Defective gene expression of the membrane complement inhibitor CD46 in patients with progressive immunoglobulin A nephropathy.

BACKGROUND: Complement is thought to play a role in immunoglobulin A nephropathy (IgAN), though the activating mechanisms are unknown. This study focused on the gene expression of CD46 and CD55, two key molecules for regulating C3 convertase activity of lectin and alternative complement pathways at a cellular level. METHODS: The transcriptional expression in peripheral white blood cells (WBCs) of CD46 and CD55 was investigated in 157 patients enrolled by the Validation of the Oxford Classification of IgAN group, looking for correlations with clinical and pathology features and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous median follow-up of 6.4 (interquartile range 2.8-10.7) years and were divided into progressors and non-progressors according to the median value of their velocity of loss of renal function per year (-0.41 mL/min/1.73 m2/year). RESULTS: CD46 and CD55 messenger RNA (mRNA) expression in WBCs was not correlated with eGFR values or proteinuria at sampling. CD46 mRNA was significantly correlated with eGFR decline rate as a continuous outcome variable (P = 0.014). A significant difference was found in CD46 gene expression between progressors and non-progressors (P = 0.013). CD46 and CD55 mRNA levels were significantly correlated (P < 0.01), although no difference between progressors and non-progressors was found for CD55 mRNA values. The prediction of progression was increased when CD46 and CD55 mRNA expressions were added to clinical data at renal biopsy (eGFR, proteinuria and mean arterial blood pressure) and Oxford MEST-C (mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, presence of any crescents) score. CONCLUSIONS: Patients with progressive IgAN showed lower expression of mRNA encoding for the complement inhibitory protein CD46, which may implicate a defective regulation of C3 convertase with uncontrolled complement activation.

In a retrospective international study, circulating miR-148b and let-7b were found to be serum markers for detecting primary IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is a worldwide disease characterized by the presence of galactose-deficient IgA1 deposits in the glomerular mesangium. A kidney biopsy for diagnosis is required. Here, we measured two miRNAs (let-7b and miR-148b), previously identified as regulators of the O-glycosylation process of IgA1, in serum samples from patients with IgAN and healthy blood donors (controls) recruited in an international multicenter study. Two predictive models, based on these miRNAs, were developed and the diagnostic accuracy of the combined biomarkers was assessed by the area under the receiver operating characteristic (ROC) curve (AUC) carried out in three steps. In a training study, the combined miRNAs were able to discriminate between 100 patients with IgAN and 119 controls (AUC, 0.82). A validation study confirmed the model in an independent cohort of 145 patients with IgAN and 64 controls (AUC, 0.78). Finally, in a test study, the combined biomarkers were able to discriminate patients with IgAN from 105 patients affected by other forms of primary glomerulonephritis, supporting the specificity (AUC, 0.76). Using the same study design, we also performed two subgroup analyses (one for Caucasians and one for East Asians) and found that race-specific models were the best fit to distinguish IgAN patients from controls. Thus, serum levels of the combined miRNA biomarker, let-7b and miR-148b, appears to be a novel, reliable, and noninvasive test to predict the probability of having IgAN.

T helper (Th)-cytokines in the urine of patients with primary glomerulonephritis treated with immunosuppressive drugs: Can they predict outcome?

BACKGROUND: Glomerulonephritides (GNs) represent common causes of chronic kidney disease associated with a wide spectrum of clinical and histological features. Various factors that activate the inflammatory cascade are involved in the development of kidney injury. The aim of this study was to estimate the urinary excretion of pro-inflammatory (IL-2, INF-γ, TNF-α, IL-6, IL-17) and anti-inflammatory (IL-4, IL-10, TGF-ß1) cytokines, as well as the chemokine MCP-1 in patients with various types of GN treated by immunosuppressive drugs and to identify any prognostic value of excreted cytokines for future renal function. PATIENTS AND METHODS: Ninety-seven patients (62 M/35 F, age 53.1 ± 15.6 years) with primary glomerulonephritis and 32 healthy controls were studied. The original diagnoses were membranous nephropathy (MN, n=36), IgA nephropathy (IgAN, n=31) and minimal changes disease or focal segmental glomerulosclerosis (MCD/FSGS, n=30). All patients had been treated with immunosuppressive drugs and, at the time of measurement of urinary cytokine excretion, were either in clinical remission or still had active disease with persistent proteinuria. RESULTS: GN patients had significantly higher levels of all cytokines and MCP-1 compared to healthy controls. A strong positive correlation between TGF-ß1 and MCP-1 concentrations was observed in all GN patients. Increased urinary excretion of all tested cytokines apart from TNF-α and TGF-ß1 was observed even in patients with clinical remission. The main difference between patients with proteinuria and those in clinical remission was the level of MCP-1 urinary excretion. The urinary excretion of MCP-1 and TGF-ß1 was significantly higher in patients with MN who showed deterioration of renal function over a follow-up period of five years. CONCLUSIONS: Increased levels of cytokines are observed in the urine of patients with different types of glomerulonephritis, even after the achievement of clinical remission with the administration of immunosuppressive drugs. Urinary excretion of MCP-1 and TGF-ß1 indicates the ongoing inflammatory and fibrotic processes in the kidney and is probably related to unfavourable outcomes.

Does treatment with corticosteroids and cyclosporine reduce transglutaminase type 2 expression in the renal tissue of patients with membranous nephropathy?

BACKGROUND/AIMS: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Transglutaminase type 2 (TG2) contributes to renal scarring through altering extracellular matrix homeostasis. In this study we hypothesized that immunosuppressive treatment would downregulate TG2 expression leading to reduced fibrosis, and subsequently TG2 would have value as a biomarker of progression of MN. METHODS: TG2 expression was studied by immunofluorescence in kidney biopsy sections from 32 patients with MN and was compared to control biopsies. All patients were subsequently treated by a combination of cyclosporine and prednisolone for at least 24 months with a repeat biopsy taken in 14 patients. RESULTS: Twenty-two out of 32 patients showed stable renal function, whereas 10 showed doubling of baseline serum creatinine and 5 of them reached end-stage renal disease during the 5-year follow-up. At the end of the follow-up, 22 out of 32 patients were in remission of nephrotic syndrome. TG2 immunostaining was increased in sections from patients with MN compared to healthy controls (p = 0.0002). TG2 at diagnosis was more intense in patients with severer interstitial fibrosis and advanced glomerular sclerosis. TG2 significantly increased in most patients in the repeat biopsies after treatment (p < 0.0001), whereas patients who showed a marked increase in interstitial fibrosis in the repeat biopsy had significantly more TG2 expression in the first biopsy (p = 0.02). CONCLUSION: TG2 expression is increased in MN patients and continues to increase despite immunosuppressive treatment. However, early detection of TG2 might be of value in MN since increased TG2 production seems to precede extensive interstitial fibrosis.

Religiosity and its relation to quality of life in Christian Orthodox cancer patients undergoing chemotherapy.

OBJECTIVES: The first objective of the current observational study was to assess the levels of religiosity in Greek Christian Orthodox cancer patients receiving chemotherapy. The second objective was to evaluate the associations between religiosity and quality of life (QoL), an endpoint of considerable importance in clinical cancer research and practice. METHOD: One hundred eighteen adult outpatients with solid tumors, who consented to participate, were administered the Systems of Belief Inventory (SBI-15R) and the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30) questionnaire. RESULTS: The analysis revealed high scores on religiosity, especially among female patients, who reported significantly higher levels of religious beliefs and practices as well as perceived social support provided by the religious community than did their male counterparts. Of all EORTC QOL-C30 subscales, only global QoL was found to be significantly associated with the SBI-15R religious beliefs subscale. The analysis revealed no significant correlations between the SBI-15R social support subscale and all QoL subscales. CONCLUSIONS: The current study reported high levels of religiosity among Greek Christian Orthodox cancer patients. However, levels of religiosity were only weakly associated with patients' QoL. The SBI-15R appeared to be a well-accepted and reliable tool, potentially useful for future research in Greek settings. Wide-scale studies from the same and diverse religious and cultural backgrounds are needed to clarify further the connections between religiosity, QoL, coping, and other health outcomes with the aim to devise appropriate multicomponent interventions to enhance patients' QoL.

Stress-induced hyperglycemia in patients with severe sepsis: a compromising factor for survival.

OBJECTIVE: To study the clinical and laboratory characteristics of patients with severe sepsis and baseline hyperglycemia and investigate the impact of hyperglycemia on the final outcome. PATIENTS: A total of 265 patients admitted with severe sepsis in 3 major hospitals in South-Western Greece, during a 1-year period, were included in the study. Patients were divided in 3 groups according to their glycemic profile at admission: patients with stress hyperglycemia (group SH, n=47), with diabetes mellitus (group DM, n=65), and with normal glucose level (group NG, n=153). Hyperglycemia was defined as an admission or in-hospital fasting glucose level of >or=126 mg/dL or a random blood glucose level of >or=200 mg/dL on >or=2 determinations. RESULTS: A total of 42.2% of patients with severe sepsis had baseline hyperglycemia with 17.7% having sepsis-induced stress hyperglycemia. No family history was noted in the SH group. A higher percentage of septic patients with stress hyperglycemia died compared with patients with normal glucose levels (42.5% versus 13.7%) and diabetics (42.5% versus 24.6%). Group DM had also a poorer prognosis than group NG (24.6% versus 13.7%). A positive correlation was detected between the fasting blood glucose levels of group SH and the severity of sepsis indicated by sepsis-related organ failure assessment score. CONCLUSION: Baseline hyperglycemia, including stress-induced hyperglycemia, is common in patients with severe sepsis. Stress-induced hyperglycemia is related to a more severe disease and poorer prognosis.

Treatment of IgA nephropathy based on the severity of clinical and histological features.

Immunoglobulin A (IgA) nephropathy (IgAN) represents a common glomerular disease treated by various therapeutic regimens. We studied 50 IgAN patients to determine the effect of different regimens selected according to severity of the disease on the clinical outcome of patients over a follow-up period of five years. Patients with normal renal function and proteinuria <1 g/24-h received no treatment (Group A, n = 6). Thοse with normal renal function, proteinuria >1 g/24-h and mild to moderate histological lesions received angiotensin-converting enzyme inhibitors (ACEi) and corticosteroids (Group B, n = 23). Patients with baseline serum creatinine (Scr) <2.5 mg/dL, proteinuria >3.5 g/24-h and severe histological lesions received ACEi, corticosteroids and other immunosuppressive drugs (Group C, n = 18). Finally, patients with Scr >2.5 mg/dL, glomerulosclerosis and tubulointerstitial fibrosis received ACEi and fish oil (Group D, n = 3). Doubling of baseline Scr was observed in nine (18%) patients; two (8.7%) patients from Group B, five (27.7%) patients from Group C and two (66.7%) patients from Group D. Of the seven (14%) patients who reached end-stage renal disease, one (4.3%) patient was from Group B, four (21.0%) patients were from Group C and two (66.7%) patients were from Group D. Reduction of proteinuria was observed in all (100%) patients from Group B and in 15 (83.3%) patients from Group C. Adverse reactions occurred in three of 18 (16%) patients treated with immunosuppressive drugs. The choice of therapeutic regimen used in the treatment of patients with IgAN could be based on the severity of clinical and histological involvement in order to achieve the maximum effect with the least of adverse reactions.

Incidence and characteristics of peripheral neuropathy during oxaliplatin-based chemotherapy for metastatic colon cancer.

AIM: The current prospective study sought to trace the incidence and severity of oxaliplatin-induced peripheral neuropathy (OXLIPN) and to determine its clinical and electrophysiological pattern. PATIENTS AND METHODS: Twenty-five adult patients scheduled to be treated with 12 courses of the oxaliplatin-based regimen, FOLFOX-4, for metastatic colon cancer participated in this study. Patients were clinically and electrophysiologically monitored at baseline and followed-up during chemotherapy. The severity of OXLIPN was summarized by means of a modified Total Neuropathy Score (TNS). RESULTS: Evidence of OXLIPN was disclosed in 16 of the 25 patients (64%). The mean TNS values for patients manifesting some grade of OXLIPN were 13.9 +/- 5.8 (range 7-28). All longitudinal comparisons concerning the motor conduction parameters failed to reach significance. By contrast, comparisons of the median changes at baseline and each of the follow-up studies revealed significant decrease in all sensory action potentials examined. CONCLUSION: Our results indicate that the majority of patients treated with the FOLFOX-4 regimen would manifest an axonal, predominately sensory peripheral neuropathy, of mild to moderate severity.