Management and treatment of glomerular diseases (part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference
Authors: Jürgen Floege, Sean J. Barbour, Daniel C. Cattran, Jonathan J. Hogan, Patrick H. Nachman, Sydney C.W. Tang, Jack F.M. Wetzels, Michael Cheung, David C. Wheeler, Wolfgang C. Winkelmayer, Brad H. Rovin, Sharon G. Adler, Charles E. Alpers, Isabelle Ayoub, Arvind Bagga, Jonathan Barratt, Dawn J. Caster, Daniel T.M. Chan, Anthony Chang, Jason Chon Jun Choo, H. Terence Cook, Rosanna Coppo, Fernando C. Fervenza, Agnes B. Fogo, Jonathan G. Fox, Keisha L. Gibson, Richard J. Glassock, David Harris, Elisabeth M. Hodson, 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, Marcus J. Moeller, Chi Chiu Mok, 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, Dario Roccatello, Pierre Ronco, William E. Smoyer, Vladimír Tesař, Joshua M. Thurman, Hernán Trimarchi, Marina Vivarelli, Giles D. Walters, Angela Yee-Moon Wang, Scott E. Wenderfer
Journal: Kidney International (2019)

The Kidney Disease: Improving Global Outcomes (KDIGO) initiative organized a Controversies Conference on glomerular diseases in November 2017. The conference focused on the 2012 KDIGO guideline with the aim of identifying new insights into nomenclature, pathogenesis, diagnostic work-up, and, in particular, therapy of glomerular diseases since the guideline's publication. It was the consensus of the group that most guideline recommendations, in particular those dealing with therapy, will need to be revisited by the guideline-updating Work Group. This report covers general management of glomerular disease, IgA nephropathy, and membranous nephropathy. The Kidney Disease: Improving Global Outcomes (KDIGO) initiative organized a Controversies Conference on glomerular diseases in November 2017. The conference focused on the 2012 KDIGO guideline with the aim of identifying new insights into nomenclature, pathogenesis, diagnostic work-up, and, in particular, therapy of glomerular diseases since the guideline's publication. It was the consensus of the group that most guideline recommendations, in particular those dealing with therapy, will need to be revisited by the guideline-updating Work Group. This report covers general management of glomerular disease, IgA nephropathy, and membranous nephropathy. The Kidney Disease: Improving Global Outcomes (KDIGO) initiative published its first 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 Given the enormous advances in understanding the pathogenesis of glomerular diseases, identification of new diagnostic biomarkers, and emerging therapies, about 100 experts from various disciplines (nephrology, pathology, rheumatology, pediatrics) and organizations (academia, pharmaceutical industry) convened on November 17–19, 2017. Through plenary and small group discussions, the conference aimed to evaluate consensus and controversies in nomenclature, general work-up and management of glomerular diseases, future needs in research, and, in particular, the critical assessment of existing guideline recommendations. This first of 2 reports covers general management of glomerular diseases. In addition, this report addresses 2 common forms of glomerulonephritis (GN), namely IgA nephropathy (IgAN) and membranous nephropathy. Primary podocytopathies, complement-mediated glomerular diseases, lupus nephritis, antineutrophil cytoplasmic antibody–associated nephritis, and monoclonal gammopathies of renal significance will be covered in the second report. These 2 conference summaries will lay the basis for the guideline updating process that began in August 2018. This section will consider newer concepts and controversies in the general management principles of glomerular disorders. Disease-specific issues, applications, or exceptions to these general statements will be discussed within each of the individual glomerular disease sections. Additional broad-based management principles for glomerular diseases may be found in chapter 2 of the 2012 KDIGO Clinical Practice Guideline for Glomerulonephritis.1Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO clinical practice guideline for glomerulonephritis.Kidney Int Suppl. 2012; 2: 139-274Google Scholar The kidney biopsy remains the cornerstone for the evaluation of glomerular disease.2Sethi S. D'Agati V.D. Nast C.C. et al.A proposal for standardized grading of chronic changes in native kidney biopsy specimens.Kidney Int. 2017; 91: 787-789Google Scholar, 3D'Agati V.D. Mengel M. The rise of renal pathology in nephrology: structure illuminates function.Am J Kidney Dis. 2013; 61: 1016-1025Google Scholar In very few and specific circumstances such as childhood steroid-sensitive nephrotic syndrome, diagnosis and treatment are often done without a kidney biopsy. In adults this approach is uncommon but may be considered in individual cases. For example, patients who have normal kidney function, acute onset of nephrotic syndrome, and are positive for anti-phospholipase A2 receptor (PLA2R) antibodies are likely to have membranous nephropathy. Treatment could be initiated without biopsy if such patients had a high risk of procedural complications, but care must be taken as other diseases may emulate all of these features.4Larsen C.P. Messias N.C. Silva F.G. et al.Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies.Mod Pathol. 2013; 26: 709-715Google Scholar, 5Dai H. Zhang H. He Y. Diagnostic accuracy of PLA2R autoantibodies and glomerular staining for the differentiation of idiopathic and secondary membranous nephropathy: an updated meta-analysis.Sci Rep. 2015; 5: 8803Google Scholar Kidney tissue is also critical for assessing the degree of histologic activity and chronicity and to identify unexpected features such as interstitial nephritis, acute kidney injury, and crescents, all factors that might significantly impact disease management. The kidney biopsy should be interpreted in the context of ethnicity, age, and hypertension, as these may modify the background kidney histology. For instance, understanding the "normal" range of age-related focal segmental glomerulosclerosis in a population might allow a better estimate of the extent of glomerular disease in an individual biopsy.6Hodgin J.B. Bitzer M. Wickman L. et al.Glomerular aging and focal global glomerulosclerosis: a podometric perspective.J Am Soc Nephrol. 2015; 26: 3162-3178Google Scholar Application of other modifiers, such as ethnicity, needs to be considered. The value of kidney tissue is likely to expand significantly in the near term. It is likely that taking a more system-related approach to the biopsy will enhance its value by providing more information important to diagnosis, prognosis, and treatment. For example, all clinical trials have treatment failures suggesting variations between individuals in the molecular pathways driving disease progression despite similar histopathology. To develop targeted therapies, identification of these pathways is necessary and will require a focus on mechanisms operative at the tissue level rather than relying solely on standard histologic findings. This also ties into the new concept of immunologic versus clinical remission.5Dai H. Zhang H. He Y. Diagnostic accuracy of PLA2R autoantibodies and glomerular staining for the differentiation of idiopathic and secondary membranous nephropathy: an updated meta-analysis.Sci Rep. 2015; 5: 8803Google Scholar, 7Beck Jr., L.H. Fervenza F.C. Beck D.M. et al.Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy.J Am Soc Nephrol. 2011; 22: 1543-1550Google Scholar, 8De Vriese A.S. Glassock R.J. Nath K.A. et al.A proposal for a serology-based approach to membranous nephropathy.J Am Soc Nephrol. 2017; 28: 421-430Google Scholar The need for electron microscopy for every biopsy remains controversial. It can be critical in some cases, for example, to differentiate between immunologically mediated and adaptive focal segmental glomerulosclerosis variants.9Sethi S. Glassock R.J. Fervenza F.C. Focal segmental glomerulosclerosis: towards a better understanding for the practicing nephrologist.Nephrol Dial Transplant. 2015; 30: 375-384Google Scholar Application at a worldwide level may be difficult, but it could possibly be leveraged by preservation of a small amount of tissue and, if judged critical to management, sent to an electron microscopy reference laboratory for evaluation. Most glomerular diseases are associated with significant proteinuria. Although ratios of albumin-to-creatinine or protein-to-creatinine (PCR) in random spot urines are commonly used, recent data highlight the poor agreement between these ratios and 24-hour urine protein measurements.10Hogan M.C. Reich H.N. Nelson P.J. et al.The relatively poor correlation between random and 24-hour urine protein excretion in patients with biopsy-proven glomerular diseases.Kidney Int. 2016; 90: 1080-1089Google Scholar Although spot albumin-to-creatinine ratio and PCR are helpful in general clinical management, they are not sufficiently accurate when therapeutic decisions about using high-risk medications are being made on small changes in proteinuria.11Reich H.N. Troyanov S. Scholey J.W. et al.Remission of proteinuria improves prognosis in IgA nephropathy.J Am Soc Nephrol. 2007; 18: 3177-3183Google Scholar, 12Lv J. Zhang H. Wong M.G. et al.Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy: the TESTING randomized clinical trial.JAMA. 2017; 318: 432-442Google Scholar In such cases, a 24-hour urine protein or PCR should be measured. Importantly, the PCR from an intended 24-hour urine collection that is at least 50% complete has been shown to accurately reflect 24-hour proteinuria.13Hebert L.A. Birmingham D.J. Shidham G. et al.Random spot urine protein/creatinine ratio is unreliable for estimating 24-hour proteinuria in individual systemic lupus erythematosus nephritis patients.Nephron Clin Pract. 2009; 113: c177-c182Google Scholar In young children, obtaining a 24-hour urine collection is usually not possible and PCR is the preferred means to assess proteinuria. Monitoring serum albumin levels in nephrotic patients also represents a valuable tool to indirectly assess the extent of proteinuria. The gold standard for estimating renal excretory function remains inulin or isotopic clearance techniques, but these are expensive and require operator expertise. Newer, accurate techniques to measure glomerular filtration rate (GFR) are evolving.14Rizk D.V. Meier D. Sandoval R.M. et al.A novel method for rapid bedside measurement of GFR.J Am Soc Nephrol. 2018; 29: 1609-1613Google Scholar Presently, the Chronic Kidney Disease Epidemiology Collaboration's (CKD-EPI) equation for estimating GFR is often used instead.15Ix J.H. Wassel C.L. Stevens L.A. et al.Equations to estimate creatinine excretion rate: the CKD epidemiology collaboration.Clin J Am Soc Nephrol. 2011; 6: 184-191Google Scholar Formulas have also been developed for children.16Gao A. Cachat F. Faouzi M. et al.Comparison of the glomerular filtration rate in children by the new revised Schwartz formula and a new generalized formula.Kidney Int. 2013; 83: 524-530Google Scholar, 17Schwartz G.J. Work D.F. Measurement and estimation of GFR in children and adolescents.Clin J Am Soc Nephrol. 2009; 4: 1832-1843Google Scholar However, estimated GFR (eGFR) equations have not been validated in specific glomerular diseases and patient populations. In addition, when estimating glomerular function in patients with high-grade proteinuria, the majority of studies still use 24-hour urine collections for creatinine clearance. Errors related to collection and laboratory measurements under these conditions can induce up to 50% of errors in GFR measurement.18Branten A.J. Vervoort G. Wetzels J.F. Serum creatinine is a poor marker of GFR in nephrotic syndrome.Nephrol Dial Transplant. 2005; 20: 707-711Google Scholar, 19Stevens L.A. Levey A.S. Measured GFR as a confirmatory test for estimated GFR.J Am Soc Nephrol. 2009; 20: 2305-2313Google Scholar, 20Inker L.A. Tonelli M. Hemmelgarn B.R. et al.Comparison of concurrent complications of CKD by 2 risk categorization systems.Am J Kidney Dis. 2012; 59: 372-381Google Scholar The accuracy of these methods may be partially compensated by frequent longitudinal measurement and use of data-smoothing techniques.21Tang L.L. Liu A. Chen Z. et al.Nonparametric ROC summary statistics for correlated diagnostic marker data.Stat Med. 2013; 32: 2209-2220Google Scholar A simple, reliable, and inexpensive biomarker of kidney function is still wanting. Macro- or microhematuria is associated with almost all glomerular disorders and identification of red cell casts may provide clues to nephritic diseases such as IgAN. Qualitatively, the routine urine dipstick can distinguish the presence or absence of microhematuria, but the capacity to quantitate hematuria has pitfalls, including timing between collection and examination, urine concentration, preparation of the urine pellet, pH of the urine, and the expertise of the examiner. The disappearance of hematuria, however, associated with complete clinical remission can be important in assessing the activity of diseases such as IgAN and antineutrophil cytoplasmic antibody vasculitis.22Geetha D. Seo P. Ellis C. et al.Persistent or new onset microscopic hematuria in patients with small vessel vasculitis in remission: findings on renal biopsy.J Rheumatol. 2012; 39: 1413-1417Google Scholar, 23Sevillano A.M. Gutierrez E. Yuste C. et al.Remission of hematuria improves renal survival in IgA nephropathy.J Am Soc Nephrol. 2017; 28: 3089-3099Google Scholar Regulatory agencies still grant approval for drugs in GN based on the classic findings of complete remission of proteinuria, as a positive outcome, and end-stage kidney disease (ESKD) (or a 50% reduction in eGFR), and/or mortality as negative outcomes. Recent collaborations among the US Food and Drug Administration, the pharmaceutical industry, and members of nephrology organizations, under the umbrella organization, the Kidney Health Initiative, are developing alternative surrogate endpoints for drug approval. The first consensus meeting culminated in a decision to allow a 40% reduction in eGFR to serve as an endpoint, but earlier endpoints are needed in these rare diseases.24Levey A.S. Inker L.A. Matsushita K. et al.GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration.Am J Kidney Dis. 2014; 64: 821-835Google Scholar In membranous nephropathy, recent data suggest that complete remission could serve as a surrogate endpoint and partial remission used as a basis for approval under the accelerated approval program in the United States.25Thompson A. Cattran D.C. Blank M. et al.Complete and partial remission as surrogate end points in membranous nephropathy.J Am Soc Nephrol. 2015; 26: 2930-2937Google Scholar Both outcomes are supported by statistical techniques that allow the prospective quantitation of the benefit of a partial remission of proteinuria based on its duration in an individual patient.26Cattran D.C. Kim E.D. Reich H. et al.Membranous nephropathy: quantifying remission duration on outcome.J Am Soc Nephrol. 2017; 28: 995-1003Google Scholar The Kidney Health Initiative group is currently evaluating surrogate endpoints in IgAN and lupus nephritis. The concept of futility can be critical to patient management. This "point of no return" is usually defined by a low eGFR, often < 30 ml/min per 1.73 m2 and/or kidney biopsy that shows a high degree of irreversible chronic changes.1Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO clinical practice guideline for glomerulonephritis.Kidney Int Suppl. 2012; 2: 139-274Google Scholar Noninvasive assessment of whole kidney chronicity/fibrosis is not ready for clinical application.27Morrell G.R. Zhang J.L. Lee V.S. Magnetic resonance imaging of the fibrotic kidney.J Am Soc Nephrol. 2017; 28: 2564-2570Google Scholar Currently, the rate of change in kidney function is likely more important than a single cross-sectional measurement of eGFR in defining futility. Additionally, age and overall wellness should be considered when determining futility. The question of futility also extends to clinical trials. Futility criteria are often used to exclude patients from clinical trials with the thought that risk will outweigh gain for such patients. Therefore, many patients miss the opportunity to participate in trials, complicating attainment of sample size and generalizability of results. It may be helpful to have more patient engagement in determining clinical trial eligibility. If the treating physician thinks it is reasonable to consider a clinical trial and their patient is fully informed, such patients could be considered if futility criteria were less rigid. This concept is commonly followed in clinical practice. Although controversial, patient engagement may become more relevant as low-risk treatments become available. Quality of life and health are important components of determining treatment value and are increasingly used by regulatory agencies to assess overall worth of a new treatment.1Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO clinical practice guideline for glomerulonephritis.Kidney Int Suppl. 2012; 2: 139-274Google Scholar In glomerular diseases, patient-related outcomes and patient-related outcome measurements are evolving, but standards for clinical practice guidelines do not yet exist. In addition to well-established progression factors such as persistent proteinuria, poorly controlled hypertension or diabetes, smoking, or widespread cardiovascular disease,28Hebert L.A. Wilmer W.A. Falkenhain M.E. et al.Renoprotection: one or many therapies?.Kidney Int. 2001; 59: 1211-1226Google Scholar new evidence supports prematurity as having an impact on nephron endowment and potentially limiting renal reserve and increasing risk of progression in glomerular diseases (Table 1).29Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Google Scholar This can be approximated by birth weight, a readily available, low-cost demographic. Its value within specific diseases is still speculative, but it could be considered as basic information that may affect treatment and outcomes of glomerular diseases.Table 1Established and emerging risk factors for progression of kidney diseaseRisk factors for progressive loss of GFREmerging risk factors for progressive loss of GFR•Persistent proteinuria•Poorly controlled hypertension•Poorly controlled diabetes mellitus•Smoking•Widespread cardiovascular disease•Use of nephrotoxic drugs•Prematurity (low birth weight) and other reasons for low nephron number29Bertram J.F. Douglas-Denton R.N. Diouf B. et al.Human nephron number: implications for health and disease.Pediatr Nephrol. 2011; 26: 1529-1533Google Scholar•Low-sleep duration and other related disorders (e.g., restless legs syndrome, sleep apnea)30Ricardo A.C. Goh V. Chen J. et al.Association of sleep duration, symptoms, and disorders with mortality in adults with chronic kidney disease.Kidney Int Rep. 2017; 2: 866-873Google Scholar•Obesity31Morales E. Valero M.A. Leon M. et al.Beneficial effects of weight loss in overweight patients with chronic proteinuric nephropathies.Am J Kidney Dis. 2003; 41: 319-327Google Scholar, 32Afshinnia F. Wilt T.J. Duval S. et al.Weight loss and proteinuria: systematic review of clinical trials and comparative cohorts.Nephrol Dial Transplant. 2010; 25: 1173-1183Google Scholar, 33Kittiskulnam P. Kanjanabuch T. Tangmanjitjaroen K. et al.The beneficial effects of weight reduction in overweight patients with chronic proteinuric immunoglobulin a nephropathy: a randomized controlled trial.J Ren Nutr. 2014; 24: 200-207Google Scholar•Gender?34Cattran D.C. Reich H.N. Beanlands H.J. et al.The impact of sex in primary glomerulonephritis.Nephrol Dial Transplant. 2008; 23: 2247-2253Google ScholarGFR, glomerular filtration rate. Open table in a new tab GFR, glomerular filtration rate. Another recently defined health risk factor is sleep hygiene. From the National Health and Nutrition Examination Survey in the CKD population, low-sleep duration and other related disorders (e.g., restless legs syndrome, sleep apnea) were associated with all-cause mortality and cardiovascular mortality. Extrapolation into the glomerular disease population seems relevant as this is a modifiable factor and can be applied broadly to all patients.30Ricardo A.C. Goh V. Chen J. et al.Association of sleep duration, symptoms, and disorders with mortality in adults with chronic kidney disease.Kidney Int Rep. 2017; 2: 866-873Google Scholar Weight reduction in obese patients may benefit glomerular diseases.31Morales E. Valero M.A. Leon M. et al.Beneficial effects of weight loss in overweight patients with chronic proteinuric nephropathies.Am J Kidney Dis. 2003; 41: 319-327Google Scholar, 32Afshinnia F. Wilt T.J. Duval S. et al.Weight loss and proteinuria: systematic review of clinical trials and comparative cohorts.Nephrol Dial Transplant. 2010; 25: 1173-1183Google Scholar, 33Kittiskulnam P. Kanjanabuch T. Tangmanjitjaroen K. et al.The beneficial effects of weight reduction in overweight patients with chronic proteinuric immunoglobulin a nephropathy: a randomized controlled trial.J Ren Nutr. 2014; 24: 200-207Google Scholar Small studies, focusing on diet and bypass surgery, have shown at least short-term benefits. Weight reduction and sleep improvement are intriguing possible additions to standard treatment approaches that are economical, widely applicable, and that foster patient engagement. Sex is another issue that is often considered to be an important part of disease risk stratification in GN. Recent data, however, suggest that different rates of progression are more driven by the histologic category, blood pressure (BP), and severity of proteinuria than by sex.34Cattran D.C. Reich H.N. Beanlands H.J. et al.The impact of sex in primary glomerulonephritis.Nephrol Dial Transplant. 2008; 23: 2247-2253Google Scholar Genetic testing has rapidly evolved and its role has expanded to include not only confirming clinical diagnoses, but also establishing inheritance patterns, differentiating heterogeneous disorders, determining appropriate treatment, guiding decisions about family planning, and determining the cause of unexplained familial kidney disorders. It is also expected to be used for identifying new risk factors for susceptibility and progression. Currently cost and unclear clinical implications limit the use of genetic testing.35Sampson M.G. Hodgin J.B. Kretzler M. Defining nephrotic syndrome from an integrative genomics perspective.Pediatr Nephrol. 2015; 30: 51-63Google Scholar, 36Preston R, Stuart HM, Lennon R. Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how? [e-pub ahead of print]. Pediatr Nephrol. https://doi.org/10.1007/s00467-017-3838-6. Accessed December 15, 2018.Google Scholar Hypertension control remains crucial to the management of GN. Although some controversy remains, data support a BP target of 125/75 mm Hg in the GN patient with proteinuria >1 g/d. Critical to the management of resistant hypertension is a careful review of the patient's dietary sodium intake. Educating the patient on how to interpret food labels and providing feedback by assessing sodium intake with 24-hour urine sodium estimates are effective strategies.37Agarwal R. Resistant hypertension and the neglected antihypertensive: sodium restriction.Nephrol Dial Transplant. 2012; 27: 4041-4045Google Scholar, 38Bibbins-Domingo K. Chertow G.M. Coxson P.G. et al.Projected effect of dietary salt reductions on future cardiovascular disease.N Engl J Med. 2010; 362: 590-599Google Scholar Sodium restriction will not only lower BP, but may enhance the antiproteinuric effects of renin–angiotensin system (RAS) blockers. The Institute of Medicine currently recommends limiting dietary sodium to <1500 mg/d (65 mmol/d), which is a 50% to 75% reduction from the average North American intake. There are no clear data on optimal sodium restriction in children. Proteinuria reduction remains a goal in virtually all glomerular diseases. The main approach is through RAS blockade. An area of controversy is whether angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should be used alone, as dual therapy and/or in combination with an aldosterone antagonist. Previously, hyperkalemia and acute kidney injury outweighed benefits of dual therapy, but recent studies indicate that with careful monitoring, combination therapy can be safe.39Voskamp P.W.M. Dekker F.W. van Diepen M. et al.Effect of dual compared to no or single renin-angiotensin system blockade on risk of renal replacement therapy or death in predialysis patients: PREPARE-2 study.J Am Soc Hypertens. 2017; 11: 635-643Google Scholar Nonetheless, the benefit for dual RAS blockade in GN with high-grade proteinuria is not clear.39Voskamp P.W.M. Dekker F.W. van Diepen M. et al.Effect of dual compared to no or single renin-angiotensin system blockade on risk of renal replacement therapy or death in predialysis patients: PREPARE-2 study.J Am Soc Hypertens. 2017; 11: 635-643Google Scholar A practical approach to ameliorating risks due to RAS blockers, particularly acute kidney injury, is by providing "sick day instructions" to withhold or decrease the dose of these medications during periods when volume depletion may occur, as with vomiting or diarrhea. Aldosterone blockade reduces cardiovascular mortality in patients with heart failure and also reduces albuminuria.40Joseph J.J. Echouffo-Tcheugui J.B. Kalyani R.R. et al.Aldosterone, renin, cardiovascular events, and all-cause mortality among African Americans: the Jackson Heart Study.JACC Heart Fail. 2017; 5: 642-651Google Scholar, 41Petrykiv S.I. Laverman G.D. Persson F. et al.Pooled analysis of multiple crossover trials to optimize individual therapy response to renin-angiotensin-aldosterone system intervention.Clin J Am Soc Nephrol. 2017; 12: 1804-1813Google Scholar, 42Antlanger M. Bernhofer S. Kovarik J.J. et al.Effects of direct renin inhibition versus angiotensin II receptor blockade on angiotensin profiles in non-diabetic chronic kidney disease.Ann Med. 2017; 49: 525-533Google Scholar However, the absolute risk-benefit ratio for aldosterone blockade in GN remains unclear. The sodium-glucose transport proteins 2 (SGLT2) inhibitors may offer a new proteinuria reduction strategy. However, in a recent study, short-term treatment with the SGLT2 inhibitor dapagliflozin did not modify renal hemodynamic function or attenuate proteinuria in nondiabetic humans with focal segmental glomerulosclerosis, possibly because of downregulation of renal SGLT2 expression in focal segmental glomerulosclerosis.43Rajasekeran H. Reich H.N. Hladunewich M.A. et al.Dapagliflozin in focal segmental glomerulosclerosis: a combined human-rodent pilot study.Am J Physiol Renal Physiol. 2018; 314: F412-F422Google Scholar Several large studies are currently investigating SGLT2 inhibitors in nondiabetic CKD (e.g., The Study of Heart and Kidney Protection With Empagliflozin [EMPA-KIDNEY], NCT03594110; Effects of Dapagliflozin in Nondiabetic Patients With Proteinuria [DIAMOND], NCT03190694; A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease [Dapa-CKD], NCT03036150). The accelerated vascular disease seen in patients with CKD includes those with GN, and recent data suggest this may be worse in some glomerular diseases than others.44Markossian T. Burge N. Ling B. et al.Controversies regarding lipid management and statin use for cardiovascular risk reduction in patients with CKD.Am J Kidney Dis. 2016; 67: 965-977Google Scholar, 45Lee T. Derebail V.K. Kshirsagar A.V. et al.Patients with primary membranous nephropathy are at high risk of cardiovascular events.Kidney Int. 2016; 89: 1111-1118Google Scholar Although traditionally statins have been used to treat hyperlipidemia and are effective, target values may not be achieved, especially in the new era of very low target low-density lipoprotein levels. Novel powerful agents such as proprotein convertase subtilisin/kexin type 9 inhibitors (e.g., evolocumab, alirocumab) need to be studied in the GN population.46Sabatine M.S. Giugliano R.P. Keech A.C. et al.Evolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med. 2017; 376: 1713-1722Google Scholar Evidence that lipid-lowering therapy in children is beneficial is of poor quality but needs to be explored given their expected longevity.47Kotur-Stevuljevic J. Peco-Antic A. Spasic S. et al.Hyperlipidemia, oxidative stress, and intima media thickness in children with chronic kidney disease.Pediatr Nephrol. 2013; 28: 295-303Google Scholar In contrast to cardiovascular benefits of statins, renal benefits are not well established.48Haynes R. Lewis D. Emberson J. et al.Effects of lowering LDL cholesterol on progression of kidney disease.J Am Soc Nephrol. 2014; 25: 1825-1833Google Scholar Concerning the risk-benefit ratio of prophylactic anticoagulation in nephrotic patients, especially in those with glomerular diseases associated with thrombotic events, decision aids are available online particularly for patients with membranous nephropathy (www.med.unc.edu/gntools).49Lee T. Biddle A.K. Lionaki S. et al.Personalized prophylactic anticoagulation decision analysis in patients with membranous nephropathy.Kidney Int. 2014; 85: 1412-1420Google Scholar, 50Barbour S.J. Greenwald A. Djurdjev O. et al.Disease-specific risk of venous thromboembolic events is increased in idiopathic glomerulonephritis.Kidney Int. 2012; 81: 190-195Google Scholar Whether non-vitamin-K antagonist oral anticoagulants can be safely used has only been demonstrated above an eGFR of 30 ml/min per 1.73 m2. Effects of more severe CKD and proteinuria on non-vitamin-K antagonist oral anticoagulant metabolism and clearance require further study.51Stamellou E. Floege J. Novel oral anticoagulants in patients with chronic kidney disease and atrial fibrillation.Nephrol Dial Transplant. 2018; 33: 1683-1689Google Scholar There is a risk of infection with most of the medications used to treat the glomerular diseases, including