End-stage Lupus Nephritis Research Articles

CCL17-producing cDC2s are essential in end-stage lupus nephritis and averted by a parasitic infection.

Lupus nephritis is a severe organ manifestation in systemic lupus erythematosus leading to kidney failure in a subset of patients. In lupus-prone mice, controlled infection with Plasmodium parasites protects against the progression of autoimmune pathology including lethal glomerulonephritis. Here, we demonstrate that parasite-induced protection was not due to a systemic effect of infection on autoimmunity as previously assumed, but rather to specific alterations in immune cell infiltrates into kidneys and renal draining lymph nodes. Infection of lupus-prone mice with a Plasmodium parasite did not reduce the levels or specificities of autoreactive antibodies, vasculitis, immune complex-induced innate activation, or hypoxia. Instead, infection uniquely reduced kidney-infiltrating CCL17-producing bone marrow-derived type 2 inflammatory dendritic cells (iDC2s). Bone marrow reconstitution experiments revealed that infection with Plasmodium caused alterations in bone marrow cells that hindered the ability of DC2s to infiltrate the kidneys. The essential role for CCL17 in lupus nephritis was confirmed by in vivo depletion with a blocking antibody, which reduced kidney pathology and immune infiltrates, while bypassing the need for parasitic infection. Therefore, infiltration into the kidneys of iDC2s, with the potential to prime local adaptive responses, is an essential regulated event in the transition from manageable glomerulonephritis to lethal tubular injury.

Proteomic analysis in lupus mice identifies Coronin-1A as a potential biomarker for lupus nephritis

BackgroundApproximately 50% of systemic lupus erythematosus (SLE) patients develop nephritis, which is among the most severe and frequent complications of the disease and a leading cause of morbidity and mortality. Despite intensive research, there are still no reliable lupus nephritis (LN) markers in clinical use that can assess renal damage and activity with a high sensitivity and specificity. To this end, the aim of this study was to identify new clinically relevant tissue-specific protein biomarkers and possible underlying molecular mechanisms associated with renal involvement in SLE, using mass spectrometry (MS)-based proteomics.MethodsKidneys were harvested from female triple congenic B6.NZMsle1/sle2/sle3 lupus mice model, and the respective sex- and age-matched C57BL/6 control mice at 12, 24 and 36 weeks of age, representing pre-symptomatic, established and end-stage LN, respectively. Proteins were extracted from kidneys, purified, reduced, alkylated and digested by trypsin. Purified peptides were separated by liquid chromatography and analysed by high-resolution MS. Data were processed by the Progenesis QIp software, and functional annotation analysis was performed using DAVID bioinformatics resources. Immunofluorescence and multiple reaction monitoring (MRM) MS methods were used to confirm prospective biomarkers in SLE mouse strains as well as human serum samples.ResultsProteomic profiling of kidney tissues from SLE and control mice resulted in the identification of more than 3800 unique proteins. Pathway analysis revealed a number of dysregulated molecular pathways that may be mechanistically involved in renal pathology, including phagosome and proximal tubule bicarbonate reclamation pathways. Proteomic analysis supported by human transcriptomic data and pathway analysis revealed Coronin-1A, Ubiquitin-like protein ISG15, and Rho GDP-dissociation inhibitor 2, as potential LN biomarkers. These results were further validated in other SLE mouse strains using MRM-MS. Most importantly, experiments in humans showed that measurement of Coronin-1A in human sera using MRM-MS can segregate LN patients from SLE patients without nephritis with a high sensitivity (100%) and specificity (100%).ConclusionsThese preliminary findings suggest that serum Coronin-1A may serve as a promising non-invasive biomarker for LN and, upon validation in larger cohorts, may be employed in the future as a screening test for renal disease in SLE patients.

Outcomes in Renal Transplant Recipients With Lupus Nephritis—A Single–Center Experience and Review of the Literature

BackgroundRenal transplantation is the renal replacement therapy of choice in patients with end–stage lupus nephritis (LN). The aim of this study was to evaluate the early and late outcomes of renal transplantation in LN patients in a single transplant center. Patients and MethodsThis study analyzed the clinical data of patients who received a renal transplant (RTx) at Gdańsk Transplantation Centre between January 1999 and December 2014. ResultsThere were 1296 RTx performed between January 1999 and December 2014, including 21 RTx in 19 LN patients (mean age 40 ± 10 years, 89% female). During the follow–up period (between 1 month and 10.5 years), 1 patient died of urosepsis and 1 of pneumonia. Three RTx recipients with antiphospholipid syndrome lost 5 kidney allografts, including 3 due to acute rejection (AR) during the first posttransplantation month. Kidney allograft survival median was 64 months. Delayed graft function (DGF) and AR were observed in 48% and 33% vs 31% and 21% of LN patients and other RTx patients, respectively (P = .1 and P = .16 for DGF and AR, respectively). The most common early posttransplantation complications were AR (31%) and perirenal hematomas (29%), and late complications were urinary tract infections (75%). Recurrence of LN in renal allograft was observed in 1 patient and was successfully treated by increasing the basic immunosuppression. ConclusionsSecondary antiphospholipid syndrome has a major influence on the outcomes of RTx in LN patients. Recurrence of LN has no clinical significance.

Renal Dnase1 Enzyme Activity and Protein Expression Is Selectively Shut Down in Murine and Human Membranoproliferative Lupus Nephritis

BackgroundDeposition 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 FindingsTotal 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/SignificanceReduction 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.

Methodologic Issues in the Validation of Putative Biomarkers and Surrogate Endpoints in Treatment Evaluation for Systemic Lupus Erythematosus

No new drugs have been approved for the treatment of systemic lupus erythematosus (SLE) by the Food and Drug Administration for the last 30 years. One barrier has been the lack of validated biomarkers and surrogate endpoints. Validation of SLE biomarkers in the past have been methodologically flawed. We put forth a conceptual framework and five critical criterion for validating putative biomarkers and bio-surrogates in this heterogeneous multi-system disease with protean manifestations. Using the example of a putative biomarker for end-stage lupus nephritis, we performed computer simulations for planning a biomarker bio-repository to support the validation process. "Random time window" sampling where a biomarker is obtained in an interval randomly selected from the total follow-up time for that subject creates survival bias. This can be avoided by the "fixed calendar window" design, in which biomarkers are measured within the same, pre-specified period for all cohort members who remain at risk during that period. In lupus nephritis where the incidence rate of end-stage renal disease is relatively low, to accumulate 300 instances of end-stage renal disease, at risk patients would have to be followed for about 5,000 person-years, implying 500 subjects followed, on average, for about 10 years. Increasing the number of biomarker determinations per subject from one to five reduces the required number of subjects by 10-15%, while further increases in the number of observations per subject yielded much smaller gains. The large numbers of subjects required for a bio-repository, makes it essential to maximize the efficiency of study designs and analyses and provides the strongest rationale for collaboration and the use of standardized measures to ensure comparability.

Pauci-immune and Immune Glomerular Lesions in Kidney Transplants for Systemic Lupus Erythematosus

Glomerular lesions in allografts in recipients with end-stage nephritis resulting from systemic lupus erythematosus (SLE) were examined to determine the spectrum of glomerular pathology in recurrent glomerulonephritis (GN). A total of 156 biopsy samples, from 49 serial allografts in 43 recipients with end-stage lupus nephritis, were examined by light microscopy, and by immunofluorescence and electron microscopy in selected cases. These were compared with control allografts (n = 35). Glomerular lesions best explained by recurrent lupus nephritis were observed in 19 of 49 allografts (38.8%) in lupus recipients. Three categories of glomerulopathies were identified: 1) immune complex glomerulopathies, including mesangial GN (28%) and membranous GN (4%); 2) atypical glomerulopathies, including acute proliferative GN (32%) and focal segmental glomerulosclerosis (12%), with scant immune deposits in glomerular capillaries, frequent endothelial tubuloreticular inclusions, and thrombotic microangiopathy; and 3) transplant-associated glomerulopathies (24%). Allografts from recipients with SLE had typical immune complex-mediated GN and atypical pauci-immune, proliferative GN and segmental glomerular sclerosis. Atypical glomerulopathies like these suggest a role for nonimmune complex-mediated glomerular injury in recurrent lupus GN.

End-stage lupus nephritis (ES-LN), risk factors for coronary heart disease (CHD) and echocardiographyc study

End-stage lupus nephritis (ES-LN), risk factors for coronary heart disease (CHD) and echocardiographyc study

Transhepatic PermCath for Hemodialysis

The establishment and maintenance of a reliable vascular access continues to be a problem in hemodialysis. We report a patient with end-stage lupus nephritis who had no alternative for vascular access and failed peritoneal dialysis. A vascular access device (PermCath, Quinton Instrument Co, Bothell, WA) was inserted using a transhepatic approach. There were no bleeding or thrombotic complications. The catheter was replaced once through the same track due to poor blood flow and reinserted once after 5 days due to infection. The patient has been doing well and receiving adequate dialytic therapy for over 1 year with this form of vascular access.

An Epidemiologic Analysis of End-stage Lupus Nephritis

We analyzed 566 patients (515 females and 51 males) with systemic lupus erythematosus who were treated in Okinawa, Japan, from 1972 to 1991 and followed until April 1993. One hundred four patients (95 females and 9 males) died, and 51 were considered to have end-stage lupus nephritis. The annual incidence and prevalence, per million population in each sex, were increased from 16.0 and 66.0 in 1972 to 46.7 and 683.9 in 1991 in the female patients, and from 4.2 and 8.3 in 1973 to 8.3 and 70.0 in 1991 in the male patients, respectively. Cox proportional hazard analysis was done to determine the effects of several covariates on patients and renal survival. The patients' survival rate improved, as the hazard ratio (HR) was decreased to 0.69 (year of diagnosis, 1982 to 1986) and to 0.48 (year of diagnosis, 1987 to 1991) when the HR in patients diagnosed before 1981 was taken as 1.00. Similarly, we examined renal survival by using the Cox proportional model. For this analysis, the date of start of dialysis therapy was regarded as the time of renal death. Male patients had significantly poor renal survival; the HR was 3.64 (95% confidence interval, 1.89 to 6.98) when the HR in the females was taken as 1.00. However, age at diagnosis and year of diagnosis did not significantly affect renal survival. The cumulated incidence of end-stage lupus nephritis from the time of diagnosis of systemic lupus erythematosus was 3.1% at 5 years, 9.4% at 10 years, 15.5% at 15 years, and 21.0% at 20 years.(ABSTRACT TRUNCATED AT 250 WORDS)

End-Stage Renal Disease in Systemic Lupus Erythematosus

The progression of lupus nephritis severe enough to require dialysis does not necessarily indicate that it is "end-stage." Ten percent to 28% of patients with lupus nephritis who develop renal failure requiring dialysis will recover enough function to come off dialysis. The clinical activity of systemic lupus erythematosus (SLE) is quiescent in most patients with end-stage lupus nephritis, regardless of the modality of dialysis treatment. Clinical and serologic remission of SLE permits judicious withdrawal of immunosuppressive therapy, as well as a favorable long-term outcome for patients that is comparable to that of nonlupus patients. The great majority of deaths in patients with end-stage lupus nephritis occur in the first 3 months of dialysis and most often result from infection. Later, infection and cardiovascular complications are common causes of death. Patients with lupus nephritis should wait at least 3 months on dialysis before receiving a kidney transplantation. Immunosuppressive therapy and graft survival rates for lupus patients are not different from those of nonlupus patients. Recurrence of lupus nephritis in the allograft is exceedingly rare.

Chronic hemodialysis in end-stage lupus nephritis: changes of clinical and serological activities.

The available data on the clinical and serological activities of systemic lupus erythematosus (SLE) in dialysis patients with end-stage lupus nephritis are limited. The clinical and serological parameters in 12 such patients prior to, at the onset of, and an average of 31 months after the institution of hemodialysis were retrospectively compared. One of the patients died of cardiopulmonary arrest within 1 week after institution of hemodialysis. All patients were clinically and serologically active prior to the onset of end-stage renal disease (ESRD). With the onset of ESRD, 2 of the 10 patients exhibited complete clinical and serological remission, and 2 patients showed clinical remission with persistent serological activity. After an average of 31 months on dialysis, the number of patients in total remission rose to 4 of 11, and the number of clinically inactive but serologically active patients was 1 of 11. Significant clinical and serological activities persisted in 6 of the 11 dialysis patients, requiring low dose steroid therapy in 3. The authors conclude that the clinical and serological activities of SLE decrease with the onset of ESRD and the institution of dialysis, leading to complete or partial remission in the majority of patients.

Maintenance Hemodialysis in End-Stage Lupus Nephritis

Maintenance Hemodialysis in End-Stage Lupus Nephritis