Glomerular Disease Corner: Managing Crescentic IgA Nephropathy

The case

A 34-year-old man presents with fatigue and is found to have blood++ and protein++ in his urine on dipstick testing. His creatinine is elevated at 2.0 mg/dL, having been 1.9 mg/dL 4 months previously (only value known). His urine protein:creatinine ratio is 350 mg/g. A biopsy demonstrates diffuse mesangial IgA deposits with associated hypercellularity. Thirty percent of his glomeruli (4/13) demonstrates fibro-cellular crescents, and there is minimal interstitial fibrosis. There are no C1q or IgM deposits noted, and his immunology is negative, consistent with a diagnosis of IgAN, with a MEST-C score of M1 E0 S0 T0 C2.

Initial management

Thirty percent to 40% of those with IgAN reach kidney failure within 20 years of diagnosis (5, 6). Measures to reduce this risk include renin-angiotensin system inhibition, blood pressure control, smoking cessation, dietary salt restriction, and weight optimization. These standard interventions are not to be underestimated—they work and do reduce risk of progressive disease (7).

With the increasing evidence base for sodium-glucose co-transporter-2 (SGLT2) inhibitors in chronic kidney disease (CKD), many clinicians feel comfortable initiating them for IgAN. The evidence arises from a subgroup analysis of 270 IgAN patients enrolled in the DAPA-CKD study (which successfully demonstrated the efficacy of dapagliflozin in reducing risk of kidney failure and mortality in CKD) (8, 9). The pre-specified analysis, which included more patients with IgAN than any other IgAN trial to date, confirmed the benefits of dapagliflozin in IgAN. The findings need to be interpreted with an element of caution. More patients receiving placebo reached the composite renal endpoint than expected, perhaps due to suboptimal deployment of standard interventions, which were not optimized prior to randomization as a requirement for the trial (8, 9). Although SGLT2 inhibitors are safe and are likely to have a role in managing IgAN, their benefits beyond standard interventions are not immediately clear.

There are no other safe treatments available for reducing risk of IgAN progression. The only option that Kidney Disease: Improving Global Outcomes (KDIGO) lists for those who have proteinuric IgAN despite 6 months of optimal standard interventions is a course of corticosteroids. This is not without risks.

The risks of immunosuppressive therapy in IgAN

The evidence base for immunosuppression, including corticosteroids, comes from a group of small, randomized clinical trials from over 10 years ago (10−12). The main drawback of these trials was that they did not deploy optimized standard interventions prior to commencing immunosuppression, so it was unclear if immunosuppression truly conferred an added benefit. TESTING and STOP-IgAN were randomized controlled trials (RCTs) designed to answer this question (13, 14). They included a 6-month run-in period of optimized standard interventions, after which patients were randomized to either receive immunosuppression or not. Both trials found minimal benefits for immunosuppression but significant risks for adverse events; TESTING was prematurely halted because of this. A second iteration of TESTING is under way, employing lower doses of immunosuppression and Pneumocystis jirovecii prophylaxis.

Although it is possible that some with IgAN may benefit from corticosteroids, at present, there are no effective methods to determine who they may be, and it is clear from STOP-IgAN and TESTING that these benefits come at a cost. In keeping with this, draft KDIGO guidelines advise these risks be very carefully considered, and corticosteroids only be trialed in those who have proteinuric disease despite standard treatment (>1 gram/day), if their estimated glomerular filtration rate (eGFR) is above 30, with a low risk of adverse events related to steroids, and accepting benefits may be minimal.

This is crescentic IgAN—does that change the risk vs. benefit profile?

Crescents are a component of the MEST-C score, which describes five histopathological lesions in IgAN that are associated with a poor prognosis, independent of traditional prognostic markers (15, 16). The presence of crescents (in at least 25% of glomeruli, defined as C2 in the MEST-C score) confers a hazard ratio (HR) of 2.29 (1.35−3.91) for end stage kidney disease or 50% decline in eGFR (4). The prognostic value of crescents has been validated internationally. Despite this, consensus is that crescents alone should not influence management. This is reflected in the draft KDIGO 2020 guidelines and is based on the evidence base available.

A number of papers have sought to address the value of immunosuppression in crescentic IgAN. The vast majority are case reports/series or uncontrolled trials reporting success, including resolution of crescents on serial biopsies. None were set up to detect the risks of immunosuppression, all were uncontrolled, and all were prone to publication bias with few negative reports available. To address these shortcomings, a number of retrospective analyses of crescentic IgAN have been conducted. These results are more variable. The largest two (7143 patients total, including Caucasians and Asians) found those who received some form of immunosuppression developed kidney failure less often than those who did not. However, benefits were either minimal (HR of 1.31 vs. 1.51), or confidence intervals were wide (4, 17). Furthermore, it was unclear if these benefits were beyond that of standard interventions. Other analyses of different cohorts reported no benefit to immunosuppression in crescentic IgAN, including one with a sample size of 1152 (18).

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The results of TESTING and STOP-IgAN are likely applicable to our case study; both included a subgroup of crescentic IgAN patients with similar characteristics. TESTING excluded crescentic patients if >50% of crescents were present, and STOP-IgAN excluded crescentic patients if they also had evidence of rapidly progressive disease. TESTING ultimately included 144 crescentic patients (55% of participants), and STOP-IgAN included 22 (14%); crescents are more commonly seen in Chinese patients, who accounted for >95% of those in TESTING. A subgroup analysis of crescentic patients in STOP-IgAN also found no benefit of immunosuppression and in fact found crescents associated with kidney failure in the immunosuppressed group but not in the standard intervention group (limited sample size to be noted) (19).

Only two RCTs specifically investigated immunosuppression in crescentic IgAN. One (n = 20) found a benefit to 5-year renal survival but was not set up to detect adverse events related to immunosuppression (20). The other (n = 15) found no benefit to serum creatinine and proteinuria at 3 years, but more than 30% in the steroid group withdrew due to side effects (21). Neither trial optimized standard interventions prior to initiating immunosuppression.

The literature therefore is at best mixed with regard to the benefits of using immunosuppression in crescentic IgAN, but the risk of adverse events remains clear and significant. This risk-benefit profile would strongly suggest avoiding immunosuppression in stable or slowly progressive crescentic IgAN.

Are there any exceptions?

There are instances in which immunosuppression is suggested for the management of IgAN by KDIGO draft guidelines, notably in the context of rapidly progressive disease and variant forms of IgAN (e.g., co-presentation with minimal change disease). However, it is important to note that the presence or absence of crescents in any of the above scenarios should not influence management decisions.

Our patient doesn't have a variant form of IgAN nor does he have crescentic glomerulonephritis (GN)—is there anything more we can do?

Yes! With the introduction of surrogate end points for clinical trials, such as eGFR slopes and proteinuria, the number of clinical trials investigating novel and repurposed treatments of IgAN has rapidly increased. Enrolling this patient in any of the available clinical trials would be the most appropriate next step. These developments, combined with advances in laboratory methods investigating the mechanisms of IgAN, are likely to drive the management of IgAN into the era of personalized and precision medicine in the not-too-distant future.