Prevalence and distribution of primary glomerular diseases in Africa: a systematic review and meta-analysis of observational studies

Glomerulonephritis (GN) is a predominant cause of kidney failure in Africa. The prevalence of primary GNs varies widely across Africa depending on the relative proportion of secondary GNs and genetic predispositions. We assessed the overall and sub-regional prevalence of primary GN and its histologic subtypes in Africa. We searched PubMed, EMBASE and African Journals Online for studies of biopsy-proven primary GNs across all age groups in Africa published between 2010 and 2022. Data for primary GNs [minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), mesangioproliferative GN (MesPGN), membranoproliferative GN (MPGN), post-infectious GN (PIGN), IgA Nephropathy (IgAN), and crescentic GN (CresGN)] were extracted. Pooled prevalence was determined using the random effects model. Seventeen eligible articles (n = 6,494 individuals) from 8 African countries met the inclusion criteria. The overall pooled prevalence of FSGS, MCD, MN, MPGN, MesPGN, PIGN, IgAN and CresGN was 26.10%, 22.40%, 8.40%, 6.40%, 6.40%, 2.60%, 2.60%, 1.40%, respectively. Only 4 studies (23.5%) used light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM) for diagnosis. There were significant differences in the distribution of histologic subtypes in the paediatric compared to the adult population and across geographic sub-regions, with West Africa having a higher prevalence of FSGS. Overall, the dominance of FSGS across most regions and age groups has implications for disease diagnosis and ongoing care. Research efforts to understand the impact of this trend on kidney disease outcomes and efforts to improve kidney biopsy practice as a means of early disease detection are needed in Africa.


Introduction
Over the last three decades, glomerulonephritis has remained the predominant cause of chronic kidney disease (CKD) in Africa, with wide variation across the regions [1,2].In North Africa, diabetes only recently surpassed glomerulonephritis as the most predominant CKD aetiology [3].In sub-Saharan Africa (SSA), a region with 48 countries and a combined population of about 1.2 billion inhabitants [4] glomerulonephritis has persisted as the most common cause of CKD in incident kidney failure patients [5,6] The prevalence of glomerulonephritis as a cause of kidney failure varies across sub-Saharan Africa ranging from 8.1% to 36.1% in West Africa [7][8][9][10][11], 10% in East Africa [12], and 25% to 32% in South Africa [13].A complex combination of bacterial, viral and parasitic infections coupled with a welldocumented genetic predisposition, the Apolipoprotein L1 (APOL1) kidney risk variants have sustained the importance of glomerulonephritis as a cause of kidney failure in Africa [14].
Although IgA nephropathy (IgAN) has been identified as the most prevalent primary glomerular disease in many European and Asian countries [15][16][17], focal segmental glomerulosclerosis (FSGS) is the most common type in other countries with increased ethnic diversity [18].A previous African study identified minimal change disease (MCD; 16.5%) and FSGS (15.9%) to be the most common primary glomerular disease in the continent and highlighted regional differences [19].Paediatric studies in Africa have also shown changes in primary glomerular disease patterns in this population [20].It is important to document possible changes in trends over time, especially of primary glomerulonephritis, given their importance to the high burden of kidney failure in Africa.Even though there are few kidney registries in Africa, documented changes identified in this study will be likely useful to improve diagnostic and treatment accuracy for clinicians and policy planning for health systems for kidney care in Africa [15].We, therefore, conducted this systematic review and meta-analysis of studies reporting biopsy-proven primary glomerulonephritis across Africa to document the burden of PGN in Africa.

Methods
This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under number CRD42022349859 and was conducted in accordance with the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [21] framework.
Search strategy: relevant studies were identified by searching PubMed, Excerpta Medica database (EMBASE), and African Journals Online (AJOL) (Figure 1).The search was limited to studies from African countries, published from January 1 st 2010 to June 30 th 2022, and without any language restriction.A further search of the bibliographies of the articles obtained from the database search was undertaken to identify other articles for inclusion in the study.The search strategy included only terms relating to or describing the spectrum of biopsyproven primary glomerular diseases in Africa.Obiagwu) independently assessed titles and abstracts for eligibility.Disagreements between the two reviewers were resolved by a third reviewer (IGO).The inclusion criteria included: 1) adult and paediatric studies undertaken only in Africa; 2) studies reporting biopsy-proven cases of PGN diagnosed using light microscopy, immunofluorescence, and/or electron microscopy; 3) enrolled a minimum of 50 participants; 4) provided data on the demographic distribution and histopathologic types of glomerular disease subtypes.Data collected included: year of publication, country, and African sub-region, study sample size, clinical indication for biopsy, mean age at biopsy, gender distribution, and the proportion of all biopsies that constitute primary glomerular diseases.The relative proportions of MCD, FSGS, IgAN, membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), mesangioproliferative glomerulonephritis (MesPGN), post-infectious glomerulonephritis (PIGN) and primary crescentic glomerulonephritis (CGN) were also recorded.The quality of included studies was assessed using the Joanna-Briggs critical appraisal tool for prevalence studies [22].Studies with a score of 0-3 were regarded as low quality, 4-6 as medium quality, and 7-9 as high-quality studies.
Data extraction and synthesis: data extraction was undertaken independently by UEE and PO, while data validation after extraction was done by AIA and UEE.The DerSimonian-Laird random effects models were used to determine the pooled prevalence of the different histologic sub-types of PGN after stabilization of the prevalence from the constituent studies using the Freeman-Tukey double arcsine transformation [23].Heterogeneity across studies was assessed using the Cochran Q and I2 statistics [24], while Egger's [25] and Begg's [26] tests were used to assess publication bias.Sub-group analyses were also undertaken to compare prevalence and patterns across African sub-regions and age groups.Pooled percentages (95% confidence interval) were used to report primary glomerular disease sub-types, while the median (interquartile range [QR]) was used to report demographic features of included studies and indications of kidney biopsy.All analyses used Stata 17.0 (StataCorp, Texas, USA).

(suite).
There was no publication bias in the assessment of each glomerular disease.

Discussion
This study identifies the burden of primary glomerular diseases in Africa and highlights important demographic and sub-regional differences in the occurrence of glomerular disease sub-types.Although not a direct extension of a previous systematic review [19], shows that there have been marked differences in the occurrence of primary glomerular diseases in the continent.The main finding from this study is the higher occurrence of FSGS and MCD across regions and age groups than other primary glomerular diseases.Other important findings include the low frequency of IgAN and PIGN and the low number of biopsies reported from studies (average number of biopsies: 382 per study or 541.2 per year studied).
Glomerulonephritis is a common cause of kidney failure in most parts of sub-Saharan Africa [5,6].Most primary glomerular diseases have a peak incidence in younger and middle-aged people and may account for the younger average age of patients with kidney failure reported in Africa, often being less than 50 years [9][10][11][12]45,46].Kidney failure is associated with a high rate of premature mortality in Africans, often due to unavailable therapeutic measures or a high cost of treatment [46,47].Early disease detection and instituting measures that slow or halt disease progression still remain the best options for reducing the burden of kidney failure and poor outcomes in Africa [46][47][48].
Evidently, the high FSGS occurrence in sub-Saharan Africa may be related to the high prevalence of apolipoprotein L1 (APOL1) kidney risk variants in these regions [49][50][51].Low prevalence of APOL1 in Arabs [52] and North Africans [53] may also explain the lower prevalence of FSGS observed in North Africa.Furthermore, the high prevalence of various environmental factors such as sub-clinical viral infections (e.g.parvovirus B19 [54] cytomegalovirus, Epstein-Barr Virus, and Simian virus [55]), which have been shown to be associated with FSGS lesions may also have a role in the observed prevalence.In most countries in Africa, kidney biopsies are often evaluated only using light microscopy and without immunohistochemistry or electron microscopy, which improves diagnostic accuracy and aids in differentiating primary from secondary patterns [56].It is unclear if this contributed to the high prevalence of FSGS, given that several advanced glomerular lesions may be seen with sclerosis.
Although some studies have identified FSGS to be more common than MCD in children [57,58] our study showed that MCD is more common in children than adults (Figure 2).Moreover, a recent systematic review of paediatric studies of patients with nephrotic syndrome in Africa over half a century showed MCD to have a higher prevalence than FSGS (38% [95% CI: 36-40%] versus 24% [95% CI: 22-25%]) [59].However, even though this study shows a higher frequency of MCD in children, the ratio of MCD to FSGS in children is much lower than that in a previous study [19] and could suggest a higher occurrence of FSGS than MCD in African children.A study from South Africa showed that FSGS, which was once considered uncommon in children, has recently emerged as one of the most challenging forms of nephrotic syndrome across all racial groups, particularly in Black children [58].Studies from other African countries are needed to corroborate this, as it shows that childhood nephrotic syndrome cannot always be assumed to be due to MCD [20], especially if it is steroid resistant.Guidelines for the treatment of steroidresistant nephrotic syndrome in children identify FSGS as the predominant type and strongly recommend early kidney biopsy and genetic testing (where available) [60].The reduced proportion of cases of PIGN in adults and children may be related to improving health services, widespread availability of antibiotics, and changes in the organisms causing PIGN.Due to these factors, epidemics of PIGN still occur, albeit in reduced frequencies [61], and pockets of African communities still have a high prevalence of PIGN [44].
The pooled prevalence of primary MN was 1.9% in children compared to 12.9% in adults.Primary MN in Africa is also a disease of adults like in other climes [62].The higher prevalence of MN in Southern Africa may be related to the greater numbers of individuals with Caucasian heritage in South Africa.Another reason for the low MN frequency in West Africa may be the decreasing number of kidney biopsies and the unavailability of serum and tissue-based tests for Phospholipase A2 receptor 1 (PLA2R) and thrombospondin type-1 domain containing 7A (THSD7A).Despite being the commonest primary glomerulopathy globally, IgAN is still rare among black Africans [63].Studies from North Africa reported a pooled prevalence close to that obtained in Europe but lower than the prevalence reported among Asian populations [64].Among various factors, the hygiene hypothesis, an alteration in the immune balance of the T helper 1 and T helper 2 subsets, has been proposed as a mechanism to explain differences in glomerular disease frequencies, particularly of IgAN, across countries [65].Genetic factors may also account for the low frequency in Africans [66].
It is also possible that the aforementioned factors contribute to major differences in the frequencies of primary GNs reported in this study in comparison with other world regions (Table 2) [18].In an international kidney biopsy survey involving 29 centers across 18 countries, FSGS was identified to be the most common primary GN in North America (19.1%) and Latin America (15.8%), while IgAN was the most common in Asia (39.5%) and Europe (22.1%)[18].Despite these differences, the reporting of FSGS and MCD from Africa appears to be much higher than reported from other world regions.Whether this represents the true frequency of these glomerular diseases or reporting due to a lack of facilities to adequately distinguish other glomerular conditions is currently unknown.However, there is a widespread lack of facilities for immunofluorescence and electron microscopy in sub-Saharan Africa, and the practice of kidney biopsy is still not well-developed among renal care practitioners in many countries in sub-Saharan Africa [19,56,67].A recent study that assessed challenges in the diagnosis and management of glomerular diseases in resourcelimited settings (mainly Africa and Asia) reported major system-level barriers that impede the implementation of guideline-driven approaches for the diagnosis and treatment of patients with glomerular disease [68].These barriers included a low performance of kidney biopsies, cost of diagnostic work-up (e.g.serologic testing) and care, and low utilization of diagnostic techniques (LM, IHC/IF, and EM are used in diagnostic work-up of only 29.2% of biopsies in Africa) [68].This could suggest over-diagnosis of FSGS and MCD from several of the studies included in our study, given that only 23.5% used LM, IHC/IF, and EM for reporting the biopsies.Only studies from North Africa and Southern Africa used all three methods of assessment to evaluate histologies.Given the importance of glomerular diseases in the overall burden of CKD and kidney failure in Africa, there is a need to improve infrastructure to improve diagnostic capacity.
A limitation of this study is the lack of studies from Central Africa which highlights the lack of kidney biopsies across several African countries and leaves an information gap in the study.It was also not possible for us to assess how the primary disease was ascertained, given that serological markers to distinguish these from secondary glomerular diseases were not reported.However, this was not a limitation of our study given that the studies included did not report these.Finally, it would have been beneficial to conduct an analysis showing the temporal trends of the different histologic subtypes in Africa, but this study covered a relatively short period (12 years) for such changes to occur.Despite these perceived limitations, our study has important values to guide decision-making regarding the occurrence of common glomerular diseases and the need for improving services to aid diagnosis.

Conclusion
Primary glomerular diseases remain a leading cause of kidney failure in Africa and affect a relatively younger population than in other climes.Overall, FSGS is the most common histologic subtype of primary glomerular diseases in Africa in adult and paediatric populations, followed by MCD.It is important to understand how high the prevalence of FSGS and MCD affects the overall kidney disease burden and outcomes in the region.Efforts to improve kidney biopsy practice as a means of early disease detection are needed in Africa, given the contribution of glomerular diseases to the burden of kidney failure on the continent.This will include increasing the infrastructure and workforce (nephropathologists, and pathology technicians) required for such services.

Figure 1 :
Figure 1: PRISMA flow chart of study selection

Figure 2 :
Figure 2: pooled prevalence of primary glomerular diseases in adult and paediatric populations in Africa

Table 1 :
summary of extracted data from all included studies Last

Table 1 (suite): summary
of extracted data from all included studies

Table 2 :
frequencies of primary glomerular disease prevalence across world regions Data from O'Shaughnessy et al.Nephrol Dial Transplant.2018 Apr 1;33(