PRESENTED BY
JÜRGEN FLOEGE

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Jürgen Floege

Immunoglobulin A (IgA) nephropathy is the most common primary glomerulonephritis worldwide. However, in spite of such high prevalence, there is still much ambiguity in the therapeutic approach to this disease.
The disease typically presents at young age with painless microhaematuria, minimal or no proteinuria and preserved renal function. The patients are often referred to urologist and cease further contacts with nephrologists. The disease usually has benign course and only 5% of these very early patients progress to end-stage renal disease (ESRD), while up to 80% either spontaneously enter into clinical remission or remain with preserved glomerular filtration rate. Unfortunately, there is currently no reliable tool to predict which of these patients will progress thus requiring prolonged follow-up for all diagnosed subjects [1, 2].

IgA nephropathy prediction tools

A recently published study by Barbour et al. presented a new risk-prediction tool in IgA nephropathy which is freely available at the https://qxmd.com/calculate/calculator_499/international-igan-prediction-tool. This tool predicts the risk of 50% decline in eGFR or ESRD in the upcoming 6.7 years [3]. It takes into account a number of factors, including age, blood pressure, estimated eGFR and proteinuria at biopsy, race, use of ACE inhibitors, ARBs or immunosuppression, and MEST scores (M – mesangial hypercellularity, E – endocapillary hypercellularity, S – segmental glomerulosclerosis, T – tubular atrophy/interstitial fibrosis, C – cellular of fibrocellular crescents). The key limitation of this tool is that it’s only valid at the time of the biopsy and further research is needed to define elements necessary for validation at a certain time point following the biopsy and after certain therapeutic measures have been introduced.
Pathohistological evaluation of renal biopsy findings in patients with IgA nephropathy is of undisputable value. In patients of the STOP-IgAN trial, higher mesangial hypercellularity was a predictor of higher annual eGFR decline, while chronic tubulointerstitial changes forecasted higher rate of ESRD [4]. The presence of crescents, endocapillary lesions and glomerular sclerosis presented no predictive value.

Current and new therapeutic approaches to IgA nephropathy

Supportive care is absolutely central in the treatment of IgA nephropathy and encompasses, besides the use of ACE inhibitors or ARBS, controlled protein intake, avoidance of dihydropyridine calcium-channel blockers as first-line antihypertensive medication, also normalizing body weight, cessation of smoking, restriction in sodium and fluid intake, along with use of diuretics, and possibly aldosterone antagonists if there is suspected aldosterone breakthrough [8, 9]. Intensive supportive care actually may even hinder the benefit of added immunosuppression [10, 11, 12]. Furthermore, the use of steroid mono-therapy was associated with a 50% higher rate of infectious complications, glucose intolerance or diabetes and weight gain [13]. The TESTING trial was supposed to shed definitive light into this matter, but although its results were consistent with potential renal benefit from methylprednisolone, it failed to provide definitive conclusions about treatment benefit as it was terminated early for safety reasons following several fatal infections in the steroid-arm [14].
Sparsentan is a promising new combined angiotensin-endothelin receptor blocker which appears to reduce proteinuria more efficiently than irbesartan and thus might contribute to better preservation of renal function in these patients [5]. It is currently tested in a phase III trial in patients with IgA nephropathy (PROTECT trial). Hydroxychloroquine also seems to decrease proteinuria in IgA nephropathy patients better than placebo with acceptable safety [6, 7]. A six months trial therapy with hydroxychloroquine followed by evaluation of its therapeutic effect and possible side effects might be considered a pragmatic approach.
Studies have shown that azathioprine added to corticosteroid therapy does not carry significant benefit to the patients with IgA nephropathy, but in turn brings more side effects [15]. Furthermore, proteinuria in IgA nephropathy does not respond to rituximab and although this drug effectively depleted B cells, it failed to reduce serum levels of galactose-deficient IgA1 in these patients [16]. There were controversial results reported on the effect of mycophenolate-mofetil therapy in IgA nephropathy, as it reduced proteinuria and stabilized eGFR in Asian populations, but not in Caucasians [17].
A novel targeted-release formulation of budesonide, designed to deliver the drug to the distal ileum, was assessed for safety and efficacy in the NEFIGAN study and at daily dose of 16 mg it efficiently reduced proteinuria and stabilized eGFR in patients with IgA nephropathy [18]. A phase III trial (NEFIGARD trial) is ongoing.
Taken all these data into consideration, the contemporary therapeutic approach to a patient with IgA nephropathy would depend on the level of proteinuria and the rate of progression of eGFR decline [5, 9]. The typical patients with persistent proteinuria above 0.5-1 g/day, with or without reduced eGFR and hypertension should be administered optimized supportive therapy for six months, and then consider corticosteroid therapy depending on the presence of proteinuria and eGFR level, patient preferences and co-morbidities (Figure 1).

Figure 1. Therapeutic approach to the patient with IgA nephropathy in 2019 [19]

What’s in the pipeline?
Several phase II to IV trials are currently in course investigating the effects of new drugs, in particular complement inhibitors, on the progression of IgA nephropathy [20-24]. According to the currently available data, avacopan reduces proteinuria and glomerular injury through C5a receptor antagonism while bortezomib may induce complete disease remission in patients with initially preserved eGFR [20, 21]. Thus these drugs present a promising potential treatment option for proteinuric patients with IgA nephropathy. On the other hand, fostamatinib and blisibimod did not present expected results and bardoxolone increased eGFR but also proteinuria [22-25]. In conclusion, there are several new approaches based on the pathogenesis of the disease that may bring positive results in the next years.

References

1. Knoop T, Vikse BE, Mwakimonga A, Leh S, Bjørneklett R. Long-term outcome in 145 patients with assumed benign immunoglobulin A nephropathy. Nephrol Dial Transplant. 2017;32(11):1841-1850. doi: 10.1093/ndt/gfx242.

2. Kunter U, Floege J. The longer the better: follow-up in seemingly ‘benign’ immunoglobulin A nephropathy. Nephrol Dial Transplant. 2017;32(11):1777-1779. doi: 10.1093/ndt/gfx236.

3. Barbour SJ, Coppo R, Zhang H, et al. Evaluating a new international risk-prediction tool in IgA nephropathy. JAMA Intern Med. 2019;179(7):942-952. doi: 10.1001/jamainternmed.2019.0600.

4. Schimpf JI, Klein T, Fitzner C, et al. Renal outcomes of STOP-IgAN trial patients in relation to baseline histology (MEST-C scores). BMC Nephrol. 2018 ;19(1):328. doi: 10.1186/s12882-018-1128-6.

5. Trachtman H, Nelson P, Adler S, et al. DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS. J Am Soc Nephrol. 2018;29(11):2745-2754. doi: 10.1681/ASN.2018010091.

6. Floege J. Antimalarials in IgA nephropathy: Did our supportive therapy armamentarium just increase? Am J Kidney Dis. 2019;74(1):6-8. doi: 10.1053/j.ajkd.2019.02.022.

7. Liu LJ, Yang YZ, Shi SF, et al. Effects of Hydroxychloroquine on Proteinuria in IgA Nephropathy: A Randomized Controlled Trial. Am J Kidney Dis. 2019;74(1):15-22. doi: 10.1053/j.ajkd.2019.01.026.

8. Floege J, Eitner F. Current therapy for IgA nephropathy. J Am Soc Nephrol. 2011;22(10):1785-94. doi: 10.1681/ASN.2011030221.

9. Floege J, Feehally J. Treatment of IgA nephropathy and Henoch-Schönlein nephritis. Nat Rev Nephrol. 2013;9(6):320-7. doi: 10.1038/nrneph.2013.59.

10. Rauen T, Eitner F, Fitzner C, et al. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. N Engl J Med. 2015;373(23):2225-36. doi: 10.1056/NEJMoa1415463.

11. Manno C, Torres DD, Rossini M, Pesce F, Schena FP. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol Dial Transplant. 2009;24(12):3694-701. doi: 10.1093/ndt/gfp356.

12. Rauen T, Fitzner C, Eitner F, et al. Effects of Two Immunosuppressive Treatment Protocols for IgA Nephropathy. J Am Soc Nephrol. 2018;29(1):317-325. doi: 10.1681/ASN.2017060713.

13. Lv J, Zhang H, Wong MG, et al. Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2017;318(5):432-442. doi: 10.1001/jama.2017.9362.

14. Pozzi C, Andrulli S, Pani A, et al. Addition of azathioprine to corticosteroids does not benefit patients with IgA nephropathy. J Am Soc Nephrol. 2010;21(10):1783-90. doi: 10.1681/ASN.2010010117.

15. Lafayette RA, Canetta PA, Rovin BH, et al. A Randomized, Controlled Trial of Rituximab in IgA Nephropathy with Proteinuria and Renal Dysfunction. J Am Soc Nephrol. 2017;28(4):1306-1313. doi: 10.1681/ASN.2016060640.

16. Floege J. Is mycophenolate mofetil an effective treatment for persistent proteinuria in patients with IgA nephropathy? Nat Clin Pract Nephrol. 2006;2(1):16-7. DOI:10.1038/ncpneph0067

17. Fellström BC, Barratt J, Cook H, et al. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet. 2017;389(10084):2117-2127. doi: 10.1016/S0140-6736(17)30550-0.

18. Floege J. What is the optimal approach to the treatment of IgA nephropathy in 2019? Oral presentation at 56th ERA-EDTA congress, Budapest, Hungary, June 14, 2019. Available the Congress Virtual Meeting

19. Hartono C, Chung M, Perlman AS, et al. Bortezomib for Reduction of Proteinuria in IgA Nephropathy. Kidney Int Rep. 2018;3(4):861-866. doi: 10.1016/j.ekir.2018.03.001

20. Open Label Study of Fostamatinib in the Treatment of IgA Nephropathy. Available at: https://clinicaltrials.gov/ct2/show/NCT02433236?term=fostamatinib&cond=IgA+nephropathy&draw=2&rank=1.

21. A Phase 2 Trial of the Safety and Efficacy of Bardoxolone Methyl in Patients With Rare Chronic Kidney Diseases – PHOENIX (PHOENIX). Available at: https://clinicaltrials.gov/ct2/show/NCT03366337?term=bardoxolone&cond=IgA+nephropathy&draw=2&rank=1.

22. BRILLIANT-SC: A Study of the Efficacy and Safety of Blisibimod Administration in Subjects With IgA Nephropathy. Available at: https://clinicaltrials.gov/ct2/show/NCT02052219?term=Blisibimod&cond=IgA+nephropathy&draw=2&rank=1.

23. Floege J. The pathogenesis of IgA nephropathy: what is new and how does it change therapeutic approaches? Am J Kidney Dis. 2011;58(6):992-1004. doi: 10.1053/j.ajkd.2011.05.033.

NDT-E Summary Articles