• 1.

    Rodrigues JC, et al. IgA nephropathy. Clin J Am Soc Nephrol 2017; 12:677686. doi: 10.2215/CJN.07420716

  • 2.

    Coppo R. Corticosteroids in IgA nephropathy: Lessons from recent studies. J Am Soc Nephrol 2017; 28:2533. doi: 10.1681/ASN.2016060647

  • 3.

    Radhakrishnan J, Cattran DC. The KDIGO practice guideline on glomerulonephritis: Reading between the (guide)lines—application to the individual patient. Kidney Int 2012; 82:840856. doi: 10.1038/ki.2012.280

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Pozzi C, et al. Corticosteroids in IgA nephropathy: A randomised controlled trial. Lancet 1999; 353:883887. doi: 10.1016/s0140-6736(98)03563-6

  • 5.

    Manno C, et al. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol Dial Transplant 2009; 24:36943701 [published correction appears in Nephrol Dial Transplant 2010; 25:1363−1364]. doi: 10.1093/ndt/gfp356

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Rauen T, et al. Intensive supportive care plus immunosuppression in IgA nephropathy. N Engl J Med 2015; 373:22252236. doi: 10.1056/NEJMoa1415463

  • 7.

    Barbour SJ, et al. The MEST score provides earlier risk prediction in IgA nephropathy. Kidney Int 2016; 89:167175. doi: 10.1038/ki.2015.322

  • 8.

    Ballardie FW, Roberts ISD. Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. J Am Soc Nephrol 2002; 13:142148. doi: 10.1681/ASN.V131142

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Vecchio M, et al. Immunosuppressive agents for treating IgA nephropathy. Cochrane Database Syst Rev 2015; CD00396. doi: 10.1002/14651858.CD003965.pub2

  • 10.

    Lv J, et al. Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy: The TESTING randomized clinical trial. JAMA 2017; 318:432442. doi: 10.1001/jama.2017.9362

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Wheeler DC, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 2021; 100:215224. doi: 10.1016/j.kint.2021.03.033

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Sen T, Heerspink HJL. A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors. Cell Metab 2021; 33:732739. doi: 10.1016/j.cmet.2021.02.016

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Cravedi P, Remuzzi G. Pathophysiology of proteinuria and its value as an outcome measure in chronic kidney disease. Br J Clin Pharmacol 2013; 76:516523. doi: 10.1111/bcp.12104

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Barratt J, Floege J. SGLT-2 inhibition in IgA nephropathy: The new standard of care? Kidney Int 2021; 100:2426. doi: 10.1016/j.kint.2021.04.002

  • 15.

    Vasquez-Rios G, Nadkarni GN. SGLT2 inhibitors: Emerging roles in the protection against cardiovascular and kidney disease among diabetic patients. Int J Nephrol Renovasc Dis 2020; 13:281296. doi: 10.2147/IJNRD.S268811

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Coppo R, et al. IgACE: A placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria. J Am Soc Nephrol 2007; 18:18801888. doi: 10.1681/ASN.2006040347

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Li PK-T, et al. Hong Kong study using valsartan in IgA nephropathy (HKVIN): A double-blind, randomized, placebo-controlled study. Am J Kidney Dis 2006; 47:751760. doi: 10.1053/j.ajkd.2006.01.017

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Praga M, et al. Treatment of IgA nephropathy with ACE inhibitors: A randomized and controlled trial. J Am Soc Nephrol 2003; 14:15781583. doi: 10.1097/01.asn.0000068460.37369.dc

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Papeta N, et al. APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy. J Am Soc Nephrol 2011; 22:19911996. doi: 10.1681/ASN.2011040434

  • 20.

    Sehic AM, et al. Increased recognition of IgA nephropathy in African-American children. Pediatr Nephrol 1997; 11:435437. doi: 10.1007/s004670050311

SGLT2 Inhibitors for the Management of IgA Nephropathy: A New Therapeutic Paradigm for an Old Entity?

George Vasquez-Rios George Vasquez-Rios, MD, is with the Division of Nephrology, Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

Search for other papers by George Vasquez-Rios in
Current site
Google Scholar
PubMed
Close
Full access

Immunoglobulin A nephropathy (IgAN) is the most common glomerular disease worldwide (1). The prevalence varies geographically, and estimates of disease burden depend on the registry data assessed. The pathophysiology of this condition includes circulating and glomerular immune complexes comprised of galactose-deficient IgA1, an IgG autoantibody (directed against the hinge region O-glycan), and C3 (1). Experimental models suggest that environmental factors can trigger aberrant IgA production in highly active sites such as the mucosal-associated lymphoid tissue (MALT) in the gastrointestinal tract, which ultimately leads to immune complex deposition in key compartments of the kidney. Mesangial cells serve not only as a glomerular capillary support network but also as highly reactive elements capable of producing inflammatory mediators after contact with IgA, leading to mesangial expansion, matrix production, and an endocapillary influx of inflammatory cells (2).

Whereas the immune-mediated nature of this condition is recognized and a topic of active study, treating patients with IgAN with immunomodulatory therapies has provided inconsistent results. In 2012, the Kidney Disease: Improving Global Outcomes (KDIGO) clinical guidelines reported the first attempt to summarize the results of the literature including the role of steroids for patients with relatively preserved kidney function (estimated glomerular filtration rate [eGFR] > 50 mL/min/1.73 m2) who had persistent proteinuria >1 g/day, despite 3–6 months of maximal renin-angiotensin-aldosterone system (RAAS) blockade (“standard of care”) (35). In 2015, the STOP-IgAN (Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy) study included 162 participants who were randomly allocated to receive standard of care (n = 80) for 6 months, adequate blood pressure and lipid profile control, as well as diet counseling, whereas 82 participants were administered immunosuppressive therapy with methylprednisolone (n = 55; those with an eGFR > 60 mL/min/1.73 m2) or cyclophosphamide C, followed by azathioprine plus prednisolone (n = 27; those with an eGFR 30−59 mL/min/1.73 m2) (6). The STOP-IgAN trial provided the important finding that adding immunosuppressive therapy to optimal standard of care may not provide substantial kidney-related benefits in patients with high-risk IgAN.

Furthermore, although the addition of immunosuppressive therapy induced remission of proteinuria in a subgroup of patients, there was no significant difference between the immunosuppression and the standard-of-care group with regard to reducing rapid kidney function decline or kidney events in the pooled analysis. This is in contrast to previous studies that had suggested a potential benefit from immunosuppressive drugs in patients with severe histologic lesions, according to the Oxford Classification (MEST-C) (7); rapidly progressive kidney disease; and high proteinuria (79).

Subsequently, the Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study recruited 262 participants with an eGFR of 20−120 mL/min/1.73 m2 and proteinuria (>1 g/day) who were randomized to receive oral methylprednisolone (0.6−0.8 mg/kg/day) versus placebo before weaning over 4−6 months (10). The study was prematurely terminated due to the high incidence of side effects in the treatment group. Since then, the TESTING Low Dose study (ClinicalTrials.gov: NCT01560052) has been actively recruiting patients with an estimated completion date of June 2023 (methylprednisolone 0.4 mg/kg/day vs. placebo).

Need for IgAN progression therapies

Because most of the clinical trials in IgAN have been limited by small sample sizes, short follow-up periods, lack of histologic data, or heterogeneity of immunosuppressive regimens, the decision to treat with immunomodulators should be carefully individualized based on key parameters, including eGFR, degree of proteinuria, extent of fibrosis vs. active histological lesions (which offer a window of opportunity), as well as the side effect profile of the given drug. Therefore, there is still a need for other therapeutic interventions for patients at high risk of progression.

Recently, a pre-specified analysis from the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial was published. This ascertained the effects of sodium glucose co-transporter 2 (SGLT2) inhibitors on the primary composite endpoint of a sustained eGFR decline of ≥50% (confirmed by a second creatinine measurement after at least 28 days), progression to end stage kidney disease (ESKD; defined as maintenance dialysis for at least 4 weeks, kidney transplantation, or eGFR < 15 mL/min/1.73 m2), or death from a kidney or cardiovascular cause over a median follow-up period of 2.1 years (11).

The study—a clinical trial with the largest number of IgAN patients to date—included 270 participants with investigator-reported IgAN of whom 254 (94%) had a biopsy-proven diagnosis. The study population was characterized by middle-aged adults, primarily of Caucasian or Asian ethnicity, with a low prevalence of diabetes mellitus, a mean eGFR of 43.8 mL/min/1.73 m2, and a median urinary albumin-to-creatinine ratio (uACR) of 900 mg/g. Participants had been taking either an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) for at least 4 weeks before randomization. No data were presented for mineralocorticoid receptor blocker use, although heart failure prevalence was low.

The primary outcome occurred in 6 (4%) participants in the treatment arm and in 20 (15%) in the placebo arm (hazard ratio [HR]: 0.29; 95% confidence interval [CI], 0.12−0.73). Additionally, the least mean squares eGFR slopes from baseline to end of treatment in the dapagliflozin group were −3.5 mL/min/1.73 m2 per year compared to −4.7 mL/min/1.73 m2 per year in the placebo group, resulting in a between-group difference of 1.2 mL/min/1.73 m2 per year (95% CI, −0.12 to 2.51 mL/min/1.73 m2 per year). These findings were consistent when evaluated by prespecified baseline eGFR and uACR categories.

Similar to the results in the entire cohort of patients in DAPA-CKD, patients in the study group exhibited reversible eGFR reductions during the first 4 weeks of therapy initiation that progressively stabilized. Also, the mean percentage difference in uACR between dapagliflozin and placebo at month 4 was −35% (95% CI, −51 to −18.9, p < 0.001), which seemed to persist throughout the study. In addition, blood pressure recordings were lower in the treatment group compared to the placebo group. Adverse events that prompted discontinuation of the study drug were comparable in the treatment (6/137) and placebo (7/133) groups. However, serious adverse events were recorded more frequently in the placebo group (12.1% vs. 25.6%).

The implications of these results are striking and confront us with a new paradigm in the treatment approach of IgAN. SGLT2 inhibitors exhibit different mechanisms within the kidney and in distant organs. Blocking Na-mediated glucose reabsorption in the proximal segments of the nephron increases the distal delivery of Na+ and Cl to the macula densa, thereby inducing a tubuloglomerular feedback that results in constriction of the afferent artery, reduction of the intraglomerular pressure, and consequently albuminuria (12).

Such hemodynamic effects could significantly alleviate the shear stress of sensitive structures such as podocytes that have been implicated in the pathophysiology of diabetic kidney disease (DKD) and could arguably play a role in IgAN progression (13). Furthermore, the natriuretic effect of SGLT2 inhibitors along with their effects on weight reduction, which are known risk factors for high intraglomerular pressure and disease progression in IgAN, could help in blood pressure control (14). However, as compared to previous results in Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) and DAPA-CKD trials, the effects of dapagliflozin on the primary outcome among IgAN patients are very pronounced starting at month 8, suggesting that not only are immediate hemodynamic effects involved, but also presumably cellular and metabolic effects play a significant role.

Pleiotropic effects of SGLT2 inhibitors include modulation of inflammatory and profibrotic mediators and regulation of toxic intracellular compounds (i.e., advanced glycation end products), among others, as demonstrated in models of type 2 diabetes mellitus (15). However, the role of these factors in the pathogenesis of IgAN is less certain. It is accepted that currently employed immunosuppressive strategies lack conclusive efficacy data, as there is a high-risk toxicity profile. Interestingly, it is possible that addressing the non-immune component of IgAN could represent a safe and effective strategy for kidney preservation while the risks and benefits of immunosuppressive therapies are discussed (Figure 1). This could be particularly important in patients without evidence of active and severe histological features, as defined by the MEST-C score (not available in DAPA-CKD). However, further studies are needed.

Figure 1
Figure 1

Beneficial effects of SGLT2 inhibitors that could be involved in IgAN disease reduction risk

Citation: Kidney News 14, 2

The pre-specified analysis of DAPA-CKD had some limitations that are worth mentioning. This study included patients who were on a “stable” dose of RAAS blockers 4 weeks prior to enrollment without detail if the given therapy was maximized. Therefore, it is unclear how much improvement could have been elicited by adding SGLT2 inhibitors to the medical regimen in patients with maximal standard therapy (14). Furthermore, it is difficult to ascertain how much of the benefits seen in the treatment group could be attributed to weight loss and blood pressure reduction, which are attainable with other less expensive and evidence-supported medications.

Certainly, recommendations on the RAAS blockade in IgAN are supported by small studies that have shown reduction in proteinuria and less kidney function deterioration. Nonetheless, none of the ACEi and/or ARB trials have shown the significant biomarker stabilization and outcome improvements demonstrated by dapagliflozin (1618). Moreover, the study population in this pre-specified analysis seems to exhibit a high risk for kidney disease progression. When observing the cumulative incidence of the primary endpoint among the patients in the placebo group by month 32, approximately 24% had experienced a combination of sustained eGFR reduction ≥50%, progression toward ESKD, or death from a kidney or cardiovascular cause, which suggests that there was a high rate of rapid progressors in the latter group.

Therefore, the effectiveness of dapagliflozin as a co-adjuvant therapy in high-risk patients should be carefully examined. Important areas of uncertainty include the safety of using SGLT2 inhibitors in patients with IgAN treated with immunosuppression (excluded in DAPA-CKD) and whether this class could be similarly beneficial among patients with lower levels of albuminuria. Although the results remained consistent when stratified by eGFR (≥45 or <45 mL/min/1.43 m2) and uACR (>1000 or <1000 mg/g per day), the effects of SGLT2 inhibitors should be carefully ascertained in both rapid and slow progressors. Moreover, it is necessary that future studies include a more heterogeneous population such as patients of African ancestry, who are documented to have increased risk for kidney progression and who have been largely underrepresented in IgAN studies (3, 19, 20).

Despite the aforementioned caveats, SGLT2 inhibitors continue to serve as an attractive therapeutic option for a vast number of patients with kidney disease. Clinical trials such as DAPA-CKD are changing the way we understand kidney disease and “raising the bar” for other candidate therapies in this field. The investigators deserve recognition for designing DAPA-CKD as the first event-driven trial of an SGLT2 inhibitor that included patients with CKD due to a broad range of etiologies such as IgAN. SGLT2 inhibitors could be considered as an “add-on” therapy when stabilization of clinical parameters is still needed despite optimal standard of care. Alternatively, they could be used in patients who are intolerant to RAAS blockers.

Future studies should evaluate the effects of SGLT2 inhibitors in a larger population of patients whose standard therapy is optimal to uncover their true potential and to evaluate their safety profile when immunosuppressive therapy is concomitantly administered. Finally, although The Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY; ClinicalTrials.gov: NCT03594110) trial should reveal the efficacy and tolerability of SGLT2 inhibitors in patients with non-diabetic CKD, dedicated IgAN trials are very much needed to continue advancing our knowledge of this condition and individualized interventions.

Acknowledgment:

The author would like to express his gratitude to Drs. Miriam Chung, Kirk N. Campbell, Joseph A. Vassalotti, and Jaime Uribarri at the Icahn School of Medicine at Mount Sinai for their valuable feedback at the time of preparing this manuscript.

References

  • 1.

    Rodrigues JC, et al. IgA nephropathy. Clin J Am Soc Nephrol 2017; 12:677686. doi: 10.2215/CJN.07420716

  • 2.

    Coppo R. Corticosteroids in IgA nephropathy: Lessons from recent studies. J Am Soc Nephrol 2017; 28:2533. doi: 10.1681/ASN.2016060647

  • 3.

    Radhakrishnan J, Cattran DC. The KDIGO practice guideline on glomerulonephritis: Reading between the (guide)lines—application to the individual patient. Kidney Int 2012; 82:840856. doi: 10.1038/ki.2012.280

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Pozzi C, et al. Corticosteroids in IgA nephropathy: A randomised controlled trial. Lancet 1999; 353:883887. doi: 10.1016/s0140-6736(98)03563-6

  • 5.

    Manno C, et al. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol Dial Transplant 2009; 24:36943701 [published correction appears in Nephrol Dial Transplant 2010; 25:1363−1364]. doi: 10.1093/ndt/gfp356

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Rauen T, et al. Intensive supportive care plus immunosuppression in IgA nephropathy. N Engl J Med 2015; 373:22252236. doi: 10.1056/NEJMoa1415463

  • 7.

    Barbour SJ, et al. The MEST score provides earlier risk prediction in IgA nephropathy. Kidney Int 2016; 89:167175. doi: 10.1038/ki.2015.322

  • 8.

    Ballardie FW, Roberts ISD. Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. J Am Soc Nephrol 2002; 13:142148. doi: 10.1681/ASN.V131142

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Vecchio M, et al. Immunosuppressive agents for treating IgA nephropathy. Cochrane Database Syst Rev 2015; CD00396. doi: 10.1002/14651858.CD003965.pub2

  • 10.

    Lv J, et al. Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy: The TESTING randomized clinical trial. JAMA 2017; 318:432442. doi: 10.1001/jama.2017.9362

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Wheeler DC, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 2021; 100:215224. doi: 10.1016/j.kint.2021.03.033

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Sen T, Heerspink HJL. A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors. Cell Metab 2021; 33:732739. doi: 10.1016/j.cmet.2021.02.016

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Cravedi P, Remuzzi G. Pathophysiology of proteinuria and its value as an outcome measure in chronic kidney disease. Br J Clin Pharmacol 2013; 76:516523. doi: 10.1111/bcp.12104

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Barratt J, Floege J. SGLT-2 inhibition in IgA nephropathy: The new standard of care? Kidney Int 2021; 100:2426. doi: 10.1016/j.kint.2021.04.002

  • 15.

    Vasquez-Rios G, Nadkarni GN. SGLT2 inhibitors: Emerging roles in the protection against cardiovascular and kidney disease among diabetic patients. Int J Nephrol Renovasc Dis 2020; 13:281296. doi: 10.2147/IJNRD.S268811

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Coppo R, et al. IgACE: A placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria. J Am Soc Nephrol 2007; 18:18801888. doi: 10.1681/ASN.2006040347

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Li PK-T, et al. Hong Kong study using valsartan in IgA nephropathy (HKVIN): A double-blind, randomized, placebo-controlled study. Am J Kidney Dis 2006; 47:751760. doi: 10.1053/j.ajkd.2006.01.017

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Praga M, et al. Treatment of IgA nephropathy with ACE inhibitors: A randomized and controlled trial. J Am Soc Nephrol 2003; 14:15781583. doi: 10.1097/01.asn.0000068460.37369.dc

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Papeta N, et al. APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy. J Am Soc Nephrol 2011; 22:19911996. doi: 10.1681/ASN.2011040434

  • 20.

    Sehic AM, et al. Increased recognition of IgA nephropathy in African-American children. Pediatr Nephrol 1997; 11:435437. doi: 10.1007/s004670050311

Save