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1.  Understanding lupus nephritis: diagnosis, management, and treatment options 
Systemic lupus erythematosus (SLE) predominantly affects women in their reproductive years. Renal disease (glomerulonephritis) is one of the most frequent and serious manifestations of SLE. Of the various histological types of lupus glomerulonephritis, diffuse proliferative nephritis carries the worst prognosis. Combined with high-dose prednisone, mycophenolate mofetil (MMF) has emerged as a first-line immunosuppressive treatment, although data regarding the efficacy of MMF on the long-term preservation of renal function are forthcoming. Cyclophosphamide is reserved for more severe forms of lupus nephritis, such as crescentic glomerulonephritis with rapidly deteriorating renal function, patients with significant renal function impairment at presentation, and refractory renal disease. Evidence for the calcineurin inhibitors in the treatment of lupus nephritis is weaker, and it concerns patients who are intolerant or recalcitrant to other agents. While further controlled trials are mandatory, B cell modulation therapies, such as rituximab, belimumab and epratuzumab are confined to refractory disease. Non-immunosuppressive measures, such as angiotensin-converting enzyme inhibitors, vigorous blood pressure control, prevention and treatment of hyperlipidemia and osteoporosis, are equally important.
doi:10.2147/IJWH.S28034
PMCID: PMC3367406  PMID: 22675266
lupus; nephritis; nephropathy; glomerulonephritis; treatment; therapy; women
2.  Treatment of young patients with lupus nephritis using calcineurin inhibitors 
World Journal of Nephrology  2012;1(6):177-183.
Recent advances in the management of lupus nephritis, together with earlier renal biopsy and selective use of aggressive immunosuppressive therapy, have contributed to a favorable outcome in children and adolescents with systemic lupus erythematosus (SLE). Nevertheless, we believe that a more effective and less toxic treatment is needed to attain an optimal control of the activity of lupus nephritis. Recent published papers and our experiences regarding treatment of young patients with lupus nephritis using calcineurin inhibitors are reviewed. Although it has been reported that intermittent monthly pulses of intravenous cyclophosphamide (IVCY) are effective for preserving renal function in adult patients, CPA is a potent immunosuppressive agent that induces severe toxicity, including myelo- and gonadal toxicity, and increases the risk of secondary malignancy. Thus, treatment for controlling lupus nephritis activity, especially in children and adolescents, remains challenging. Cyclosporine A (CsA) and tacrolimus (Tac) are T-cell-specific calcineurin inhibitors that prevent the activation of helper T cells, thereby inhibiting the transcription of the early activation genes of interleukin (IL)-2 and suppressing T cell-induced activation of tumor necrosis factor-α, IL-1β and IL-6. Therefore, both drugs, which we believe may be less cytotoxic, are attractive therapeutic options for young patients with lupus nephritis. Recently, a multidrug regimen of prednisolone (PDN), Tac, and mycophenolate mofetile (MMF) has been found effective and relatively safe in adult lupus nephritis. Since the mechanisms of action of MMF and Tac are probably complementary, multidrug therapy for lupus nephritis may be useful. We propose as an alternative to IVCY, a multidrug therapy with mizoribine, which acts very similarly to MMF, and Tac, which has a different mode of action, combined with PDN for pediatric-onset lupus nephritis. We also believe that a multidrug therapy including CsA and Tac may be an attractive option for young patients with SLE and lupus nephritis
doi:10.5527/wjn.v1.i6.177
PMCID: PMC3782217  PMID: 24175257
Calcineurin inhibitor; Cyclosporine A; Lupus nephritis; Multidrug therapy; Systemic lupus erythematosus; Tacrolimus
3.  Mycophenolate mofetil as maintenance therapy for proliferative lupus nephritis: a long-term observational prospective study 
Arthritis Research & Therapy  2010;12(6):R208.
Introduction
While the role of mycophenolate mofetil (MMF) in the management of lupus nephritis has been increasingly recognized, limited information is available regarding its efficacy and safety as a long-term maintenance treatment. The aim of the present study was to evaluate the efficacy and safety profile of MMF as maintenance therapy for proliferative lupus nephritis.
Methods
Thirty-three consecutive patients with proliferative lupus nephritis received induction therapy with five to seven monthly intravenous (iv) pulses of cyclophosphamide (CYC) plus iv steroids followed by oral MMF 2 g/day as maintenance therapy for a median time of 29 months (range 9 to 71 months). Primary end points were the achievement of renal remission, complete renal remission, disease remission - renal and extrarenal -, the occurrence of renal relapse, chronic renal failure and death. Secondary end points were the extrarenal disease activity and drug adverse events. The clinical and laboratory parameters were compared during follow-up by means of nonparametric statistical tests. Time to event analysis was performed according to the Kaplan-Meier method.
Results
A significant improvement of all renal parameters was observed at the end of the induction treatment and at the latest follow-up compared to baseline. The rate of patients achieving renal remission until the end of follow-up was 73%, whereas that of complete renal remission was 58%. The median survival times in the Kaplan-Meier analyses were 7 and 16 months, respectively. Remission was maintained in all but four (12%) patients who relapsed within 19 to 39 months after initial response. At the end of follow-up, 51% of the patients had reached disease remission. The median survival time of disease remission was 18 months. Extrarenal manifestations were well controlled in most of the patients. In one patient receiving MMF, extrarenal activity led to treatment discontinuation. Non life-threatening drug adverse events developed in 18 patients (58%) and included infections, amenorrhea, myelotoxicity, gastrointestinal complications, hypercholesterolemia, alopecia and drug intolerance. None of the patients developed chronic renal insufficiency or died from any cause.
Conclusions
MMF appeared to be efficacious and safe as maintenance treatment for proliferative lupus nephritis.
doi:10.1186/ar3184
PMCID: PMC3046515  PMID: 21059275
4.  Safety and immunogenicity of the quadrivalent HPV vaccine in female Systemic Lupus Erythematosus patients aged 12 to 26 years 
Background
Women with SLE have higher rates of persistent human papilloma virus (HPV) infections and precancerous lesions than healthy women. HPV vaccine is safe and effective in healthy females aged 9–26 years. There are limited data on the safety and immunogenicity of HPV vaccine in females with SLE, and none in adolescents with SLE. Our study evaluates the safety and immunogenicity of recombinant quadrivalent HPV vaccine, Gardasil, in adolescents and young women with SLE.
Methods
This is a prospective, open-label study. Exclusion criteria included disease exacerbation within past 30 days; rituximab or cyclophosphamide within 6 months; pregnancy. Vaccine was administered at months 0, 2, and 6. Physical examination, SLEDAI scores and laboratory studies were performed at months 0, 2, 4, 6 and 7. Each patient’s SLEDAI scores and laboratory profile in the year prior to vaccine administration were used as controls for that patient. Primary outcome measures were change in SLEDAI and mean HPV antibody titers.
Results
27 patients, 12 to 26 years, were enrolled; 20 completed the study. Nine had mild/moderate lupus flares. Mean SLEDAI scores decreased from 6.14 pre-vaccination to 4.49 post-vaccination (p = 0.01). Of 12 patients with lupus nephritis, two experienced worsening renal function during/after the study and progressed to renal failure within 18 months of the study. Both had Class IV lupus nephritis with high chronicity scores (≥ 8) on renal biopsies performed within one year prior to study entry. Seropositivity post-vaccine was >94% for HPV 6, 11, 16 and 18.
Conclusions
Quadrivalent HPV vaccine seems generally safe and well tolerated in this series of adolescents and young women with SLE, with no increase in mean SLEDAI scores. Progression to renal failure in two patients was most likely secondary to pre-existing severe renal chronicity and not secondary to HPV vaccination. Immunogenicity to the quadrivalent HPV vaccine was excellent, with the seropositivity rate >94% in all four HPV types.
doi:10.1186/1546-0096-11-29
PMCID: PMC3751269  PMID: 23924237
Human papillomavirus; Lupus; Safety; Immunogenicity; Pediatric; Vaccine
5.  Childhood-onset systemic lupus erythematosus. 
OBJECTIVES: To describe the initial clinicolaboratory manifestations and short-term outcome in a series of Nigerian children with systemic lupus erythematosus (SLE). METHODS: A nonrandomized prospective study of consecutive cases of childhood-onset SLE. Baseline and follow-up clinicolaboratory data were collected and analyzed. Each patient was followed up for 12 months. RESULTS: Eleven children were studied. There were seven girls (F:M, 1.75). Mean ages at lupus onset and diagnosis were 10.0 +/- 2.53 years and 11.2 +/- 2.53 years, respectively. Mean time at onset of renal disease following SLE symptoms onset was 1.22 +/- 0.93 years. All cases were misdiagnosed prior to presentation; diagnosis was delayed in nine patients. Lupus activity was mild, moderate and severe in two, five and four patients, respectively. Hypertension (n = 5), nephrotic syndrome (n = 6), microerythrocyturia (n = 6) and acute renal failure (n = 7) were associated morbidities. Of the 27 presenting clinical features, 17 were nondiagnostic, while 10 were diagnostic. Fever (n = 9) was a major nondiagnostic symptom; major diagnostic manifestations were lupus nephritis (n = 11), arthritis (n = 10) and serositis (n = 7). Catastrophic antiphospholipid syndrome was diagnosed in three. The glomerular lesions were nonproliferative (n = 1), focal (n = 3) and diffuse (n = 7) proliferative lupus nephritis. Complete remission rate at end-point was 71.4%. Fourteen percent of the patients relapsed. Renal survival and mortality rates were 86.0% and 30.0%, respectively. CONCLUSION: In this study, severe renal and extrarenal comorbidities were common; mortality rate was also high. High frequency of misdiagnosis and delayed diagnosis were probably responsible for these.
PMCID: PMC2574347  PMID: 17668644
6.  A Treatment Algorithm for Children with Lupus Nephritis to Prevent Developing Renal Failure 
Chronic kidney disease is one of the most common complication of systemic lupus erythematosus, which if untreated can lead to the end-stage renal disease (ESRD). Early diagnosis and adequate treatment of lupus nephritis (LN) is critical to prevent the chronic kidney disease incidence and to reduce the development of ESRD. The treatment of LN has changed significantly over the past decade. In patients with active proliferative LN (Classes III and IV) intravenous methylprednisolone 1 g/m2/day for 1-3 days then prednisone 0.5-1.0 mg/kg/day, tapered to <0.5 mg/kg/day after 10-12 weeks of treatment plus mycophenolate mofetile (MMF) 1.2 g/m2/day for 6 months followed by maintenance lower doses of MMF 1-2 g/day or azathioprine (AZA) 2 mg/kg/day for 3 years have proven to be efficacy and less toxic than cyclophosphamide (CYC) therapy. Patients with membranous LN (Class V) plus diffuse or local proliferative LN (Class III and Class IV) should receive either the standard 6 monthly pulses of CYC (0.5-1 g/m2/month) then every 3rd month or to a shorter treatment course consisting of 0.5 g/m2 IV CYC every 2 weeks for six doses (total dose 3 g) followed by maintenance therapy with daily AZA (2 mg/kg/day) or MMF (0.6 g/m2/day) for 3 years. Combination of MMF plus rituximab or MMF plus calcineurin inhibitors may be an effective co-therapy for those refractory to induction or maintenance therapies. This report introduces a new treatment algorithm to prevent the development of ESRD in children with LN.
PMCID: PMC4018632  PMID: 24829707
End-stage renal disease; lupus; nephritis; treatment algorithm
7.  Successful Treatment of Refractory Thrombocytopenia with Mycophenolate Mofetil in a Patient with Systemic Lupus Erythematosus 
Journal of Korean Medical Science  2005;20(5):883-885.
While mild thrombocytopenia in systemic lupus erythematosus (SLE) is frequently seen in the context of active disease, severe thrombocytopenia causing significant bleeding is not that common. Corticosteroids are considered the first line therapy for severe thrombocytopenia in SLE. Second-line therapeutic agents or splenectomy have been reported to be effective for patients who fail to respond to steroids or those who require moderate doses of steroids to maintain the platelet counts. Recent randomized controlled studies have shown that mycophenolate mofetil (MMF) is an efficacious and safe therapeutic agent in patients with proliferative forms of lupus nephritis. However, little information has been available regarding the role of MMF in the treatment of immune thrombocytopenia complicated with SLE. Hereby I describe a patient with SLE in whom thrombocytopenia was refractory to corticosteroids, intermittent intravenous cyclophosphamide, azathioprine, cyclosporine, intravenous gamma globulin, danazol, and splenectomy, and whose platelet counts eventually normalized during therapy with MMF. In this patient, thrombocytopenia is initially thought to be associated with active SLE involving major organ. However, after immunosuppressive agents were given, the refractory nature of thrombocytopenia seems to be an isolated phenomenon, independently of SLE activity.
doi:10.3346/jkms.2005.20.5.883
PMCID: PMC2779290  PMID: 16224167
Lupus Erythematosus, Systemic; Thrombocytopenia; mycophenolate mofetiI
8.  Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial 
Annals of the Rheumatic Diseases  2010;69(12):2083-2089.
Background
Long-term immunosuppressive treatment does not efficiently prevent relapses of lupus nephritis (LN). This investigator-initiated randomised trial tested whether mycophenolate mofetil (MMF) was superior to azathioprine (AZA) as maintenance treatment.
Methods
A total of 105 patients with lupus with proliferative LN were included. All received three daily intravenous pulses of 750 mg methylprednisolone, followed by oral glucocorticoids and six fortnightly cyclophosphamide intravenous pulses of 500 mg. Based on randomisation performed at baseline, AZA (target dose: 2 mg/kg/day) or MMF (target dose: 2 g/day) was given at week 12. Analyses were by intent to treat. Time to renal flare was the primary end point. Mean (SD) follow-up of the intent-to-treat population was 48 (14) months.
Results
The baseline clinical, biological and pathological characteristics of patients allocated to AZA or MMF did not differ. Renal flares were observed in 13 (25%) AZA-treated and 10 (19%) MMF-treated patients. Time to renal flare, to severe systemic flare, to benign flare and to renal remission did not statistically differ. Over a 3-year period, 24 h proteinuria, serum creatinine, serum albumin, serum C3, haemoglobin and global disease activity scores improved similarly in both groups. Doubling of serum creatinine occurred in four AZA-treated and three MMF-treated patients. Adverse events did not differ between the groups except for haematological cytopenias, which were statistically more frequent in the AZA group (p=0.03) but led only one patient to drop out.
Conclusions
Fewer renal flares were observed in patients receiving MMF but the difference did not reach statistical significance.
doi:10.1136/ard.2010.131995
PMCID: PMC3002764  PMID: 20833738
9.  Renal Dnase1 Enzyme Activity and Protein Expression Is Selectively Shut Down in Murine and Human Membranoproliferative Lupus Nephritis 
PLoS ONE  2010;5(8):e12096.
Background
Deposition of chromatin-IgG complexes within glomerular membranes is a key event in the pathogenesis of lupus nephritis. We recently reported an acquired loss of renal Dnase1 expression linked to transformation from mild to severe membranoproliferative lupus nephritis in (NZBxNZW)F1 mice. As this may represent a basic mechanism in the progression of lupus nephritis, several aspects of Dnase1 expression in lupus nephritis were analyzed.
Methodology/Principal Findings
Total nuclease activity and Dnase1 expression and activity was evaluated using in situ and in vitro analyses of kidneys and sera from (NZBxNZW)F1 mice of different ages, and from age-matched healthy controls. Immunofluorescence staining for Dnase1 was performed on kidney biopsies from (NZBxNZW)F1 mice as well as from human SLE patients and controls. Reduced serum Dnase1 activity was observed in both mesangial and end-stage lupus nephritis. A selective reduction in renal Dnase1 activity was seen in mice with massive deposition of chromatin-containing immune complexes in glomerular capillary walls. Mice with mild mesangial nephritis showed normal renal Dnase1 activity. Similar differences were seen when comparing human kidneys with severe and mild lupus nephritis. Dnase1 was diffusely expressed within the kidney in normal and mildly affected kidneys, whereas upon progression towards end-stage renal disease, Dnase1 was down-regulated in all renal compartments. This demonstrates that the changes associated with development of severe nephritis in the murine model are also relevant to human lupus nephritis.
Conclusions/Significance
Reduction in renal Dnase1 expression and activity is limited to mice and SLE patients with signs of membranoproliferative nephritis, and may be a critical event in the development of severe forms of lupus nephritis. Reduced Dnase1 activity reflects loss in the expression of the protein and not inhibition of enzyme activity.
doi:10.1371/journal.pone.0012096
PMCID: PMC2938370  PMID: 20856893
10.  Association of Serum Nitrate and Nitrite Levels With Longitudinal Assessments of Disease Activity and Damage in Systemic Lupus Erythematosus and Lupus Nephritis 
Arthritis and rheumatism  2008;58(1):263-272.
Objective
Reactive intermediate production is an essential component of the innate immune response that is induced during disease activity in murine lupus. This study was undertaken to determine whether a marker of systemic nitric oxide (NO) production correlates with prospectively studied disease activity in human systemic lupus erythematosus (SLE) and lupus nephritis patients.
Methods
Eighty-three SLE patients and 40 control subjects were studied longitudinally. The SLE group included 23 patients with lupus nephritis documented by renal biopsy and 26 with a history of lupus nephritis. During each visit, following a 24-hour low-nitrate diet, traditional markers of disease activity and damage were determined. Serum nitrate plus nitrite (NOx) levels were determined by chemiluminescence detection.
Results
NOx levels were higher in SLE patients than in controls during the first visit. In univariate longitudinal analyses, NOx levels were associated with SLE Disease Activity Index scores. In multivariate analyses, NOx levels were associated with serum levels of C3 and creatinine and the urinary protein:creatinine ratio. Among patients with lupus nephritis, those with proliferative lesions had higher NOx levels, and higher NOx levels were associated with accumulation of renal damage and lack of response to therapy.
Conclusion
This is the first study to prospectively demonstrate longitudinal associations between serum NOx levels and markers of SLE and lupus nephritis disease activity. The more pronounced association with proliferative lupus nephritis and with longitudinal response to lupus nephritis therapy provides a rationale for the study of reactive intermediates as biomarkers of disease activity and therapeutic targets in proliferative lupus nephritis.
doi:10.1002/art.23153
PMCID: PMC2733831  PMID: 18163495
11.  Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis 
PLoS ONE  2013;8(12):e84450.
Lupus nephritis is a cause of significant morbidity in systemic lupus erythematosus (SLE) and its genetic background has not been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for association with lupus nephritis, its severe form proliferative nephritis and renal outcome, in two Swedish cohorts. Cohort I (n = 567 SLE cases, n =  512 controls) was previously genotyped for 5676 SNPs and cohort II (n = 145 SLE cases, n = 619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK.
Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysis of cohort I, four highly linked SNPs in STAT4 were associated with lupus nephritis with genome wide significance with p = 3.7×10−9, OR 2.20 for the best SNP rs11889341. Strong signals of association between IRF5 and an HLA-DR3 SNP marker were also detected in the lupus nephritis case versus healthy control analysis (p <0.0001). An additional six genes showed an association with lupus nephritis with p <0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). In the case-only meta-analysis of the two cohorts, the STAT4 SNP rs7582694 was associated with severe renal insufficiency with p  = 1.6×10−3 and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.
doi:10.1371/journal.pone.0084450
PMCID: PMC3873995  PMID: 24386384
12.  Serum levels of autoantibodies against C-reactive protein correlate with renal disease activity and response to therapy in lupus nephritis 
Arthritis Research & Therapy  2009;11(6):R188.
Introduction
Serum levels of C-reactive protein (CRP) seldom reflect disease activity in systemic lupus erythematosus (SLE). We have previously shown that autoantibodies against neo-epitopes of CRP often occur in SLE, but that this does not explain the modest CRP response seen in flares. However, we have repeatedly found that anti-CRP levels parallel lupus disease activity, with highest levels in patients with renal involvement; thus, we aimed to study anti-CRP in a material of well-characterized lupus nephritis patients.
Methods
Thirty-eight patients with lupus nephritis were included. Treatment with corticosteroids combined with cyclophosphamide, mycophenolate mofetil or rituximab was started after baseline kidney biopsy. A second biopsy was taken after ≥ 6 months. Serum creatinine, cystatin C, complement, anti-dsDNA, anti-CRP and urinalysis were done on both occasions. Biopsies were evaluated regarding World Health Organisation (WHO) class and indices of activity and chronicity. Renal disease activity was estimated using the British Isles Lupus Assessment Group (BILAG) index.
Results
At baseline, 34/38 patients had renal BILAG-A; 4/38 had BILAG-B. Baseline biopsies showed WHO class III (n = 8), IV (n = 19), III to IV/V (n = 3) or V (n = 8) nephritis. Seventeen out of 38 patients were anti-CRP-positive at baseline, and six at follow-up. Overall, anti-CRP levels had dropped at follow-up (P < 0.0001) and anti-CRP levels correlated with renal BILAG (r = 0.29, P = 0.012). A positive anti-CRP test at baseline was superior to anti-dsDNA and C1q in predicting poor response to therapy as judged by renal BILAG. Baseline anti-CRP levels correlated with renal biopsy activity (r = 0.33, P = 0.045), but not with chronicity index. Anti-CRP levels were positively correlated with anti-dsDNA (fluorescence-enhanced immunoassay: r = 0.63, P = 0.0003; Crithidia luciliae immunofluorescence microscopy test: r = 0.44, P < 0.0001), and inversely with C3 (r = 0.35, P = 0.007) and C4 (r = 0.29, P = 0.02), but not with C1q (r = 0.14, P = 0.24). No associations with urinary components, creatinine, cystatin C or the glomerular filtration rate were found.
Conclusions
In the present study, we demonstrate a statistically significant correlation between anti-CRP levels and histopathological activity in lupus nephritis, whereas a baseline positive anti-CRP test predicted poor response to therapy. Our data also confirm previous findings of associations between anti-CRP and disease activity. This indicates that anti-CRP could be helpful to assess disease activity and response to therapy in SLE nephritis, and highlights the hypothesis of a pathogenetic role for anti-CRP antibodies in lupus nephritis.
doi:10.1186/ar2880
PMCID: PMC3003497  PMID: 20003354
13.  Time to Renal Disease and End-Stage Renal Disease in PROFILE: A Multiethnic Lupus Cohort 
PLoS Medicine  2006;3(10):e396.
Background
Renal involvement is a serious manifestation of systemic lupus erythematosus (SLE); it may portend a poor prognosis as it may lead to end-stage renal disease (ESRD). The purpose of this study was to determine the factors predicting the development of renal involvement and its progression to ESRD in a multi-ethnic SLE cohort (PROFILE).
Methods and Findings
PROFILE includes SLE patients from five different United States institutions. We examined at baseline the socioeconomic–demographic, clinical, and genetic variables associated with the development of renal involvement and its progression to ESRD by univariable and multivariable Cox proportional hazards regression analyses. Analyses of onset of renal involvement included only patients with renal involvement after SLE diagnosis (n = 229). Analyses of ESRD included all patients, regardless of whether renal involvement occurred before, at, or after SLE diagnosis (34 of 438 patients). In addition, we performed a multivariable logistic regression analysis of the variables associated with the development of renal involvement at any time during the course of SLE.
In the time-dependent multivariable analysis, patients developing renal involvement were more likely to have more American College of Rheumatology criteria for SLE, and to be younger, hypertensive, and of African-American or Hispanic (from Texas) ethnicity. Alternative regression models were consistent with these results. In addition to greater accrued disease damage (renal damage excluded), younger age, and Hispanic ethnicity (from Texas), homozygosity for the valine allele of FcγRIIIa (FCGR3A*GG) was a significant predictor of ESRD. Results from the multivariable logistic regression model that included all cases of renal involvement were consistent with those from the Cox model.
Conclusions
Fcγ receptor genotype is a risk factor for progression of renal disease to ESRD. Since the frequency distribution of FCGR3A alleles does not vary significantly among the ethnic groups studied, the additional factors underlying the ethnic disparities in renal disease progression remain to be elucidated.
Fcγ receptor genotype is a risk factor for progression of renal disease to ESRD but does not explain the ethnic disparities in renal disease progression.
Editors' Summary
Background.
Systemic lupus erythematosis (SLE, commonly known as “lupus”) is an illness of many manifestations that appear to result from the immune system attacking components of the body's own cells. One of the unfortunate effects of SLE is kidney damage, which can, in a minority of patients, progress to kidney failure (formally called “end-stage renal disease,” or ESRD). Compared to White Americans, other ethnic groups tend to develop renal complications of lupus more often and with worse outcomes.
Why Was This Study Done?
It is unclear why some people with lupus develop kidney problems. The purpose of this US-based study was to confirm the factors that increase the risk of kidney damage and kidney failure, particularly in racial and ethnic minority patients, and to determine which of these factors accelerate the pace of kidney disease. Knowing these risk factors could allow the development and targeting of interventions, such as screening tests and preventive treatments, to prevent long-term loss of kidney function in patients with lupus.
What Did the Researchers Do and Find?
The researchers measured a number of factors in a multi-ethnic group of 1,008 patients with lupus, almost half of whom had some degree of kidney involvement. They found that those who developed kidney damage after being diagnosed with lupus tended to be younger, to have had lupus for a longer time, and to have experienced more effects of lupus in general than those who did not have kidney involvement. Those who developed kidney problems were also more likely to have been unemployed, to have had fewer years of formal education, and to have had high blood pressure before developing kidney involvement. African-American and Texan Hispanic individuals with lupus were more likely to develop kidney involvement, and tended to develop it more rapidly, than White Americans or Puerto Rican Hispanic ethnicity. Actual kidney failure (ESRD requiring dialysis or kidney transplantation) was more likely to occur among Texan Hispanics with kidney involvement than in the other ethnic groups. Diabetes and high blood pressure were not found to predict ESRD, but people with a particular variant of a protein that helps antibodies bind to cells (know as Fc-gamma receptor IIIa, or FcγRIIIa) were found to be more likely to develop ESRD, and to develop it more quickly.
What Do These Findings Mean?
These results suggest that the emergence and progression of kidney disease in patients with lupus depends on medical, genetic, and socioeconomic factors. Because no single test or intervention can be expected to address all of these factors, those treating patients with lupus must remain aware of the complexity of their patients lives at a variety of levels. In particular, ethnic disparities in the risk of serious kidney disease remain to be addressed.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030396.
MedlinePlus page on lupus
Lupus Foundation of America
American College of Rheumatology pages on lupus
Wikipedia entry on lupus (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030396
PMCID: PMC1626549  PMID: 17076550
14.  Monocyte procoagulant activity in glomerulonephritis associated with systemic lupus erythematosus. 
Journal of Clinical Investigation  1985;75(3):861-868.
Monocyte infiltration and activation of the coagulation system have been implicated in the pathophysiology of glomerulonephritis. In this study, spontaneous procoagulant activity (PCA) was measured in circulating mononuclear cells to determine whether elevated PCA correlated with the presence of proliferative glomerulonephritis in patients with systemic lupus erythematosus (SLE). No increase in PCA was found in 20 patients with end-stage renal failure, 8 patients with glomerulonephritis without SLE, and 10 patients undergoing abdominal surgical or orthopedic procedures as compared with 20 normal controls. In eight patients with SLE but with no apparent active renal disease, PCA was not elevated above normal basal levels. Seven additional patients with SLE who had only mesangial proliferation on biopsy also had no increase in PCA. In contrast, eight patients with focal or diffuse proliferative lupus nephritis, and one patient with membranous nephritis who ultimately developed a proliferative lesion, had a marked increase in PCA with greater than 100 times the base-line levels. The activity was shown to originate in the monocyte fraction of the mononuclear cells and was shown to be capable of cleaving prothrombin directly. The prothrombinase activity was not Factor Xa, because it was not neutralized by anti-Factor X serum and was not inhibited by an established panel of Factor Xa inhibitors. Monocyte plasminogen activator determinations did not correlate with renal disease activity. We conclude that monocyte procoagulant activity, a direct prothrombinase, seems to correlate with endocapillary proliferation in lupus nephritis and could be a mediator of tissue injury.
Images
PMCID: PMC423616  PMID: 4038982
15.  Multicenter Retrospective Analysis of the Effectiveness and Safety of Rituximab in Korean Patients with Refractory Systemic Lupus Erythematosus 
Autoimmune Diseases  2012;2012:565039.
Objective. Although two recent randomized placebo-controlled trials of rituximab (RTX) failed to demonstrate efficacy in systemic lupus erythematosus (SLE), clinicians continue to use off-label RTX for cases refractory to current treatments. We evaluated the effectiveness and safety of rituximab for patients with refractory SLE in Korea. Methods. We retrospectively analyzed multicenter patients treated with RTX in Korea. Results. 39 SLE patients treated with RTX were included in the following manner: lupus nephritis 43.6%, hematologic 33.3%, arthritis 7.8%, myositis 7.8%, and others 7.7%. All patients had responded poorly to at least one conventional immunosuppressive agent (mean 2.5 ± 1.1, cyclophosphamide 43.6%, mycophenolate mofetil 48.7%, and other drugs) before RTX. Clinical improvements (complete or partial remission) occurred in patients with renal disease, hematologic disease, arthritis, myositis, and other manifestations at 6 months after RTX. The SLEDAI score was significantly decreased from 10.8 ± 7.1 at baseline to 6.7 ± 4.0 at 6 months, 6.2 ± 4.1 at 12 months, and 5.5 ± 3.6 at 24 months after RTX (P < 0.05). Among 28 clinical responders, 4 patients experienced a relapse of disease at 25 ± 4 months. Infections were noted in 3 patients (7.7%). Conclusion. RTX could be an effective and relatively safe therapeutic option in patients with severe refractory SLE until novel B-cell depletion therapy is available.
doi:10.1155/2012/565039
PMCID: PMC3523406  PMID: 23304457
16.  Mycophenolate Mofetil in the Treatment of Systemic Lupus Erythematosus 
The Eurasian Journal of Medicine  2009;41(3):180-185.
Mycophenolate mofetil (MMF) is an immunosuppressive agent that has been shown to be effective in transplant patients. It is also efficacious in the management of lupus nephritis and useful in the treatment of autoimmune conditions because its mechanisms of action target T- and B- lymphocytes, leading to suppression of the cell-mediated immune response and antibody formation. MMF has been used successfully to treat immune-mediated conditions like myasthenia gravis, autoimmune hepatitis and immune cytopenias. However, the conditions for its optimal use for non-renal manifestations (e.g., hematological, neuropsychiatric, myocardial, pulmonary or cutaneous symptoms) in lupus patients are unclear. There have yet to be any randomized, controlled trials to guide the optimal dose and duration of MMF treatment in such situations. MMF is well tolerated and safe to use, although there are reports of serious adverse effects including urticaria, myopathy, Epstein-Barr virus-associated B-cell lymphoma, cytomegalovirus infection and disseminated varicella zoster infection. Immunosuppressive treatment with MMF and supportive care over the past few decades have led to improved clinical outcomes in patients with severe lupus nephritis. A favorable long-term prognosis can be ensured provided that effective treatment is instituted early, before irreversible renal parenchymal damage occurs. Another area of concern for patients is the increased cost of long-term MMF use.
PMCID: PMC4261281  PMID: 25610099
Systemic lupus erythematosus; Mycophenolate mofetil; Treatment
17.  Usefulness of ISN/RPS Classification of Lupus Nephritis 
Journal of Korean Medical Science  2009;24(Suppl 1):S7-S10.
About 50-80% of patients with lupus suffer from lupus nephritis which is one of major causes of morbidity and mortality. Renal pathologists and nephrologists should evaluate the degree of histological damages to establish therapeutic plans for lupus nephritis. In order to standardize definitions, to emphasize clinically relevant lesions, and to improve interobserver reproducibility, the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification was proposed. Recently, several retrospective validation studies concerning the utility of the ISN/RPS classification, especially among class IV, were performed. In these reports, reproducibility is improved by the definition of diagnostic term, but the outcome related with classification, especially in class IV, is controversial. We performed retrospective analysis of 99 biopsy-proven subjects with lupus nephritis in our facility using the ISN/RPS classification. The class IV-G group tended to exhibit a worse renal outcome, but the difference compared with IV-S was not significant. In a Cox proportional hazards models, Independent histological predictors of poor renal outcome were extracapillary proliferation, glomerular sclerosis and fibrous crescents, while hyaline thrombi and fibrous adhesions were of favorable renal outcome. Both were similarly observed in IV-G and IV-S. The more qualitative categorization by the response to standard treatment may be needed to emphasize clinically relevant lesion related to renal outcome.
doi:10.3346/jkms.2009.24.S1.S7
PMCID: PMC2633180  PMID: 19194566
ISN/RPS Classification; Lupus; Lupus Nephritis; Outcome
18.  Rituximab therapy for juvenile-onset systemic lupus erythematosus 
Rituximab (RTX), an anti-CD20 monoclonal antibody, has been proposed for use in the therapy of systemic lupus erythematosus (SLE). We present the initial long-term experience of the safety and efficacy of rituximab for treatment of SLE in children. Eighteen patients (mean age 14 ± 3 years) with severe SLE were treated with rituximab after demonstrating resistance or toxicity to conventional regimens. There was a predominance of female (16/18) and ethnic African (13/18) patients. All had lupus nephritis [World Health Organization (WHO) classes 3–5] and systemic manifestations of vasculitis. Clinical disease activity of the SLE was scored with the SLE-disease activity index 2K (SLEDAI-2K). Patients were followed-up for an average of 3.0 ± 1.3 years (range 0.5 to 4.8 years). B-cell depletion occurred within 2 weeks in all patients and persisted for up to 1 year in some. Clinical activity scores, double-stranded DNA (dsDNA) antibodies, renal function and proteinuria [urine protein to creatinine ratio (Upr/cr)] improved in 93% of the patients. Five patients required multiple courses of RTX for relapse, with B-cell repopulation. One died of infectious endocarditis related to severe immunosuppression. In conclusion, our data support the efficacy of rituximab as adjunctive treatment for SLE in children. Although rituximab was well tolerated by the majority of patients, randomized controlled trials are required to establish its long-term safety and efficacy.
doi:10.1007/s00467-007-0694-9
PMCID: PMC2214826  PMID: 18097688
Rituximab; Systemic lupus erythematosus; Children
19.  Urine levels of HMGB1 in Systemic Lupus Erythematosus patients with and without renal manifestations 
Arthritis Research & Therapy  2012;14(4):R184.
Introduction
Lupus nephritis (LN) is a severe and frequent manifestation of systemic lupus erythematosus (SLE). Its pathogenesis has not been fully elucidated but immune complexes are considered to contribute to the inflammatory pathology in LN. High Mobility Group Box 1 (HMGB1) is a nuclear non-histone protein which is secreted from different types of cells during activation and/or cell death and may act as a pro-inflammatory mediator, alone or as part of DNA-containing immune complexes in SLE. Urinary excretion of HMGB1 might reflect renal inflammatory injury. To assess whether urinary HMGB1 reflects renal inflammation we determined serum levels of HMGB1 simultaneously with its urinary levels in SLE patients with and without LN in comparison to healthy controls (HC). We also analyzed urinary HMGB1 levels in relation with clinical and serological disease activity.
Methods
The study population consisted of 69 SLE patients and 17 HC. Twenty-one patients had biopsy proven active LN, 15 patients had a history of LN without current activity, and 33 patients had non-renal SLE. Serum and urine levels of HMGB1 were both measured by western blotting. Clinical and serological parameters were assessed according to routine procedures. In 17 patients with active LN a parallel analysis was performed on the expression of HMGB1 in renal biopsies.
Results
Serum and urinary levels of HMGB1 were significantly increased in patients with active LN compared to patients without active LN and HC. Similarly, renal tissue of active LN patients showed strong expression of HMGB1 at cytoplasmic and extracellular sites suggesting active release of HMGB1. Serum and urinary levels in patients without active LN were also significantly higher compared to HC. Urinary HMGB1 levels correlated with SLEDAI, and showed a negative correlation with complement C3 and C4.
Conclusion
Levels of HMGB1 in urine of SLE patients, in particular in those with active LN, are increased and correlate with SLEDAI scores. Renal tissue of LN patients shows increased release of nuclear HMGB1 compared to control renal tissue. HMGB1, although at lower levels, is, however, also present in the urine of patients without active LN. These data suggest that urinary HMGB1 might reflect both local renal inflammation as well as systemic inflammation.
doi:10.1186/ar4015
PMCID: PMC3580580  PMID: 22892043
20.  Immunohistochemical study of the human glomerular C3b receptor in normal kidney and in seventy-five cases of renal diseases: loss of C3b receptor antigen in focal hyalinosis and in proliferative nephritis of systemic lupus erythematosus. 
Journal of Clinical Investigation  1982;69(4):900-912.
The presence and distribution of C3b receptors in normal human kidneys and in biopsies from 75 patients with renal disease were investigated by immunohistochemical techniques using monospecific rabbit antibody to the 205,000-mol wt glycoprotein that is the C3b receptor of human peripheral blood cells. Anti-C3b receptor bound exclusively to podocytes in normal renal cortex, and was homogeneously distributed on the plasma membrane of these cells. Biosynthesis of the receptor by the podocyte was suggested by the presence of antigenic activity in the Golgi apparatus. Although occupancy of receptor sites following the interaction of kidney sections with aggregated IgG preincubated with normal serum inhibited binding to glomeruli of C3b coated cells, the C3b receptor remained accessible to anti-C3b receptor antibody. No staining of podocytes was found in extra-capillary proliferating cells in rapidly progressive glomerulonephritis (GN). Segmental loss of staining was found in focal hyalinosis, nodular diabetic glomerulosclerosis, and amyloidosis while no detectable C3b receptor antigen was found in severe proliferative nephritis of systemic lupus erythematosus (SLE). Normal staining of podocytes was found in other nephropathies with endocapillary proliferation such as acute GN and mesangial GN and in renal diseases associated with immune deposits containing C3 such as mesangial proliferative and membranous SLE nephritis, idiopathic membranous GN, membranoproliferative GN types I and II, mesangial GN with IgA or C3 deposition and Henoch Schönlein's purpura. Loss of C3b receptor antigen in the diffuse proliferative nephritis of SLE distinguishes it both from nonproliferative lupus nephritis and other immunologically mediated proliferative GN.
Images
PMCID: PMC370144  PMID: 7042757
21.  The spectrum of renal thrombotic microangiopathy in lupus nephritis 
Introduction
Among various lupus renal vascular changes, thrombotic microangiopathy (TMA) presented with the most severe clinical manifestations and high mortality. The pathogenesis of TMA in systemic lupus erythematosus (SLE) was complicated. The aim of this study was to assess clinical manifestations, laboratory characteristics, pathological features and risk factors for clinical outcomes of lupus nephritis patients co-existing with renal TMA in a large cohort in China.
Methods
Clinical and renal histopathological data of 148 patients with biopsy-proven lupus nephritis were retrospectively analyzed. Serum complement factor H, A Disintegrin and Metalloprotease with Thrombospondin type I repeats 13 (ADAMTS-13) activity, antiphospholipid antibodies and C4d deposition on renal vessels were further detected and analyzed.
Results
In the 148 patients with lupus nephritis, 36 patients were diagnosed as co-existing with renal TMA based on pathological diagnosis. Among the 36 TMA patients, their clinical diagnoses of renal TMA were as followings: 2 patients combining with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 2 patients combining with anti-phospholipid syndrome, 2 patients with malignant hypertension, 1 patient with scleroderma and the other 29 patients presenting with isolated renal TMA. Compared with the non-renal TMA group, patients with renal TMA had significantly higher urine protein (7.09 ± 4.64 vs. 4.75 ± 3.13 g/24h, P = 0.007) and serum creatinine (159, 86 to 215 vs. 81, 68 to 112 μmol/l, P <0.001), higher scores of total activity indices (AI) (P <0.001), endocapillary hypercellularity (P <0.001), subendothelial hyaline deposits (P = 0.003), interstitial inflammation (P = 0.005), glomerular leukocyte infiltration (P = 0.006), total chronicity indices (CI) (P = 0.033), tubular atrophy (P = 0.004) and interstitial fibrosis (P = 0.018). Patients with renal TMA presented with poorer renal outcome (P = 0.005) compared with the non-TMA group. Renal TMA (hazard ratio (HR): 2.772, 95% confidence interval: 1.009 to 7.617, P = 0.048) was an independent risk factor for renal outcome in patients with lupus nephritis. The renal outcome was poorer for those with both C4d deposition and decreased serum complement factor H in the TMA group (P = 0.007).
Conclusions
There were various causes of renal TMA in lupus nephritis. Complement over-activation via both classical and alternative pathways might play an important role in the pathogenesis of renal TMA in lupus nephritis.
doi:10.1186/ar4142
PMCID: PMC3672792  PMID: 23320601
22.  Acute tubulointerstitial nephritis complicating Legionnaires' disease: a case report 
Introduction
Legionnaires' disease is recognized as a multi-systemic illness. Afflicted patients may have pulmonary, renal, gastrointestinal tract and central nervous system complications. However, renal insufficiency is uncommon. The spectrum of renal involvement may range from a mild and transient elevation of serum creatinine levels to anuric renal failure requiring dialysis and may be linked to several causes. In our present case report, we would like to draw attention to the importance of the pathological documentation of acute renal failure by reporting a case of a patient with acute tubulointerstitial nephritis complicating Legionnaires' disease.
Case presentation
A 55-year-old Caucasian man was admitted to our hospital for community-acquired pneumonia complicated by acute renal failure. Legionella pneumophila serogroup type 1 was diagnosed. Although the patient's respiratory illness responded to intravenous erythromycin and ofloxacin therapy, his renal failure worsened, he became anuric, and hemodialysis was started. A renal biopsy was performed, which revealed severe tubulointerstitial nephritis. After initiation of steroid therapy, his renal function improved dramatically.
Conclusions
This case highlights the importance of kidney biopsies in cases where acute renal failure is a complicating factor in Legionnaires' disease. If the presence of acute tubulointerstitial nephritis can be confirmed, it will likely respond favorably to steroidal treatment and thus irreversible renal damage and chronic renal failure will be avoided.
doi:10.1186/1752-1947-6-100
PMCID: PMC3359167  PMID: 22475340
Legionnaires' disease; acute renal failure; tubulointerstitial nephritis; renal biopsy
23.  Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis 
Rheumatology (Oxford, England)  2010;49(5):960-971.
Objectives. Clinical and laboratory markers in current use have limited specificity and sensitivity for predicting the development of renal disease in lupus patients. In this longitudinal study, we investigated whether urinary neutrophil gelatinase-associated lipocalin (uNGAL) predicts active nephritis and renal flares in lupus patients with and without a history of biopsy-proven lupus nephritis.
Methods. Renal disease activity and flare status was determined by SLEDAI and BILAG scores. Random effects models were used to determine whether uNGAL was a significant predictor for renal disease activity in SLE patients, and for renal flares in patients with established nephritis. To assess the predictive performance of uNGAL, receiver operating characteristic (ROC) curves were constructed using the previous visit’s uNGAL level. These curves were then compared with curves constructed with currently used biomarkers. Cut-offs determined by ROC curves were tested in an independent validation cohort.
Results. uNGAL was found to be a significant predictor of renal disease activity in all SLE patients, and a significant predictor for flare in patients with a history of biopsy-proven nephritis, in multivariate models adjusting for age, race, sex and anti-double-stranded (ds)DNA antibody titres. As a predictor of renal flare in patients with biopsy-proven nephritis, uNGAL outperformed anti-dsDNA antibody titres. These results were confirmed in an independent validation cohort.
Conclusions. uNGAL predicts renal flare in patients with a history of biopsy-proven nephritis with high sensitivity and specificity. Furthermore, uNGAL is a more sensitive and specific forecaster of renal flare in patients with a history of lupus nephritis than anti-dsDNA antibody titres.
doi:10.1093/rheumatology/kep468
PMCID: PMC2853702  PMID: 20144927
Systemic lupus erythematosus; Lupus nephritis; Neutrophil gelatinase-associated lipocalin; Systemic Lupus Erythematosus Disease Activity Index; British Isles Lupus Assessment Group; Biomarkers
24.  The outcome of proliferative lupus nephritis with pulse cyclophosphamide therapy 
Indian Journal of Nephrology  2011;21(3):160-165.
Proliferative lupus nephritis deserves aggressive therapy and cyclophosphamide plays a pivotal role. Thirty nine patients with proliferative lupus nephritis (Class III-7 patients and Class IV- 32 patients) with a median follow up of 38 months were considered for this observational study. All the patients received induction therapy with intravenous methylprednisolone. Cyclophosphamide was given intravenously initially in monthly pulses for six months and later quarterly pulses until remission was achieved or until the target dose (200 mg/kg) was reached. The treatment with intravenous methylprednisolone was repeated in the event of a nephritic flare. Later the corticosteroid was reduced to a minimum effective dose and cyclophosphamide was changed to either azathioprine or mycophenolate mofetil. At the time of the last follow up, 82.05% of the patients were in remission (complete remission 51.28% and partial remission 30.77%). The median interval to achieve remission in responders was 15 months. Early diagnosis (P=0.04), a higher creatinine clearance at presentation (P=0.02), and concurrent use of an ACEI or an ARB (P=007) significantly favored attaining remission. Five patients experienced a doubling of serum creatinine and one of them became dialysis dependent. Risk of doubling of serum creatinine correlated with a low Ccr (P=0.03) at presentation, occurrence of renal flares (P=0.034) and failure to achieve remission (P=0.0001). The parameters like serum creatinine, serum C3, serum C4, activity and chronicity indices on renal biopsy, hypertension were not statistically significant. Therapy with cyclophosphamide, if initiated early, helps in inducing remission and hence can retard the progression to CKD.
doi:10.4103/0971-4065.83933
PMCID: PMC3161432  PMID: 21886974
Chronic kidney disease; cyclophosphamide; lupus nephritis; remission
25.  Systemic lupus erythematosus with nephritis. 
Archives of Disease in Childhood  1981;56(10):779-783.
Thirty-six patients with the onset of symptoms of systemic lupus erythematosus before age 20 years (23 aged less than 15 years at onset) were studied during a 15-year period. All had clinical evidence of nephritis. They were followed for a mean of 5 years (range 6 months to 13 years) or until death. Survival was calculated to be 77% at 10 years for those aged less than 15, and 74% for those aged less than 20, from the onset of clinical nephritis. At referral, renal function was already impaired in two-thirds of patients. Renal biopsies showed mild focal or proliferative changes in 19% of patients, membranous lesions in 11%, and diffuse proliferative lesions in 70%. Three (8%) patients died during follow-up, all from sepsis, and 3 (8%) others required chronic haemodialysis for terminal renal failure. The prognosis even of severe lupus nephritis in childhood and adolescence has improved in recent years. Side effects of treatment remain an important cause of death and morbidity.
PMCID: PMC1627322  PMID: 7305417

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