Ali Mehdi, MD, MEd, is a board-certified nephrologist at Cleveland Clinic, where he also serves as assistant professor of medicine at the Lerner College of Medicine at Case Western Reserve University.

Ali Mehdi, MD, MEd

Clinicians treating IgA nephropathy (IgAN) face a disease that can behave in strikingly different ways from one patient to the next, from a rapid decline in kidney function to a slower course marked by hematuria and proteinuria. Matching that variability to the right treatment remains one of the field's harder problems.

Why IgA Nephropathy Risk Stratification Still Falls Short

"IgA nephropathy is a heterogeneous disease," Ali Mehdi, MD, MEd, a board-certified nephrologist at Cleveland Clinic and assistant professor of medicine at the Lerner College of Medicine at Case Western Reserve University, said in an interview with HCPLive. "We have patients who present with a fast, progressive kidney disease where they lose kidney function pretty rapidly over a few years, and we have patients who have hematuria and proteinuria, that it's an indolent progression towards the need of renal replacement therapy down the line."

Current Risk Tools Rely on Damage Already Done

Clinicians currently lean on a mix of clinical and pathologic markers to gauge a patient's trajectory. "We do have some ways to monitor these patients and risk stratify based on clinical parameters like proteinuria, like estimated GFR, and then pathologic parameters that we get from a kidney biopsy," Mehdi said, pointing to tools such as the Oxford Classification (1). Those measures help estimate a patient's risk of progressing to end-stage kidney disease, but Mehdi was direct about their limits. "That is not a perfect way to do it, and we are learning more from clinical trials how to better do it and better identify which patient would benefit more from what disease," he said.

Part of what's driving renewed attention to risk stratification, Mehdi said, is a broader shift in how the field understands IgAN's natural history. Where the disease was once considered relatively benign, a substantial share of patients, even those with seemingly indolent presentations, are now known to eventually require renal replacement therapy, sometimes decades after diagnosis in patients who are first affected in their 30s or 40s. That recognition has already been incorporated into the updated Kidney Disease: Improving Global Outcomes (KDIGO) guidelines (2).

Phenotyping, Not Just Biomarkers, Is the Next Target

Mehdi said the next step is moving past biomarkers that reflect damage already done, such as estimated GFR slope and proteinuria, toward phenotyping that reflects the biology driving a given patient's disease. "I'd like to be able to better phenotype my patients based on disease parameters that would tell me that this patient is high risk and would benefit from treatment X or Y, or would not benefit from treatment X or Y," he said. He expects that shift within the next 5 to 10 years, with the potential to change how clinicians select treatment for individual patients.

Trimarchi H, Barratt J, Cattran DC, et al. Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. 

Kidney Disease: Improving Global Outcomes (KDIGO) IgAN/IgAV Work Group. KDIGO 2025 clinical practice guideline for the management of immunoglobulin A nephropathy (IgAN) and immunoglobulin A vasculitis (IgAV). 

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Cleveland Clinic's Ali Mehdi, MD, MEd, on the limits of current IgA nephropathy risk tools and where phenotyping could take treatment next.

IgA nephropathy (IgAN) is no longer considered the benign disease it was once thought to be, with a growing share of patients now expected to eventually need renal replacement therapy.

HCPLive: IgA nephropathy care has changed dramatically in a relatively short period of time over the last few decades. What do you think has been the biggest paradigm shift in how clinicians should think about this disease?

Mehdi: I think the biggest thing that we've learned over the past few years is that IgA nephropathy is not the benign disease that we all unfortunately learned back in medical school and as nephrology fellows. We now realize that a big percentage of patients, even those who present with a seemingly indolent disease, will end up requiring renal replacement therapy at some point down the line. In a disease like IgA, the problem is that this could be decades down the line, but when you think of a disease that really starts at age 30 or 40, decades down the line is still a young adult, basically. So I think that's been the biggest realization about IgA, and that clearly made its way into the updated KDIGO guidelines for how we should be managing IgA nephropathy. It has already transformed how we approach, how we diagnose, how we risk stratify, and how we treat those patients.

HCPLive: IgAN is a heterogeneous disease, with patients experiencing different rates of progression and treatment responses. How should clinicians account for that variability when making treatment decisions?

Mehdi: We are still learning how to risk stratify our patients. IgA nephropathy is a heterogeneous disease. We have patients who present with fast, progressive kidney disease where they lose kidney function pretty rapidly over a few years, and we have patients who have hematuria and proteinuria with an indolent progression toward the need for renal replacement therapy down the line. We do have some ways to monitor these patients and risk stratify based on clinical parameters like proteinuria and estimated GFR, and then pathologic parameters that we get from a kidney biopsy, and that helps us establish the risk of progression toward end-stage kidney disease in the foreseeable future. That is not a perfect way to do it, and we are learning more from clinical trials about how to better identify which patient would benefit from what. That is an evolving chapter that's being written, and the heterogeneity doesn't help, but there's a lot of data hopefully coming over the next few years.

HCPLive: What is one change you hope to see in IgA nephropathy care over the next few years?

Mehdi: I think the biggest change I would like to see is being better able to phenotype patients to realize who would benefit from what treatment when. I think that would help us drastically, as opposed to relying on biomarkers of disease, biomarkers of the damage that's already been set, meaning estimated GFR slope and proteinuria. I'd like to be able to better phenotype my patients based on disease parameters that would tell me that this patient is high risk and would benefit from treatment X or Y, or would not benefit from treatment X or Y. I think that is bound to happen over the next 5 to 10 years, and it will dramatically shift the way we treat and manage our patients.

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Rethinking IgA Nephropathy Risk and Treatment, With Ali Mehdi, MD, MEd