the development of proteinuria. Proteinuria suggestive of MN was strongly associated with an abnormal protein-creatinine ratio (P: = 0.001), but was not significantly different between subjects and controls (8.7% versus 6.5%; P: = 0.5). Genetic influences or environmental exposures in these subjects may be responsible for the proteinuria, suggesting underlying glomerular basement membrane damage. Discordance between the HBV carrier state and patterns of proteinuria in the study group suggest that HBV and MN may not be causally related or may reflect exceptional interaction between specifically vulnerable individuals and HBV.

HBV and proteinuria in relatives and contacts of children with hepatitis B virus-associated membranous nephropathy.

BACKGROUND: Hepatitis B virus (HBV)-associated membranous nephropathy (HBVMN) is an important cause of childhood nephrotic syndrome in regions endemic for the virus, but little is understood of the biosocial context in which the disease develops. We evaluated HBV status and proteinuria in family members and household contacts of index children with HBVMN to test the hypothesis that HBV carriage and asymptomatic proteinuria are closely linked and may be causally associated. METHODS: Thirty-one black children with biopsy-proven HBVMN were the index cases. One hundred and fifty-two family members and 43 black household contacts were the subjects of the study. We assessed HBV carrier status by testing for HBV antigens and antibodies using enzyme-linked immunosorbent assays (ELISA) and for HBV DNA by using slot-blot hybridization and the polymerase chain reaction. Sequencing of the precore region of HBV was done in a subset of both index cases and subjects. Proteinuria was assessed by measuring the urinary protein/creatinine ratio. RESULTS: Seventy-two (37%) of the 195 family members and household contacts were HBV carriers, and 53 (27%) had a protein/creatinine ratio greater than the physiological limit. The frequency of abnormal proteinuria was not significantly different in those with [22 out of 72 (30.5%)] or without [33 out of 104 (32%)] HBV carriage. This lack of association remained when carriers were classified into those who were HBsAg positive only and those with active viral replication (HBsAg and/or HBeAg and/or HBV DNA; P = 0.01). Family members were more predisposed to HBV carriage than household contacts, but abnormal proteinuria was present with equal frequency (P = 0.48). Age had a significant impact on proteinuria, with children less than five years being more likely to have abnormal proteinuria (P = 0.008). The prevalence of abnormal proteinuria in family members and household contacts of the index cases was more than that in community-based controls. The 10 index HBVMN cases and the 14 family members and household contacts who were tested all had HBV of genotype A. CONCLUSION: These results suggest that the family members and household contacts of children with HBVMN are at very high risk of HBV carriage; they also have asymptomatic proteinuria at a significantly higher rate than community-based controls. The HBV carrier status was not associated with proteinuria, a finding supported by peak prevalences of proteinuria in those under five years but no corresponding peak for HBV carriage. Proteinuria may indicate glomerular basement membrane dysfunction. Environmental and social factors may underpin development of these two covert disorders, but are insufficient to account for the index cases of HBVMN. The emergence of children with HBVMN from such households additionally depends on unidentified and possibly genetic factors.

Hepatitis B virus-associated nephropathy in black South African children.

Hepatitis B virus (HBV)-related membranous nephropathy (MN) is prominent in secondary nephrotic syndromes (NS) in Africa, but the features of this disease and the spectrum of associated glomerulopathies have not been adequately documented in black children. HBV was detected in 93 children with NS included in this study. In 70 patients the histological type was membranous; 46 were followed for a mean of 3.4 years (range 1-11 years). Spontaneous elimination of both HBsAg and HBeAg occurred in 10 (21.7%) patients; 16 (34.8%) cleared HBeAg alone. Co-existing liver disease occurred in 18 (25.7%) and hypocomplementemia (C3,C4) in 47.1% and 11.4% of children, respectively. Sixty-five (92.9%) patients had normal renal function, 1 (1.4%) impaired renal function, 3 (4.3%) chronic renal insufficiency, and 1 (1.4%) end-stage renal disease at last hospital visit. Twelve patients were in remission, all having cleared HBeAg. HBVMN was clinically indistinguishable from 24 children with idiopathic MN, although biochemical characteristics were different. This report delineates the natural history of HBV infection in black South African children with NS, the majority of whom have MN. Disease remission in HBVMN parallels elimination of HBV antigens, particularly HBeAg. Comparison of HBVMN with idiopathic MN revealed clinically indistinguishable characteristics but unexplained biochemical differences.

Post-dysenteric hemolytic uremic syndrome in children during an epidemic of Shigella dysentery in Kwazulu/Natal.

We report 81 of 107 cases of hemolytic uremic syndrome (HUS), admitted between July 1994 and February 1996, following an outbreak of Shigella dysenteriae type 1 dysentery in Kwazulu/Natal. All patients, excluding 1, were black with a mean age of 38 months (range 1-121); 50 (61.7%) were males. The mean duration of dysentery was 11.3 days (range 1-41) and HUS 15 days (range 1-91). Most patients had acute oliguric renal failure (90.1%), 42 (51.6%) required peritoneal dialysis. Complications included encephalopathy 30 (37.0%), convulsions 12 (14.8%) and hemiplegia 2 (2.3%), gastrointestinal perforation 8 (9.9%), protein losing enteropathy 26 (32.1%), toxic megacolon 4 (4.9%), rectal prolapse 5 (6.2%), hepatitis 11 (13.6%), myocarditis 5 (6.2%), congestive cardiac failure 3 (3.7%), cardiomyopathy 3 (3.7%), infective endocarditis 1 (1.2%), septicemia 15 (18.5%), disseminated intravascular coagulation 17 (21%). Leukemoid reactions were found in 74 (91.3%) patients, hyponatremia in 56 (69.1%), and hypoalbuminemia in 67 (82.7%). Stool culture for Shigella dysenteriae type I was positive in only 7 (8.6%) patients; Shiga toxin assays were not performed. Outcome was as follows: recovery 32 (39.5%), impaired renal function 8 (9.9%), chronic renal failure 26 (32.1%), end-stage renal disease 1 (1.2%), and death 14 (17.3%) patients.

Intensive pulse therapies for focal glomerulosclerosis in South African children.

Seven children with steroid-resistant focal segmental glomerulosclerosis (SR-FGS) were placed on a therapeutic protocol of methylprednisolone (MP), oral prednisone (pred) and oral cyclophosphamide (CYC) given over 16 months (regimen A). Another 5 children with SR-FGS were treated with a shorter course of intravenous CYC (monthly doses over 6 months), intravenous MP (3 consecutive daily doses) and oral pred 2 mg/kg (alternate days) (regimen B). With regimen A, 1 child had a short remission, and in the others, oedema subsided, the urine protein/ creatinine ratio decreased, haematuria disappeared and the estimated glomerular filtration rate (GFR) increased. The observation period was 21-42 months and the drugs were well tolerated. With regimen B, 2 patients went into complete remission, 1 had partial remission, 1 failed to respond and another died because of severe concurrent infections. In the responding children, oedema cleared, the urine protein/ creatinine ratio decreased, haematuria disappeared and the GFR rose. The follow-up was between 3 and 34 months. Minor side effects were alopecia and transient hypertension. Both regimens improved the quality of life of most children. Compared with regimen A, regimen B is six times less costly with a quarter of the number of hospital visits. These observations may be of value in designing appropriate multicentre controlled trials, which have been advocated recently, for the rational and optimum management of SR-FGS.

Nephrotic syndrome in South African children: changing perspectives over 20 years.

We review our 20-year experience of 636 children with nephrotic syndrome (NS) in Durban, South Africa; 306 (48.2%) were blacks, 307 (48.2%) Indians and 23 (3.6%) were a mixed group (coloured); 91 (14.3%) could not be categorised and were excluded from the analysis. In Indian children, 134 of 286 (46.8%) had biopsy-proven minimal change NS (MCNS) and 94.8% of these were steroid sensitive (SS); 60 (21%) had SSNS but without renal biopsy; 59 (20.6%) had focal segmental glomerulosclerosis (FSGS), with only 4.4% of these being SS. In blacks, membranous nephropathy accounted for 40% of cases; 86.2% were associated with hepatitis B virus antigens. Typical SSNS continues to be uncommon among blacks. Only 14.4% had either biopsy-proven SS-MCNS or SSNS; 32 had MCNS lesions on biopsy, but 18 were steroid resistant (SR); 67 of 236 (28.4%) had FSGS, all of whom were SR. Among coloured patients, 5 of 23 (21.7%) had biopsy-proven SS-MCNS and or unbiopsied SSNS; 10 (43.5%) had FSGS and 6 of 23 (26.1%) had membranous nephropathy. Proliferative lesions were present in only 2 of 23 (8.6%) coloured patients and was uncommon in all population groups. Overall mortality was 3.1%. In brief, this is the largest reported series of NS among children in Africa and shows a typical pattern in Indians, an unusual pattern of histological types in blacks and an intermediate picture in coloureds.

Epstein-Barr virus-induced systemic lupus erythematosus.

Evidence of virus-induced systemic lupus erythematosus (SLE) is illustrated by documentation of a 10-year old girl who developed SLE (satisfying ARA criteria) soon after infection with Epstein-Barr virus (EBV) infection. She showed complete remission 24 months later following an aggressive course of immunosuppressive therapy. The appearance and disappearance of serological evidence of EBV infection, followed by the onset and complete clinical and serological remission of SLE, which in this case had unusually mild complications, suggest a causal relationship.

Rickets in black children beyond infancy in Natal.

OBJECTIVE: To determine the clinical spectrum of rickets among black children admitted to King Edward VIII Hospital, Durban. DESIGN: Prospective study of black children with rickets beyond infancy. SETTING: Hospital-based population; King Edward VIII Hospital, Durban. PARTICIPANTS: A total of 37 patients, aged 1-12 years, were recruited over a 3-year period. None had been on vitamin D or calcium supplementation prior to investigation. OUTCOME MEASURES: Rickets was diagnosed clinically, radiologically and biochemically (by a raised alkaline phosphatase value of > 350 IU). Gastro-intestinal, hepatic and renal glomerular causes were excluded in all patients using standard clinical and laboratory criteria. RESULTS: Twenty-three patients were diagnosed as having privational rickets. Nine had 25-hydroxyvitamin D (25-OHD) levels of < 10 ng/ml while 14 had levels within the normal range and were suspected of having dietary calcium deficiency. Ten had a phosphopenic variety of rickets; the remaining 4 had healing or healed rickets on the basis of radiological assessment and normal biochemical values. Pain together with difficulty in walking and bowing of the lower limbs were the main reasons for presentation. The main clinical findings were thickened wrists and ankles and rickety rosary (100%), stunting (85%), anterior bowing of lower limbs (70%) and genu valgum (65%). The calcium and vitamin D deficiency group showed a much better clinical, biochemical and radiological response to therapy than the phosphopenic group on follow-up (18 patients). CONCLUSION: This is the first substantial report on rickets in the older child in Natal, which extends the findings from Transvaal, thereby establishing a recognisable pattern of rickets beyond infancy in South Africa. It draws attention to the common clinical presentations which may alert health professionals to the presence of this problem. This report demonstrates that the two commonest types are privational rickets (due to calcium and/or vitamin D deficiency) and phosphopenic rickets.

Improved outcome of systemic lupus erythematosus among children in Durban, South Africa.

As systemic lupus erythematosus (SLE) is an uncommon disorder of childhood and is rarely seen among children in developing countries, management is not based on secure criteria and is often a matter of individual preference. In our previous experience, all four children suffering from SLE died soon after diagnosis. Aggressive therapy has been recommended to deal with such problems in the third world. We now report improved management of four more children with SLE seen since 1988 at King Edward VIII Hospital and observed for from 21 to 57 months. All our patients had evidence of renal involvement, with severe disease in two patients confirmed on renal biopsy; three had neurological involvement. The mainstay of treatment was a combination of steroids, azathioprine and chloroquine together with pulse methylprednisolone or cyclophosphamide for severe relapses. Disease activity was closely monitored, using clinical and laboratory criteria. Following therapy, all patients are in a stable condition and in clinical remission; one has mild renal impairment. These early results suggest that the judicious use of a few drugs, together with regular and meticulous follow-up, can greatly improve the prognosis of childhood SLE, even in third world countries.