- To evaluate the accuracy on non-biopsy methods in diagnosis of glomerulonephritis in low- and middle-income countries based on a systematic review of data from published literature.
Glomerular diseases account for a significant proportion of chronic kidney disease in low-income and middle-income countries (LMICs) (Ke et al., 2022). The epidemiology of glomerulonephritis is characterized inadequately in LMICs, largely owing to unavailable nephropathology services or uncertainty of the safety of the kidney biopsy procedure, In contrast to high-income countries where IgA nephropathy is the dominant primary glomerular disease, focal segmental glomerulosclerosis is common in large populations across Latin America, Africa, Middle East, and South East Asia, while IgA nephropathy is common in Chinese populations (Tonelli et al., 2021). Despite having a high prevalence of known genetic and viral risk factors that trigger focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis also is common in adults and children in some African countries (Osman, 2018). Treatment of glomerular diseases in adults and children in LMICs largely is dependent on corticosteroids in combination with other immunosuppressive therapy, which often is cyclophosphamide because of its ready availability and low cost of treatment, despite significant adverse effects (Bajpai et al., 2024). Partial and/or complete remission status reported from studies of glomerular disease subtypes vary across LMIC regions, with high rates of kidney failure, mortality, and disease, and treatment complications often reported (Furia et al., 2019). Improving the availability of nephropathology services and ensuring availability of specific therapies are key measures to improving glomerular disease outcomes in LMICs (Tannor et al., 2024).
Epidemiologic data of primary glomerular diseases in western France, Between January 1, 1976, and December 31, 2002, histologic diagnosis of primary glomerular disease (PGD) was made in 898 patients born and living at the time of diagnosis in a region of France, comprising 412,735 inhabitants, of whom 391,265 were aged from 10 to 85 years. The prevalence of PGD during a 75-year exposure to risk (10 to 85 years of age) was evaluated to 6.9 in 1000 (8.2 in 1000 males and 5.1 in 1000 females) during the 27-year period. The most common PGD was Iga Nepropathy (IgAN) with a prevalence of 2.4 in 1000 (3.6 in 1000 males and 1.3 in 1000 females). The annual incidence of PGD was evaluated separately for two consecutive 10-years periods: period a (1976 to 1985), period B (1986 to 1995) and for one 7-year period: period C (1996 to 2002). Within each of these three periods, annual incidence of PGD was 89, 76, and 65 per million inhabitants. During this 27-year period, the annual incidences of membrano proliferative glomerulonephritis (GN) and membranou nephropathy were declining and the incidence of crescentic proliferative GN was strongly progressing, whereas annual incidence of nephrosis remained stable. The incidence of IgAN remained the same throughout the three periods: 28, 28, and 26 per million inhabitants. Whereas the incidence of IgAN was three- to fourfold higher in the adult aged from 20 to 59 years than in the elderly during the periods A (38 vs. 11 per million inhabitants) and B (37 vs. 12 per million inhabitants), the incidence became similar whatever age groups during the last period C (20 to 59 years, 25 per million inhabitants; 60 to 79 years, 27 per million inhabitants; and 80 years and over, 28 per million inhabitants. The stability of annual incidence according to period and age, which is demonstrated for the first time during the last period, provides a new evidence of a role for genetic factors in the pathogenesis of IgAN.
Studies largely led by Holdsworth et al., 26 have shown that most proliferative glomerular diseases are driven by a TH1 response. One might then hypothesize that such diseases as MPGN, mesangial proliferative glomerulonephritis (GN; of the non-IgA type), and poststreptococcal GN may be more frequent in developing countries. MPGN is one of the most common glomerular diseases in Africa (such as Nigeria),3, 4 the West Indies (Trinidad),27 eastern Europe (Poland),28 Turkey,29 and east China (Holdsworth, Kitching, & Tipping, 1999).
Glomerular disease is the leading drivers of non-diabetic chronic kidney disease disability-adjusted life years in resource-limited countries. Proper diagnosis and treatment relies on resources including kidney biopsy, ancillary testing, and access to evidence-based therapies.
We conducted a cross-sectional internet-based survey cascaded through society mailing lists among nephrologists in countries of Asia, Africa, and Eastern Europe. In a study collected the data on respondent demographics, their ability to perform and appropriately interpret a kidney biopsy, and their access to complementary investigations and treatment practices.
A total of 298 kidney care specialists from 33 countries (53.3% from Asia and 44.6% from Africa; 64% from academic or university hospitals) participated in the survey. Of these specialists, 85% performed kidney biopsy. About 61% of the respondents could not obtain a kidney biopsy in more than 50% of patients with suspected glomerular disease. About 43% of the respondents from Africa had access to only light microscopy. Overall, the inability to undertake and fully evaluate a biopsy and perform ancillary investigations were more profound in Africa than in Asia. Overall, 59% of participants reported that more than 75% of their patients meet the cost of diagnosis and treatment by out-of-pocket payments. Empirical use of immune suppression was higher in Africa than in Asia. The main barriers for diagnosis and treatment included delayed presentation, incomplete diagnostic work-up, and high cost of treatment.
Kidney transplantation improves both the quality of life and survival for patients with kidney failure compared to being on dialysis (Wolfe 1999). Furthermore, in patients with type 1diabetes mellitus (T1DM) and kidney failure, simultaneous pancreas-kidney (SPK) transplantation is the optimal management for achieving ideal glycaemic control and kidney allograft function (Lindahl, 2014). Short to medium-term allograft outcomes and patient survival after transplantation have been improving since the introduction of calcineurin inhibitors (CNIs) from approximately 60% one-year survival in the early 1980s to above 90% currently (Arend 1997; Coemans 2018; Hariharan 2000; Meier-Kriesche 2004; Wang 2016). However, improvements in longer-term outcomes have largely been incremental. Ten-year allograft survival rates for deceased donor transplantation rose only from 42.3% for transplants conducted in the late 1990s to 51% for those performed in 2008. Similarly, for living donor transplantation, the respective increment was from 60.5% to 69% (Hariharan 2021; Hart 2020).
Sex and gender and kidney disease Prior work has reported conflicting data on the association between sex and gender of patients with chronic kidney disease (CKD) and with kidney transplants. Kidney function deteriorates faster in adult males with CKD compared to women (Carrero 2018), yet death is similar in adults of both sexes once treated with kidney replacement therapy (KRT). This comparable death rate contrasts with the general population, where women typically have a longer life expectancy than men (Hecking 2014). In children, girls treated with maintenance dialysis have a higher death rate, with the risk of death being at least 1.2 times higher than boys of the same age (adjusted Hazzard Ratio (HR) 1.16 to 1.28) (Ahearn 2019; Mitsnefes 2013). Early observational data also showed conflicting outcomes in adults after transplantation. Data from a registry analysis in
Japan reported similar one-year graft survival rates between recipient sexes in the 1980s (Shibue 1987) whilst a retrospective analysis of transplants performed at Vanderbilt University Hospital found a 10% to 16% higher graft survival rate among female recipients (Richie 1983). There are, similarly, conflicting results with regards to the relationship between recipient sex and outcomes following SPK transplantation (Douzdjian 1996; Li 2016; Messner 2019). Reasons for these conflicting results with both kidney and SPK transplantation are not well understood and further evaluating them can be useful to the overall patient prognosis. These reasons may include differences due to allosensitization, hormonal effects of oestrogen, pharmacokinetic effects of different medications, donor-recipient size mismatch and sociocultural context, all of which contribute to a currently poorly defined relationship between recipient sex/gender and post-transplantation outcomes.
Female transplant recipients are more likely to be sensitized compared to men, having higher levels of pre-and post-transplant donor-specific antibodies (DSAs) (Bromberger 2017). This may be due to a greater number of sensitising events, primarily pregnancy (Porrett 2018; Redfield 2016). The presence of DSAs may increase the risk of graft loss in a transplant-naive individual by 23% (Redfield 2016).
The role of sex hormones is not clearly understood, but they are thought to play an important modulatory role in immune system function. Oestradiol could improve graft function and reduce cellular infiltration (Muller 1999), yet oestrogen could also stimulate antibody production from B-cells and promote differentiation of CD4+ T cells into Th2 cells, enhancing the immune response to environmental factors (Taneja 2018). Testosterone contrastingly causes immune suppression by promoting Treg differentiation and reducing lymphopoiesis (Trigunaite 2015), with testosterone deficient males having an elevated number of B-cell precursors in the bone marrow (Gubbels 2018).
Kidney biopsy is an important tool for making diagnoses and for assessing the drug treatment requirements and disease prognosis in the management of kidney disease. There are variations in the rate of complications associated with kidney biopsies across countries, and this depends on various clinical and technical factors.
Percutaneous native kidney biopsy (PNKB) is an important tool for guiding clinicians towards making diagnosis of kidney disease, deciding on treatment options and prognosticating on disease outcomes. Kidney biopsy was introduced to medicine in 1944 and later in 1951 by Iversen and Brun, and has since provided clinicians with valuable information about kidney disease and its management. Improvements in the technique, including use of ultrasound and use of automated mechanisms, have been associated with reduced complications. Although some studies show that PNKB is a safe procedure and frequently show that significant complication to occur in less than 1% of cases, higher rates of kidney biopsy−related complications have been reported in other studies. In a single-center study of 1055 adults from the United States, major complications occurred in 6.6% of biopsies, transfusions were required in 5.3%, and 1 death (0.09%) resulted following PNKB bleeding. However, a 5-year nationwide study in the United States involving 118,064 adults who had PNKB reported 1.8% mortality, some of which was thought to be related to pre-existing comorbidities in the patients. Factors associated with biopsy complications have been found to include the biopsy technique, size of the biopsy needle, experience of the operator, and range of the biopsy protocol (including complete blood count, international normalized ratio/prothrombin time, activated partial thromboplastin time, serum creatinine, and medication review).
In a systematic review on kidney biopsy complications, the focus was mainly on bleeding complications and procedures that were carried out using automated needles and real-time ultrasound guidance. The authors reported macroscopic hematuria in 3.5% of cases (95% confidence interval [CI] = 2.2%−5.1%), blood transfusion in 0.9% (95% CI = 0.4%−1.5%) and a significantly higher rate of transfusion with 14-gauge compared with smaller needles (2.1% vs. 0.5%; P = 0.009). Their review did not include low- and middle-income countries (LMICs). The aim of this systematic review and meta-analysis is to summarize available evidence on the rates of complications in patients undergoing PNKB in LMICs. It is anticipated that the results of our study will be useful in improving kidney care in this region, where conditions requiring PNKB for diagnosis and for guiding decisions on treatment (e.g., glomerulonephritis) are very common.
Glomerulonephritis (GN) represents a diverse group of kidney diseases characterized by inflammation of the glomeruli, which can result in significant morbidity and mortality if left undiagnosed or untreated (Romagnani, Kitching, Leung, & Anders, 2023). Early diagnosis and management are crucial for improving patient outcomes, particularly in resource-limited settings. Traditionally, kidney biopsy has been considered the gold standard for diagnosing glomerulonephritis (Anders, Kitching, Leung, & Romagnani, 2023). However, biopsy procedures are invasive, costly, and not always feasible in low- and middle-income countries (LMICs) due to limited healthcare infrastructure, expertise, and access to necessary resources (Casuscelli, et al., 2023). Diseases affecting the renal glomeruli are prevalent in clinical practice and represent a leading cause of end-stage renal disease (ESRD) globally (Al-Worafi, 2024). In the United States, glomerular diseases were responsible for 51% of the 305,876 cases of treated ESRD reported to the U.S. Renal Data System between 1991 and 1995 (Diaz-Requena et al.,2022). This included 115,938 cases of diabetic nephropathy (37.9%) and 41,333 cases of nondiabetic glomerular disease (13.5%). While some glomerular diseases do not lead to progressive renal failure, they remain significant contributors to morbidity and represent a substantial financial burden on healthcare systems (Sethi, De Vriese, & Fervenza, 2022).
The clinical presentation of glomerulonephritis can be diverse, with common symptoms including hematuria, proteinuria, edema, and hypertension. Acute GN often manifests with rapid-onset symptoms, while chronic GN may present insidiously with nonspecific symptoms such as fatigue and weight gain (Brant Pinheiro, et al., 2022). Physical examination findings such as swelling of the legs, periorbital edema, and high blood pressure can guide the clinician toward suspicion of GN (Zhan et al., 2024).
Laboratory tests play a pivotal role in the diagnosis of glomerulonephritis. Urine analysis is the primary diagnostic tool, with the presence of hematuria, proteinuria, and red blood cell casts being indicative of glomerular injury. Proteinuria is typically quantified using urine protein-to-creatinine ratio or 24-hour urine collection, with greater than 3.5 grams per day suggesting nephrotic syndrome (Ardalan, et al., 2022).
Blood tests are also important for assessing renal function and determining the underlying etiology of GN. Serum creatinine and urea levels are commonly elevated in patients with GN, reflecting impaired kidney function, specific biomarkers can be used to identify various forms of glomerulonephritis. For example, antistreptolysin O (ASO) titers and anti-DNAse B levels are useful in diagnosing post-streptococcal glomerulonephritis, while anti-glomerular basement membrane (anti-GBM) antibodies are suggestive of Goodpasture syndrome (Wada et al., 2023).
Immunological testing plays a significant role in identifying the underlying cause of glomerulonephritis, particularly in distinguishing between primary and secondary forms. Serum levels of circulating immune complexes, complement proteins, and autoantibodies can provide insight into autoimmune or systemic causes of GN. For instance, systemic lupus erythematosus (SLE) is often associated with positive ANA and anti-dsDNA antibodies, leading to a diagnosis of lupus nephritis (Linke, Tiegs, & Neumann, 2022).
In cases of crescentic glomerulonephritis, which involves rapid progressive renal failure, anti-GBM antibodies or ANCA (antineutrophil cytoplasmic antibodies) can help distinguish between Goodpasture syndrome and pauci-immune vasculitis, respectively. The use of multiplex immunoassays and enzyme-linked immunosorbent assays (ELISA) has improved the sensitivity and specificity of these tests (Sethi, & Fervenza, 2019).
Kidney biopsy remains the gold standard for diagnosing glomerulonephritis and determining its subtype. It is particularly essential in cases of unexplained renal impairment or when the diagnosis is unclear based on non-invasive tests. The biopsy involves obtaining a small sample of kidney tissue for histopathological examination, which can identify the type of glomerulonephritis and reveal the degree of damage to the glomeruli (Wendt et al., 2024).
The increase in glomerular cellularity manifests in various patterns, including mesangial proliferative GN, diffuse endocapillary GN, membranoproliferative GN, crescentic GN, and necrotizing GN. Over time, these patterns may progress to sclerosing GN (Lin, et al., 2021). For decades, the renal community has focused on these injury patterns, with diseases often named after them, such as membranoproliferative GN. While these patterns frequently reflect the severity, acuteness, or chronicity of the injury and may even suggest an underlying cause, different etiologies can produce similar injury patterns (Qing et al., 2022), for instance, membranoproliferative GN may arise from the accumulation of complement factors due to alternative pathway dysregulation (C3 GN), immune complexes from chronic infections like hepatitis C, or monoclonal immunoglobulins from paraprotein disorders. Similarly, necrotizing and crescentic GN can result from diverse conditions, such as ANCA-associated GN, C3 GN, or fibrillary GN, despite their differing etiologies (Koirala, Sharma, Jhaveri, Jain, & Geetha, 2024).
Histopathological findings, including the presence of glomerular crescents, segmental sclerosis, or immune deposits, are crucial in diagnosing specific forms of GN (Kronbichler, Bajema, Geetha, & Säemann, 2023), For instance, the presence of IgA deposits is characteristic of IgA nephropathy, whereas granular deposits of immunoglobulin and complement in the glomeruli are seen in lupus nephritis. The biopsy also provides information on the extent of glomerular damage, aiding in prognosis and guiding treatment decisions (Chauveau et al., 2024).
Advances in imaging techniques, particularly in renal ultrasonography and magnetic resonance imaging (MRI), have enhanced the ability to diagnose glomerulonephritis. Ultrasonography is commonly used to assess kidney size and the presence of abnormalities such as cortical atrophy or increased echogenicity, which can be indicative of chronic kidney damage. However, it lacks specificity in diagnosing the underlying cause of glomerulonephritis (Anders, Kitching, Leung, & Romagnani, 2023).
MRI, on the other hand, provides detailed imaging of the kidneys and has emerged as a useful tool in evaluating renal blood flow and glomerular filtration. Recent developments in contrast-enhanced MRI techniques, including dynamic contrast-enhanced imaging, offer the potential for non-invasive assessment of kidney function, although this technique is still in the research phase (Najafian, Lusco, Alpers, & Fogo, 2022).
In recent years, molecular diagnostics have shown promise in improving the early detection and diagnosis of glomerulonephritis. Specific biomarkers, including urinary exosomes and microRNAs, are being studied for their potential to detect GN at an early stage and monitor disease progression. These biomarkers could provide a more sensitive and specific alternative to traditional urine and blood tests. Additionally, genetic testing has been explored in certain forms of glomerulonephritis, particularly in conditions with a hereditary component such as Alport syndrome. Genetic mutations in the COL4A3, COL4A4, and COL4A5 genes are associated with progressive renal disease, and molecular screening can assist in diagnosis and genetic counseling for affected families (Netti, Troise, Rossini, Catalano, et al., 2024).
Despite advancements in diagnostic techniques, several challenges remain in the diagnosis of glomerulonephritis (L’Imperio et al., 2024). The clinical overlap between different forms of GN and other renal diseases can complicate the diagnosis, nephrotic syndrome, a common presentation of GN, can be caused by multiple etiologies, including diabetes mellitus, minimal change disease, and membranous nephropathy. This requires careful differential diagnosis using a combination of clinical, laboratory, and histopathological criteria, the lack of standardized guidelines for diagnostic testing, particularly in terms of biomarker usage, limits the widespread adoption of newer techniques. Access to specialized diagnostic tests, such as kidney biopsy and advanced imaging, may also be limited in resource-constrained settings (Muthukumaran, Wanchoo, Seshan, & Gudsoorkar, 2024).
Kidney biopsies are invasive procedures, associated with risks such as bleeding, infection, and pain. Consequently, non-biopsy methods for diagnosing glomerulonephritis have gained attention as potential alternatives that could offer accurate, less invasive diagnostic options (Kitamura et al., 2023).
Recent advancements in imaging modalities, particularly ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT), have contributed to the non-invasive diagnosis of glomerulonephritis. Doppler ultrasound, in particular, has been explored for evaluating renal blood flow and glomerular filtration rate, parameters that are often altered in cases of glomerulonephritis. Some studies have suggested that renal ultrasonography, when combined with clinical data, may provide insight into the underlying pathology, particularly in cases of chronic GN or nephrotic syndrome (Nair et al., 2019). However, while these imaging techniques can provide valuable information regarding kidney structure, their role in identifying the specific type of glomerulonephritis remains limited, MRI with contrast agents has been suggested as a potential tool for assessing renal inflammation and fibrosis, which are characteristic features of glomerulonephritis (Muthukumar et al., 2018). While studies have shown promising results in detecting structural changes, MRI is often limited by its cost, availability, and the need for specialized training, making it less accessible compared to ultrasound, while these imaging techniques show potential in detecting glomerular inflammation, they cannot definitively distinguish between the different subtypes of glomerulonephritis.
Genetics, demographics, socio-economic, and environmental factors have been suggested to influence the incidence of glomerulonephritis (GN) across various populations. While the patterns of glomerular diseases are well-documented in many European, American, and Asian populations, there is limited data on the incidence of biopsy-proven GN in low –and middle income countries. Most nephrologists agree that renal biopsies should be performed in cases of nephrotic syndrome (NS), proteinuria exceeding 1 g/day, proteinuria combined with hematuria, and acute kidney injury (AKI). Such procedures provide valuable pathological findings that inform treatment decisions and prognostic assessments. However, impaired renal function alone is not typically considered a valid indication for renal biopsy. This is due to the increased risk of bleeding in patients with compromised renal function and the possibility that biopsied tissue may not yield sufficient diagnostic information if chronic renal damage is predominant. Nevertheless, studies suggest that foregoing renal biopsies in patients with renal impairment could lead to missed diagnoses of treatable conditions, such as interstitial nephritis, which can progress rapidly to end-stage renal disease (ESRD) without timely intervention. Systemic diseases like systemic lupus erythematosus (SLE), vasculitis, and allergic purpura can also impair kidney function, making renal biopsy an essential tool for assessing the activity and severity of these conditions.
Biomarkers have emerged as another non-invasive diagnostic tool for glomerulonephritis. These are molecules that can be detected in blood, urine, or other bodily fluids, reflecting the underlying disease process. Urinary biomarkers such as albumin, proteinuria, and hematuria have long been used to assess kidney function and detect glomerular damage (Wang et al., 2020). Recent studies have highlighted the utility of specific biomarkers, such as urinary interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), which may provide insights into the pathogenesis of glomerulonephritis (Jiang et al., 2021).
Although these biomarkers show promise in detecting glomerular injury, their sensitivity and specificity remain a subject of ongoing research. Some biomarkers, such as KIM-1, may indicate early stages of glomerular damage, but they cannot reliably differentiate between the different types of glomerulonephritis (Sivagnanam et al., 2020). In recent years, genetic testing and molecular profiling have emerged as valuable tools in the non-biopsy diagnosis of glomerulonephritis. Genetic mutations have been identified in several forms of glomerulonephritis, including in diseases such as Alport syndrome and focal segmental glomerulosclerosis (FSGS) (Hu, Wang, Wang, Pei, Zeng, & Xu, 2024). Molecular profiling using next-generation sequencing techniques allows for the identification of genetic alterations that may contribute to the pathogenesis of glomerulonephritis, offering a potential diagnostic approach that complements traditional biopsy techniques (D’Agati et al., 2019).
The application of genetic testing in the diagnosis of glomerulonephritis holds promise, challenges remain regarding the interpretation of genetic data, particularly in cases where mutations are rare or not well understood, the cost and availability of genetic testing may limit its widespread application in clinical practice (Nayebirad, Ramandi, Nili, Atef-Yekta, Tamartash, Salehi, & Kavosi, 2023).
Clinical decision-making models that incorporate data from clinical presentation, laboratory tests, imaging, and biomarkers have shown promise in improving the accuracy of non-biopsy diagnoses of glomerulonephritis. In particular, machine learning algorithms and artificial intelligence (AI) are being explored for their ability to analyze complex datasets and predict the presence or absence of glomerulonephritis (Zhou et al., 2022). These models have the potential to offer personalized diagnostic approaches, with the ability to factor in a wide array of clinical variables and suggest possible diagnoses with high accuracy.
The accuracy of non-biopsy methods in the diagnosis of glomerulonephritis is still evolving, with several promising tools being explored (Bruschi, Candiano, Angeletti, Lugani, & Panfoli, 2023). Imaging techniques, biomarkers, genetic testing, and artificial intelligence are among the leading non-invasive methods, but each has its limitations, while biomarkers and imaging can provide valuable insights into kidney function and inflammation, they may not always offer the specificity required to distinguish between different subtypes of glomerulonephritis (Windpessl et al., 2023). Genetic testing holds promise but faces challenges related to accessibility and data interpretation. The integration of artificial intelligence into clinical decision-making models may offer a more accurate and personalized approach to diagnosis (Sethi, & Fervenza, 2019).
