A pathophysiology-based approach to the diagnosis and treatment of lupus nephritis

Lupus is no longer an unknown chameleon of medicine. Significant progress has been made on unraveling the pathogenesis of lupus and lupus nephritis, and how to treat the disease. Here we provide an update on the pathophysiology of lupus and its related kidney disease, consider areas of controversy in disease management, and discuss the unmet needs of lupus nephritis and how to address these needs. We focus on rethinking how innovative therapies for lupus nephritis should be evaluated and evolving strategies to more efficiently mitigate irreversible nephron loss in patients with lupus nephritis. Lupus is no longer an unknown chameleon of medicine. Significant progress has been made on unraveling the pathogenesis of lupus and lupus nephritis, and how to treat the disease. Here we provide an update on the pathophysiology of lupus and its related kidney disease, consider areas of controversy in disease management, and discuss the unmet needs of lupus nephritis and how to address these needs. We focus on rethinking how innovative therapies for lupus nephritis should be evaluated and evolving strategies to more efficiently mitigate irreversible nephron loss in patients with lupus nephritis. The diagnosis of lupus nephritis (LN) implies significant morbidity and mortality, especially if LN cannot be controlled and ongoing loss of nephrons occurs. This is illustrated by a recent outcomes analysis of an inception cohort of 1827 new systemic lupus erythematosus (SLE) patients followed up from 1999 to 2012.1Hanly J.G. O'Keeffe A.G. Su L. et al.The frequency and outcome of lupus nephritis: results from an international inception cohort study.Rheumatology (Oxford). 2016; 55: 252-262Crossref PubMed Scopus (259) Google Scholar The cohort was 89% women, of which were 49% white, 17% black, 15% Asian, and 15% Hispanic. The overall incidence of LN in this population was 38%. After adjusting for sex, enrollment age, and race/ethnicity, the hazard ratio for death (vs. no LN) was 3.2-fold, and the 10-year cumulative incidence of end-stage renal disease (ESRD) and death among the LN patients was 10.1% and 5.9%, respectively. Although significant progress has been made in understanding the pathogenesis of SLE, management of LN remains unsatisfactory. In this review we focus on recent advances in the pathophysiology of LN and how to further improve LN management and outcomes using these advances. The central paradigm of SLE is the loss of immune tolerance to nuclear autoantigens, based on bypassing checkpoint mechanisms that normally assure self-tolerance.2Goodnow C.C. Multistep pathogenesis of autoimmune disease.Cell. 2007; 130: 25-35Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar Checkpoint mechanisms include, for example, avoidance of nuclear material exposure to immune recognition receptors via strict compartmentalization to the intracellular space, apoptotic rather than necrotic cell death, rapid phagocytosis of dead cells, and masking of any potential autoadjuvant activity of self-nucleic acids, for example by the methylation of immunostimulatory RNA and DNA sequences.3Lech M. Anders H.J. The pathogenesis of lupus nephritis.J Am Soc Nephrol. 2013; 24: 1357-1366Crossref PubMed Scopus (280) Google Scholar The genetic heterogeneity of the global population implies that everyone maintains immune tolerance a bit differently,4Ghodke-Puranik Y. Niewold T.B. Immunogenetics of systemic lupus erythematosus: a comprehensive review.J Autoimmun. 2015; 64: 125-136Crossref PubMed Scopus (158) Google Scholar which is also supported by a variable prevalence of SLE in different populations. Patients with SLE carry an unfortunate combination of genetic variants that compromises immune tolerance to nuclear material at many of the aforementioned checkpoints, often at the same time. Importantly, each patient has his or her own combination of genetic susceptibilities, and therefore SLE is usually not monogenic but is a polygenic disorder inherited as a Mendelian trait.4Ghodke-Puranik Y. Niewold T.B. Immunogenetics of systemic lupus erythematosus: a comprehensive review.J Autoimmun. 2015; 64: 125-136Crossref PubMed Scopus (158) Google Scholar Familial SLE or sporadic monogenic SLE does occur but is rare and only seen when a single (mutation-like) gene variant elicits a very prominent effect on tolerance, such as complement C4 or TREX1 deficiency.5Aggarwal R. Sestak A.L. D'Sousa A. et al.Complete complement deficiency in a large cohort of familial systemic lupus erythematosus.Lupus. 2010; 19: 52-57Crossref PubMed Scopus (30) Google Scholar, 6Crow Y.J. Manel N. Aicardi-Goutieres syndrome and the type I interferonopathies.Nat Rev Immunol. 2015; 15: 429-440Crossref PubMed Scopus (556) Google Scholar Therefore, SLE is a clinically defined syndrome with several causes rather than a disease with a single cause.7Rahman A. Isenberg D.A. Systemic lupus erythematosus.N Engl J Med. 2008; 358: 929-939Crossref PubMed Scopus (1449) Google Scholar Hormonal or X-chromosomal factors certainly play an important role as the male-female ratio of SLE is 1:9. A unifying pathway present in every SLE patient is the overt autovaccination/immunization to nuclear material exemplified by the presence of antinuclear antibodies.7Rahman A. Isenberg D.A. Systemic lupus erythematosus.N Engl J Med. 2008; 358: 929-939Crossref PubMed Scopus (1449) Google Scholar This implies, potentially, that lifelong immune memory is established in the memory T cells of lymphoid organs and in long-lived plasma cells in the bone marrow.8Hiepe F. Dörner T. Hauser A.E. et al.Long-lived autoreactive plasma cells drive persistent autoimmune inflammation.Nat Rev Rheumatol. 2011; 7: 170-178Crossref PubMed Scopus (263) Google Scholar The concept of autovaccination is useful because patients can understand that after autovaccination has occurred their immune systems will remain primed like after other vaccine shots, and so there is no cure for SLE but lifelong monitoring and suppression of autoimmune disease activity are necessary.8Hiepe F. Dörner T. Hauser A.E. et al.Long-lived autoreactive plasma cells drive persistent autoimmune inflammation.Nat Rev Rheumatol. 2011; 7: 170-178Crossref PubMed Scopus (263) Google Scholar The diagnostic hallmark of circulating antinuclear antibodies consists of various specificities depending on the dominant antigens during the autovaccination process.7Rahman A. Isenberg D.A. Systemic lupus erythematosus.N Engl J Med. 2008; 358: 929-939Crossref PubMed Scopus (1449) Google Scholar This humoral autoimmunity is accompanied by less clinically evident expansion of autoreactive T cells and T cell–mediated autoimmunity. Epitope spreading can cause additional autoimmune manifestations such as secondary Sjogren's syndrome or antiphospholipid antibody syndrome in patients with lupus.9Cornaby C. Gibbons L. Mayhew V. et al.B cell epitope spreading: mechanisms and contribution to autoimmune diseases.Immunol Lett. 2015; 163: 56-68Crossref PubMed Scopus (101) Google Scholar Loss of immune tolerance and antinuclear antibodies production does not necessarily produce any clinical symptoms (Figure 1a). Often, however, immune recognition of endogenous nucleic acids via Toll-like receptors 7 and 9 induces interferon-α–dependent antiviral immunity, which manifests clinically as fatigue, fever, arthralgia, and myalgia, as may be seen in any viral infection.10Anders H.J. Pseudoviral immunity - a novel concept for lupus.Trends Mol Med. 2009; 15: 553-561Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 11Patole P.S. Zecher D. Pawar R.D. et al.G-rich DNA suppresses systemic lupus.J Am Soc Nephrol. 2005; 16: 3273-3280Crossref PubMed Scopus (85) Google Scholar, 12Pawar R.D. Ramanjaneyulu A. Kulkarni O.P. et al.Inhibition of Toll-like receptor-7 (TLR-7) or TLR-7 plus TLR-9 attenuates glomerulonephritis and lung injury in experimental lupus.J Am Soc Nephrol. 2007; 18: 1721-1731Crossref PubMed Scopus (187) Google Scholar This central role of antiviral immunity in the pathogenesis of SLE has been referred to as "pseudoantiviral immunity."13Migliorini A. Anders H.J. A novel pathogenetic concept-antiviral immunity in lupus nephritis.Nat Rev Nephrol. 2012; 8: 183-189Crossref PubMed Scopus (48) Google Scholar SLE activity can be influenced by environmental factors that contribute to DNA unmasking (certain drugs) and massive cell death (ultraviolet light), or that provide an unspecific immunostimulatory effect to autoreactive lymphocyte clones (infections).7Rahman A. Isenberg D.A. Systemic lupus erythematosus.N Engl J Med. 2008; 358: 929-939Crossref PubMed Scopus (1449) Google Scholar A recent meta-analysis of genome-wide association studies revealed that the risk of an SLE patient developing LN depends on additional genetic variants that create a predisposition for significant renal damage during the systemic autoimmune state of SLE.14Chung S.A. Brown E.E. Williams A.H. et al.Lupus nephritis susceptibility loci in women with systemic lupus erythematosus.J Am Soc Nephrol. 2014; 25: 2859-2870Crossref PubMed Scopus (89) Google Scholar Some gene variants may promote mesangial cell proliferation; others affect basement membrane stability (COLA41) or the multifaceted functions of integrin-alpha M (Mac-1/complement receptor-3, CD11b). Such additional "weaknesses" or susceptibility factors determine whether a patient develops signs of nephritis, that is, hematuria and proteinuria. Immune complex glomerulonephritis in SLE can present in different ways depending on the primary site of immune complex deposition (Figure 1b).15Anders H.J. Fogo A.B. Immunopathology of lupus nephritis.Semin Immunopathol. 2014; 36: 443-459Crossref PubMed Scopus (40) Google Scholar It was previously thought that circulating IC deposit passively in the glomerular sieve, but rather IC form in situ via the recognition of intrarenal lupus autoantigens in the mesangium, subendothelial space, or outside the glomerular basement membrane between podocyte foot processes. Once formed, immune complexes activate complement, which can injure adjacent cells, leading to either mesangial LN (International Society of Nephrology/Renal Pathology Society class I, II), endothelial-proliferative LN (class III, IV), nephrotic syndrome (class V), or various combinations of these.15Anders H.J. Fogo A.B. Immunopathology of lupus nephritis.Semin Immunopathol. 2014; 36: 443-459Crossref PubMed Scopus (40) Google Scholar The precise location of IC formation inside the glomerulus determines the type of glomerular cell that is preferentially activated and injured, for example, the mesangial cell in class II (low risk of chronic kidney disease [CKD] and ESRD), the glomerular endothelial cell in class III/IV (high risk of CKD and ESRD), or the podocyte in class V and VI (high risk of CKD and ESRD) (Figure 1). Necrotizing and crescentic glomerulonephritis are less common lesions of this process. Secondary podocytopathy causing podocyte loss and progression from focal-segmental to focal-global glomerulosclerosis is the pathomechanism that turns class III/IV into VI and underlies a progressive decline of glomerular filtration rate (GFR) to ESRD. LN patients of African ancestry show a high prevalence of APOL1 gene risk alleles, which implies a risk for faster CKD progression and ESRD.16Freedman B.I. Langefeld C.D. Andringa K.K. et al.End-stage renal disease in African Americans with lupus nephritis is associated with APOL1.Arthritis Rheumatol. 2014; 66: 390-396Crossref PubMed Scopus (197) Google Scholar IC accumulation also occurs in peritubular capillaries, causing interstitial inflammation and, in advanced disease, tertiary lymphoid organ formation in the renal interstitium.17Chang A. Henderson S.G. Brandt D. et al.In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis.J Immunol. 2011; 186: 1849-1860Crossref PubMed Scopus (247) Google Scholar Isolated tubulointerstitial nephritis with predominant B and plasma cell infiltrates, as seen in primary Sjögren's syndrome, is less common. Intrarenal inflammation is maintained via local cytokine and chemokine production, which attracts leukocytes into the glomerulus and interstitium, which further amplify local inflammation, renal cell loss, and nephron atrophy.18Allam R. Anders H.J. The role of innate immunity in autoimmune tissue injury.Curr Opin Rheumatol. 2008; 20: 538-544Crossref PubMed Scopus (81) Google Scholar, 19Kurts C. Panzer U. Anders H.-J. et al.The immune system and kidney disease: basic concepts and clinical implications.Nat Rev Immunol. 2013; 13: 738-753Crossref PubMed Scopus (442) Google Scholar This process is associated with extensive intrarenal microRNA expression and subsequent excretion in the urine, but the functional contributions of these microRNAs to the progression of lupus nephritis in vivo has not yet been well characterized. Although GFR is not always impaired during the first episode of LN, subsequent flares often show decreased renal excretory function as a late marker of underlying progressive nephron loss (Figure 2). On renal biopsy, nephron loss presents as glomerulosclerosis as well as interstitial fibrosis and tubular atrophy, referred to as chronic lesions downstream of the injury process.20Weening J.J. D'Agati V.D. Schwartz M.M. et al.The classification of glomerulonephritis in systemic lupus erythematosus revisited.J Am Soc Nephrol. 2004; 15: 241-250Crossref PubMed Scopus (1462) Google Scholar Kidney disease in SLE may not always be IC-mediated LN.21Anders H.J. Weening J.J. Kidney disease in lupus is not always 'lupus nephritis'.Arthritis Res Ther. 2013; 15: 108PubMed Google Scholar Thrombotic microangiopathy is far more frequently found in kidney biopsies of lupus patients than previously reported.22Song D. Wu L.H. Wang F.M. et al.The spectrum of renal thrombotic microangiopathy in lupus nephritis.Arthritis Res Ther. 2013; 15: R12Crossref PubMed Scopus (142) Google Scholar It may occur as a complication of SLE-related secondary antiphospholipid antibody syndrome or independent from the presence of antiphospholipid antibodies.22Song D. Wu L.H. Wang F.M. et al.The spectrum of renal thrombotic microangiopathy in lupus nephritis.Arthritis Res Ther. 2013; 15: R12Crossref PubMed Scopus (142) Google Scholar CKD in older SLE patients without previous episodes of LN may be a consequence of underlying nephron loss due to the nephropathy of aging (Figure 2). Of considerable concern in patients who have had SLE for a long time and have been treated with corticosteroids for many years is the development of treatment-induced diseases that can impact the kidney. For example, this can occur in the setting of steroid-induced diabetes or atherosclerosis, leading to diabetic nephropathy or renovascular disease, respectively. Drug toxicity is a general concern, especially in patients with SLE-related arthritis who are often given nonsteroidal anti-inflammatory drugs.21Anders H.J. Weening J.J. Kidney disease in lupus is not always 'lupus nephritis'.Arthritis Res Ther. 2013; 15: 108PubMed Google Scholar Recently, we identified an SLE patient with "refractory" class V LN whose persistent proteinuria and rapid progression to ESRD was driven by a homozygous nephrin mutation.23Romagnani P, Giglio S, Angelotti ML, et al. Next generation sequencing and functional analysis of patient urine renal progenitor-derived podocytes to unravel the diagnosis underlying refractory lupus nephritis. Nephrol Dial Trans, in press.Google Scholar This implies that not only (repeat) kidney biopsies but eventually genetic testing may be needed to unravel the cause of kidney disease in individual SLE patients.24Vivante A. Hildebrandt F. Exploring the genetic basis of early-onset chronic kidney disease.Nat Rev Nephrol. 2016; 12: 133-146Crossref PubMed Scopus (198) Google Scholar A critical factor for the successful management of LN is being able to differentiate active nephritis from chronic kidney damage.25Anders H.J. Jayne D.R. Rovin B.H. Hurdles to the introduction of new therapies for immune-mediated kidney diseases.Nat Rev Nephrol. 2016; 12: 205-216Crossref PubMed Scopus (38) Google Scholar This distinction will guide treatment for LN. Presently, disease activity and damage in response to treatment are assessed by measuring renal function and proteinuria. Kidney histology is generally only examined at LN diagnosis or flare, and it is assumed that changes in proteinuria and renal function reflect disease activity within the kidneys. This assumption has been challenged by assessing renal histology during LN treatment. Protocol repeat kidney biopsy data provide a unique look at how the kidney responds to LN treatment and, more importantly, how well histologic response is reflected by serum creatinine concentration (SCr) or estimated GFR and proteinuria.25Anders H.J. Jayne D.R. Rovin B.H. Hurdles to the introduction of new therapies for immune-mediated kidney diseases.Nat Rev Nephrol. 2016; 12: 205-216Crossref PubMed Scopus (38) Google Scholar Biopsies done before and during treatment have shown histologic and clinical findings to be discordant. Six-month biopsies, done after completing induction therapy for proliferative LN, showed that about half the patients still had active renal lesions despite having achieved a complete clinical remission (SCr stable or improved, proteinuria < 500 mg/d).26Malvar A. Pirruccio P. Lococo B. et al.Histologic versus clinical remission in proliferative lupus nephritis.Nephrol Dial Transplant. 2015;Aug 6; ([e-pub ahead of print]) (pii: gfv296, accessed May 29, 2016)PubMed Google Scholar Conversely, at the 6-month biopsy 19% of patients had achieved a complete histologic remission with no evidence of LN activity, but most (62%) of these patients still had proteinuria well over 500 mg/d. Similarly, in a Swedish cohort (n = 57) a protocol biopsy about 8 months after the start of induction therapy showed persistent inflammatory activity in 19.5% of complete clinical responders and persistent clinical findings in 41% of patients with complete histologic remission.27Zickert A. Sundelin B. Svenungsson E. Gunnarsson I. Role of early repeated renal biopsies in lupus nephritis.Lupus Sci Med. 2014; 1: e000018Crossref Scopus (75) Google Scholar After 3.5 years of treatment, 18.8% of complete clinical responders still had an National Institutes of Health activity index > 2 on repeat biopsy, and 42% of complete histologic responders still had persistent proteinuria.28Alvarado A.S. Malvar A. Lococo B. et al.The value of repeat kidney biopsy in quiescent Argentinian lupus nephritis patients.Lupus. 2014; 23: 840-847Crossref PubMed Scopus (60) Google Scholar Persistent histologic activity in the absence of clinical signs after long-term immunosuppression is concerning, adding uncertainty to the management of maintenance immunosuppressive therapy. Similarly, patients with persistent proteinuria after treatment may no longer have histologic activity, but the presence of proteinuria may discourage tapering maintenance therapy. These findings suggest that repeat biopsies combined with clinical data may be helpful in making treatment decisions. Alternatively, clinical measures or biomarkers that more accurately reflect what is occurring in the kidneys are needed. Because clinical measures of kidney function and proteinuria are not sufficiently robust biomarkers of histologic activity, novel biomarkers of disease activity, response to therapy, and long-term outcomes have been sought. Although no putative LN biomarker has been independently validated, several interesting candidates have been identified. For example, urine white blood cell subsets from 19 patients with active proliferative LN were compared with inactive LN or SLE patients with no LN (SLE controls, n = 79).29Kopetschke K. Klocke J. Grießbach A.-S. et al.The cellular signature of urinary immune cells in Lupus nephritis: new insights into potential biomarkers.Arthritis Res Ther. 2015; 17: 94Crossref PubMed Scopus (44) Google Scholar Not surprisingly, patients with active LN (based on biopsy in 74% of patients) had significantly more urine macrophages, T cells, and B cells than controls. Receiver operating characteristic analysis was done to determine if any subtype of urine leukocyte could differentiate active from inactive LN. Urine CD8+ and CD4+ T cells had areas under the receiver operating characteristic curve of 1.0 (sensitivity and specificity 100%) and 0.998 (sensitivity and specificity 98%), respectively, suggesting outstanding diagnostic discrimination. Urine T cells were also diagnostically superior to proteinuria (area under the curve = 0.92, sensitivity = 94%, specificity = 84%) and SCr (area under the curve = 0.60, sensitivity = 47%, specificity = 79%). Several urine proteins have been proposed as biomarkers of LN.30Brunner H.I. Bennett M.R. Mina R. et al.Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis.Arthritis Rheum. 2012; 64: 2687-2697Crossref PubMed Scopus (112) Google Scholar To develop a noninvasive measure of renal histologic activity, 16 putative LN biomarkers described in the literature, plus the traditional clinical biomarkers of complement levels, proteinuria, and eGFR were tested to identify a diagnostic panel that could differentiate between pediatric patients with an NIH activity index > 10 and ≤ 10.31Brunner HI, Bennett MR, Abulaban K, et al. Development of a novel renal activity index of lupus nephritis in children & young adults [e-pub ahead of print]. Arthritis Care Res (Hoboken). http://dx.doi.org/10.1002/acr.22762, accessed May 29, 2016.Google Scholar Urine for biomarker analysis was obtained at the time of diagnostic kidney biopsy. Using stepwise logistic modeling, the optimal panel included 6 novel biomarkers like MCP-1, KIM-1, and NGAL, but no clinical variables. The diagnostic metrics of this panel are excellent, with an area under the curve of 0.92, sensitivity of 90%, specificity of 86%, positive likelihood ratio of 6.3, and a false-positive rate of 14%. This biomarker panel needs to be tested in independent LN cohorts, including adults, before it can be applied clinically. A potential criticism concerns the cut-off level of 10 for activity index. This may not be as useful as being able to detect lower levels of renal activity, because it has been shown that a persistent histologic activity index > 2 after induction therapy portends a poor overall prognosis for long-term kidney function.32Alsuwaida A. Husain S. Alghonaim M. et al.Strategy for second kidney biopsy in patients with lupus nephritis.Nephrol Dial Transplant. 2012; 27: 1472-1478Crossref PubMed Scopus (53) Google Scholar Treating a patient requires first to set treatment goals (Table 1). The standard-of-care approach to LN induction therapy for proliferative disease is aggressive immunosuppression with either cyclophosphamide or mycophenolate mofetil combined with the potent anti-inflammatory activity of high-dose corticosteroids.33Kidney Disease Improving Global Outcomes (KDIGO)KDIGO Clinical Practice Guidelines for Glomerulonephritis.Kidney Int. 2012; : 139-274Google Scholar Induction lasts from 3 to 6 months and is followed by a prolonged maintenance phase with mycophenolate mofetil or azathioprine and lower doses of corticosteroids.33Kidney Disease Improving Global Outcomes (KDIGO)KDIGO Clinical Practice Guidelines for Glomerulonephritis.Kidney Int. 2012; : 139-274Google Scholar The duration of maintenance is not clear, and there are few prospective data to guide duration, but this phase generally lasts at least a year and often much longer.33Kidney Disease Improving Global Outcomes (KDIGO)KDIGO Clinical Practice Guidelines for Glomerulonephritis.Kidney Int. 2012; : 139-274Google Scholar In clinical trials, response to therapy is mainly adjudicated in the short term, often 6 to 12 months after starting treatment, although the goal of treatment is long-term preservation of kidney function. Renal response is based on clinical criteria that include proteinuria, SCr or estimated GFR, and the urinalysis or urine red blood cells, and proteinuria is the most significant component of all current response criteria.34Rovin B.H. Stillman I.E. The kidney in systemic lupus erythematosus.in: Lahita R.G. Systemic Lupus Erythematosus. Academic Press, London2011: 769-814Crossref Scopus (16) Google Scholar, 35Wofsy D. Hillson J.L. Diamond B. Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions.Arthritis Rheum. 2012; 64: 3660-3665Crossref PubMed Scopus (135) Google Scholar There is no consensus on what the levels of proteinuria, serum creatinine, and hematuria should be. Modest differences in remission criteria may significantly affect clinical trial outcomes.35Wofsy D. Hillson J.L. Diamond B. Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions.Arthritis Rheum. 2012; 64: 3660-3665Crossref PubMed Scopus (135) Google Scholar, 36Furie R. Nicholls K. Cheng T.T. et al.Efficacy and safety of abatacept in lupus nephritis: a twelve-month randomized, double-blind study.Arthritis Rheumatol. 2014; 66: 379-389Crossref PubMed Scopus (237) Google Scholar Additionally, renal remission criteria have not been studied prospectively to prove they predict long-term kidney outcomes.Table 1Treatment goals in lupus nephritisTreatment target by priorityRecommended intervention1. Lupus nephritis-related mortalityChloroquine or hydroxychloroquineControl of blood pressure and hyperlipidemia2. SLE and LN activity to avoid ESRDImmunosuppression no less and no more than necessary3. Hyperfiltration and proteinuria to avoid ESRDRenin-angiotensin-aldosterone system inhibition4. Avoid drug toxicityInfections: Reduce or eliminate corticosteroids, PJP prophylaxis, vaccination, rigorous infection controlGonadal function: Reduce or eliminate cyclophosphamide, prophylaxis with GHRH analogs, sperm and egg bankingMalignancy: Avoid lifetime cumulative cyclophosphamide of over 30 gramsFractures: Reduce or eliminate corticosteroids, vitamin D supplementation, osteomimetic drugs, bone density monitoringBirth defects: Use rigorous contraception during therapy with mycophenolate mofetil, renin-angiotensin aldosterone inhibition, vitamin K antagonistic oral anticoagulants5. SymptomsNephrotic syndrome: loop of Henle diureticsESRD, end-stage renal disease; GHRH, growth hormone–releasing hormone; LN, lupus nephritis; PJP, pneumocystis jeroveccii pneumonia; SLE, systemic lupus erythematosus. Open table in a new tab ESRD, end-stage renal disease; GHRH, growth hormone–releasing hormone; LN, lupus nephritis; PJP, pneumocystis jeroveccii pneumonia; SLE, systemic lupus erythematosus. To address the question of short-term response criteria and long-term kidney function, post hoc analyses of the Euro-Lupus Nephritis and MAINTAIN trials were done to determine whether SCr, proteinuria, or hematuria within the first year of treatment predicted an SCr < 1 mg/dl after 7 or more years of follow-up.37Dall'Era M. Cisternas M.G. Smilek D.E. et al.Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the Euro-Lupus Nephritis cohort.Arthritis Rheumatol. 2015; 67: 1305-1313Crossref PubMed Scopus (171) Google Scholar, 38Tamirou F. Lauwerys B.R. Dall'Era M. et al.A proteinuria cut-off level of 0.7 g/day after 12 months of treatment best predicts long-term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial.Lupus Sci Med. 2015; 2: e000123Crossref Scopus (105) Google Scholar The Euro-Lupus Nephritis trial compared low-dose with high-dose cyclophosphamide for induction treatment of LN,39Houssiau F.A. Vasconcelos C. D'Cruz D. et al.Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.Arthritis Rheum. 2002; 46: 2121-2131Crossref PubMed Scopus (817) Google Scholar and MAINTAIN compared azathioprine with mycophenolate mofetil as maintenance therapy.38Tamirou F. Lauwerys B.R. Dall'Era M. et al.A proteinuria cut-off level of 0.7 g/day after 12 months of treatment best predicts long-term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial.Lupus Sci Med. 2015; 2: e000123Crossref Scopus (105) Google Scholar A proteinuria level < 0.7–0.8 g/d at 12 months was the best short-term endpoint for a long-term SCr < 1 mg/dl, with positive and negative predictive values of 88% to 94% and 31% to 67%, respectively. Predictive value was not improved by adding SCr or urine red blood cells to proteinuria at 12 months. Although these results suggest that if proteinuria falls below 0.7 to 0.8 g/d after 12 months of therapy patients have a high likelihood of maintaining good long-term kidney function, this cannot be recommended as the only endpoint for future LN trials because its negative predictive value is poor, and many patients with higher 12-month proteinuria levels did well long term. Additionally, the Euro-Lupus Nephritis and MAINTAIN trials enrolled mainly Caucasian LN patients, and these results may not apply to all populations. Nonetheless, the data suggest that the urine sediment may not need to be a component of renal response criteria for multicenter clinical trials, probably because urinalyses are difficult to standardize across centers. Despite the aggressive nature of standard-of-care treatment, only 15% to 40% of patients achieve a complete renal response after 1 year.40Rovin B.H. Parikh S.V. Lupus nephritis: the evolving role of novel therapeutics.Am J Kidney Dis. 2014; 63: 677-690Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar The overall ESRD rate due to LN is about 5 cases