Efficacy of steroid and immunosuppressant combined therapy in Chinese patients with Henoch-Schönlein purpura nephritis: A retrospective study.

Suitable and efficient treatments for Henoch-Schönlein purpura nephritis (HSPN) with proteinuria remains unclear. Whether steroids combined with immunosuppressive agents improves prognosis compared to steroid therapy alone also remains controversial. This study explored whether combined therapy reduces proteinuria in HSPN patients with different pathological features. Chinese patients (n = 84) diagnosed with HSPN with proteinuria by renal biopsy between 2010 and 2019 were retrospectively studied. Patients were grouped into the steroid group (control) or the combined steroid and immunosuppressant group. Estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2/y) and proteinuria were measured. The primary outcome progression was analyzed using Kaplan-Meier survival curves. The effect of the combined therapy on renal outcome was analyzed by multivariable Cox regression. Propensity score matching and sensitivity analysis were used to explore whether pathological features impacted prognosis. Patients who received combined steroid and immunosuppressant therapy were more likely to recover from HSPN and had proteinuria <3 g/24 h (P = 0.02) or 1 g/24 h (P = 0.03). Multiple Cox regression analysis confirmed that this decrease was independent of renin-angiotensin system blockers. Further sensitivity analysis showed that combined therapy was effective in patients with crescents (P = 0.02). However, combined steroid and immunosuppressant therapy was not more effective in patients with endocapillary hypercellularity (E), tubular atrophy/interstitial fibrosis (T), or segmental sclerosis (S). Combined steroid and immunosuppressant therapy was significantly associated with HSPN remission, and more effectively decreased proteinuria during the initial disease phase.

Hypertensive nephropathy is associated with an increased risk of myeloma, skin, and renal cancer.

Previous studies suggest an increased cancer risk in hypertension. Patients with hypertensive nephropathy have not been studied. A national registry study was performed to assess the presence and size of this association. Clinical data and cancer diagnoses for all patients with biopsy-proven hypertensive nephropathy between 1985 and 2015 in Denmark were extracted from four national registries and compared with age- and sex-adjusted national cancer rates. The risk of cancer was twice the background population. It was raised for renal cancer (odds ratio 10.4), myeloma (13.2), skin cancer (7.9), and other/unspecified (1.8). No increase in incidence was seen until 1 year before renal biopsy and then rose rapidly. It was again normal 5 years after biopsy. Hypertensive nephropathy is associated with an increased risk of myeloma, skin, renal, and other cancers. Screening of patients with hypertensive nephropathy, in the presence of reduced renal function or significant proteinuria, may be indicated.

Validation of the Boston University staging system in AL amyloidosis.

Objectives: We aimed to externally validate Lilleness' et al. Boston University (BU) prognostic score that replaced NT-proBNP with brain natriuretic peptide (BNP), which will allow centres without access to NT-proBNP to accurately stage and prognosticate AL amyloidosis. Patients/methods: Forty-four were identified that had BNP, NTpro-BNP and TnI taken simultaneously, with a mean follow up of 7.3 years. Median age of the 44 patients was 67 years and 27% were female, with 61% having cardiac involvement, and 61% having renal involvement. Results: Using the BU BNP-based staging system, we identified 12/44 (27%) of patients as stage I, 18/44 (41%) of patients as stage II and 14/44 (31%) of patients as stage III. This correlated closely with stratification via the Mayo score, with only one patient miscategorised (97.7% agreement, k = 0.98). Median overall survival for our BU stage I was not reached, stage II was 40 months and stage III was 5 months (long rank p = .0012). Mayo 2004 median overall survival was identical for stages I, II and III. Conclusion: We have provided external validation of the BU staging system, a novel prognostic scoring system incorporating BNP, instead of NT-proBNP, for AL amyloidosis.

Mortality among United States aerospace materials manufacturing workers.

OBJECTIVES: To evaluate long-term mortality rates among aerospace material manufacturing workers as follow-up to an earlier observed excess of nephritis/nephrosis. METHODS: Subjects were 2020 workers ever employed in the facility during 1963-2014. Vital status through 2014 was determined for all subjects and cause of death for 99.2% of 492 deaths. We computed standard mortality ratios (SMR) and internal relative risks. RESULTS: SMRs for nephritis/nephrosis were unremarkable. We observed statistically significant elevated SMRs for kidney cancer among all workers and for the category "other lymphatic hematopoietic tissue cancer" (4/5 deaths from multiple myeloma) among long-term workers with potential plant exposure. CONCLUSIONS: We found no evidence of elevated mortality rates for nephritis/nephrosis. Study limitations precluded robust evaluation of whether the elevated rates for kidney cancer and other lymphatic hematopoietic tissue cancer were related to occupational factors at the study site. Our findings for these two cancers warrant continued mortality follow-up.

Outcomes of 847 childhood-onset systemic lupus erythematosus patients in three age groups.

Objective The objective of this study was to assess outcomes of childhood systemic lupus erythematosus (cSLE) in three different age groups evaluated at last visit: group A early-onset disease (<6 years), group B school age (≥6 and <12 years) and group C adolescent (≥12 and <18 years). Methods An observational cohort study was performed in ten pediatric rheumatology centers, including 847 cSLE patients. Results Group A had 39 (4%), B 395 (47%) and C 413 (49%). Median disease duration was significantly higher in group A compared to groups B and C (8.3 (0.1-23.4) vs 6.2 (0-17) vs 3.3 (0-14.6) years, p < 0.0001). The median Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI) (0 (0-9) vs 0 (0-6) vs 0 (0-7), p = 0.065) was comparable in the three groups. Further analysis of organ/system damage revealed that frequencies of neuropsychiatric (21% vs 10% vs 7%, p = 0.007), skin (10% vs 1% vs 3%, p = 0.002) and peripheral vascular involvements (5% vs 3% vs 0.3%, p = 0.008) were more often observed in group A compared to groups B and C. Frequencies of severe cumulative lupus manifestations such as nephritis, thrombocytopenia, and autoimmune hemolytic anemia were similar in all groups ( p > 0.05). Mortality rate was significantly higher in group A compared to groups B and C (15% vs 10% vs 6%, p = 0.028). Out of 69 deaths, 33/69 (48%) occurred within the first two years after diagnosis. Infections accounted for 54/69 (78%) of the deaths and 38/54 (70%) had concomitant disease activity. Conclusions This large multicenter study provided evidence that early-onset cSLE group had distinct outcomes. This group was characterized by higher mortality rate and neuropsychiatric/vascular/skin organ damage in spite of comparable frequencies of severe cumulative lupus manifestations. We also identified that overall death in cSLE patients was an early event mainly attributed to infection associated with disease activity.

[Kidney allotransplantation from alive related donor in patients with Alport syndrome].

AIM: To evaluate the results of kidney transplantation from alive related donor in patients with Alport syndrome and to compare with those in patients with kidney hypoplasia. MATERIAL AND METHODS: We have analyzed 8 and 27 medical records of patients with Alport syndrome and kidney hypoplasia respectively. Following parameters were used - Kaplan-Meier survival analysis, Wilcox overall risk, percentage of transplants loss and mortality (Fisher's exact test calculation). RESULTS: It is concluded that percentage of transplants loss and mortality rate as well as overall survival and risk were similar in both groups. CONCLUSION: Despite risk of anti-GBM nephritis development in patients with Alport syndrome results are comparable with those after transplatation for chronic renal failure caused by other reasons.

Trends in Disparity by Sex and Race/Ethnicity for the Leading Causes of Death in the United States-1999-2010.

CONTEXT: Temporal trends in disparities in the leading causes of death within and between US demographic subgroups indicate the need for and success of interventions to prevent premature death in vulnerable populations. Studies that report recent trends are limited and outdated. OBJECTIVE: To describe temporal trends in disparities in death rates by sex and race/ethnicity for the 10 leading causes of death in the United States during 1999-2010. DESIGN: We used underlying cause of death data and population estimates from the National Vital Statistics System to calculate age-adjusted death rates for the 10 leading causes of death during 1999-2010. We measured absolute and relative disparities by sex and race/ethnicity for each cause and year of death; we used weighted linear regression to test for significance of trends over time. RESULTS: Of the 10 leading causes of death, age-adjusted death rates by sex and race/ethnicity declined during 1999-2010 for 6 causes and increased for 4 causes. But sex and racial/ethnic disparities between groups persisted for each year and cause of death. In the US population, the decreasing trend during 1999-2010 was greatest for cerebrovascular disease (-36.5%) and the increasing trend was greatest for Alzheimer disease (52.4%). For each sex and year, the disparity in death rates between Asian/Pacific Islanders (API) and other groups varied significantly by cause of death. In 2010, the API-non-Hispanic black disparity was largest for heart disease, malignant neoplasms, cerebrovascular diseases, and nephritis; the API-American Indian/Alaska Native disparity was largest for unintentional injury, diabetes mellitus, influenza and pneumonia, and suicide; and the API-non-Hispanic white disparity was largest for chronic lower respiratory diseases and Alzheimer disease. CONCLUSIONS: Public health practitioners can use these findings to improve policies and practices and to evaluate progress in eliminating disparities and their social determinants in vulnerable populations.

Decay-accelerating factor 1 deficiency exacerbates leptospiral-induced murine chronic nephritis and renal fibrosis.

Leptospirosis is a global zoonosis caused by pathogenic Leptospira, which can colonize the proximal renal tubules and persist for long periods in the kidneys of infected hosts. Here, we characterized the infection of C57BL/6J wild-type and Daf1-/- mice, which have an enhanced host response, with a virulent Leptospira interrogans strain at 14 days post-infection, its persistence in the kidney, and its link to kidney fibrosis at 90 days post-infection. We found that Leptospira interrogans can induce acute moderate nephritis in wild-type mice and is able to persist in some animals, inducing fibrosis in the absence of mortality. In contrast, Daf1-/- mice showed acute mortality, with a higher bacterial burden. At the chronic stage, Daf1-/- mice showed greater inflammation and fibrosis than at 14 days post-infection and higher levels at all times than the wild-type counterpart. Compared with uninfected mice, infected wild-type mice showed higher levels of IL-4, IL-10 and IL-13, with similar levels of α-smooth muscle actin, galectin-3, TGF-ß1, IL-17, IFN-γ, and lower IL-12 levels at 90 days post-infection. In contrast, fibrosis in Daf1-/- mice was accompanied by high expression of α-smooth muscle actin, galectin-3, IL-10, IL-13, and IFN-γ, similar levels of TGF-ß1, IL-12, and IL-17 and lower IL-4 levels. This study demonstrates the link between Leptospira-induced murine chronic nephritis with renal fibrosis and shows a protective role of Daf1.

Enhanced auto-antibody production and Mott cell formation in FcµR-deficient autoimmune mice.

The IgM-Fc receptor (FcµR) is involved in IgM homeostasis as evidenced by increased pre-immune serum IgM and natural auto-antibodies of both IgM and IgG isotypes in Fcmr-deficient C57BL/6 (B6) mice. To determine the impact of Fcmr-ablation on autoimmunity, we introduced the Fcmr null mutation onto the Fas-deficient autoimmune-prone B6.MRL Fas (lpr/lpr) mouse background (B6/lpr). Both IgM and IgG auto-antibodies against dsDNA or chromatin appeared earlier in FcµR(-) B6/lpr than FcµR(+) B6/lpr mice, but this difference became less pronounced with age. Splenic B2 cells, which were 2-fold elevated in FcµR(+) B6/lpr mice, were reduced to normal B6 levels in FcµR(-) B6/lpr mice, whereas splenic B1 cells were comparable in both groups of B6/lpr mice. By contrast, marginal zone (MZ) B cells were markedly reduced in FcµR(-) B6/lpr mice compared with either FcµR(+) B6/lpr or wild type (WT) B6 mice. This reduction appeared to result from rapid differentiation of MZ B cells into plasma cells in the absence of FcµR, as IgM antibody to a Smith (Sm) antigen, to which MZ B cells are known to preferentially respond, was greatly increased in both groups (B6/lpr and B6) of FcµR(-) mice compared with FcµR(+) B6/lpr or B6 mice. Mott cells, aberrant plasma cells with intra-cytoplasmic inclusions, were also increased in the absence of FcµR. Despite these abnormalities, the severity of renal pathology and function and survival were all indistinguishable between FcµR(-) and FcµR(+) B6/lpr mice. Collectively, these findings suggest that FcµR plays important roles in the regulation of auto-antibody production, Mott cell formation and the differentiation of MZ B cells into plasma cells in B6.MRL Fas (lpr/lpr) mice.

Avosentan is protective in hypertensive nephropathy at doses not causing fluid retention.

Multiple studies indicate that endothelin antagonism may have a protective effect for chronic kidney disease. Despite that, clinical studies using avosentan have been halted due to adverse effects including fluid overload. Therefore, we aimed at investigating whether avosentan may have protective effects against hypertensive nephropathy at doses below those inducing fluid-retention. We used double transgenic rats (dTGR), overexpressing both the human renin and angiotensinogen gene, which develop malignant hypertension. Effects of avosentan alone or in combination with low-dose of valsartan (angiotensin AT1 receptor antagonist) on end-organ damage were studied. Avosentan induced a decrease of diuresis (18.3%) with a consequent decrease in hematocrit (8.3%) only at the highest dose investigated (100mg/kg). Treatment with the combination of avosentan and valsartan (10 and 0.1mg/kg, once daily by gavage, respectively) decreased albuminuria to a greater extent than each compound given alone (avosentan: 19.6mg/24h; valsartan: 12.9mg/24h; avosentan+valsartan: 1.7mg/24h, data are median values). Histological severity score also showed a drastic reduction of kidney damage. Furthermore, avosentan alone or in combination therapy dramatically decreased mortality compared to the 100% in untreated animals. These data support a therapeutic effect of avosentan at doses below those inducing fluid overload.

Causes of death in peritoneal dialysis patients with different kidney diseases and comorbidities: a retrospective clinical analysis in a Chinese center.

OBJECTIVES: The objective of the study is to identify and compare the different causes of death among peritoneal dialysis (PD) patients varying in baseline characteristics, including gender, age, primary diseases, and comorbidities and to assess risk factors for first-year death. METHODS: The clinical data of 179 PD patients who were regularly followed up in our hospital and died between January 2006 and February 2011 were retrospectively reviewed. RESULTS: Median age at PD catheter implantation was 73 years. The most common primary diseases leading to ESRD were diabetic nephropathy (DN; 26.3 %), chronic glomerulonephritis (CGN; 24.6 %), and hypertensive nephropathy (HN; 21.8 %). The main causes of death in the DN and CGN groups were infections (42.6 %) and cardiocerebrovascular accidents (34.1 %), respectively. Patients with systemic vasculitis (SV) had the highest mortality rate from infection (71.4 %). Cox regression model showed that, compared with patients with CGN, those who had primary disease of DN, renal amyloidosis, multiple myeloma, or vasculitis were at higher risk of first-year death. Cerebrovascular disease, chronic heart failure, and/or lower serum albumin at baseline were also risk factors for first-year death. CONCLUSIONS: The main causes of death in PD patients with DN and CGN were infections and cardiocerebrovascular accidents, respectively. Risk factors for first-year death included the primary diseases, cerebrovascular diseases, chronic heart failure, and lower serum albumin at baseline.

Etiology and outcomes of acute kidney injury in Chinese children: a prospective multicentre investigation.

BACKGROUND: The incidence of AKI appears to have increasing trend. Up to now, prospective, multi-center, large-sample epidemiological study done on pediatric AKI on aspects of epidemiological characteristics, causes and outcomes have not reported. It is necessary to develop prospective, multi-center, large-sample epidemiological study in our country on pediatric AKI. The aim of this study was to determine the clinical features, etiology, and outcomes of acute kidney injury (AKI) in Chinese children. METHOD: Paediatric patients (≤18 years old) admitted to 27 hospitals (14 children's hospitals and 13 general hospitals) affiliated with the Medical University were investigated. AKI was defined using the 2005 Acute Kidney Injury Network criteria. RESULTS: During the study period, 388,736 paediatric patients were admitted. From this total, AKI was diagnosed in 1,257 patients, 43 of whom died. The incidence and mortality of AKI was 0.32% and 3.4% respectively. The mean (± SD) age of patients was 48.4 ± 50.4 months. Among the 1,257 AKI paediatric patients, 632 were less than one year old. Among the AKI paediatric patients, 615 (48.9%) were in stage 1, 277 (22.0%) in stage 2, and 365 (29.0%) in stage 3. The most common causes of AKI were renal causes (57.52%), whereas postrenal (25.69%) and prerenal (14.96%) causes were the least common. The three most common causes of AKI according to individual etiological disease were urolithiasis (22.35%), of which exposure to melamine-contaminated milk accounted for the highest incidence (63.7%); acute glomerulonephritis (10.10%); and severe dehydration (7.48%). A total of 43 AKI patients (3.4%) died during their hospital stay; 15 (34.9%) of the 43 died as a result of sepsis. CONCLUSION: Primary renal diseases are a major risk factor for paediatric AKI in China. In terms of specific etiological disease, urolithiasis (postrenal disease) was the leading cause of paediatric AKI in 2008, when the disease was linked to exposure to melamine-contaminated milk. Sepsis is the leading cause of death in Chinese paediatric AKI patients. Future studies should focus on effective ways of controlling renal disorders and sepsis to improve the clinical management of paediatric AKI in China.

Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK).

Oxidative stress is acknowledged to play a role in kidney disease progression. Genetic variants that affect the capacity to handle oxidative stress may therefore influence the outcome of kidney disease. We examined whether genetic variants of the GSTM1 gene, a member of a superfamily of glutathione S-transferases, influence the course of kidney disease progression in participants of the African American Study of Kidney Disease (AASK) trial. Groups with and without the common GSTM1 null allele, GSTM1(0), differed significantly in the time to a glomerular filtration rate (GFR) event or dialysis (P = 0.04) and in the time to GFR event, dialysis, or death (P = 0.02). The hazard ratios (HR) for the time to a GFR event or dialysis in those with two or one null allele relative to those possessing none were 1.88 [95% confidence interval (CI), 1.07 to 3.30, P = 0.03] and 1.68 (95% CI, 1.00 to 2.84, P < 0.05), respectively. For the time to GFR event, dialysis, or death, the HR for two null alleles was 2.06 (95% CI, 1.20 to 3.55, P = 0.01) and for one null allele 1.70 (95% CI, 1.02 to 2.81, P = 0.04). We demonstrated that GSTM1 directly regulates intracellular levels of 4-hydroxynonenal (4-HNE) in vascular smooth muscle cells. Furthermore, we showed that renal 4-HNE levels and GSTM1 are both increased after reduction of renal mass (RRM) in the mouse. We conclude that GSTM1 is normally upregulated in chronic kidney disease (CKD) in a protective response to increased oxidative stress. A genetic variant that results in loss of GSTM1 activity may be deleterious in CKD.

A cohort mortality study of workers in a soup manufacturing plant.

There has been no study of disease risk or exposures in workers in soup manufacturing plants. These workers may have hazardous exposures to biological and chemical cancer-causing agents at the workplace. The authors report here on mortality in 1,779 workers from a plant in Baltimore, Maryland. Standardized mortality ratios (SMRs) were estimated using the US population for comparison. Significantly increased mortality was observed for cancer of the floor of the mouth, colon cancer, epilepsy, and chronic nephritis in certain groups. Significantly decreased SMRs were observed for some causes. The findings are important, given the complete absence of data on this occupational group. It is not known whether the associations observed are related to occupational or nonoccupational exposures, or due to chance. The findings do, however, indicate that further studies of this occupational group are warranted.

Kidney allograft inflammation and fibrosis, causes and consequences.

This study assessed the development of allograft interstitial fibrosis and inflammation (GIF+"i"), a histologic pattern associated with reduced graft survival. Included are 795 adults, recipients of kidney allografts from 2000 to 2006. GIF+"i" was diagnosed in surveillance and clinical biopsies that had no transplant glomerulopathy. With time, posttransplant increasing number of grafts showed GIF+"i" and these patients had reduced death-censored graft survival (HR = 4.33 (2.49-7.53), p < 0.0001). Development of GIF+"i" was related to prior acute cellular rejection (ACR), BK nephropathy (PVAN), increasing number of HLA mismatches, retransplantation and DGF. However, 46.4% of GIF+"i" cases had no history of ACR or PVAN. Anti-HLA antibodies at transplant did not relate to GIF+"i" and these patients had no increased frequency of new antibody formation posttransplant. Post-ACR biopsies showed that GIF+"i" developed more commonly after clinically and/or histologically more severe ACR. Graft inflammation persisted in 38.7 and 29.6% of grafts 2 and 12 months post-ACR. Twelve months post-ACR, 27.1% of biopsies developed moderate-severe GIF and 51.8% showed GIF and inflammation. Persistent inflammation and progressive GIF is often subclinical but may lead to graft failure. GIF+"i" can be initiated by multiple etiologies but it is often postinfectious or due to persistent cellular immune-mediated injury.

HCaRG accelerates tubular repair after ischemic kidney injury.

The repair of the kidney after ischemia/reperfusion injury involves proliferation of proximal tubular epithelial cells as well as cell migration and differentiation. Immediately after reperfusion, expression of hypertension-related calcium-regulated gene (HCaRG/COMMD5) decreases, but its expression increases even higher than baseline during repair. HCaRG inhibits proliferation and accelerates wound healing and differentiation in cultured cells, but whether HCaRG can stimulate renal repair after ischemia/reperfusion injury is unknown. Here, transgenic mice overexpressing human HCaRG survived longer and recovered renal function faster than littermate controls after ischemia/reperfusion (64% versus 25% survival at 7 days). Proliferation of proximal tubular epithelial cells stopped earlier after ischemia/reperfusion injury, E-cadherin levels recovered more rapidly, and vimentin induction abated faster in transgenic mice. HCaRG overexpression also reduced macrophage infiltration and inflammation after injury. Taken together, these data suggest that HCaRG accelerates repair of renal proximal tubules by modulating cell proliferation of resident tubular epithelial cells and by facilitating redifferentiation.

Relationship between urinary cadmium and mortality in habitants of a cadmium-polluted area: a 22-year follow-up study in Japan.

BACKGROUND: Several studies have suggested that the exposure to cadmium (Cd) increased mortalities from renal diseases, cardiovascular diseases and malignant neoplasm, including lung cancer and prostate cancer among inhabitants living in Cd-polluted areas and factory workers. This study aimed to assess the influence of environmental exposure to Cd on long term outcome of inhabitants living in an area polluted by Cd. METHODS: A 22-year follow-up study was conducted with 3119 inhabitants (1403 men and 1716 women) living in the Cd polluted Kakehashi River basin in Japan. The subjects were divided into 4 groups according to the amount of urinary Cd level (< 3.0 µg/g creatinine (Cr), 3.0 - 4.9 µg/g Cr, 5.0 - 9.9 µg/g Cr, and ≥ 10.0 µg/g Cr). Mortality was calculated by the person-years method. Hazards ratios (HR) and 95% confidence intervals (CI) were assessed by the Cox's proportional hazard model. RESULTS: Compared with urinary Cd < 3.0 µg/g Cr group, the HR of 5.0 - 9.9 µg/g Cr and ≥ 10.0 µg/g Cr groups were significantly increased after adjustment for age in both sexes: 1.24 (95%CI 1.01 - 1.51) and 1.48 (95%CI 1.17 - 1.90) for men; 1.64 (95%CI 1.17 - 2.28) and 1.78 (95%CI 1.27 - 2.50) for women. The most frequent cause of death was malignant neoplasm in men and cardiovascular diseases in women. The significant increase in mortality risk for cardiovascular diseases was observed in the subjects with ≥ 10 µg/g Cr in both sexes: 1.79 for men (95%CI 1.02 - 3.12) and 2.38 for women (95%CI 1.11 - 5.07). When the subjects were divided into 2 categories (< 20 µg/g Cr and ≥ 20 µg/g Cr), the HR of the urinary Cd ≥ 20 µg/g Cr group for nephritis and nephrosis were 4.82 (95%CI 1.07 - 21.61) in men and 7.92 (95%CI 1.77 - 35.33) in women, respectively. The significant increase was not observed for malignant neoplasm. CONCLUSION: These results suggest a dose-response relationship between Cd body burden and mortality for cardiovascular diseases, cerebrovascular diseases and nephritis and nephrosis.

Anti-programmed cell death 1 antibody reduces CD4+PD-1+ T cells and relieves the lupus-like nephritis of NZB/W F1 mice.

Programmed cell death 1 (PD-1) is an immunosuppressive receptor that transduces an inhibitory signal into activated T cells. Although a single nucleotide polymorphism in the gene for PD-1 is associated with susceptibility to systemic lupus erythematosus, the role of PD-1 in systemic lupus erythematosus is still not well understood. In this study, we used NZB/W F1 mice, a model of lupus-like nephritis, to examine the function of PD-1 and its ligands. PD-1 was predominantly expressed on CD4(+) T cells that infiltrated the kidney, and CD4(+)PD-1(high) T cells produced higher levels of IFN-gamma than CD4(+)PD-1(low) or CD4(+)PD-1(-) T cells. Stimulation with PMA/ionomycin caused splenic CD4(+)PD-1(+) T cells to secrete high levels of IFN-gamma, IL-10, low levels of TNF-alpha, faint levels of IL-2, IL-21, and no IL-4, IL-17. In vivo anti-PD-1 mAb treatment reduced the number of CD4(+)PD-1(+) T cells in the kidney of NZB/W F1 mice and significantly reduced their mortality rate (p = 0.03). Conversely, blocking PD-L1 using an anti-PD-L1 mAb increased the number of CD4(+)PD-1(+) T cells in the kidney, enhanced serum IFN-gamma, IL-10, and IgG2a ds-DNA-Ab levels, accelerated the nephritis, and increased the mortality rate. We conclude that CD4(+)PD-1(high) T cells are dysregulated IFN-gamma-producing, proinflammatory cells in NZB/W F1 mice.

Residual daily urine volume association with inflammation and nutrition status in maintenance hemodialysis patients.

BACKGROUND: This study determines the clinical significance of residual renal function (RRF), defined as residual daily urine volume (RDUV), in maintenance hemodialysis (MHD) patients. METHODS: This multi-center study enrolled 704 MHD patients. Geographic, hematological, biochemical, and dialysis-related data were obtained. Values for nutritional and inflammatory markers were analyzed together with RDUV. RESULTS: In total, 670 of 704 patients (95.2%) with HD duration greater than 1 year had abnormal RDUV (<500 ml). Patients with higher RRF were younger, had shorter HD duration, higher prevalence of hypertension and levels of serum albumin, high density lipoprotein (HDL), and lower mid-week inter-dialysis body weight increase (MIBWI), cardio-thoracic ratio, levels of intact parathyroid hormone, high sensitivity C-reactive protein (Hs CRP), and KT/V (Daugirdes) values than those with low RRF. Stepwise multiple regression analysis demonstrated that RRF was positively correlated with serum albumin, HDL levels, and presence of hypertension, and negatively correlated with age, HD duration, and MIBWI in MHD patients. Moreover, after adjusting factors that were significantly related to serum albumin or Hs CRP, RRF was still positively correlated with serum albumin (0.000137 +/- 0.000585, p = 0.0197) and negatively correlated with log Hs CRP (-0.000184 +/- 0.000952, p = 0.0533). A one-liter increase in RDUV was associated with a 1.4 g/L increase in serum albumin level in MHD patients. CONCLUSION: This clinical study first demonstrated that RRF affects nutritional and inflammatory status in MHD patients. Because malnutrition and inflammation can cause high mortality in MHD patients, preserving RRF is important for these patients.

Indole-3-carbinol improves survival in lupus-prone mice by inducing tandem B- and T-cell differentiation blockades.

Indole-3-carbinol (I3C), derived from cruciferous vegetables, alters estrogen metabolism. Since lupus is estrogen dependent, we reasoned that I3C might be effective in SLE. I3C significantly thwarted disease progression and prolonged survival in (NZBxNZW) F1 mice. Immunofluorescent and serologic analyses in treated animals indicated a transient blockade in B-cell maturation with increased immature B cells, decreased mature B cells, and a significant reduction of certain autoantibodies. Subsequently, a delay in T-cell maturation occurred in the treated group, manifested by significantly increased naive T cells, decreased mature and memory T cells, and decreased CD4:CD8 T-cell ratios. T cells from the I3C cohort, stimulated in vitro with various mitogens, exhibited enhanced responsiveness. Con A-stimulated T cells from I3C-treated mice produced Th1 cytokines, whereas those from control animals produced Th2 cytokines. Our studies suggest immunological mechanisms by which I3C ameliorates SLE in mice and provide a rationale for its use as an adjunctive therapy for human lupus.