Pathologically, the main predictor of disease progression is advanced sclerosis on biopsy. Severe tubulointerstitial disease is the strongest predictor, followed by significant glomerulosclerosis. Clinically, the strongest predictors of progression are a reduced glomerular filtration rate, high levels of proteinuria, and hypertension. At least for now, proteinuria is the modifiable risk factor and biomarker to follow and target for patients with IgAN and C3G until better biomarkers are available.

IgAN is the most common cause of primary glomerular disease in the world, and it is still a very frequent cause of end-stage kidney disease. We have gotten better at risk stratification, but there is still room for improvement. The International IgAN Prediction Tool score incorporates the patient's age, race, gender, proteinuria, kidney function, blood pressure, medications, and recent kidney biopsy to try to define the risk of progressive disease over the next 3 to 5 years. Limitations include that it has not been validated worldwide (or in children) and that it requires a recent kidney biopsy, although the updated prediction tool can be used for risk stratification 1 or 2 year(s) post biopsy. 

In practice, clinicians often need to make a judgment about a patient’s risk based on their general profile, including their most recent biopsy score, blood pressure, proteinuria, and kidney function. As such, the 2021 Kidney Disease: Improving Global Outcomes guidelines emphasize proteinuria, where patients with normal kidney function, relatively mild to moderate findings of inflammation or scar on biopsy, and modest proteinuria (ie, <0.5 g/day) typically have good long-term prognoses, with lower rates of progression to kidney failure. Monitoring is required for this group of patients, despite their low-risk status. An emphasis on maintaining a healthy lifestyle, avoiding tobacco, and making sure that they do not develop hypertension is a reasonable initial approach for healthy patients in this group. Renin-angiotensin-aldosterone system inhibition to reduce the level of proteinuria may be considered, as these patients may do well without additional medical treatment.

In contrast, individuals with persistent proteinuria (eg, >0.5-1 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 the rate in those without persistent proteinuria, and we need to do a better job preventing this progression. 

As in patients with IgAN, the presence of active inflammation and kidney scarring can indicate a worse prognosis and an increased risk of progression to severe kidney disease in individuals with C3G. Hematuria and proteinuria develop when there is injury to the mesangium and to the downstream podocytes that are responsible for preventing proteinuria. Inflammation in the tubules leads to tubular injury and scarring, and eventually you get glomerular scarring, tubular interstitial scarring, loss of kidney structure, and loss of kidney function.

While proteinuria and glomerular inflammation both offer prognostic information, we would like to develop better biomarkers. Glomerular inflammation is not inherently a poor biomarker, but kidney biopsy and hematuria are presently our main ways of observing it, and the laboratories do not have a very reliable way to standardize hematuria results across patients. And so, although hematuria is probably an important prognostic biomarker, it is a difficult biomarker to standardize and incorporate into clinical studies.