Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression.

Renal DNase I is lost in advanced stages of lupus nephritis. Here, we determined if loss of renal DNase I reflects a concurrent loss of urinary DNase I, and whether absence of urinary DNase I predicts disease progression. Mouse and human DNase I protein and DNase I endonuclease activity levels were determined by western blot, gel, and radial activity assays at different stages of the murine and human forms of the disease. Cellular localization of DNase I was analyzed by immunohistochemistry, immunofluorescence, confocal microscopy, and immunoelectron microscopy. We further compared DNase I levels in human native and transplanted kidneys to determine if the disease depended on autologous renal genes, or whether the nephritic process proceeded also in transplanted kidneys. The data indicate that reduced renal DNase I expression level relates to serious progression of lupus nephritis in murine, human native, and transplanted kidneys. Notably, silencing of renal DNase I correlated with loss of DNase I endonuclease activity in the urine samples. Thus, urinary DNase I levels may therefore be used as a marker of lupus nephritis disease progression and reduce the need for renal biopsies.

Prevalence and risk factors for coronary artery calcification following kidney transplantation for systemic lupus erythematosus.

OBJECTIVES: Patients with SLE who undergo kidney transplantation are at increased risk of premature cardiovascular disease. The current study aimed to investigate the prevalence of coronary artery calcification in transplanted SLE patients without coronary symptoms and to explore risk factors associated with coronary atherosclerosis. METHODS: This was a cross-sectional study in transplanted SLE patients with a functioning graft. Evaluation included laboratory tests, SLE disease activity indices, multi-slice CT for quantification of coronary calcification (Agatston score >400 = high calcification, <400 = mild to moderate calcification). Arterial and aortic stiffness was assessed by carotid-femoral pulse wave velocity (PWV). RESULTS: Thirty-nine patients were analysed, three of whom had a prior history of coronary events. Coronary artery calcification was present in 82% of patients (n = 32), with 36% (n = 14) with a high level of arterial calcification. Multivariate regression analysis showed the following factors to be independently associated with high coronary calcification: PWV (0.41, 95% CI 0.17, 0.66, P = 0.001), time since diagnosis of LN (0.66, 95% CI 0.43, 0.71, P < 0.001) and BMI (0.39, 95% CI 0.15, 0.63, P = 0.002). Immunosuppression regimen was not significantly different between groups. CONCLUSIONS: Coronary artery calcification is widespread in transplanted SLE patients despite a normal profile of conventional cardiovascular risk factors. The risk of calcification increases with disease duration, BMI and PWV in this population.

Rosuvastatin in diabetic hemodialysis patients.

A randomized, placebo-controlled trial in diabetic patients receiving hemodialysis showed no effect of atorvastatin on a composite cardiovascular endpoint, but analysis of the component cardiac endpoints suggested that atorvastatin may significantly reduce risk. Because the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) trial included patients with and without diabetes, we conducted a post hoc analysis to determine whether rosuvastatin might reduce the risk of cardiac events in diabetic patients receiving hemodialysis. Among the 731 participants with diabetes, traditional risk factors such as LDL-C, smoking, and BP did not associate with cardiac events (cardiac death and nonfatal myocardial infarction). At baseline, only age and high-sensitivity C-reactive protein were independent risk factors for cardiac events. Assignment to rosuvastatin associated with a nonsignificant 16.2% reduction in risk for the AURORA trial's composite primary endpoint of cardiac death, nonfatal MI, or fatal or nonfatal stroke (HR 0.84; 95% CI 0.65 to 1.07). There was no difference in overall stroke, but the rosuvastatin group had more hemorrhagic strokes than the placebo group (12 versus two strokes, respectively; HR, 5.21; 95% CI 1.17 to 23.27). Rosuvastatin treatment significantly reduced the rates of cardiac events by 32% among patients with diabetes (HR 0.68; 95% CI 0.51 to 0.90). In conclusion, among hemodialysis patients with diabetes mellitus, rosuvastatin might reduce the risk of fatal and nonfatal cardiac events.

Inflammation-associated graft loss in renal transplant recipients.

BACKGROUND: Although short-term graft survival has improved substantially in renal transplant recipients, long-term graft survival has not improved over the last decades. The lack of knowledge of specific causes and risk factors has hampered improvements in long-term allograft survival. There is an uncertainty if inflammation is associated with late graft loss. METHODS: We examined, in a large prospective trial, the inflammation markers high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) and their association with chronic graft dysfunction. We collected data from the Assessment of Lescol in Renal Transplant trial, which recruited 2102 maintenance renal transplant recipients. RESULTS: Baseline values were hsCRP 3.8 ± 6.7 mg/L and IL-6 2.9 ± 1.9 pg/mL. Adjusted for traditional risk factors, hsCRP and IL-6 were independently associated with death-censored graft loss, the composite end points graft loss or death and doubling of serum creatinine, graft loss or death. CONCLUSION: The inflammation markers hsCRP and IL-6 are associated with long-term graft outcomes in renal transplant recipients.

Premature cardiovascular disease in patients with systemic lupus erythematosus influences survival after renal transplantation.

OBJECTIVE: To assess graft and patient survival as well as causes for graft loss and patient death after renal transplantation in patients with systemic lupus erythematosus (SLE). METHODS: Eighty-seven renal transplantations were performed in 77 patients with SLE from 1972 to 2005. Each recipient with SLE was matched (for date of transplant, age, donor source [living versus deceased], and sex) with 2 renal graft recipients who had non-SLE glomerulonephritis, and the SLE and non-SLE groups were compared with regard to graft survival and patient survival. RESULTS: The mean ± SD age of SLE patients at the time of transplantation was 37.4 ± 12.8 years, and the majority of SLE patients were female (80.5%). SLE patients were well matched to control transplant patients for date of transplant, age, and donor source (living versus deceased donor). The death-censored graft survival rate for SLE patients receiving transplants corresponded closely to that for the control groups; the 1-, 5-, and 10-year graft survival rates were 88%, 81%, and 71%, respectively, for SLE patients, and 91%, 83%, and 74%, respectively, for patients with non-SLE glomerulonephritis (P = 0.31). Patient survival differed significantly; the rates of survival for recipients with SLE were 94%, 83%, and 71% at 1, 5, and 10 years, respectively. The corresponding rates of patient survival in the non-SLE glomerulonephritis cohort were 96%, 92%, and 85% (P = 0.018). Cardiovascular events were the most prominent cause of death in SLE patients (66.7%, versus 39.5% in the control group; P = 0.03). CONCLUSION: Transplant patients with SLE have a graft survival rate that matches that of recipients with non-SLE glomerulonephritis. SLE patients who receive transplants have a lower survival rate than control patients. The excessive mortality in SLE is attributed to a greater number of cardiovascular deaths.

[Lupus-nephritis--diagnosis and treatment]. / Lupusnefritt--diagnostikk og behandling.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune, multiorgan disease that usually affects young women. The kidneys are affected (lupus nephritis) in close to one fifth of the patients. Over the past decade earlier diagnosis and improved treatment of lupus nephritis has resulted in substantial improvement of renal function and patient survival. Despite these advances, 10 - 15 % of SLE patients with lupus nephritis progress to end-stage renal disease, requiring dialysis or renal transplantation. The article outlines main principles for diagnosing and treating lupus nephritis, according to current practice at Oslo University Hospital. MATERIAL AND METHODS: National and international guidelines (on treatment of lupus nephritis), literature identified through a non-systematic search in PubMed and our own clinical experience form the basis for the article. RESULTS: In lupus nephritis, low-dose cyclophosphamide and corticosteroids are topical treatment for induction therapy, and mycophenolate mofetil is an alternative treatment. We recommend maintenance treatment with azathioprine or mycophenolate mofetil for at least two years. Treatment with rituximab may be considered in patients with refractory lupus nephritis. INTERPRETATION: Subtypes and activity of the renal disease are decisive for choice of treatment.

Recurrent lupus nephritis after kidney transplantation: a surveillance biopsy study.

OBJECTIVES: To determine the incidence of recurrent lupus nephritis (LN) in renal transplant recipients with systemic lupus erythematosus (SLE). METHODS: All patients with SLE that had undergone transplant with a functioning graft were asked in 2008 to participate in a cross-sectional study. The study included a standardised clinical examination, laboratory tests and a biopsy of the transplanted kidney. RESULTS: A total of 41 (93%) of a cohort of 44 patients with SLE with renal transplants participated. Of the biopsies, 3 were indication biopsies and 38 were surveillance biopsies. In all, 22 patients (54%) had biopsy-proven recurrence of LN. The majority of the cases were subclinical and characterised as class I/class II LN. Proteinuria (mg protein/mmol creatinine) was significantly increased in patients with recurrence, 70.6 (104.9) mg/mmol versus 11.9 (6.7) mg/mmol in patients without recurrence (p=0.038). Lupus anticoagulant was found more frequently in the patients with recurrence, nine versus two patients (p=0.033). Recurrence of LN was associated with receiving a kidney from a living donor (p=0.049). In all, 83% (34 of 41) had chronic allograft nephropathy in the transplanted kidneys with no difference between patients with recurrence or without. CONCLUSIONS: Subclinical recurrence of LN is common in patients with renal transplants with SLE. The majority of the patients have chronic allograft nephropathy.

Effect of fluvastatin on cardiac outcomes in kidney transplant patients with systemic lupus erythematosus: a randomized placebo-controlled study.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE), with or without end-stage renal failure, are at increased risk of premature cardiovascular disease. Although statin therapy has been found to reduce cardiovascular risk in the general population, its effectiveness in kidney transplant recipients with SLE has not been examined. This study was undertaken to investigate the effect of fluvastatin on cardiac end points in a randomized controlled trial of renal transplant patients with SLE. METHODS: Patients with SLE were identified from among participants in the Assessment of Lescol in Renal Transplantation trial, a randomized, double-blind, placebo-controlled study of the effect of fluvastatin (40-80 mg/day) on cardiovascular outcomes in renal transplant recipients. Patients were randomized to either a group receiving fluvastatin or a placebo group for the duration of the 5-6-year trial, and then invited to continue in a 2-year open-label extension during which all participants, regardless of original group, received fluvastatin. Patients were followed up for a total of 7-8 years for assessment of the primary end point of major cardiac events, comprising nonfatal myocardial infarction, cardiac death, and coronary intervention procedures. RESULTS: Fluvastatin reduced low-density lipoprotein cholesterol levels by 29.2% (95% confidence interval [95% CI] 18.3-40%), from a mean +/- SD of 4.0 +/- 0.9 mmoles/liter to 2.8 +/- 1.1 mmoles/liter, and total cholesterol by 19.6% (95% CI 11.7-27.5%), from 6.4 +/- 0.9 mmoles/liter to 5.1 +/- 1.1 mmoles/liter. Compared with placebo-treated patients, patients randomized to receive fluvastatin exhibited a 73.4% reduction in the risk of major cardiac events (relative risk 26.6 [95% CI 5.9-119.4], P = 0.064). CONCLUSION: Our results indicate that the effect of fluvastatin on cardiac events in renal transplant recipients with SLE is similar to that observed with statin therapy in the renal transplant population as a whole.