Update on Lupus Nephritis: Core Curriculum 2020

Systemic lupus erythematosus is a multisystem autoimmune disease that commonly affects the kidneys. Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus and a major risk factor for morbidity and mortality. The pathophysiology of LN is heterogeneous. Genetic and environmental factors likely contribute to this heterogeneity. Despite improved understanding of the pathogenesis of LN, treatment advances have been few and risk for kidney failure remains unacceptably high. This installment in the Core Curriculum of Nephrology provides an up-to-date review of the current understanding of LN epidemiology, pathogenesis, diagnosis, and treatment. Challenging issues such as the management of LN in pregnancy, timing of transplantation, and the evolving role of corticosteroid use in the management of LN are discussed. We review the currently accepted approach to care for patients with LN and highlight deficiencies that need to be addressed to better preserve long-term kidney health and improve outcomes in LN. Systemic lupus erythematosus is a multisystem autoimmune disease that commonly affects the kidneys. Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus and a major risk factor for morbidity and mortality. The pathophysiology of LN is heterogeneous. Genetic and environmental factors likely contribute to this heterogeneity. Despite improved understanding of the pathogenesis of LN, treatment advances have been few and risk for kidney failure remains unacceptably high. This installment in the Core Curriculum of Nephrology provides an up-to-date review of the current understanding of LN epidemiology, pathogenesis, diagnosis, and treatment. Challenging issues such as the management of LN in pregnancy, timing of transplantation, and the evolving role of corticosteroid use in the management of LN are discussed. We review the currently accepted approach to care for patients with LN and highlight deficiencies that need to be addressed to better preserve long-term kidney health and improve outcomes in LN. FEATURE EDITOR:Asghar RastegarADVISORY BOARD:Ursula C. BrewsterMichael ChoiAnn O’HareManoocher SoleimaniThe Core Curriculum aims to give trainees in nephrology a strong knowledge base in core topics in the specialty by providing an overview of the topic and citing key references, including the foundational literature that led to current clinical approaches. FEATURE EDITOR: Asghar Rastegar ADVISORY BOARD: Ursula C. Brewster Michael Choi Ann O’Hare Manoocher Soleimani The Core Curriculum aims to give trainees in nephrology a strong knowledge base in core topics in the specialty by providing an overview of the topic and citing key references, including the foundational literature that led to current clinical approaches. Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease that predominantly affects women of child-bearing age and often involves the kidneys. Lupus nephritis (LN) occurs in ~50% of patients with SLE and is the most common, but not the only, cause of kidney injury in SLE. Men with SLE tend to have more aggressive disease with higher rates of renal and cardiovascular involvement and are more likely to develop kidney failure than women. Patients with SLE who develop LN present at a younger age than patients with SLE without nephritis. Additionally, LN typically develops early in the disease course, generally within the first 6 to 36 months, and may be present at initial diagnosis. Risk factors for the development of LN include younger age, male sex, and non-European ancestry. In the United States, the incidence of LN is higher in black (34%-51%), Hispanic (31%-43%), and Asian (33%-55%) compared with white (14%-23%) patients. Black and Hispanic patients have worse outcomes and are more likely to progress to kidney failure than white patients. Black and Hispanic patients tend to have more severe underlying histopathology, higher serum creatinine levels, and more proteinuria than white patients at LN diagnosis. Additionally, autoantibodies strongly associated with LN, including anti-Sm, anti-Ro, and anti-ribonucleoprotein antibodies, are more frequently positive in black compared with white patients. The reasons for these racial and ethnic differences are not completely understood, but genetic and socioeconomic factors likely contribute. Mortality associated with lupus is significantly higher in those with LN compared with those without LN, and death directly attributable to kidney disease occurs in 5% to 25% of patients with proliferative LN within 5 years of onset. Furthermore, 10% to 30% of patients with LN progress to kidney failure requiring kidney replacement therapy (KRT). Patients with proliferative forms of LN (class III, IV, or III/IV + V) are at highest risk for requiring KRT. Achieving a complete clinical response to treatment is critical to preserving long-term kidney health. In one study, patients who achieved a complete clinical response had 92% kidney survival at 10 years compared to 43% in partial responders and 13% in nonresponders. Overall, the kidney failure risk associated with LN improved from the 1970s to 2000. However, since 2000, the rate of LN requiring KRT has remained consistent and there is evidence to suggest that these rates are increasing now, particularly in black populations. ►Chen YE, Korbet SM, Katz RS, Schwartz MM, Lewis EJ; Collaborative Study Group. Value of a complete or partial remission in severe lupus nephritis. Clin J Am Soc Nephrol. 2008;3:46-53. ★ ESSENTIAL READING►Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus. 2006;15:308-318. ★ ESSENTIAL READING►Franco C, Yoo W, Franco D, Xu Z. Predictors of end stage renal disease in African Americans with lupus nephritis. Bull NYU Hosp Jt Dis. 2010;68(4):251-256.►Korbett SM, Schwartz MM, Evans J, Lewis EJ; Collaborative Study Group. Severe lupus nephritis: racial differences in presentation and outcome. J Am Soc Nephrol. 2007;18(1):244-254. ★ ESSENTIAL READING►Seligman VA, Lum RF, Olson JL, Li H, Criswell LA. Demographic differences in the development of lupus nephritis: a retrospective analysis. Am J Med. 2002;112(9):726-729.►Tan, Petri, Fang H, Magder LS, Petri MA. Differences between male and female systemic lupus erythematosus in a multiethnic population. J Rheumatol. 2012;39(4):759-769.►Tektonidou M, Dasgupta A, Ward M. Risk of end-stage renal disease in patients with lupus nephritis, 1970-2015: a systematic review and Bayesian meta-analysis. Arthritis Rheumatol. 2016;68:1432-1441. SLE occurs in genetically predisposed individuals who are exposed to environmental triggers. Several risk alleles associated with SLE have also been implicated in LN, but genetic studies specifically evaluating LN are lacking. Genome-wide association studies have identified risk genes in LN that are not otherwise seen in patients with SLE without nephritis, including apolipoprotein L1 (APOL1), platelet-derived growth factor receptor alpha (PDGFRA), and hyaluronan synthase 2 (HAS2). Genetic modifications in HLA alleles are also associated with LN. HLA-DR4 and HLA-DR11 appear to protect against LN, while HLA-DR3 and HLA-DR15 confer increased risk. A recent genome-wide association study identified more than 50 genetic polymorphisms associated with multiple physiologic processes known to be aberrant in LN. Genetic variations likely contribute to the racial and ethnic disparities of lupus and LN. For example, allelic variants in Fc receptor IIA for immunoglobulin G (IgG; Fcγ RIIA) are more common in black patients with SLE and specifically in LN compared with controls without SLE, possibly contributing to a reduced capacity for immune complex clearance in black patients. Allelic variants in the APOL1 gene are associated with increased risk for kidney failure in black populations and in LN; those with 2 risk alleles for APOL1 have more than 2.5-fold increased risk for developing kidney failure compared with those without risk alleles. The presence of risk alleles alone is not enough to explain the development of SLE or LN, and not all patients with SLE have variants that increase risk. Larger studies involving racially and ethnically diverse cohorts are needed to better appreciate the contribution of genetics to LN. ►Freedman BL, Langfeld CD, Andringa KK, et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1 Arthritis Rheumatol. 2014;66(2):390-396.►Iwamoto T, Niewold T. Genetics of human lupus nephritis. Clin Immunol. 2017;185:32-39. ★ ESSENTIAL READING►Monroe M, James J. Genetics of lupus nephritis: clinical implications. Semin Nephrol. 2015;35(5):396-409. ★ ESSENTIAL READING Abnormalities in innate and adaptive immunity contribute to the pathogenesis of lupus. Characteristically, autoantibodies directed against nuclear and cellular antigens are produced, leading to immune complex formation and accumulation of immune complexes in glomeruli. Immune complexes may deposit in glomeruli from the circulation or may form in situ if autoantibodies target intrinsic glomerular antigens (such as annexin 2) or antigens that are released during apoptosis and/or arise when apoptotic debris (including chromatin) is incompletely cleared. Chromatin can also activate intrarenal dendritic cells, increase the interaction of T and B cells, and enhance the production of anti-chromatin antibodies. Intraglomerular immune complexes can activate complement and engage leukocyte Fc receptors to initiate intrarenal inflammation and injury. Complement-mediated kidney damage, especially through the alternative pathway, has been observed in murine and human LN. Interstitial plasma cells generated from T- and B-cell aggregates within the kidney tubulointerstitium may also produce clonally restricted autoantibodies. This kidney-specific autoimmunity is facilitated by intrarenal interferon α (IFN-α) expression. Immune complexes are ligands for Toll-like receptors (TLRs), specifically TLR7 and TLR9. TLR7/9 engagement induces IFN-α expression by plasmacytoid dendritic cells, which enhances production of antigen-presenting cells, encourages autoreactive B-cell differentiation to plasma cells, and enhances production of CD4 helper T (TH) and CD8 memory T cells, leading to further autoantibody generation and immune complex formation. Abnormalities in B-cell tolerance leading to autoantibody production is seen in lupus. Human regulatory T cells normally suppress B- and T-cell–mediated autoantibody production but are reduced in number and functionally defective in SLE. Autoreactive B cells process and present self-antigens to T cells, promoting proinflammatory cytokine activation. TH1 cytokines are particularly overexpressed in LN kidneys and promote inflammation through macrophage, complement, and Fc receptor activation. In addition, TH1 cells promote differentiation and proliferation of B cells and assist class switching of autoantibodies to isotypes that are more specific for renal antigens. For example, IgG1 and IgG3 autoantibodies have been associated with LN and promote intrarenal inflammation through complement-mediated leukocyte recruitment. Immune complex clearance by leukocytes is impaired by the presence of low-affinity Fcγ receptors and autoantibodies to C1q and C3b. Engagement of low-affinity Fcγ receptors by immune complexes promotes leukocyte activation. Activated neutrophils and macrophages directly injure the kidney through secretion of oxygen free radicals and proteolytic enzymes. Dying neutrophils release neutrophil extracellular traps. These chromatin structures bind autoantigens and further stimulate IFN-α secretion from dendritic cells, amplifying intrarenal autoimmunity. ►Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235-238.►Birmingham DJ, Bitter JE, Rovin BH, et al. Relationship of circulating anti-C3b and anti-C1q IgG to lupus nephritis and its flare. Clin J Am Soc Nephrol. 2016;11(1):47-53.►Birmingham DJ, Hebert LA. The complement system in lupus nephritis. Semin Nephrol. 2015;35(5):444-454. ★ ESSENTIAL READING►Caster D, Korte E, Merchant M, et al. Autoantibodies targeting glomerular annexin A2 identify patients with proliferative lupus nephritis. Proteomics Clin Appl. 2015;9(0):1012-1020.►Foster MH. T cells and B cells in lupus nephritis. Semin Nephrol. 2007;27:47-58.►Gallagher KM, Lauder S, Rees IW, et al. Type I interferon (IFN alpha) acts directly on human memory CD4+ T cells altering their response to antigen. J Immunol. 2009;183:2915-2920.►Lech M, Anders HJ. The pathogenesis of lupus nephritis. J Am Soc Nephrol. 2013;24(9):1357-1366. ★ ESSENTIAL READING►Masutani K, Akahoshi M, Tsuruya K, et al. Predominance of Th1 immune response in diffuse proliferative lupus nephritis. Arthritis Rheum. 2001;44:2097-2106.►Rönnblom L, Alm GV, Eloranta ML. The type I interferon system in the development of lupus. Semin Immunol. 2011;23:113-121. ★ ESSENTIAL READING►Tucci M, Quatraro C, Lombardi L, Pellegrino C, Dammacco F, Silvestris F. Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: role of interleukin-18. Arthritis Rheum. 2008;58:251-262. Case 1: A 32-year-old woman with a history of SLE associated with malar rash and polyarthritis is referred to you for evaluation of proteinuria discovered by routine urinalysis.Question 1: Which of the following is correct regarding the diagnostic workup of LN?a)Proliferative LN does not occur with urine protein excretion < 1,000 mg/db)An absence of dysmorphic red blood cells (RBCs; acanthocytes) on urine microscopy rules out LNc)Spot urinary protein-creatinine ratios (UPCRs) are unreliable for accurate assessment of proteinuria in patients with LNd)Urine concentration (specific gravity) does not influence interpretation of proteinuria with urine dipstickFor the answer to the question, see the following text. Case 1: A 32-year-old woman with a history of SLE associated with malar rash and polyarthritis is referred to you for evaluation of proteinuria discovered by routine urinalysis. Question 1: Which of the following is correct regarding the diagnostic workup of LN?a)Proliferative LN does not occur with urine protein excretion < 1,000 mg/db)An absence of dysmorphic red blood cells (RBCs; acanthocytes) on urine microscopy rules out LNc)Spot urinary protein-creatinine ratios (UPCRs) are unreliable for accurate assessment of proteinuria in patients with LNd)Urine concentration (specific gravity) does not influence interpretation of proteinuria with urine dipstick For the answer to the question, see the following text. The clinical identification of LN can be challenging because patients often lack overt signs of kidney disease, especially early. Instead, LN is most commonly discovered after careful examination of urine and laboratory data in patients with lupus. Assessment of serum creatinine level, urine dipstick testing, and urine sediment examination are necessary screening tools for LN evaluation. Many patients will have findings suggestive of LN at the initial diagnosis of SLE, and patients with SLE should undergo screening for LN at diagnosis, at least yearly thereafter, and any time there is concern for a lupus flare. A positive test result for blood and/or protein on urine dipstick in a patient with lupus is suggestive of nephritis, but should be interpreted with caution. The urine dipstick may be falsely negative for proteinuria when the urine concentration is dilute (ie, low specific gravity) or falsely positive for significant proteinuria when urine is highly concentrated (ie, high specific gravity). Additionally, the urine dipstick is highly sensitive for blood and may be falsely positive or represent bleeding from a nonglomerular source, such as menstruation in a young woman. Therefore, urine microscopy should always accompany the dipstick. Findings specific for glomerular bleeding associated with nephritis include dysmorphic RBCs, specifically acanthocytes (Fig 1A) and RBC casts (Fig 1B). Microscopic hematuria is present in ~80% of patients with LN, while RBC casts are present in 30%. White blood cells and white blood cell casts (Fig 1C) in the absence of infection may also be present and are consistent with intrarenal inflammation that can be present in LN. By definition, proteinuria must be present to clinically diagnose LN. Nephrotic-range proteinuria (protein excretion > 3.5 g/d) is found in up to 50% of cases. Quantification of proteinuria can be performed either by measuring UPCR in a random spot specimen or a 24-hour urine collection. UPCR from a spot sample, though convenient, can be inaccurate in LN, over- or underestimating the true level of proteinuria. Thus, although a spot urine specimen can be used to screen and follow trends in individual patients, for critical clinical decisions such as changing treatment, it should be verified by a 24-hour urine collection. Measurement of UPCR in 24-hour urine attenuates collection errors. Even an intended 24-hour collection that is at least 50% complete correlates well with a complete 24-hour collection. A first-morning-void UPCR also accurately reflects 24-hour proteinuria in LN. The gold standard for diagnosis and classification of LN is the percutaneous kidney biopsy. Though the proteinuria threshold for which a biopsy should be considered is not well defined, evidence from observational studies suggests that urine protein excretion greater than 500 to 1,000 mg/d is associated with significant kidney inflammation, especially during the first episode of LN when the kidney may not have a lot of long-term damage that could result in proteinuria without inflammation. Because early disease recognition and treatment is important to long-term preservation of kidney health, we recommend a kidney biopsy when urine protein excretion exceeds 500 mg/d. Biopsy should be done at any level of proteinuria with decreased glomerular filtration rate (GFR) that is not readily attributed to another cause, for example, a new medication. Alternatively, a biopsy may not be required if the only clinical abnormalities indicative of LN are asymptomatic microscopic hematuria or proteinuria with protein excretion < 500 mg/d in the absence of active urine sediment. A general approach to the diagnosis and management of LN is shown in Figure 2. Returning to question 1, the correct answer is (c). There is ample evidence that the correlation of UPCRs from spot and 24-hour specimens is modest at best, and the former should not be used for initial workup of a patient with suspected LN. Regarding (a), proliferative LN may occur at even low levels of proteinuria. Answer (b) is incorrect because although acanthocytes are specific for glomerular bleeding, their absence does not rule out nephritis. Answer (d) is wrong because on urine dipstick, a concentrated or dilute urine specimen can lead to a falsely high- or low-level proteinuria read out, respectively. ►Cameron JS. Lupus nephritis. J Am Soc Nephrol. 1999;10(2):413-424. ★ ESSENTIAL READING►Shidham G, Ayoub I, Birmingham D, Hebert LA. Limited reliability of the spot urine protein/creatinine ratio in the longitudinal evaluation of patients with lupus nephritis. Kidney Int Rep. 2018;3(5):1057-1063. ★ ESSENTIAL READING►Woolhandler S, Pels RJ, Bor DH, Himmelstein DU, Lawrence RS. Dipstick urinalysis screening of asymptomatic adults for urinary tract disorders. I. Hematuria and proteinuria. JAMA. 1989;262(9):1214-1219. Case 2: An 18-year-old woman with a history of SLE has class IV LN diagnosed. She is treated with mycophenolate mofetil (MMF) and prednisone. After 2 months of stable laboratory readings on treatment, her kidney function starts to worsen and she develops new-onset hypertension. Over 2 weeks, her serum creatinine level increases from 0.9 to 3.5 mg/dL. Blood pressure is now 160/90 mm Hg. She has been adherent to treatment.Question 2: Which of the following are appropriate next steps?a)Given the patient has proved unresponsive to MMF, she should be switched to intravenous (IV) cyclophosphamideb)Check antiphospholipid antibody (APLA) titersc)Increase prednisone to 60 mg dailyd)Start rituximab treatmentFor the answer to the question, see the following text. Case 2: An 18-year-old woman with a history of SLE has class IV LN diagnosed. She is treated with mycophenolate mofetil (MMF) and prednisone. After 2 months of stable laboratory readings on treatment, her kidney function starts to worsen and she develops new-onset hypertension. Over 2 weeks, her serum creatinine level increases from 0.9 to 3.5 mg/dL. Blood pressure is now 160/90 mm Hg. She has been adherent to treatment. Question 2: Which of the following are appropriate next steps?a)Given the patient has proved unresponsive to MMF, she should be switched to intravenous (IV) cyclophosphamideb)Check antiphospholipid antibody (APLA) titersc)Increase prednisone to 60 mg dailyd)Start rituximab treatment For the answer to the question, see the following text. At present, kidney biopsy is used to establish a diagnosis of LN or other processes involving the kidneys in a patient with lupus; to correctly classify LN, which may have therapeutic and prognostic implications; and to determine the extent of acute and chronic kidney injury, which has therapeutic implications. Besides LN, kidney injury in patients with lupus could be due to thrombotic microangiopathy (TMA)/antiphospholipid nephropathy, non–immune complex podocytopathy, tubulointerstitial nephritis, acute tubular necrosis, renovascular disease, or nephrotoxicity from medications (Fig 2). TMA may be present in up to 25% of cases of kidney injury associated with SLE. Importantly, treatment of TMA is different from LN and early recognition of TMA is critical to preserving GFR because the ischemia that results from TMA can rapidly lead to accumulation of chronic kidney damage. Lupus podocytopathy is seen in 1% to 2% of patients with SLE and presents with nephrotic syndrome. Clinically it is difficult to distinguish lupus podocytopathy from LN, especially class V LN. However, histologically, lupus podocytopathy is more readily distinguished from LN. Light microscopy reveals normal-appearing glomeruli or glomeruli with a focal segmental glomerulosclerosis pattern with or without mesangial proliferation. Electron microscopy demonstrates diffuse foot-process effacement and an absence of subendothelial or subepithelial deposits. Additionally, lupus podocytopathy is more amenable to treatment and often rapidly responds to corticosteroid therapy alone. Although the role of a kidney biopsy at first presentation of kidney involvement in lupus is well established, the role for a repeat kidney biopsy is less clear. Generally, repeat kidney biopsies have been done on a “for cause” basis, for example, a flare of LN, treatment-resistant disease, or in cases in which it is unclear whether persistent proteinuria is due to active disease or chronic nephrosclerosis (Fig 3). Protocol repeat biopsies are more controversial, but emerging data from observational cohort studies suggest that such biopsies may assist in making treatment decisions and help predict long-term renal outcomes. Protocol repeat biopsies have shown considerable discrepancies between clinical and histologic findings. For example, repeat biopsies done after 6 to 8 months of treatment in patients with a complete clinical response showed significant persistent histologic activity in 20% to 50% of cases. Additionally, 40% to 60% of patients had persistent proteinuria with protein excretion > 500 mg/d and were not considered to have achieved complete remission but showed no histologic activity on repeat biopsy. Recently, a prospective randomized controlled trial (RCT) studied the role of a protocol repeat biopsy in patients who had been in complete renal remission for 1 year and had received at least 36 months of immunosuppressive treatment. Therapy was withdrawn in all these patients and they were followed up prospectively for 24 months to assess for LN flare. Overall, 11 of 36 patients experienced a flare, 10 of whom had a histologic activity index > 2 on the repeat biopsy despite being in clinical remission. These observations suggest that a repeat biopsy done when considering withdrawal of maintenance immunosuppression may help guide that decision. For question 2, the correct answer is (b). Rapid decline in kidney function accompanied by new-onset hypertension in a patient who has been otherwise stable and adherent to medications should raise the possibility of antiphospholipid antibody syndrome. The workup of antiphospholipid antibody syndrome includes checking APLA titers and assessing for venous and arterial thromboembolism and TMA. Although LN can definitely relapse, a very severe relapse after 2 months of stable disease without extrarenal symptoms is less likely. Therefore, the other answers are incorrect. Additionally, the clinical presentation is concerning for a TMA. ►De Rosa M, Azzato F, Tobili JE, et al. A prospective observational cohort study highlights kidney biopsy findings of lupus nephritis patients in remission who flare following withdrawal of maintenance therapy. Kidney Int. 2018;94(4):788-794. ★ ESSENTIAL READING►Malvar A, Pirruccio P, Alberton V, et al. Histologic versus clinical remission in proliferative lupus nephritis. Nephrol Dial Transplant. 2017;32(8):1338-1344. ★ ESSENTIAL READING►Parikh SV, Alvarado A, Malvar A, Rovin BH. The kidney biopsy in lupus nephritis: past, present, and future. Semin Nephrol. 2015;35(5):465-477. Case 3: A 24-year-old woman with a history of LN treated with low-dose cyclophosphamide followed by maintenance with MMF presents for her 1-year follow-up. Creatinine level is 0.9 mg/dL and proteinuria of 0.6 g/d. She has RBCs (1+) on urine dipstick. She is worried about her long-term kidney health and asks about her renal prognosis.Question 3: Based on the current evidence, which one of the following statements is correct about her long-term kidney health?a)She has a favorable long-term kidney prognosis based on 12-month proteinuria levelb)She has a poor long-term kidney prognosis due to persistent hematuria at 12 monthsc)The combination of 12-month hematuria and proteinuria is more predictive of long-term kidney health than proteinuria level aloneFor the answer to the question, see the following text. Case 3: A 24-year-old woman with a history of LN treated with low-dose cyclophosphamide followed by maintenance with MMF presents for her 1-year follow-up. Creatinine level is 0.9 mg/dL and proteinuria of 0.6 g/d. She has RBCs (1+) on urine dipstick. She is worried about her long-term kidney health and asks about her renal prognosis. Question 3: Based on the current evidence, which one of the following statements is correct about her long-term kidney health?a)She has a favorable long-term kidney prognosis based on 12-month proteinuria levelb)She has a poor long-term kidney prognosis due to persistent hematuria at 12 monthsc)The combination of 12-month hematuria and proteinuria is more predictive of long-term kidney health than proteinuria level alone For the answer to the question, see the following text. Treatment response in LN is defined clinically and generally stratified into complete (CR), partial (PR), and no response. Guideline definitions for clinical response in LN have been suggested by several organizations (Table 1). Although there is no consensus definition of CR across guidelines, proteinuria is the most important clinical variable used to define response. In general, a reduction in protein excretion to <0.5 g/d based on a 24-hour urine collection with normal serum creatinine or serum creatinine level within 15% of previous baseline is considered a CR. Urine sediment findings are also important for individual patients but have not been found useful in multicenter clinical trials due to issues of reproducibility. PR requires > 50% reduction in proteinuria and to non-nephrotic levels, with serum creatinine level within 25% of previous baseline. Patient who do not achieve CR or PR are considered nonresponders. Nonresponders include patients who show some response but do not meet PR criteria, have no improvement in parameters, or are worse.Table 1Clinical Response Criteria According to Current GuidelinesGuidelineComplete Response CriteriaPartial Response CriteriaNo ResponseKDIGODecline in UPCR to ≤0.5 g/g (≤50 mg/mmol); return of Scr to previous baseline>50% decrease in UPCR; if there was nephrotic-range proteinuria, then reduction to <3,000 mg/g [<300 mg/mmol] also; stabilization (±25%), or improvement of Scr, but not to normalFailure to achieve a complete or partial remissionACRUPCR < 0.2 g/g; normal Scr, or 25% improvement in eGFR if abnormal at LN flare; inactive urine sedimentUPCR of 0.2-2 g/g; eGFR at baseline level or improves 25% if abnormal at LN flare; inactive urine sedimentNo change or worsening proteinuria; decline in eGFR by ≥25%; active urine sedimentEULAR/ERA-EDTAUPCR < 0.5 g/g (<50 mg/mmol); GFR within 10% of previous normal≥50% reduction in UPCR, to less than nephrotic range; near-normal GFR (within 10% of prior baseline) by 12 mo of treatment<50% reduction in proteinuria or persistent nephrotic proteinuria; abnormal GFR (>10% decrease from prior baseline)Dutch SLE Working GroupProteinuria < 0.5 g/24 h; Scr within 25% of baseline before flareReduction in proteinuria by >50% to <3 g/24 h; Scr within 25% of prior baseline by 6-12 mo of treatmentPersistent proteinuria with <50% reduction or persistently >3 g/24 h after 6-12 mo; doubling of Scr within 3 mo of starting therapyAbbreviations: ACR, American College of Rheumatology; eGFR, estimated glomerular filtration rate; EULAR/ERA-E