We investigated nationwide prevalence, incidence, and sociodemographics of SLE and lupus nephritis among Medicaid-enrolled children.
Children aged 3 to <18 years with SLE (≥3 International Classification of Diseases, 9th Revision, codes of 710.0, all >30 days apart) were identified from Medicaid Analytic eXtract data (2000–2004), containing all inpatient and outpatient Medicaid claims for 47 U. S states and the District of Columbia. Lupus nephritis was identified from ≥2 ICD-9 billing codes >30 days apart for glomerulonephritis, proteinuria or renal failure. We calculated prevalence and incidence of SLE and lupus nephritis among Medicaid-enrolled children overall and within sociodemographic groups.
Of 30,420,597 Medicaid-enrolled children during these years, 2,959 with SLE were identified. SLE prevalence was 9.73 (95% CI 9.38 – 10.08) per 100,000. Of these, 84% were female, 40% African-American, 25% Hispanic and 21% White; 42% resided in the South. 1,106 (37%) of children with SLE had lupus nephritis: prevalence 3.64 (95% CI 3.43 – 3.86) per 100,000. The average annual incidence of SLE was 2.22 (95% CI 2.05–2.40) and that of lupus nephritis was 0.72 (95%CI 0.63– 0.83) cases per 100,000 Medicaid enrollees per year. Prevalence and incidence rates of lupus and lupus nephritis increased with age, were higher in girls than boys, and in all non-White than White racial/ethnic groups.
SLE prevalence and incidence rates among Medicaid-enrolled children in the U.S. are high compared to studies in other populations. These represent the first population-based estimates of lupus nephritis prevalence and incidence in the U.S. to date.
Systemic lupus erythematosus; pediatric; nephritis; incidence; prevalence; Medicaid; children; disparities
Large administrative databases such as Medicaid billing databases could be used to study care and outcomes of lupus nephritis if these patients could be correctly identified from claims data. We aimed to develop and validate an algorithm for the correct identification of cases of lupus nephritis using ICD-9 billing codes. We used the Research Patient Data Resource (RPDR) query tool at our institution to identify patients with potential lupus nephritis. We compared four ICD-9 code based strategies, identifying patients seen between 2000 - 2007 with Medicaid medical insurance with greater than two claims for a diagnosis of SLE (ICD-9 code 710.0) and a combination of greater than two nephrologist visits and/or renal ICD-9 codes. We assessed performance using the positive predictive value (PPV). 234 subjects were identified and medical records reviewed. Our third strategy, based on a combination of lupus and renal ICD-9 codes and nephrologist encounter claims, had the highest PPV (88%) for the identification of patients with lupus nephritis. This strategy may offer a sound method of identifying patients with lupus nephritis for health services research in addition to serving as a model for using claims data as a way to better understand rare diseases such as lupus.
Lupus nephritis; medical claims data
Little is known about the sociodemographic correlates of kidney transplantation and survival among U.S. children with lupus nephritis-associated ESRD. We aimed to identify predictors of listing for kidney transplantation (wait-listing), kidney transplantation, and mortality among children with lupus nephritis-associated ESRD.
Children aged 5–18 years with new onset lupus nephritis-associated ESRD were identified in the U.S. Renal Data System (1995–2006). We investigated demographic and clinical characteristics, causes of death and predictors of wait-listing, kidney transplantation, and mortality during the first 5 years of ESRD. Cox proportional hazards models were used.
583 children had incident lupus nephritis-associated ESRD. Mean age at ESRD onset was 16.2 years (SD 2.4); 51% were African American and 24% Hispanic. Within 5 years 292 (49%) were wait-listed, 193 (33%) received a kidney transplant and 131 (22%) died. Main causes of death were cardiopulmonary (31%) and infectious (16%). Children in the Northeast and West (vs. South) were more than twice as likely to be wait-listed (P<0.001, P<0.001) and over 50% more likely to be transplanted (P<0.04). There were fewer kidney transplants among older vs. younger (OR 0.59, P=0.009), African American vs. white (OR 0.48, P<0.001), Hispanic vs. non-Hispanic (OR 0.63, P=0.03) children, and those with Medicaid vs. private insurance (OR 0.7, P=0.03). Mortality was almost double among African American vs. white children (OR 1.83, P<0.001).
Among U.S. children with lupus nephritis-associated ESRD age, race, ethnicity, insurance and geographic region were associated with significant variation in 5-year wait-listing for kidney transplant, kidney transplantation and mortality.
Systemic Lupus Erythematosus; Pediatric Rheumatology; Nephritis; Survival; End Stage Renal Disease; Children; Disparities; Outcomes
Despite numerous randomized clinical trials over the last three decades for identifying the optimal treatment option for lupus nephritis, renal involvement still significantly impacts the survival and quality of life of patients with lupus and the search for the ideal immunosuppressive regimen is far from complete. The purpose of this review is to summarize the major recent achievements in the field. More specifically, the following topics will be discussed: intravenous cyclophosphamide versus mycophenolate mofetil (MMF) for induction; azathioprine versus MMF for maintenance; targeted therapies. The review will address clues for optimal global care, such as the need for complete initial evaluation, the importance of patient education, the unmasking of non-compliance to therapy, the reason for an early treatment switch in non-responding patients, the need for prolonged immunosuppression, optimal renal protection, and prevention of cardiovascular disease and other comorbidities.
Objective. To compare the efficacy and safety of mycophenolate mofetil (MMF) and intravenous cyclophosphamide (IVC) as induction treatment for lupus nephritis (LN), by race, ethnicity and geographical region.
Methods. A total of 370 patients with active Class III–V LN received MMF (target dose 3.0 g/day) or IVC (0.5–1.0 g/m2/month), plus tapered prednisone, for 24 weeks. Renal function, global disease activity, immunological complement (C3 and C4) and anti-dsDNA levels are the outcomes that were assessed in this study.
Results. MMF was not superior to IVC as induction treatment (primary objective). There were important pre-specified interactions between treatment and race (P = 0.047) and treatment and region (P = 0.069) (primary endpoint). MMF and IVC response rates were similar for Asians (53.2 vs 63.9%; P = 0.24) and Whites (56.0 vs 54.2%; P = 0.83), but differed in the combined Other and Black group (60.4 vs 38.5%; P = 0.03). Fewer patients in the Black (40 vs 53.9%; P = 0.39) and Hispanic (38.8 vs 60.9%; P = 0.011) groups responded to IVC. Latin American patients had lower response to IVC (32 vs 60.7%; P = 0.003). Baseline disease characteristics were not predictive of response. The incidence of adverse events (AEs) was similar across groups. Serious AEs were slightly more prevalent among Asians.
Conclusions. MMF and IVC have similar efficacy overall to short-term induction therapy for LN. However, race, ethnicity and geographical region may affect treatment response; more Black and Hispanic patients responded to MMF than IVC. As these factors are inter-related, it is difficult to draw firm conclusions about their importance.
Trial registration. National Institutes of Health, www.clinicaltrials.gov, registration number NCT00377637.
Cyclophosphamide; Lupus nephritis; Mycophenolate mofetil; Race; Randomized clinical trial
Treatment with sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to be efficacious in the MRL/lpr and NZB × NZW F1 mouse models of lupus nephritis, indicating a critical role for the mTOR pathway in both models. This type of demonstration of efficacy in animal models is usually a pre-requisite for advancement into clinical development. However, efficacy in an animal model often has not translated to the desired activity in the clinic. Therefore, a more profound understanding of the mechanistic similarities and differences between various animal models and human diseases is highly desirable.
Transcriptional profiling was performed on kidneys from mice with lupus nephritis; from mice who had efficacious drug treatment; and from mice before they developed nephritis. Analysis of variance with false discovery rate adjusted to p < 0.05 and an average fold change of two or more was used to identify transcripts significantly associated with disease and response to therapy. Pathway analyses (using various bioinformatics tools) were carried out to understand the basis for drug efficacy in the mouse model. The relevance in human lupus of the pathways identified in the mouse model was explored using information from several databases derived from the published literature.
We identified a set of nephritis-associated genes in mouse kidney. Expression of the majority of these returned to asymptomatic levels on sirolimus treatment, confirming the correlation between expression levels and symptoms of nephritis. Network analysis showed that many of these nephritis genes are known to interact with the mTOR pathway. This led us to ask what human diseases are linked to the mTOR pathway. We constructed the mTOR pathway interactome consisting of proteins that interact with members of the mTOR pathway and identified a strong association between mTOR pathway genes and genes reported in the literature as being involved in human lupus.
Our findings implicate the mTOR pathway as a critical contributor to human lupus. This broad pathway-based approach to understanding the similarities in, and differences between, animal models and human diseases may have broader utility.
Little is known about patterns of use of initial kidney replacement therapies among patients with LN end-stage renal disease (LN ESRD). We aimed to identify sociodemographic and clinical factors associated with variation in initial kidney replacement therapies among LN ESRD patients.
Patients with incident LN ESRD (1995–2006) were identified in the US Renal Data System. Age, sex, race, ethnicity, medical insurance, employment status, residential region, clinical factors and comorbidities were considered as potential predictors of ESRD treatment choice -- peritoneal dialysis (PD), hemodialysis (HD) or pre-emptive kidney transplantation -- in age-adjusted and multivariable-adjusted logistic regression analyses.
Of 11,317 individuals with incident LN ESRD, 82.0% initiated HD; 12.2% PD, and 2.8% underwent pre-emptive kidney transplantation. Receiving initial PD was significantly associated with earlier calendar year, female sex, higher albumin and hemoglobin, and lower serum creatinine levels. African Americans (vs. Whites), Medicaid beneficiaries and those with no health insurance (vs. private insurance), and those unemployed (vs. employed) had significantly reduced PD initiation. Comorbidities including congestive heart failure, peripheral vascular disease and inability to ambulate were also associated with decreased PD. Many sociodemographic and clinical factors favoring PD were associated with pre-emptive kidney transplant (vs. dialysis) as well.
Few patients with LN ESRD receive initial PD or pre-emptive kidney transplantation. Race, ethnicity, employment and medical insurance type are strongly associated with initial kidney replacement therapy choice. Future studies need to investigate the appropriateness of sociodemographic and clinical variation and the comparative effectiveness of kidney replacement therapies for LN ESRD.
peritoneal dialysis; hemodialysis; kidney transplantation; survival; lupus; nephritis; end-stage renal disease; chronic kidney disease; systemic lupus erythematosus; African American; Hispanic; race; women
Lupus nephritis is one of the most serious manifestations and one of the strongest predictors of a poor outcome in systemic lupus erythematosus (SLE). Recent evidence implicated a potential role of interlukin-17 (IL-17) in the pathogenesis of lupus nephritis. However, the correlation between IL-17 expression level and the severity of lupus nephritis still remains incompletely understood. In this study, we found that serum IL-17 expression level was associated with the severity of lupus nephritis, which was evaluated by histopathology of kidney sections and urine protein. Of note, we showed that enforced expression of IL-17 using adenovirus construct that expresses IL-17 could enhance the severity of lupus nephritis, while blockade of IL-17 using neutralizing antibody resulted in decreased severity of lupus nephritis. Consistently, we observed an impaired induction of lupus nephritis in IL-17-deficient mice. Further, we revealed that IL-17 expression level was associated with immune complex deposition and complement activation in kidney. Of interest, we found that IL-17 was crucial for increasing anti-double-stranded DNA (dsDNA) antibody production in SLE. Our results suggested that IL-17 expression level positively correlated with the severity of lupus nephritis, at least in part, because of its contribution to anti-dsDNA antibody production. These findings provided a novel mechanism for how IL-17 expression level correlated with disease pathogenesis and suggested that management of IL-17 expression level was a potential and promising approach for treatment of lupus nephritis.
Race and ethnicity are important predictors of prognosis in lupus nephritis. This study was conducted to determine the clinical features, epidemiological profile, and short-term outcomes in patients of lupus nephritis from a single center in Eastern India. A total of 86 patients of class III/IV lupus nephritis were studied. Seventy-eight of them received cyclophosphamide for induction and eight of them received mycophenolate. The patients were evaluated for response, estimated glomerular filtration rate (eGFR), and proteinuria at 6 months. About 44% patients had a partial or complete response at 6 months and 64% at 1 year. The factors correlating with response at 6 months were older age at diagnosis, hypertension, activity, and chronicity indices and duration of symptoms prior to therapy. Chronicity index and hypertension were the predictors of response by logistic regression at 6 months. Compared to the Caucasian and African American patients, patients with proliferative lupus in Eastern India presented with a lower eGFR, lower proteinuria, and higher chronicity scores. Older age at diagnosis, hypertension, activity, chronicity indices, and duration of symptoms correlated with response. Short-term outcomes were similar to those described in Caucasian patients.
Lupus nephritis; prognostic markers; race; remission; short term
This study describes patterns of choosing a provider and of consumer satisfaction among prepaid Medicaid beneficiaries in Monroe County, New York, and compares their level of satisfaction to that of fee-for-service Medicaid beneficiaries. Two interview surveys were conducted with AFDC and HR (general assistance) Medicaid eligibles, the first under the fee-for-service system servicing the Medicaid population, and the second 18 months after the introduction of a mandatory, prepaid managed care system for Medicaid beneficiaries. The results show significant ethnic differences in patient choice of provider and provider site. Given the choice, Medicaid beneficiaries switch from clinics as their usual source of care to private physician practice. Under prepayment, white Medicaid beneficiaries tripled their affiliations with private doctors, while "others" doubled theirs. The results also demonstrate higher levels of patient satisfaction with "humaneness of doctors" and with "quality of care" among those beneficiaries under prepaid care, than previously documented for those under fee-for-service. The evaluations of humaneness and quality of medical system may reflect the respondents' perceptions that the process of receiving care under prepaid, managed care is somehow different, no longer second class, and better that it was under the fee-for-service Medicaid.
T cells that express IL-17 infiltrate the kidneys of patients with systemic lupus erythematosus. A significant proportion of these cells are CD3+CD4−CD8− double-negative T cells. In this study, we show that double-negative T cells from MRL/lpr mice express high amounts of IL-17 and that as disease progressively worsens, the expression of IL-17 and of IL-23 receptor in lymphocytes from these mice increases. Lymph node cells from lupus-prone mice, but not control mice, treated in vitro with IL-23 induce nephritis when transferred to non-autoimmune, lymphocyte-deficient Rag-1−/− mice. Kidney specimens from these recipient mice show significant Ig and complement deposition. The data indicate that an aberrantly active IL-23/IL-17 axis contributes to the development of nephritis in lupus-prone mice.
To test the effect of a consumer-directed model (Cash and Counseling) of Medicaid personal care services (PCS) or home-and community-based waiver services (HCBS) on the cost of Medicaid services.
Data Sources/Study Setting
Medicaid claims data were collected for all enrollees in the Cash and Counseling demonstration. Demonstration enrollees included those eligible for PCS (in Arkansas), those assessed to receive such services (in New Jersey), and recipients of Medicaid HCBS (in Florida). Enrollment occurred from December 1998 through April 2001. The follow-up period covered up to 24 months after enrollment.
Demonstration volunteers were randomly assigned to have the option to participate in Cash and Counseling (the treatment group), or to receive Medicaid services as usual from an agency (the control group). Ordinary least squares regressions were used to estimate the effect of the program on costs for Medicaid PCS/waiver services and other Medicaid services, while controlling for consumers' preenrollment characteristics and preenrollment Medicaid spending. Models were estimated separately for nonelderly and elderly adults in each state and for children in Florida.
Data Extraction Methods
Each state supplied claims data for demonstration enrollees.
Largely because the program increased consumers' ability to get the authorized amount of paid care, expenditures for personal care/waiver services were higher for the treatment group than for the control group in each state and age group, except among the elderly in Florida. Higher costs for personal care/waiver services were partially offset by savings in other Medicaid services, particularly those related to long-term care. During year 1, total Medicaid costs were generally higher for the treatment group than for the control group, with treatment–control cost differences ranging from 1 percent (and statistically insignificant) for the elderly in Florida to 17 percent for the elderly in Arkansas. In year 2, these cost differences were generally greater than in year 1. Only in Arkansas did the treatment–control difference in total cost shrink over time—to less than 5 percent (and statistically insignificant) in year 2.
Medicaid costs were generally higher under Cash and Counseling because those in the traditional system did not get the services they were entitled to. Compared with the treatment group, (1) control group members were less likely to receive any services at all (despite being authorized for them), and (2) service recipients received a lower proportion of the amount of care that was authorized. In addition, a flaw in Florida's reassessment procedures led to treatment group members receiving more generous benefit amounts than control group members. To keep total Medicaid costs per recipient at the level incurred under the traditional system, consumer-directed programs need to be carefully designed and closely monitored.
Consumer-direction; personal care; costs
To determine if the incidence of end-stage renal disease (ESRD) due to lupus nephritis has decreased from 1996 to 2004.
Patients age 15 or older with incident ESRD due to lupus nephritis in 1996-2004 and living in one of the 50 United States (U.S.) or the District of Columbia were identified using the U.S Renal Data System, a national population-based registry of all patients receiving renal replacement therapy for ESRD. Incidence rates were computed for each calendar year, using population estimates of the U.S. census as denominators.
Over the 9 year study period, 9199 new cases of ESRD due to lupus nephritis were observed. Incidence rates, adjusted to the age-, sex- and race-composition of the U.S. population in 2000, were 4.4 per million in 1996 and 4.9 per million in 2004. Compared to the pooled incidence rate in 1996-1998, the relative risk of ESRD due to lupus nephritis in 1999-2000 was 0.99 (95% Confidence Interval (CI) 0.93 – 1.06), in 2001-2002 was 0.99 (95% CI 0.92 – 1.06), and in 2003-2004 was 0.96 (95% CI 0.89 – 1.02). Findings were similar in analyses stratified by sex, age group, race, and socioeconomic status.
There was no decrease in the incidence of ESRD due to lupus nephritis between 1996 and 2004. This may reflect the limits of effectiveness of current treatments, or limitations in access, use, or adherence to treatment.
systemic lupus erythematosus; lupus nephritis; end-stage renal disease; incidence
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.
Systemic lupus erythematosus; Lupus nephritis; Neutrophil gelatinase-associated lipocalin; Systemic Lupus Erythematosus Disease Activity Index; British Isles Lupus Assessment Group; Biomarkers
Twenty-seven patients with histologically confirmed lupus nephritis were studied to identify the incidence of lupus band and its significance to histological patterns of nephritis and complement levels. It was found that the kidney involvement is 2.5 times more frequent in lupus band positive patients. The association of a positive lupus and low C3 level signifies the presence of diffuse proliferative glomerulonephritis rather than membranous glomerulonephritis. The results, together with earlier reports, are discussed.
To analyze the implementation of Medicaid preferred drug lists (PDLs) in a number of states and determine its impact on quality of care and cost relative to other segments of healthcare.
We reviewed research and case studies found by searching library databases, primarily MEDLINE and EBSCOHost, and searching pertinent journals. Keywords initially included “drug lists,” “prior authorization,” “prior approval,” and “Medicaid.” We added terms such as “influence use of other healthcare services,” “quality of care,” and “overall economic impact.” We mainly used primary sources.
Based on our literature review, we determined that there are a number of issues regarding Medicaid PDLs that need to be addressed. Some issues include: (a) the potential for PDLs to influence the utilization of other healthcare services, (b) criteria used by Medicaid for determining acceptance of drugs onto a PDL, (c)the effect of PDL implementation on compliance to new regimens, (d) the potential effects of restricting medication availability on quality of care, (e) administrative costs associated with PDLs, and (f) satisfaction rates among patients and medical providers. This review highlighted expected short-term cost savings with limited degree of compromised quality of PDL implementation, but raised the concern about the potential long-term decline in quality of care and overall economic impact.
The number of concerns raised indicates that further studies are warranted regarding both short-term cost benefits as well as potential long-term effects of Medicaid PDL implementation. Objective analysis of these effects is necessary to ensure cost-effectiveness and quality of care.
preferred drug lists; medicaid; healthcare costs; managed care
Kidney disease is one of the most serious manifestations of systemic lupus erythematosus (SLE). Despite the improvement in the medical care of SLE in the past two decades, the prognosis of lupus nephritis remains unsatisfactory. Besides exploring more effective but less toxic treatment modalities that will further improve the remission rate, early detection and treatment of renal activity may spare patients from intensive immunosuppressive therapies and reduce renal damage. Conventional clinical parameters such as creatinine clearance, proteinuria, urine sediments, anti-dsDNA, and complement levels are not sensitive or specific enough for detecting ongoing disease activity in the lupus kidneys and early relapse of nephritis. Thus, novel biomarkers are necessary to enhance the diagnostic accuracy and sensitivity of lupus renal disease, prognostic stratification, monitoring of treatment response, and detection of early renal flares. This paper reviews promising biomarkers that have recently been evaluated in longitudinal studies of lupus nephritis.
To determine the risk factors for recurrent lupus nephritis, allograft loss, and survival among systemic lupus erythematosus (SLE) kidney transplant patients.
The archival records of all SLE kidney transplant recipients (American College of Rheumatology criteria) from June 1977 – June 2007 were reviewed. Patients who died or lost the allograft within 90 days of the transplant were excluded. Time-to-event (above outcomes) was examined by univariable and multivariable proportional Cox regressions.
Two hundred-twenty of nearly 7000 renal transplantations were performed in 202 SLE patients during the 30-year interval; 177 patients met the entry criteria. These patients were predominantly women (80%) and African American (57%); mean age was 35.6 years and mean disease duration 11.2 years. Recurrent lupus nephritis ensued in 20 patients (11.3%), allograft loss in 39.0% and death in 20.3%. In all three regressions, African American ethnicity was found to be associated with a shorter time-to-the-event (HR=4.63; 95% CI 1.29 – 16.65 for recurrent lupus nephritis, HR=2.71; 95% CI 1.35 – 5.44 for allograft loss and HR=3.14; 95% CI 1.21 – 8.14 for survival). Recurrent lupus nephritis was not a significant factor for allograft loss or survival. In patients with recurrent lupus nephritis, the lesion in the engrafted kidney was predominantly mesangial (WHO Class II) as opposed to proliferative or membranous (WHO Class III, IV, V) in the native kidney.
African American ethnicity was independently associated with poorer outcomes, but recurrent lupus nephritis is not a risk factor for either allograft loss or survival. Recurrent lupus nephritis is infrequent and benign.
Podocytes are highly specialized epithelial cells that form part of the filtration barrier in the kidney, and their loss reflects a malfunction in glomerular filtration, which is usually associated with the progression of the disease. Glomerulonephritis is a serious complication that develops in about 50% of the lupus patients and is characterized by proteinuria arising from direct or indirect podocyte injury. To assess the possible role of podocytes in the pathogenesis of lupus nephritis (LN). Urinary and glomerular podocytes were detected in the kidney biopsies of patients (n = 17) with lupus nephritis, and from control biopsies obtained during autopsies. The WT-1 protein was used as a podocyte marker. The cumulative excretion of urinary podocytes was detected in the urinary sediments of LN patients and normal healthy controls, and the specimens were analyzed by immunohistochemistry, immunofluorescence, and enzyme-linked immunosorbent assay. The apoptotic index was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Gross proteinuria in lupus patients was determined via 24-hour urine samples, and the results were analyzed by Student t test. Biopsy specimens from 17 patients with class-III or IV LN had lower levels of glomerular WT-1 expression than the levels found in normal kidneys (P < 0.0001). The reduction of glomerular podocytes in patients with lupus nephritis correlated with the cumulative excretion of urinary podocytes (P < 0.0001) and proteinuria. There was no correlation between the urinary podocytes and the apoptotic index in the LN urinary sediments. A decrease in glomerular podocytes is associated with their cumulative excretion in urinary sediments; therefore, such findings correlate with proteinuria in lupus nephritis patients.
Lupus nephritis; podocytes; proteinuria; WT-1 marker
The prognostic importance of hypertension at the onset of clinical lupus nephritis is not well established. We studied retrospectively 44 patients with lupus nephritis in order to ascertain the prevalence of hypertension at presentation and to investigate a possible association between hypertension and renal functional impairment. A correlation was also sought between hypertension and histological class of lupus nephritis. Hypertension was graded as mild (diastolic 95-99 mmHg), moderate (100-114) or severe (> 115). Impaired renal function (creatinine > 120 mumol/l) was graded as mild (120-200 mumol/l), moderate (200-350 mumol/l), or severe (> 350 mumol/l). Histological class and the presence of hypertensive renal vascular lesions was recorded. The prevalence of hypertension was 38%. There were 17 hypertensives and 27 normotensives. The incidence of renal impairment was greater in the hypertensives, 47% vs 18.5% (p = 0.04). Mean serum creatinine was also higher higher in this group (p = 0.02). The presence of hypertensive renal vascular lesions identified a high-risk subgroup who had a higher incidence of renal functional impairment and worse renal function than the hypertensive group as a whole. Even at an early stage, hypertension and hypertensive renal vascular lesions correlated well with renal functional impairment. Aggressive treatment of hypertension is therefore essential in early lupus nephritis in order to prevent further deterioration of renal function as the disease evolves.
Our previous study revealed that administration of syngeneic female BALB/c mice with excessive self activated lymphocyte-derived DNA (ALD-DNA) could induce systemic lupus erythematosus (SLE) disease, indicating that overload of self-DNA might exceed normal clearance ability and comprise the major source of autoantigens in lupus mice. Serum amyloid P component (SAP), an acute-phase serum protein with binding reactivity to DNA in mice, was proved to promote the clearance of free DNA and prevent mice against self-antigen induced autoimmune response. It is reasonable to hypothesize that SAP treatment might contribute to alleviation of SLE disease, whereas its role in ALD-DNA-induced lupus nephritis is not fully understood.
The ratios of SAP to DNA significantly decreased and were negatively correlated with the titers of anti-dsDNA antibodies in ALD-DNA-induced lupus mice, indicating SAP was relatively insufficient in lupus mice. Herein a pcDNA3-SAP plasmid (pSAP) was genetically constructed and intramuscularly injected into BALB/c mice. It was found that SAP protein purified from the serum of pSAP-treated mice bound efficiently to ALD-DNA and inhibited ALD-DNA-mediated innate immune response in vitro. Treatment of ALD-DNA-induced lupus mice with pSAP in the early stage of SLE disease with the onset of proteinuria reversed lupus nephritis via decreasing anti-dsDNA autoantibody production and immune complex (IC) deposition. Further administration of pSAP in the late stage of SLE disease that had established lupus nephritis alleviated proteinuria and ameliorated lupus nephritis. This therapeutic effect of SAP was not only attributable to the decreased levels of anti-dsDNA autoantibodies, but also associated with the decreased infiltration of lymphocytes and the reduced production of inflammatory markers.
These results suggest that SAP administration could effectively alleviated lupus nephritis via modulating anti-dsDNA antibody production and the inflammation followed IC deposition, and SAP-based intervening strategy may provide new approaches for treating SLE disease.
Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE) since it is the major predictor of poor prognosis. In susceptible individuals suffering of SLE, in situ formation and deposit of immune complexes (ICs) from apoptotic bodies occur in the kidneys as a result of an amplified epitope immunological response. IC glomerular deposits generate release of proinflammatory cytokines and cell adhesion molecules causing inflammation. This leads to monocytes and polymorphonuclear cells chemotaxis. Subsequent release of proteases generates endothelial injury and mesangial proliferation. Presence of ICs promotes adaptive immune response and causes dendritic cells to release type I interferon. This induces maturation and activation of infiltrating T cells, and amplification of Th2, Th1 and Th17 lymphocytes. Each of them, amplify B cells and activates macrophages to release more proinflammatory molecules, generating effector cells that cannot be modulated promoting kidney epithelial proliferation and fibrosis. Herein immunopathological findings of LN are reviewed.
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease with frequent flares. Our aim was to evaluate the beta 2-microglobulin/cystatin C (β2M/CysC) index versus other markers as a predictor factor for assessment of SLE reactivation.
We prospectively analyzed 42 patients with lupus nephritis. Disease activity was classified using SLEDAI-2K and BILAG. Routine renal function and laboratory markers of SLE activity were performed, as well as serum β2M (Sβ2M)/serum CysC (SCysC) and Sβ2M/serum creatinine (SCreat) indexes determinations.
The 42 enrolled patients had a mean age of 37.7 ± 13.1 years, 88% were female and 67% Caucasians; mean estimated glomerular filtration rate was 61.9 ± 20.0 ml/min/1.73 m2. There was a strong correlation between SCreat versus SCysC (r = 0.887), SCreat versus Sβ2M (r = 0.865), and SCysC versus Sβ2M (r = 0.880). Multivariate analysis showed that the Sβ2M/SCreat index is a prognostic factor predicting active lupus nephritis.
As SCysC is a good marker of renal function, it would be expected that the Sβ2M/SCysC index could be a better indicator of renal activity than Sβ2M/SCreat, but in the present study it did not add relevant clinical information in the assessment of renal activity in SLE.
Beta 2-microglobulin; Cystatin C; Systemic lupus erythematosus; Disease activity; Relapse; Biomarker
Polymorphisms in the SLAM family of leukocyte cell surface regulatory molecules have been associated with lupus-like phenotypes in both humans and mice. The murine Slamf gene cluster lies within the lupus-associated Sle1b region of mouse chromosome 1. Non-autoreactive C57BL/6 (B6) mice that have had this region replaced by syntenic segments from other mouse strains (i.e. 129, NZB and NZW) are B6 congenic strains that spontaneously produce non-nephritogenic lupus-like autoantibodies. We have recently reported that genetic ablation of the SLAM family member CD48 (Slamf2) drives full-blown autoimmune disease with severe proliferative glomerulonephritis (CD48GN) in B6 mice carrying 129 sequences of the Sle1b region (B6.129CD48-/-). We also discovered that BALB/c mice with the same 129-derived CD48-null allele (BALB.129CD48-/-) have neither nephritis nor anti-DNA autoantibodies, indicating that strain specific background genes modulate the effects of CD48 deficiency. Here we further examine this novel model of lupus nephritis in which CD48 deficiency transforms benign autoreactivity into fatal nephritis. CD48GN is characterized by glomerular hypertrophy with mesangial expansion, proliferation and leukocytic infiltration. Immune complexes deposit in mesangium and in sub-endothelial, sub-epithelial and intramembranous sites along the glomerular basement membrane. Afflicted mice have low grade proteinuria, intermittent hematuria and their progressive renal injury manifests with elevated urine NGAL levels and with uremia. In contrast to the lupus-like B6.129CD48-/- animals, neither BALB.129CD48-/- mice nor B6 × BALB/c F1.129CD48-/- progeny have autoimmune traits, indicating that B6-specific background genes modulate the effect of CD48 on lupus nephritis in a recessive manner.
CD48(Slamf2); lupus nephritis; anti-DNA autoantibodies; systemic lupus erythematosus; murine lupus; Sle1b
It is unknown whether recent advances lupus nephritis (LN) treatment have led to changes in the incidence of end-stage renal disease (ESRD) secondary to LN, or in the characteristics, therapies, and outcomes of patients with LN ESRD.
Patients with incident LN ESRD (1995–2006) were identified in the US Renal Datasystem. Trends in sociodemographic and clinical characteristics were assessed. We tested for temporal changes in standardized incidence rates (SIRs) for sociodemographic groups using Poisson regression. Changes in rates of waitlisting for kidney transplant, kidney transplantation, and all-cause mortality were examined using crude and adjusted time-to-event analyses.
12,344 incident cases of LN ESRD were identified. Mean age at ESRD onset was 41 years; 81.6% were female and 49.5% African American. SIRs for LN ESRD among those ages 5–39, African Americans, and in the US Southeast increased significantly from 1995–2006. Increases in body mass index and the prevalence of both diabetes and hypertension were detected. Mean serum hemoglobin at ESRD onset increased, while that of serum creatinine decreased over time. More patients used hemodialysis and fewer peritoneal dialysis. There was a slight increase in pre-emptive kidney transplantation at ESRD onset, but kidney transplantation rates within the first three years of ESRD declined. Mortality did not change over 12 years of study.
The characteristics of LN ESRD patients and their initial therapies have changed in recent years. While SIRs rose in younger patients, among African Americans and in the South, outcomes did not improve in over a decade of evaluation.
incidence; dialysis; transplantation; survival; lupus; nephritis; end-stage renal disease; chronic kidney disease; systemic lupus erythematosus; African American; Hispanic; race; women