Biomarkers to Predict Progression in IgA Nephropathy

IgA nephropathy is the most common primary GN worldwide and is a frequent cause of ESKD, especially in Asia. Work performed over the past few decades has led to significant advances in the understanding of common steps in its pathogenesis. Currently, the best predictors of progression are histologic (using the Oxford Classification) and nonspecific clinical (eGFR, BP, proteinuria, age, ethnicity) parameters. These have recently been utilized together in a risk-prediction tool, which accurately predicts the risk of a patient developing a 50% decline in eGFR or development of ESKD out to 7 years after biopsy (1). This tool does not, however, provide the clinician with information upon which to base treatment decisions for a particular patient. As with other glomerular diseases, there is a pressing need to identify suitable biomarkers in IgA nephropathy, to aid with diagnosis, treatment decisions, and risk prediction for progressive disease. Currently, this is performed by kidney biopsy, an invasive procedure that provides a single snapshot in time. Thresholds to perform a biopsy vary between centers, and a biomarker, or panel of biomarkers, that could provide information about the risk of progression earlier in the disease course would be immensely useful in identifying those who may benefit from earlier intervention, and could also help to enrich clinical trials, where negative findings in previous studies may be partly attributable to the inclusion of patients at low risk of progression. An ideal biomarker (or panel) should be measured from an easily available source (e.g., blood or urine), be sensitive and specific for the condition, allow early diagnosis, change in response to treatment, have prognostic value, and be biologically plausible (2). A striking example of this in the nephrology field is the anti-phospholipase A2 receptor antibody, the identification of which has not only led to a paradigm shift in the diagnosis and management of primary membranous nephropathy, but also to significant advances in the understanding of this condition. Discovery of reliable biomarkers in IgA nephropathy, however, has proven to be more challenging. The well documented heterogeneity in epidemiology, presentation, and clinical course has raised the possibility that IgA nephropathy may not be a single disease. This is emphasized by the marked differences observed in the clinical course between different ethnic groups. For example, in Chinese patients, there are reported differences in sex distribution, incidence, severity of the clinical course, levels of IgA1 O-galactosylation, and frequency of a common risk variant of the C1GALT1 gene responsible for IgA1 O-galactosylation compared with white patients (3). In contrast to primary membranous nephropathy, where genome-wide association studies found strong associations with single nucleotide polymorphisms in two distinct loci, HLA-DQA1 and PLA2R1, in IgA nephropathy associations with multiple single nucleotide polymorphisms have been identified but with much lower significance, in regions coding for HLA, complement, and proteins responsible for the maintenance of the intestinal barrier, reflecting the polygenic and likely heterogeneous pathogenesis of this condition (4,5). The diagnosis of IgA nephropathy still relies on the same techniques as those used in its initial description over 50 years ago to demonstrate dominant or codominant mesangial IgA deposition. It is possible, however, that varying pathophysiologic pathways converge to a final common histologic pattern of injury that currently we label as IgA nephropathy but are, in fact, distinct diseases. If this is the case, it is important to acknowledge that this is likely to be reflected by an array of pathway-specific biomarkers and therapeutic targets, and therefore drug responsiveness, that we currently cannot delineate in our IgA nephropathy cohorts. In this edition of CJASN, Chen et al. (6) report the results of a study assessing the relationship between plasma levels of IgA1 that lack terminal galactose residues in its hinge region (termed galactose-deficient IgA1 [GdIgA1]) and complement component C3 in a large cohort of patients with IgA nephropathy and the associated risk of progressive disease. Prior studies from China and Japan suggested that the plasma IgA/C3 ratio may be a useful diagnostic and prognostic biomarker of IgA nephropathy (7). The study by Chen et al. included 1210 patients who had been followed up for a median of 43 months. The follow-up period included a large number of events that made up the combined end point: 165 patients who had a 50% decline in kidney function and 114 patients who reached ESKD. They found that the risk of the combined endpoint correlated with increased levels of plasma GdIgA1, but this relationship reached a plateau once the GdIgA1 level reached a threshold limit. When the GdIgA1 level was quantified as a ratio to plasma C3 (GdIgA1/C3 ratio), this relationship became a linear one. This study included one of the largest IgA nephropathy cohorts studied to date, with a large number of progression events captured. However, some features limit the generalizability of their findings. The study recruited from a single center in Beijing, China. The cohort differs markedly from what might be more familiar in North America and Europe: half were women, mean age of the cohort was 35 years old, 59% of cases had crescents (C1 or C2 score) in their kidney biopsy, and 46% were treated with corticosteroids or other immunosuppressive agents. Are these findings biologically plausible? The relationship between higher levels of GdIgA1 and risk of progressive kidney disease in IgA nephropathy is consistent with previous findings (8). Levels of GdIgA1 are raised in patients with IgA nephropathy, and this form of IgA1 is also found within the mesangial deposits. GdIgA1 is thought to act as a neo-antigen, promoting formation of immune-complexes with anti-IgA1 IgG or IgA; these immune complexes then deposit in the mesangium, and glomerular injury ensues. This has been termed the multihit hypothesis of IgA nephropathy (9). Consistent with this hypothesis IgA, GdIgA1, anti-GdIgA1 IgG, and anti-GdIgA1 IgA are elevated in IgA nephropathy, with anti-GdIgA1 IgG performing best as a biomarker for diagnosis in terms of sensitivity and specificity (10). However, a significant degree of overlap still exists with healthy individuals and other kidney diseases, so that it has not yet been possible to use GdIgA1 or related autoantibodies as a diagnostic biomarker. In the study by Chen et al. it is not clear why the relationship between levels of GdIgA1 and progression reached a plateau, and one possible explanation could be the particular kinetics of their ELISA assay, the subtleties of which have varied between groups who measure this, making it difficult to make comparisons between studies. It is important to note that GdIgA1 levels have been observed to be significantly lower in Chinese patient cohorts when compared with white patients, yet the disease is more prevalent and aggressive in the Chinese population (3). In addition, GdIgA1 levels did not alter in response to immunosuppressive treatments in this study, and therefore the relative contribution of GdIgA1 compared with other pathogenetic pathways in promoting disease progression is becoming less clear. Chen et al. also found that lower plasma levels of C3 correlated with disease progression. This is again conceivable, given the importance of complement activation in the progression of IgA nephropathy. C3 is often codeposited with IgA, and there is mounting evidence that alternative and lectin pathway activity is associated with more progressive disease (7). A number of complement inhibitors targeting various points in the alternative and lectin pathways are currently being studied in clinical trials in IgA nephropathy. It is therefore plausible that in this cohort, the GdIgA1/C3 ratio reflects pathogenic pathway activation, disease activity, and consequent progression, given the potential role of both IgA1 O-galactosylation and complement activity in the pathogenesis of IgA nephropathy. Applicability to other populations will require further validation studies with a standardized ELISA technique. The GdIgA1/C3 ratio has not been formally assessed to determine whether it adds value to the current IgA nephropathy risk predictor, and as this is an observational study, it does not at present help us to decide which group of patients to treat and with which agent to use. The observation that GdIgA1 levels did not change in response to immunosuppressive treatment is interesting, and likely reflects the limitations of our current therapeutic approaches. The way that IgA nephropathy is diagnosed has changed remarkably little over the past 50 years. Moving forward, more investment is needed to identify biomarkers, so that we can move away from broad pathologic classifications, and deliver a precision medicine approach to diagnosis and risk stratification in IgA nephropathy. This is particularly important now as a multitude of new therapies are being developed for use and we are going to need reliable and pathway-specific biomarkers to ensure we give the right drug to the right "patient with IgA nephropathy" at the right time in their disease. This will require the continued international collaborative effort of the global IgA nephropathy community to recruit large numbers of patients into international registries, with longitudinal bioresource sampling and accurate follow-up data, so that we can take a multiplatform approach to phenotyping this disease. This study represents a step in the right direction, and the authors should be congratulated for studying one of the largest IgA nephropathy cohorts to date. Efforts such as this, and registries including International Renal Rare Disease Registry (RaDaR) and the Cure Glomerulonephropathy Network (CureGN) will be instrumental if we are going to be able to deliver on these ambitious aims. Disclosures Dr. Barratt reports grants and/or consultancies with Calliditas Therapeutics, GlaxoSmithKline, Novartis, Omeros, and Retrophin outside the submitted work. Dr. Cheung reports grants from GlaxoSmithKline and Retrophin and consultancy fees from Retrophin outside the submitted work.