Complement and Podocytopathies: Do We Have a New Biomarker?

Minimal change disease (MCD) is defined by the absence of visible glomerular lesions on light microscopy and effacement of foot processes on electron microscopy. MCD is the main cause of nephrotic syndrome (NS) in children (75-90%)1Eddy A.A. Symons J.M. Nephrotic syndrome in childhood.Lancet. 2003; 362: 629-639Abstract Full Text Full Text PDF PubMed Scopus (672) Google Scholar, with most cases responding to corticosteroid treatment; kidney biopsy is thus typically not performed in children with nephrotic syndrome unless steroid resistance is observed. However, MCD only explains 10-15% of NS in adults2Floege J. Amann K. Primary glomerulonephritides.Lancet. 2016; 387: 2036-2048Abstract Full Text Full Text PDF PubMed Google Scholar, who demonstrate higher incidence of steroid resistance or dependence and poorer kidney survival. In contrast to MCD, focal segmental glomerulosclerosis (FSGS) shows segmental solidification of the glomerular tuft. Its prevalence and incidence are difficult to approximate, but FSGS seems to be increasing worldwide and is a major contributor to end-stage kidney disease (ESKD)3Rosenberg Avi Z. Kopp Jeffrey B. Focal Segmental Glomerulosclerosis.Clinical Journal of the American Society of Nephrology. 2017; 12: 502-517Crossref PubMed Scopus (0) Google Scholar. Plasma factors, adaptive changes, genetic predisposition, infections, and drugs, among others, have been linked to the development of various forms of FSGS. Treatment guidance and prognostic insights in FSGS rely on integration of findings from clinical history, kidney biopsy, laboratory values, and, increasingly, genetic testing. Both MCD and FSGS are histological lesions in the broad spectrum of podocytopathies. However, in these morphologic descriptions the podocyte injury can be caused by multiple pathological pathways4Wooin Ahn, Andrew S. Bomback. Approach to Diagnosis and Management of Primary Glomerular Diseases Due to Podocytopathies in Adults: Core Curriculum 2020. American Journal of Kidney Disease 2020;75(6):955-964.Google Scholar (Figure 1). Moving forward from histological description to an etiologic classification would offer clear benefits, not only at the diagnostic level, but especially in therapeutic management and long-term prognosis improvement. The development of biomarkers with high sensitivity and specificity to discriminate the different pathogeneses of podocytopathies therefore remains a holy grail. Uncontrolled complement activation can cause or contribute to glomerular injury in multiple kidney diseases like atypical hemolytic uremic syndrome or C3 glomerulopathy, with clear therapeutic implications. However, in MCD and FSGS, complement-level data from studies analyzing plasma, urine, and kidney biopsies, both in patients and animal models5Han R. Hu S. Qin W. et al.C3a and suPAR drive versican V1 expression in tubular cells of focal segmental glomerulosclerosis.JCI Insight. 2019; 4e122912Crossref Scopus (3) Google Scholar,6Trachtman H. Laskowski J. Lee C. et al.Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome.Am J Physiol Renal Physiol. 2021; 321: F505-f516Crossref Scopus (11) Google Scholar, is limited and can be confounded by other phenotypic variation (infections, drugs, etc). In this issue, Cambier et al.7Alexandra Cambier, Natacha Patey, Virginie Royal et al. Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease: a Prospective study. Kidney International Reports – In press.Google Scholar analyzed urinary terminal complement components - membrane attack complex (MAC, C5b-9), cytolytic effectors of innate and adaptative immunity, and C5a, a potent anaphylatoxin and chemotactic agent - as potential biomarkers for different podocytopathies. Fifty-six subjects with biopsy proven MCD (n=15) or FSGS (n=41) and proteinuria > 1 g/g creatinine were recruited in 4 Canadian hospitals from 2006 to 2023. Compared to FSGS, MCD patients were younger at the time of urinary sampling (33±22 vs 48±19 years, p=0.02), with higher eGFR (99±32 vs 53±37 mL/min/1.73m2Floege J. Amann K. Primary glomerulonephritides.Lancet. 2016; 387: 2036-2048Abstract Full Text Full Text PDF PubMed Google Scholar, p<0.001), lower albuminemia (22±9 vs 31±10 g/L, p=0.002), and lower proteinuria (3.1 vs 5.1 g/g, p=0.40). FSGS patients were classified as primary disease in up to 58% of cases (24/41); 2 were drug-induced, 1 genetic, 1 maladaptive (previous different GN), and 13 uncertain cause. All MCD subjects achieved complete remission with preserved kidney function, while only 25/41 (60.9%) FSGS subjects experienced partial remission (with frequent relapses) and 15/41 developed kidney failure. Kidney biopsies were reviewed by a blinded nephropathologist within a median of 2 (0-18) months from urinary sampling. Five subjects with glomeruli showing only adhesions but no evidence of segmental sclerosis were classified as a “potential FSGS.” In addition, histology also evaluated interstitial fibrosis and tubular atrophy (IFTA), arteriosclerosis and arteriolar hyalinosis (scaled 0 to 3+), and foot process effacement (FPE) by EM (diffuse ≥ 75% versus segmental < 75%). In the analysis of complement factors, FSGS subjects presented higher urinary MAC (C5b-9) levels (8.7 μg/mmol of creatinine) than MCD cases (0.8 μg/mmol of creatinine; p <0.001). Likewise, higher levels of MAC were found in primary FSGS (12.5 μg/mmol of creatinine) compared to those considered secondary or of undetermined cause (4.8 μg/mmol of creatinine), although the difference was not statistically significant (p=0.09). Urinary MAC threshold > 2 μg/mmol of creatinine in the entire cohort was 73% sensitive and 93% specific for FSGS, increasing its sensitivity up to 93% in cases with proteinuria ≥ 3g/g creatinine. FSGS patients also showed significantly higher urinary levels of C5a (1.26 μg/mmol of creatinine) compared to MCD patients (0.06 μg/mmol of creatinine; p<0.001), with high sensitivity and specificity. Cambier et al.7Alexandra Cambier, Natacha Patey, Virginie Royal et al. Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease: a Prospective study. Kidney International Reports – In press.Google Scholar propose these results support a role of complement activation in the pathogenesis of FSGS and, consequently, a potential therapeutic intervention. The search for pathophysiological mechanisms and new therapeutic targets in diseases without specific treatments is undoubtedly a crucial driving force for investigations like theirs. However, enthusiasm should not outweigh caution. First, in the present cohort, the FSGS population is significantly older, and many patients already had advanced chronic kidney disease (CKD: 5 patients stage G3a; 15 patients stage G3b; 7 patients stage G4; and 3 patients stage G5) compared to MCD subjects. Additionally, in the FSGS group, several patients had borderline or normal albuminemia, proteinuria less than 3 g/g creatinine, and higher histological chronicity findings (IFTA, arteriosclerosis and arteriolar hyalinosis) than MCD patients (11/15 showed no chronic changes). Furthermore, the patients with secondary FSGS had higher urinary complement component levels than MCD cases. Do terminal complement components in the urine reflect the activity of FSGS lesions or are they just reflective of the severity and chronicity of kidney injury? To reduce these confounding factors, investigations like this should aim to study populations with FSGS and MCD balanced by age and kidney function. In this observational study7Alexandra Cambier, Natacha Patey, Virginie Royal et al. Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease: a Prospective study. Kidney International Reports – In press.Google Scholar, the authors reported no urinary complement activation in MCD subjects. However, previous studies6Trachtman H. Laskowski J. Lee C. et al.Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome.Am J Physiol Renal Physiol. 2021; 321: F505-f516Crossref Scopus (11) Google Scholar showed an increase in blood and urinary C4a levels in patients with nephrotic syndrome compared to healthy controls (with no differences between patients with MCD and FSGS). Urinary C5b-9 levels were higher in patients with nephrotic syndrome (part of NEPTUNE cohort) and trended higher in 15 pediatric patients with idiopathic nephrotic syndrome (validation cohort). These prior studies8Yoshiki Morita, Hiroshi Ikeguchi Jiro Nakamura, et al. Complement activation products in the urine from proteinuric patients. J Am Soc Nephrol 2000;11(4):700-707.Google Scholar suggest that the degree of urinary complement fragments could be a nonspecific result of plasma complement proteins spilling into the urinary space and may be influenced by impairment of kidney function, level of proteinuria, and metabolic acidosis. Complement activation frequently occurs in physiological situations, is not harmful in all conditions, and is most frequently self-limiting. A study of a larger cohort of patients, with inclusion of patients with different clinical presentations (steroid-resistant and steroid-responsive nephrotic syndrome) and degrees of kidney damage, alongside inclusion of a control group, would allow a better assessment of the potential role of complement activation in the podocytopathies. Because glomerular diseases are dynamic processes, the time between biopsy and urinary complement components collection should be as short as possible when evaluating the possible correlation between histology and biomarkers. Finally, a prospective study of the evolution of complement-level biomarkers, reflecting the patient's clinical parameters and treatments received, could allow greater opportunities to evaluate a biomarker's ability to predict outcome. The search for new biomarkers in podocytopathies is crucial and will offer better pathophysiological knowledge of these entities and improvements in the diagnostic process that, hopefully, allow the development of novel therapeutic targets to improve kidney outcomes. The work by Cambier et al.7Alexandra Cambier, Natacha Patey, Virginie Royal et al. Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease: a Prospective study. Kidney International Reports – In press.Google Scholar is a valuable contribution to this field in promoting the hypothesis that complement is implicated in FSGS development. Nevertheless, more studies are necessary in a broader population of podocytopathy patients, at varying time points of the disease course, before we can move beyond interesting studies like this towards therapeutic trials of complement-targeting therapies. Download .pdf (.09 MB) Help with pdf files A Prospective Study on Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change DiseaseKidney International ReportsPreviewMinimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are related podocytopathies with distinct kidney outcomes. Surprisingly, elevated urinary activation fragments have been found in FSGS despite little complement deposition on immunofluorescence (IF) staining. Whether complement activation distinguishes FSGS from MCD, participating in the development of segmental lesions, remains unknown. Full-Text PDF Open Access

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