Background: IgA nephropathy (IgAN) is the commonest primary glomerulonephritis worldwide and a significant cause of chronic kidney disease and end-stage renal disease. It is widely accepted that ...genetic factors play a role in the pathogenesis of IgAN. However, the identity of these genetic factors remains uncertain. Summary: Critical to all genetic studies is a precise phenotypic definition of the disease. It is well recognised that IgAN displays striking phenotypic variation, raising the possibility that it may not be a single disease and it may not be the same disease in different parts of the world. In this review, we discuss the challenges that this phenotypic variation poses to interpreting genetic data and the current evidence for specific gene involvement in IgAN, focusing particularly on data from European IgAN cohorts. Key Messages: With advances in genetic techniques, in particular next-generation sequencing, and an increased understanding of the importance of copy number variations, epigenetics and transcriptomics, it is likely that we will gain a greater understanding of the genetic basis for IgAN. However, due to the lack of consistency in epidemiological clinicopathological studies both within and between continents, this will only be achieved if we are able to more precisely phenotype IgAN populations. Facts from East and West: The reported prevalence of IgAN is higher in Asia than in Europe and North America. However, differences in use of biopsy for the diagnosis of IgAN should be taken into account in analysing data from both East and West. In Europe, IgAN affects men more frequently than women; this is not the case in Asia. Familial IgAN has been more frequently reported in Europe than in Asia. Within Europe, familial IgAN is more evident in southern than in northern populations. Changes in the pattern of serum IgA1 O-glycosylation is a common finding in IgAN patients in the East and West. SNPs within the gene coding for the enzyme C1GALT1 have been reported in Chinese and European patients. However, there is no evidence for a role of gene polymorphism of the C1GALT1 chaperone cosmc in Europeans. Genetic variants in the HLA gene family have been observed in populations from the East and West. Associations between IgAN and variants of the TAP1/PSMB and DEFA genes were observed in Asian but not in Western patients. Association with the angiotensin-converting enzyme gene was seen only in Asian patients.
ObjectivesThe Global Kidney Health Atlas (GKHA) is a multinational, cross-sectional survey designed to assess the current capacity for kidney care across all world regions. The 2017 GKHA involved 125 ...countries and identified significant gaps in oversight, funding and infrastructure to support care for patients with kidney disease, especially in lower-middle-income countries. Here, we report results from the survey for the second iteration of the GKHA conducted in 2018, which included specific questions about health financing and oversight of end-stage kidney disease (ESKD) care worldwide.SettingA cross-sectional global survey.ParticipantsKey stakeholders from 182 countries were invited to participate. Of those, stakeholders from 160 countries participated and were included.Primary outcomesPrimary outcomes included cost of kidney replacement therapy (KRT), funding for dialysis and transplantation, funding for conservative kidney management, extent of universal health coverage, out-of-pocket costs for KRT, within-country variability in ESKD care delivery and oversight systems for ESKD care. Outcomes were determined from a combination of desk research and input from key stakeholders in participating countries.Results160 countries (covering 98% of the world’s population) responded to the survey. Economic factors were identified as the top barrier to optimal ESKD care in 99 countries (64%). Full public funding for KRT was more common than for conservative kidney management (43% vs 28%). Among countries that provided at least some public coverage for KRT, 75% covered all citizens. Within-country variation in ESKD care delivery was reported in 40% of countries. Oversight of ESKD care was present in all high-income countries but was absent in 13% of low-income, 3% of lower-middle-income, and 10% of upper-middle-income countries.ConclusionSignificant gaps and variability exist in the public funding and oversight of ESKD care in many countries, particularly for those in low-income and lower-middle-income countries.
In IgA nephropathy (IgAN), serum IgA1 with abnormal O-glycosylation deposits in the glomerular mesangium. The underlying mechanism of this IgA1 O-glycosylation abnormality is poorly understood, but ...recent evidence argues against a generic defect in B cell glycosyltransferases, suggesting that only a subpopulation of IgA1-committed B cells are affected. For investigation of whether the site of antigen encounter influences IgA1 O-glycosylation, the O-glycosylation of serum IgA1 antibodies against a systemic antigen, tetanus toxoid (TT), and a mucosal antigen, Helicobacter pylori (HP), was studied in patients with IgAN and control subjects. Serum IgA1 was purified from cohorts of patients with IgAN and control subjects with HP infection and after systemic TT immunization. The IgA1 samples were applied to HP- and TT-coated immunoplates to immobilize specific antibodies, and IgA1 O-glycosylation profiles were assessed by binding of the O-glycan-specific lectin Vicia villosa using a modified ELISA technique. Although total serum IgA1 had raised lectin binding in IgAN, the O-glycosylation of the specific IgA1 antibodies to TT and HP did not differ between patients and control subjects. In both groups, IgA1 anti-HP had higher lectin binding than IgA1 anti-TT. This study demonstrates that IgA1 O-glycosylation normally varies in different immune responses and that patients produce the full spectrum of IgA1 O-glycoforms. IgA1 with high lectin binding was produced in response to mucosal HP infection in all subjects. The raised circulating level of this type of IgA1 in IgAN is likely to be a consequence of abnormal systemic responses to mucosally encountered antigens rather than a fundamental defect in B cell O-glycosylation pathways.
The role of immunosuppression in IgAN remains controversial despite a growing evidence base of randomized controlled trials (RCTs). In IgAN with nephrotic syndrome the role for corticosteroids is ...limited to cases with minimal change on light microscopy. In crescentic IgAN, the use of immunosuppression is supported only by anecdotal data, and outcome may be poor especially when glomerular filtration rate is impaired severely at presentation or there are pathologic features of chronic injury. In slowly progressive IgAN, prediction of outcome now is based both on clinical and pathologic features. Most RCTs have studied patients with urine protein levels greater than 1 g/24 h and only a minority have enrolled patients with a glomerular filtration rate less than 60 mL/min. The Supportive versus immunosuppressive Therapy of Progressive IgA nephropathy (STOP) IgAN study emphasized the efficacy of supportive therapy (including blood pressure control and renin-angiotensin system blockade) in decreasing proteinuria to less than the usually accepted threshold for the use of corticosteroids. Earlier RCTs of corticosteroids usually did not deploy supportive therapy optimally. The recent Therapeutic Evaluation of STeroids in IgA Nephropathy Global (TESTING) study closed prematurely because of excess toxicity, but the high dose of corticosteroids seemed to provide benefit. Guidelines provide valuable information about the quality and limitations of available evidence that needs to be personalized in application to the individual patient's medical and nonmedical circumstances to ensure wise clinical decision making.
Since its first description more than 40 years ago, IgA nephropathy has become the most common pattern of primary glomerulonephritis identified in all areas of the world where renal biopsy is ...routinely performed. This review discusses advances in our understanding of the pathogenesis of IgA nephropathy, principally focusing on work published in the past 5 years. It has been recognized for some time that one of the most consistent features of IgA nephropathy is an alteration in the complement of serum IgA1 O-glycoforms, with an overrepresentation of poorly galactosylated IgA1 O-glycoforms both in the serum and mesangial deposits of patients with IgA nephropathy. New data suggest that poorly galactosylated IgA1 O-glycoforms might act either as autoantigens driving the formation of glycan-specific antibodies, or antigens for cross-reactive antimicrobial antibodies. Formation of these circulating and mesangial IgA-containing immune complexes appears pivotal to the pathogenesis of IgA nephropathy and there is strong in vitro data to support their role in activation of mesangial cells, induction of podocyte injury, and activation of proximal tubular epithelial cells. Genetic factors are likely to influence many facets of pathogenesis both in primary and familial IgA nephropathy, however, to date work in this area has failed to identify consistent candidate genes.
Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: Observations in three patients.
In IgA nephropathy (IgAN), circulating IgA1 molecules display an abnormal pattern of ...O-glycosylation. This abnormality may potentially contribute to mesangial IgA1 deposition, but this is unproven because the O-glycosylation of mesangial IgA1 has not been analyzed.
IgA1 was eluted from glomeruli isolated from the kidneys of three IgAN patients obtained after nephrectomy or at postmortem. Serum from these patients, other patients with IgAN, and controls was subjected to the same treatment as the glomerular eluates. The O-glycosylation of eluted and serum IgA1 was measured by lectin binding using an enzyme-linked immunosorbent assay-based system.
In all three cases, the lectin binding of IgA1 eluted from the glomeruli of IgAN patients was markedly higher than that of the serum IgA1 of the same individual, and also all but one of a series of serum IgA1 samples from other patients and controls.
The higher lectin binding of glomerular compared with serum IgA1 suggests that O-glycosylated IgA1 molecules abnormally and selectively deposit in the kidney. These results provide the first evidence that mesangial IgA1 is abnormally O-glycosylated, and support a direct role for abnormal IgA1 O-glycosylation in the mechanism of mesangial IgA deposition in IgAN.
ISN (the International Society of Nephrology) is a global organization with more than 9,000 members in 130 countries. The ISN's mission is to "advance the diagnosis, treatment, and prevention of ...kidney diseases in the developing and developed world". ISN delivers this mission in low-resource settings through its five education and training programs available exclusively to low- and middle-income countries. These programs are designed to enable sustainable growth in capacity in nephrology and related disciplines to provide the basis for the improvement of care for kidney patients worldwide. ISN also directs its efforts towards advocacy for kidney health and kidney care, seeking to increase understanding of kidney disease among the general population, health professionals, and health policy makers. Such advocacy is challenging because of the complexity of kidney health messages; there is a need to emphasize affordable healthcare solutions for prevention and treatment of acute kidney injury (AKI), as well as the prevention and management of chronic kidney disease (CKD), and the provision of renal replacement therapy (both chronic dialysis and kidney transplantation) that is both affordable and ethically acceptable.
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