Persistent Isolated C3 Hypocomplementemia as a Strong Predictor of End-Stage Kidney Disease in Lupus Nephritis

Giovanni Maria Rossi, Umberto Maggiore, Francesco Peyronel, Paride Fenaroli, Marco Delsante, Giuseppe Daniele Benigno, Davide Gianfreda, Maria Letizia Urban, Zerai Manna, Lois Johanna Arend, Serena Bagnasco, Augusto Vaglio, Enrico Fiaccadori, Avi Z. Rosenberg, Sarfaraz Hasni, Lucio Manenti

Research output: Contribution to journalArticlepeer-review


Introduction: Proliferative lupus nephritis (LN) progresses to end-stage kidney disease (ESKD) in roughly 10% of the cases despite treatment. Other than achieving <0.8 g/24h proteinuria at 12 months after treatment, early biomarkers predicting ESKD or death are lacking. Recent studies encompassing not only LN have highlighted the central role of the alternative complement pathway (ACP), with or without histological evidence of thrombotic microangiopathy (TMA), as a key promotor of renal death. Methods: We assessed whether persistent isolated C3 hypocomplementemia (PI-LowC3), that is not accompanied by C4 hypocomplementemia, 6 months after kidney biopsy, is associated with an increased risk of death or ESKD in proliferative LN. Results: We retrospectively followed-up 197 patients with proliferative LN (51 with PI-LowC3) for a median of 4.5 years (interquartile-range: 1.9−9.0), 11 of whom died and 22 reached ESKD. After adjusting for age, gender, ethnicity, hypertension, mycophenolate, or cyclophosphamide use, PI-LowC3 was associated with a hazard ratio [HR] of the composite outcome ESKD or death of 2.46 (95% confidence interval [CI]: 1.22−4.99, P = 0.012). These results were confirmed even after controlling for time-varying estimated glomerular filtration rate (eGFR) measurements in joint longitudinal-survival multiple regression models. After accounting for the competing risk of death, PI-LowC3 patients showed a strikingly increased risk of ESKD (adjusted HR 3.41, 95% CI: 1.31−8.88, P = 0.012). Conclusion: Our findings support the use of PI-LowC3 as a low-cost readily available biomarker, allowing clinicians to modify treatment strategies early in the course of disease and offering a rationale for complement blockade trials in this particularly at-risk subgroup of LN patients.

Original languageEnglish (US)
Pages (from-to)2647-2656
Number of pages10
JournalKidney International Reports
Issue number12
StatePublished - Dec 2022


  • ESKD
  • complement system
  • glomerular disease
  • lupus nephritis
  • renal pathology
  • thrombotic microangiopathy

ASJC Scopus subject areas

  • Nephrology


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