Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference
Authors: Brad H. Rovin, Dawn J. Caster, Daniel C. Cattran, Keisha L. Gibson, Jonathan J. Hogan, Marcus J. Moeller, Dario Roccatello, Michael Cheung, David C. Wheeler, Wolfgang C. Winkelmayer, Jürgen Floege, Sharon G. Adler, Charles E. Alpers, Isabelle Ayoub, Arvind Bagga, Sean J. Barbour, Jonathan Barratt, Daniel T.M. Chan, Anthony Chang, Jason Chon Jun Choo, H. Terence Cook, Rosanna Coppo, Fernando C. Fervenza, Agnes B. Fogo, Jonathan G. Fox, Richard J. Glassock, David Harris, Elisabeth M. Hodson, Jonathan J. Hogan, Elion Hoxha, Kunitoshi Iseki, J. Charles Jennette, Vivekanand Jha, David W. Johnson, Shinya Kaname, Ritsuko Katafuchi, A. Richard Kitching, Richard A. Lafayette, Philip K.T. Li, Adrian Liew, Jicheng Lv, Ana Malvar, Shoichi Maruyama, Juan Manuel Mejía-Vilet, Chi Chiu Mok, Patrick H. Nachman, Carla M. Nester, Eisei Noiri, Michelle M. O'Shaughnessy, Seza Özen, Samir M. Parikh, Hyeong-Cheon Park, Chen Au Peh, William F. Pendergraft, Matthew C. Pickering, Evangéline Pillebout, Jai Radhakrishnan, Manish Rathi, Pierre Ronco, William E. Smoyer, Sydney C.W. Tang, Vladimír Tesař, Joshua M. Thurman, Hernán Trimarchi, Marina Vivarelli, Giles D. Walters, Angela Yee-Moon Wang, Scott E. Wenderfer, Jack F.M. Wetzels
Journal: Kidney International (2019)

In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a diverse panel of experts in glomerular diseases together to discuss the 2012 KDIGO glomerulonephritis guideline in the context of new developments and insights that had occurred over the years since its publication. During this KDIGO Controversies Conference on Glomerular Diseases, the group examined data on disease pathogenesis, biomarkers, and treatments to identify areas of consensus and areas of controversy. This report summarizes the discussions on primary podocytopathies, lupus nephritis, anti-neutrophil cytoplasmic antibody–associated nephritis, complement-mediated kidney diseases, and monoclonal gammopathies of renal significance. In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a diverse panel of experts in glomerular diseases together to discuss the 2012 KDIGO glomerulonephritis guideline in the context of new developments and insights that had occurred over the years since its publication. During this KDIGO Controversies Conference on Glomerular Diseases, the group examined data on disease pathogenesis, biomarkers, and treatments to identify areas of consensus and areas of controversy. This report summarizes the discussions on primary podocytopathies, lupus nephritis, anti-neutrophil cytoplasmic antibody–associated nephritis, complement-mediated kidney diseases, and monoclonal gammopathies of renal significance. The Kidney Disease: Improving Global Outcomes (KDIGO) initiative published its first ever guideline on glomerular diseases in 2012.1Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO clinical practice guideline for glomerulonephritis.Kidney Int Suppl. 2012; 2: 139-274Google Scholar Since then our understanding of the pathogenesis of glomerular diseases has markedly advanced, new diagnostic biomarkers have entered the clinical arena, and many new therapies have been assessed in clinical trials. Therefore, a conference consisting of about 100 experts from various disciplines (nephrology, pathology, rheumatology, pediatrics) and organizations (academia, pharmaceutical industry) was convened on November 17–19, 2017. The goals were to evaluate the progress that has been made in the evaluation and management of glomerular diseases, assess continuing gaps in knowledge, and identify the existing guideline recommendations that should be revisited in the next update. The attendees were especially encouraged to outline the most controversial aspects of glomerular diseases. This second of 2 reports covers the primary podocytopathies, complement-mediated glomerular diseases, lupus nephritis (LN), anti-neutrophil cytoplasmic antibody (ANCA)-associated nephritis, and monoclonal gammopathies of renal significance. Each disease-specific working group was asked to consider disease terminology, pathogenesis, biomarkers, treatment, and recommendations for future studies. Taken together, these 2 conference summaries will lay the basis for the guideline updating process that began in August 2018. The terms "minimal change disease" (MCD) and "focal segmental glomerulosclerosis" (FSGS) remain relevant. Although there may be pathophysiologic overlap between MCD and FSGS, the presence of focal and segmental sclerosis by light microscopy has diagnostic and prognostic importance. To discriminate between MCD and FSGS by kidney biopsy, at least 20 glomeruli are needed, and biopsies performed soon after diagnosis may only show MCD, but the patients may later develop FSGS.2Corwin H.L. Schwartz M.M. Lewis E.J. The importance of sample size in the interpretation of the renal biopsy.Am J Nephrol. 1988; 8: 85-89Google Scholar However, in children, kidney biopsy is not usually performed in patients that respond to prednisone treatment. Response to prednisone treatment and timing of relapses allows classification of childhood nephrotic syndrome.3Vivarelli M. Massella L. Ruggiero B. et al.Minimal change disease.Clin J Am Soc Nephrol. 2017; 12: 332-345Google Scholar There was consensus that the designations "steroid-sensitive" and "steroid-resistant" nephrotic syndrome are clinically useful disease descriptions in children and that most steroid-sensitive idiopathic nephrotic syndromes in children are MCD. Response to therapy is often of more prognostic value than biopsy histology. The terms "primary/idiopathic FSGS" should be reserved for FSGS caused by as yet unknown permeability factors. Patients with genetic, adaptive (in the setting of reduced nephron mass), drug-induced, and viral-induced FSGS should not be designated as primary.4Rosenberg A.Z. Kopp J.B. Focal segmental glomerulosclerosis.Clin J Am Soc Nephrol. 2017; 12: 502-517Google Scholar Primary FSGS is often characterized by acute-onset heavy proteinuria and diffuse podocyte foot process effacement histologically. Other FSGS subtypes typically show more modest proteinuria and segmental foot process effacement.5De Vriese A.S. Sethi S. Nath K.A. et al.Differentiating primary, genetic, and secondary FSGS in adults: a clinicopathologic approach.J Am Soc Nephrol. 2018; 29: 759-774Crossref Scopus (127) Google Scholar Further efforts are warranted to better define these FSGS subgroups in the context of their presumed pathogenesis. A role for dysfunctional T cells in MCD was proposed over 40 years ago.6Shalhoub R.J. Pathogenesis of lipoid nephrosis: a disorder of T-cell function.Lancet. 1974; 2: 556-560Google Scholar More recently, a role for B cells has become evident, supported by efficacy of immunoadsorption and B-cell depletion in inducing remission.3Vivarelli M. Massella L. Ruggiero B. et al.Minimal change disease.Clin J Am Soc Nephrol. 2017; 12: 332-345Google Scholar Thus far none of the reported circulating permeability factor candidates have been independently validated in primary FSGS.7Maas R.J. Deegens J.K. Wetzels J.F. Permeability factors in idiopathic nephrotic syndrome: historical perspectives and lessons for the future.Nephrol Dial Transplant. 2014; 29: 2207-2216Google Scholar Soluble urokinase-type plasminogen activator receptor may be a novel prognostic biomarker for chronic kidney disease, but does not appear to have a role as a diagnostic biomarker or to represent the permeability factor in FSGS.8Hayek S.S. Sever S. Ko Y.A. et al.Soluble urokinase receptor and chronic kidney disease.N Engl J Med. 2015; 373: 1916-1925Google Scholar Cardiotrophin-like cytokine-1, a member of the interleukin 6 cytokine family, may be a candidate FSGS permeability factor. Cardiotrophin-like cytokine-1 has been identified in the plasma of patients with FSGS and has been found to decrease nephrin expression in podocyte culture. In patients with recurrent FSGS, its concentration may be up to 100 times that of normal subjects. Angiopoietin-like-4, a secreted glycoprotein, is highly upregulated in the serum and in podocytes in experimental models of MCD and in the human disease. This biomarker has relevant potential in patients with steroid-sensitive nephrotic syndrome.9Clement L.C. Avila-Casado C. Mace C. et al.Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome.Nat Med. 2011; 17: 117-122Google Scholar, 10McCarthy E.T. Sharma M. Savin V.J. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis.Clin J Am Soc Nephrol. 2010; 5: 2115-2121Google Scholar It has been suggested that MCD/FSGS may be mediated by podocyte CD80 (B7-1) expression induced after an innocuous event such as an infection.11Shin J.I. Kronbichler A. Rituximab for patients with nephrotic syndrome.Lancet. 2015; 385: 225-226Google Scholar However, CD80 overexpression on podocytes could not be confirmed.12Novelli R. Gagliardini E. Ruggiero B. et al.Any value of podocyte B7-1 as a biomarker in human MCD and FSGS?.Am J Physiol Renal Physiol. 2016; 310: F335-F341Scopus (32) Google Scholar A role for glomerular parietal epithelial cells in the pathogenesis of virtually all histological types of FSGS lesions has also been proposed.13Shankland S.J. Smeets B. Pippin J.W. et al.The emergence of the glomerular parietal epithelial cell.Nat Rev Nephrol. 2014; 10: 158-173Google Scholar There are no validated biomarkers ready for clinical use in MCD or FSGS. The histological subtype of FSGS as defined by the Columbia classification14D'Agati V.D. Fogo A.B. Bruijn J.A. et al.Pathologic classification of focal segmental glomerulosclerosis: a working proposal.Am J Kidney Dis. 2004; 43: 368-382Google Scholar may support decision making and help with anticipating response to treatment and prognosis,15D'Agati V.D. Alster J.M. Jennette J.C. et al.Association of histologic variants in FSGS clinical trial with presenting features and outcomes.Clin J Am Soc Nephrol. 2013; 8: 399-406Google Scholar but it is not specific for underlying disease mechanisms. Immunostaining of kidney biopsy specimens for parietal epithelial cell activation markers may improve sensitivity for detecting sclerotic lesions when distinguishing primary FSGS from MCD.16Smeets B. Stucker F. Wetzels J. et al.Detection of activated parietal epithelial cells on the glomerular tuft distinguishes early focal segmental glomerulosclerosis from minimal change disease.Am J Pathol. 2014; 184: 3239-3248Google Scholar Proteomic analysis of kidney biopsy specimens may provide additional insights. Genetic testing for pediatric nephrotic syndrome and adult FSGS is controversial, but it should be considered for patients with congenital and infantile forms of nephrotic syndrome (children <1 year of age) or less than 2 years of age with steroid-resistant nephrotic syndrome, nephrotic syndrome associated with other syndromic features, or familial forms of steroid-resistant nephrotic syndrome/FSGS.17Gbadegesin R.A. Winn M.P. Smoyer W.E. Genetic testing in nephrotic syndrome—challenges and opportunities.Nat Rev Nephrol. 2013; 9: 179-184Google Scholar, 18Lovric S. Ashraf S. Tan W. et al.Genetic testing in steroid-resistant nephrotic syndrome: when and how?.Nephrol Dial Transplant. 2016; 31: 1802-1813Google Scholar, 19Sadowski C.E. Lovric S. Ashraf S. et al.A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.J Am Soc Nephrol. 2015; 26: 1279-1289Google Scholar Adding to the controversy of when to perform genetic testing, single gene mutations have been found in up to 30% of patients under age 25.18Lovric S. Ashraf S. Tan W. et al.Genetic testing in steroid-resistant nephrotic syndrome: when and how?.Nephrol Dial Transplant. 2016; 31: 1802-1813Google Scholar Testing should target relevant genes based on patient characteristics and contemporary knowledge. The role of high-risk apolipoprotein L1 genotypes in the development of glomerulosclerosis is still under investigation and the conference attendees agreed that data are still insufficient to support using this information to guide clinical decisions. Genetic testing may be considered for inclusion and stratification in clinical trials. Biospecimens should routinely be collected, and patients consented for later genetic analysis. Ethical issues should be addressed before recommending genetic analyses. While immunomodulatory therapies are the first-line treatment in primary/idiopathic FSGS caused by a permeability factor, other FSGS subtypes respond better to blood pressure control and correction of abnormal glomerular hemodynamics, such as glomerular hypertension (e.g., in adaptive FSGS), or other specific interventions. The use of immunomodulatory therapy after causative FSGS mutations are identified is controversial. Rare reports of varying degrees of remission in these patients may or may not reflect the nonimmune modulating effects of these therapies.20Trautmann A. Schnaidt S. Lipska-Zietkiewicz B.S. et al.Long-term outcome of steroid-resistant nephrotic syndrome in children.J Am Soc Nephrol. 2017; 28: 3055-3065Google Scholar Following identification of causative mutations, treatment should include known directed therapies for specific mutations (e.g., coenzyme Q-10, vitamin B12 where applicable),18Lovric S. Ashraf S. Tan W. et al.Genetic testing in steroid-resistant nephrotic syndrome: when and how?.Nephrol Dial Transplant. 2016; 31: 1802-1813Google Scholar antiproteinuric therapy, and prompt discontinuation of immunosuppressive therapy in those with no early signal of response.21Trautmann A. Bodria M. Ozaltin F. et al.Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.Clin J Am Soc Nephrol. 2015; 10: 592-600Google Scholar Because ∼80% of children with incident nephrotic syndrome have MCD on biopsy and of the remaining patients, some will respond to corticosteroid therapy, the conference attendees agreed that there are no data to challenge the practice of treating all pediatric nephrotic patients with corticosteroids first, except those younger than 9 to 10 months of age. Due to the increased incidence of steroid-resistant nephrotic syndrome and FSGS with age, consideration to biopsy children older than 12 years prior to treatment is recommended. In children with steroid-sensitive nephrotic syndrome, recent data from randomized controlled trials do not support steroid exposure beyond 8 to 12 weeks.22Teeninga N. Kist-van Holthe J.E. van Rijswijk N. et al.Extending prednisolone treatment does not reduce relapses in childhood nephrotic syndrome.J Am Soc Nephrol. 2013; 24: 149-159Google Scholar, 23Sinha A. Saha A. Kumar M. et al.Extending initial prednisolone treatment in a randomized control trial from 3 to 6 months did not significantly influence the course of illness in children with steroid-sensitive nephrotic syndrome.Kidney Int. 2015; 87: 217-224Google Scholar, 24Yoshikawa N. Nakanishi K. Sako M. et al.A multicenter randomized trial indicates initial prednisolone treatment for childhood nephrotic syndrome for two months is not inferior to six-month treatment.Kidney Int. 2015; 87: 225-232Google Scholar Controversies remain about the minimum duration of corticosteroid therapy required to define steroid resistance. The 2012 KDIGO guideline recommended at least 8 weeks of corticosteroids in children before defining steroid resistance. While consensus was not reached, the need for a globally accepted definition of "steroid resistance" to improve comparability of future clinical trials was recognized. The efficacy of low-dose daily corticosteroids over alternate day dosing for maintaining remission in relapsing nephrotic syndrome is promising.25Yadav M. Sinha A. Hari P. Bagga A. Efficacy of low-dose daily versus alternate day prednisone in children with frequently relapsing nephrotic syndrome (FRNS): open-label randomized controlled trial (RCT). Abstract FP-S25-09.Pediatr Nephrol. 2016; 31: 1752Google Scholar Therapy with alternative immunosuppressive agents should be considered in children with frequently relapsing nephrotic syndrome. While data support the use of cyclophosphamide (CYC), levamisole, mycophenolate mofetil (MMF), calcineurin inhibitors (CNIs), and rituximab (RTX), the precise order of therapy is not well determined.26Iijima K. Sako M. Nozu K. et al.Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial.Lancet. 2014; 384: 1273-1281Google Scholar Data are emerging to support an early role of RTX in the management of children with steroid-dependent nephrotic syndrome. A direct action of RTX on podocytes was not confirmed, supporting B-cell depletion as RTX's primary mechanism of action.27Kim A.H. Chung J.J. Akilesh S. et al.B cell-derived IL-4 acts on podocytes to induce proteinuria and foot process effacement.JCI Insight. 2017; 2 (pii:81836)Google Scholar Post hoc analyses suggest that targeting higher area under the serum/plasma concentration-time curves for MMF could result in similar numbers of children maintaining remission with MMF as with CNIs, but this needs to be confirmed in randomized controlled trials.28Gellermann J. Weber L. Pape L. et al.Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome.J Am Soc Nephrol. 2013; 24: 1689-1697Google Scholar Nephrotic patients have a high risk of infection regardless of immunosuppression. The 2012 KDIGO guideline provides some recommendations regarding vaccinations in children but does not highlight the importance of hepatitis B screening and vaccination, especially in those receiving B-cell depleting therapies.29Masse V. Al Jijakli A. Genet P. et al.Screening and management of hepatitis B virus before the first rituximab infusion: We must do better!.Blood. 2014; 124 (Available at:): 2754http://www.bloodjournal.org/content/124/21/2754Date accessed: March 15, 2018Google Scholar Vaccination against meningococci should also be included as based on expert opinion. In adults, recommending a minimum duration of 16 weeks of high-dose corticosteroids as first-line therapy for FSGS or MCD was felt to be controversial, given its potential for toxicity. However, data to support alternative first-line agents or combination therapies with lower doses of corticosteroids are insufficient. The conference attendees agreed that CNIs or CYC should remain as second-line agents in adults with frequently relapsing or steroid-dependent MCD. RTX is an emerging second-line therapy in MCD in adults although evidence is observational only. The recommendation for CNIs and MMF as second- and third-line treatments, respectively, for FSGS should be maintained. Randomized controlled trials are underway to investigate the value of RTX in adult MCD (Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome; NCT03298698) and the CD80 inhibitor abatacept, regardless of CD80 expression on podocytes, in MCD and FSGS (Pilot Study to Evaluate the Safety and Efficacy of Abatacept in Adults and Children 6 Years and Older With Excessive Loss of Protein in the Urine Due to Either Focal Segmental Glomerulosclerosis or Minimal Change Disease; NCT02592798). It will be important to distinguish between primary and secondary FSGS for clinical trials and include only those patients for which an investigational therapy may be effective. Immunologic therapies should focus on primary FSGS; antifibrotic therapies could recruit all forms of FSGS. Recommendations from the 2012 guideline that should be revisited are outlined in Supplementary Table S1. While the term "membranoproliferative" glomerulonephritis (GN) retains value as a histologic descriptor of glomerular injury, our increasing understanding of C3 glomerulopathy (C3G) and the monoclonal gammopathies of renal significance (MGRS) (paraprotein-associated kidney diseases) illustrate the need for nomenclature based on pathogenesis and injury pattern. Additionally, the histology of these specific etiologies is not always membranoproliferative GN. Therefore, updated clinical practice guidelines should emphasize a diagnostic approach to GN that considers both pathobiology and renal histology, such as that outlined in Table 1.30Sethi S. Haas M. Markowitz G.S. et al.Mayo Clinic/Renal Pathology Society Consensus report on pathologic classification, diagnosis, and reporting of GN.J Am Soc Nephrol. 2016; 27: 1278-1287Google Scholar Over time, and with greater understanding of these diseases, using such a scheme may lead to the elimination of membranoproliferative GN as a distinct category of GN in clinical practice guidelines. The following discussion highlights controversies that exist within this framework, including the issue of overlapping disease mechanisms, the conundrum of common kidney biopsy features, and the inevitable fact that some cases will remain "idiopathic" in nature.31Fervenza F.C. Sethi S. Glassock R.J. Idiopathic membranoproliferative glomerulonephritis: does it exist?.Nephrol Dial Transplant. 2012; 27: 4288-4294Google ScholarTable 1A pathogenesis-based approach to glomerulonephritisAdapted from Sethi S, Haas M, Markowitz GS, et al. Mayo Clinic/Renal Pathology Society Consensus report on pathologic classification, diagnosis, and reporting of GN. J Am Soc Nephrol. 2016;27:1278–1287,30Sethi S. Haas M. Markowitz G.S. et al.Mayo Clinic/Renal Pathology Society Consensus report on pathologic classification, diagnosis, and reporting of GN.J Am Soc Nephrol. 2016; 27: 1278-1287Google Scholar with permission. Copyright © 2016 the American Society of Nephrology.Pathogenic typeDisease examplesImmune complex glomerulonephritisIgA nephropathyLupus nephritisFibrillary glomerulonephritis (polyclonal/DNAJB9-positive subtype)Infection-associated glomerulonephritisMixed (types II and III) cryoglobulinemic glomerulonephritisPauci-immune glomerulonephritisANCA-associated vasculitisANCA-negative pauci-immune glomerulonephritisAntiglomerular basement membrane glomerulonephritisAntiglomerular basement membrane diseaseMonoclonal Ig-associated glomerulonephritisMonoclonal Ig deposition disease (LCDD, HCDD, LHCDD)Proliferative glomerulonephritis with monoclonal Ig depositsMonoclonal (type I) cryoglobulinemic glomerulonephritisImmunotactoid glomerulopathyFibrillary glomerulonephritis (monoclonal subtype)Complement-mediated glomerulonephritisC3 glomerulonephritisDense deposit diseaseANCA, anti-neutrophil cytoplasmic antibody; DNAJB9, DNA J homolog subfamily B member 9; HCDD, heavy chain deposition disease; LCDD, light chain deposition disease; LHCDD, light and heavy chain deposition disease. Open table in a new tab ANCA, anti-neutrophil cytoplasmic antibody; DNAJB9, DNA J homolog subfamily B member 9; HCDD, heavy chain deposition disease; LCDD, light chain deposition disease; LHCDD, light and heavy chain deposition disease. The use of nonroutine histological techniques, including pronase to unmask hidden epitopes,32Nasr S.H. Galgano S.J. Markowitz G.S. et al.Immunofluorescence on pronase-digested paraffin sections: a valuable salvage technique for renal biopsies.Kidney Int. 2006; 70: 2148-2151Google Scholar, 33Larsen C.P. Ambuzs J.M. Bonsib S.M. et al.Membranous-like glomerulopathy with masked IgG kappa deposits.Kidney Int. 2014; 86: 154-161Google Scholar, 34Messias N.C. Walker P.D. Larsen C.P. Paraffin immunofluorescence in the renal pathology laboratory: more than a salvage technique.Mod Pathol. 2015; 28: 854-860Google Scholar, 35Larsen C.P. Messias N.C. Walker P.D. et al.Membranoproliferative glomerulonephritis with masked monotypic immunoglobulin deposits.Kidney Int. 2015; 88: 867-873Google Scholar C4d staining to distinguish C3G from Ig-mediated and postinfectious GN,36Sethi S. Nasr S.H. De Vriese A.S. et al.C4d as a diagnostic tool in proliferative GN.J Am Soc Nephrol. 2015; 26: 2852-2859Google Scholar and staining for the DNA J homolog subfamily B member 9 protein in fibrillary GN37Andeen N.K. Yang H.Y. Dai D.F. et al.DnaJ homolog subfamily B member 9 is a putative autoantigen in fibrillary GN.J Am Soc Nephrol. 2018; 29: 231-239Google Scholar, 38Dasari S. Alexander M.P. Vrana J.A. et al.DnaJ heat shock protein family B member 9 is a novel biomarker for fibrillary GN.J Am Soc Nephrol. 2018; 29: 51-56Google Scholar may also help in the diagnosis and possibly in understanding the pathogenesis of GN with an membranoproliferative glomerulonephritis pattern. Most of these techniques need additional verification. C3G is caused by abnormal complement activation, deposition and/or degradation. Drivers of disease are reviewed in recent consensus39Pickering M.C. D'Agati V.D. Nester C.M. et al.C3 glomerulopathy: consensus report.Kidney Int. 2013; 84: 1079-1089Google Scholar and KDIGO Controversies Conference reports.40Goodship T.H. Cook H.T. Fakhouri F. et al.Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.Kidney Int. 2017; 91: 539-551Google Scholar While it was generally agreed that human and animal data support the role of complement in well-described scenarios, as a matter of practicality it continues to be difficult to substantiate the causal role of either single nucleotide changes or C3 nephritic factors in the majority of cases.41Servais A. Noel L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Google Scholar, 42Iatropoulos P. Daina E. Curreri M. et al.Cluster analysis identifies distinct pathogenetic patterns in C3 glomerulopathies/immune complex-mediated membranoproliferative GN.J Am Soc Nephrol. 2018; 29: 283-294Google Scholar Furthermore, the interpretation of published data is confounded by heterogeneity in the kidney biopsy criteria used for diagnosis. Addressing these controversies is especially important given that targeted anticomplement agents are available. The role of biomarkers in the diagnosis and management of C3G has been summarized recently.40Goodship T.H. Cook H.T. Fakhouri F. et al.Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.Kidney Int. 2017; 91: 539-551Google Scholar The utility of biomarkers such as soluble C5b-9 levels for predicting treatment response remains unclear. Controversy remains regarding the clinical utility of an extended biomarker assessment at diagnosis, and the use of serial complement testing requires further study. Testing for paraproteins in C3G has also received increased attention.43Zand L. Kattah A. Fervenza F.C. et al.C3 glomerulonephritis associated with monoclonal gammopathy: a case series.Am J Kidney Dis. 2013; 62: 506-514Google Scholar A contemporary approach to the treatment of C3G has been outlined,40Goodship T.H. Cook H.T. Fakhouri F. et al.Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.Kidney Int. 2017; 91: 539-551Google Scholar derived mostly from case reports and retrospective case series. An important knowledge gap in the treatment of C3G is the absence of a robust understanding of its natural history. Current treatments have been empirically extrapolated from other glomerular diseases. The optimal duration of therapy remains unclear. Current treatment guidelines focus on inhibiting definable pathways (inflammation or terminal complement activity) with available targeted therapeutics (antiproliferative agents or terminal complement blockers). Treatment of active disease with MMF and corticosteroids has shown promise in 2 retrospective case series,44Avasare R.S. Canetta P.A. Bomback A.S. et al.Mycophenolate mofetil in combination with steroids for treatment of C3 glomerulopathy: a case series.Clin J Am Soc Nephrol. 2018; 13: 406-413Google Scholar, 45Rabasco C. Cavero T. Roman E. et al.Effectiveness of mycophenolate mofetil in C3 glomerulonephritis.Kidney Int. 2015; 88: 1153-1160Google Scholar but was not found to be effective in a third case series in patients with more severe baseline kidney disease.46Caliskan Y. Torun E.S. Tiryaki T.O. et al.Immunosuppressive treatment in C3 glomerulopathy: is it really effective?.Am J Nephrol. 2017; 46: 96-107Google Scholar For patients with C3G and monoclonal gammopathy, a recent retrospective case series found superior hematologic and renal response rates, as well as renal survival, for patients treated with clone-directed chemotherapy compared with conservative or immunosuppressive treatment.47Chauvet S. Fremeaux-Bacchi V. Petitprez F. et al.Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy.Blood. 2017; 129: 1437-1447Google Scholar Preclinical and clinical studies have elucidated the pathogenesis of some paraprotein-associated kidney diseases. For example, heavy chain deposition disease is caused by a truncated Ig heavy chain that lacks the first constant domain (CH1 deletion).48Vignon M. Cohen C. Faguer S. et al.The clinicopathologic characteristics of kidney diseases related to monotypic IgA deposits.Kidney Int. 2017; 91: 720-728Google Scholar, 49Bonaud A. Bender S. Touchard G. et al.A mouse model recapitulating human monoclonal heavy chain deposition disease evidences the relevance of proteasome inhibitor therapy.Blood. 2015; 126: 757-765Google Scholar Specific physiochemical properties of the truncated heavy chain may explain its tropism for the kidney.50Bridoux F. Javaugue V. Bender S. et al.Unravelling the immunopathological mechanisms of heavy chain deposition disease with implications for clinical management.Kidney Int. 2017; 91: 423-434Google Scholar Most patients with heavy chain deposition disease have an underlying plasma cell clone that does not meet criteria for multiple myeloma (i.e., a MGRS), and evidence of the truncated heavy chain can be found in the serum and bone marrow.50Bridoux F. Javaugue V. Bender S. et al.Unravelling the immunopathological mechanisms of heavy chain deposition disease with implications for clinical management.Kidney Int. 2017; 91: 423-434Google Scholar In MGRS, pathogenic Igs are from plasma cell or B-cell clones. Targeting these clones may improve outcomes,47Chauvet S. Fremeaux-Bacchi V. Petitprez F. et al.Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy.Blood. 2017; 129: 1437-1447Google Scholar, 50Bridoux F. Javaugue V. Bender S. et al.Unravelling the immunopathological mechanisms of heavy chain deposition disease with implications for clinical management.Kidney Int. 2017; 91: 423-434Google Scholar, 51Cohen C. Royer B. Javaugue V. et al.Bortezomib produces hig