The current approaches to CMKDs such as C3G and immunoglobulin A nephropathy (IgAN) are outlined in the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 "Clinical Practice Guideline for the Management of Glomerular Diseases." Optimal treatment strategies using currently available therapeutics have not been established for either C3G or IgAN, and that is the common background from which the 2021 treatment recommendations were developed.

The recommended approaches for C3G and IgAN in patients with stable disease are largely based on risk stratification and response to initial supportive care measures. For those without acute kidney injury or rapidly progressive disease, the usual optimized supportive care measures are generally recommended and include angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, whereas the escalation to immunosuppressive therapy is recommended in higher-risk scenarios. 

For example, the KDIGO guidelines state that patients with C3G and excessive proteinuria may be candidates for mycophenolate mofetil (MMF) and steroids, an opinion that was based on 4 retrospective cohorts and on an extrapolation of data from other nonrelated proliferative glomerulonephritides. We do not know why MMF is effective in some patients with C3G. It is not an anticomplement therapy, but it does appear to be efficacious in a subset of patients. Nonetheless, because its efficacy is variable, it would not be unusual for a trial of 6 months of therapy to result in no improvement. 

Terminal complement blockade with the anti–complement 5 monoclonal antibody eculizumab might also be considered, but this agent has not been proven to be more effective than MMF with steroids for C3G. Whether you consider MMF with steroids or eculizumab, C3G is a very heterogeneous disorder, and nonresponse is a distinct possibility, which underscores the important role of clinical trials. For this reason, we encourage most patients to enroll in a clinical trial if they are eligible. For C3G, we would be interested in protocols exploring the use of alternative pathway blockade.

An ongoing challenge in CMKDs is that we need better surrogate markers of renal function, prognosis, and response to treatment. Serum creatinine levels provide only an estimate of renal function, and it takes time for that estimate to change. If you are measuring glomerular filtration rate, you may observe the rate declining in real time. Further, many patients with C3G are young and have otherwise healthy kidneys because they have not had hypertension, diabetes, or other chronic disorders. These individuals may have compensatory hyperfiltration, which can bring creatinine levels back into the normal range very easily, escaping detection. Many of these patients remain undiagnosed until significant damage has already occurred.

The natural history of C3G is slowly being defined, and we have struggled with case definitions and disease heterogeneity; however, the progression to end-stage renal disease has been reported in up to 50% of patients within the first 5 years of diagnosis. It is often assumed that C3G will be aggressive in those who have it and that it will ultimately, perhaps, require dialysis and transplantation. Thus, there is great interest in novel therapies and in clinical trials. For C3G, we would be particularly interested in alternative complement pathway inhibition of some kind.