It is important to start by remembering that IgAN is a lifelong disease. The risk stratification of patients with IgAN is key to understanding what may happen in an individual patient during the 20 or 30 years after diagnosis. We have some predictive tools, but they are not perfect. And, when evaluating individual patient risk, both clinical and histological criteria should be considered. 

The International IgAN Prediction Tool is useful, but it only gives you a 5-year risk, and we do not have data on longer-term risk. The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) committee recommends the International IgAN Prediction Tool to risk stratify patients at the time of kidney biopsy. Unfortunately, the risk stratification tools that are currently in use do not tell us whether to treat or how best to treat—they only tell us who is at risk. It is then up to the clinician to incorporate all of the available information and decide whether the patient should be immunosuppressed, and, if so, what kind of immunosuppression they should receive. There is an unmet need for such tools that could inform us when and how to treat individual patients with IgAN, and hopefully this will be addressed in the future. 

Supportive care should be aggressively pursued because it is known to affect long-term outcomes. Blood pressure control is very important for all patients with IgAN. Angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors should be considered in all patients with IgAN with proteinuria greater than 0.5 g per day, irrespective of hypertension status. Proteinuria is currently the main surrogate marker for monitoring long-term disease progression. Unfortunately, there is no biomarker available yet for patients with IgAN that is both diagnostic and prognostic in terms of immune activity. Repeat renal biopsies may help reveal if the patient has progressive fibrosis and ongoing inflammatory activity, and I think that they are currently underutilized. 

IgAN is the most common cause of primary glomerular disease in the world and a very frequent cause of ESRD. We need to identify patients with IgAN earlier in the course of their disease, and we need a better set of therapies to stall or prevent the progression to ESRD.

As Dr Radhakrishnan noted, the approach to IgAN depends on the risk stratification of the patient. The International IgAN Prediction Tool score incorporates the patient's age, race, gender, proteinuria, kidney function, blood pressure, medications, and kidney biopsy findings to define the risk of progressive disease over the next 3 to 5 years. This score has not been validated in all parts of the world, and it requires a kidney biopsy within the last 2 years. Clinicians may have to rely on the most recent biopsy score, blood pressure, proteinuria, and kidney function, and then make a clinical judgment about the patient's risk. 

The 2021 KDIGO guidelines focus mainly on proteinuria. Patients with modest proteinuria (ie, <0.5 g/day) typically have a good long-term prognosis, with a lower rate of progression to kidney failure over 30 years. Patients with persistent proteinuria (ie, >1 g/day) despite lifestyle modifications and despite a more than 3-month attempt at maximizing renin-angiotensin-aldosterone system inhibition require additional therapy to prevent progression to dialysis. The rate of progression to dialysis in these patients is higher than in those without persistent proteinuria, and we need to do a better job preventing this progression. 

When the KDIGO guidelines were published, the risk-benefit ratio of corticosteroids was not clear enough across all patient populations to make a global recommendation, so clinicians were advised to make an individualized risk-benefit decision. Patients with no obvious contraindication may consider a course of corticosteroids, but there is an uncertain benefit and clear risk of harm. Further, because we do not have a definitive therapeutic recommendation with these guidelines, consideration of clinical trial participation is encouraged. The guidelines noted that there may be a rationale for the use of other approaches, which, at that time, included hydroxychloroquine and calcineurin, but there was not enough supportive evidence to make a definitive treatment recommendation. 

There is a certain cohort of patients with IgAN who actually do reasonably well with only supportive care, so it makes sense to start with this approach. In patients on supportive care who continue to have a certain degree of proteinuria, additional therapy will need to be considered. In prior days, clinicians were utilizing steroid therapy a lot more frequently than they are now; so, the current approach in patients with IgAN is to move them away from steroids and transition them to chronic therapy sooner. 

As Dr Lafayette noted, the KDIGO guidelines define those at high risk of progression to chronic kidney disease as patients who have a proteinuria level of 0.75 to 1 g per day despite receiving 90 days or more of optimized supportive care. The patients who meet this threshold should be evaluated for additional treatment, such as the addition of immunosuppressive therapy. There have been reasonable suggestions that, in such patients with IgAN, you probably want to begin treating the proteinuria a lot sooner and more aggressively. 

The real dilemma is that we are not really sure what to do next in patients with progressive IgAN, as it has not been made completely clear whether to consider a classic immunosuppressive therapy such as mycophenolate mofetil or some other approach. We still have a lot to learn about the pathologic mechanisms of IgAN and which targets will give us the most bang for our buck, so to speak. It may be somewhere in the complement cascade, but we still do not know. The pathology of IgAN has been described as the 4-hit hypothesis, which postulates that 4 separate pathophysiological processes are needed for IgAN to develop. I think that one of the largest unmet needs in IgAN is knowing which of those 4 hits to therapeutically target to safely and effectively slow disease progression.