Understanding the ‘C3’ in C3G: Your Guide to Monitoring Complement Activity

Closely monitoring lab results allows your providers to move from reactive treatment to proactive management: Rather than trying to fix problems after they happen, lab results can  help you anticipate and prevent them. Lab reports show an evaluation of “complement biomarkers,” and can be used to create a roadmap for disease activity, treatment efficacy, and clinical trial opportunities.

C3 and C4

The complement system’s major functions are to identify and eliminate foreign materials, and promote inflammatory and immune responses to those targets, explains Rossana Malatesta Muncher, MD, a pediatric nephrologist at Texas Children's and an assistant professor at Baylor College of Medicine in Houston. “Sometimes these proinflammatory processes will target host tissues,” she says. “So when C3 is low, we know it is being consumed somewhere and when put in the right clinical context and using confirmatory testing, we can get to the right diagnosis. Low C3 can be seen in infections, angioedema, inflammatory, and autoimmune conditions.”

In C3G, levels of C4 are usually normal because it’s part of a different pathway. “C3 is on the alternative pathway and C4 is on the classic pathway,” says Dr. Malatesta Muncher. “Other complements like C1, C2, and C4 on the classic pathway are also not affected by C3G but are affected with other disease processes. Laboratory testing along with a kidney biopsy will help differentiate among the many different renal conditions.”

Serum Membrane Attack Complex (sMAC)

This level might be measured as part of a broader testing panel, but, according to Marc Richards, MD, a nephrologist and the director of the Florida Kidney Physicians Glomerulonephritis Center of Excellence in Boca Raton, sMAC testing takes a specialized lab and it’s unclear what it means for the severity of the disease.

“As complement activation occurs in the kidney, it disrupts the structure of the glomerular basement membrane of the kidney’s filter, allowing for protein in the blood to leak into the urine,” says Neil Agarwal, MD, a nephrologist and an assistant professor of medicine at the University of Maryland School of Medicine in Baltimore. “A higher protein-to-creatinine ratio is suggestive of more disease activity and damage to the kidneys, allowing for larger amounts of protein leakage into the urine.”

The uPCR is calculated by comparing the amounts of protein and creatinine (a waste product from muscle cells) in your urine. Because your body processes creatinine at a steady rate, its measurement is included to account for differences in urine concentration.

“Urine protein to creatinine is an easy way to quantify how much protein the patient has in the urine and therefore disease progress,” says Malatesta Muncher. “This is done with the urine sample that is given at your nephrologist visit and does not need a 24-hour collection, which is challenging for some people.”

The uPCR can be regarded as a "dashboard" for monitoring kidney damage, as it serves as a real-time monitor of kidney health.

Biomarkers are important for making an initial diagnosis, predicting progression, and monitoring response to treatment.

“Measuring complement levels such as C3 and C4 is a mainstay of the diagnostic approach to patients with proteinuria or hematuria, especially in the absence of underlying diabetes,” says Dr. Richards. “A deficiency in C3 or C4 along with proteinuria could make it likely that one has underlying C3G or IC-MPGN, in which case a kidney biopsy would be necessary for diagnosis.”

He points out that tracking creatinine, proteinuria, and complement levels is the most straightforward way to tell how well a particular treatment is working. “In some circumstances, assessing specific levels of compounds or genetic defects affecting regulation of the complement cascade is necessary and can be trended over time,” he says.

Patients with elevated urine protein levels are at increased risk for progression to kidney failure. “Medications are intended to reduce urinary protein levels to aid in preserving renal function,” says Dr. Agarwal. “Those with significantly elevated protein levels may benefit from newer medications such as pegcetacoplan and iptacopan, to try and preserve renal function in the long term.”

He notes that among adults with C3G, low C3 levels have been associated with worse outcomes. “Improvement in C3 levels with treatment in individuals who have low serum C3 levels at diagnosis may indicate treatment response,” Agarwal says. “However, patients with normal serum C3 levels can still have C3G activity.”

Ongoing research and clinical trials are evaluating new medications that may improve care for C3G and IC-MPGN. Complement levels and other biomarkers play a role in whether you can take part.

• While a kidney biopsy is generally needed to confirm a diagnosis of C3G or IC-MPGN, routine lab tests provide a "real-time" look at how the disease is behaving day-to-day.
• C3 is an immune system protein that’s broken down quickly in C3G; when you have the disease, your level is usually, but not always, low.
• Protein in your urine is the most direct indicator that your kidney’s filters are being damaged by immune system overactivity.