Tubulointerstitial nephritis and uveitis (TINU) syndrome: a report of 6 cases with renal biopsy and electron microscopy evaluation.

TINU syndrome is a rare, immune-mediated entity, characterized by oculorenal inflammation. Diagnosis requires exclusion of all other causes of tubulointerstitial nephritis (TIN). We present six patients with clinical, laboratory and renal biopsy findings denotative of TINU syndrome. All our patients experienced ocular and renal manifestations, defined by bilateral uveitis and photosensitivity, along with decline of renal function. In some patients, increased serum creatinine was accompanied by non-nephrotic range proteinuria, glucosuria or "full blown" Fanconi syndrome. The rest of the laboratory evaluation was normal apart from the presence of elevated erythrocyte sedimentation rate (ESR) and increased urine ß2-microglobulin, as well as normochromic, normocytic anemia in some cases. All patients underwent renal biopsy. Histochemical (pas, masson, silver, Congo-red) and immunohistochemical stains for immune cell populations (CD3, CD20, CD4, CD8, PGM1, CD138) and for the assessment of ß2-microglobulin were conducted. Electron microscopy examination of the biopsies was also performed. Follow-up, ranging from 18 months to 10 years, was available for four patients. Histological evaluation revealed interstitial inflammatory infiltration consisting mainly of lymphocytes, with a T-cell predominance, along with several macrophages. Inflammation severity varied among different patients, with some showing scarce foci of immune cell clusters, while others demonstrated a dense, diffuse interstitial infiltration. Interestingly, in two cases, a granulomatous pattern, characterized by non-necrotic, ill-defined granulomas was detected. Tubulitis was also encountered in some patients. A divergence was noted regarding chronicity index, with different levels of tubular atrophy, interstitial fibrosis and global glomerulosclerosis among different cases. ß2-Microglobulin immunohistochemical evaluation revealed substantially diminishment of cytoplasmic staining in tubular epithelial cells compared to control kidneys. The most notable finding derived from electron microscopy examination was the presence, in one patient, of scattered granular electron-dense-deposits along some tubular basement membranes. First line treatment included steroids, supplemented in some cases by additional immunosuppressive agents. Three patients experienced partial or complete response, while progressive renal damage was observed in a case with severe chronic lesions and persistence of inflammation-triggering factor. Our cases seem to represent progressive stages within the continuum of disease evolution. Patients with more prominent inflammation might represent a more initial state, while those with more severe chronicity index, probably depict more advanced stages. While the predominance of T-cells predicates a cell-mediated autoimmune mechanism, as the driving force of the disease occurrence, the presence of immune-complexes in more advanced stages might indicate the involvement of humoral immunity as a late event during disease course.

Bilateral Recurrent Uveitis in a Young Patient with Family History of Spondyloarthritis: Spondyloarthritis or Not?

We present the case of a young man with a strong family history of SpA, who was referred to the Rheumatology Clinic due to bilateral uveitis refractory to treatment with corticosteroids. The patient's renal function gradually deteriorated and a subsequent biopsy was positive for interstitial nephritis. After excluding all other systemic diseases, the diagnosis of TINU syndrome was confirmed. Although rare, TINU syndrome should be considered in the differential diagnosis of non-infective uveitis especially in the presence of urinalysis abnormalities.

The Association Between Handgrip Strength and Predialysis Serum Sodium Level in Patients With Chronic Kidney Disease Stage 5D.

Purpose: Handgrip strength (HGS) is a useful tool for the systematic assessment of muscle function related to nutritional status. Reduced HGS has been associated with adverse clinical outcomes in chronic kidney disease (CKD) stage 5D patients. In the same patients, predialysis low serum sodium (sNa) has been associated with malnutrition and mortality. Here, we investigated the role of predialysis sNa on muscle function in CKD-5D patients. Methods: We evaluated 45 patients on hemodialysis (HD) and 28 patients on peritoneal dialysis (PD) with HGS measurement, bioimpedance analysis, anthropometric measures, and malnutrition inflammation score (MIS). According to established diagnostic criteria, reduced HGS was defined as strength below 30 and 20 Kg in men and women, respectively. Predialysis sNa values were defined as the mean of all predialysis measurements during the preceding 6 months. Data analysis was performed separately for each of the HD and PD groups. Results: The proportions of reduced HGS did not differ between the HD (66%) and PD (54%) groups, respectively. Patients in the HD group as compared to those in the PD group had higher serum albumin and potassium and mid-arm muscle circumference and lower residual renal function (RRF) and residual urine volume. Multivariate logistic analysis, after controlling for muscle mass, nutritional biomarkers, MIS, fluid overload and RRF, showed that for every 1 mmol/l increase of sNa the odds of reduced HGS was decreased by 60% (OR = 0.40, 95% CI: 0.16-0.99) and 42% (OR = 0.58, 95% CI: 0.36-0.93) in HD and PD patients, respectively. However, stratified analysis indicated that lower sNa levels predicted reduced HGS in individuals with a background of malnutrition, inflammation, overhydration and less preserved RRF, representing unfavorable conditions strongly related to muscle wasting in the dialysis setting. Conclusions: Predialysis sNa is a strong and independent determinant of HGS, a reliable nutritional marker in CKD-5D stage patients. However, according to our findings, lower sNa levels appear to be a marker of underlying unfavorable conditions that are heavily associated with reduced HGS, rather than a causal determinant of reduced HGS. Whether optimizing sNa levels improves patient muscle performance requires further investigations.

PLA2R-Negative Membranous Nephropathy Presenting as a Prodrome of IgG4-Related Autoimmune Pancreatitis.

Membranous nephropathy (MN) with tubulointerstitial nephritis (TIN) is an established manifestation of immunoglobulin G4 (IgG4)-related disease (IgG4-RD). A pathological feature aiming to distinguish between primary and secondary MN is the presence or absence of glomerular staining for phospholipase A2 receptor (PLA2R), respectively. Isolated MN without TIN has been rarely reported in the context of IgG4-RD. This case report describes a patient with a history of MN successfully treated with steroids and cyclophosphamide, who, 3 years later, presented with unexplained exacerbation of diabetes mellitus due to IgG4-related autoimmune pancreatitis. Pancreatitis was treated, and diabetes improved after treatment with steroids. Based on the presence of isolated IgG4 glomerular capillary deposits along with negative staining for PLA2R and the metachronous appearance of autoimmune pancreatitis, MN was retrospectively classified as secondary to IgG4-RD. Isolated IgG4-positive/PLA2R-negative MN without TIN can be a prodrome of IgG4-RD, reminiscent of MN secondary to neoplasms.

The P274S Mutation of Lecithin-Cholesterol Acyltransferase (LCAT) and Its Clinical Manifestations in a Large Kindred.

RATIONALE & OBJECTIVE: Lecithin-cholesterol acyltransferase (LCAT) catalyzes the maturation of high-density lipoprotein. Homozygosity for loss-of-function mutations causes familial LCAT deficiency (FLD), characterized by corneal opacities, anemia, and renal involvement. This study sought to characterize kidney biopsy findings and clinical outcomes in a family with FLD. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 2 (related) index patients with clinically apparent FLD were initially identified. 110 of 122 family members who consented to genetic analysis were also studied. PREDICTORS: Demographic and laboratory parameters (including lipid profiles and LCAT activity) and full sequence analysis of the LCAT gene. Kidney histologic examination was performed with samples from 6 participants. OUTCOMES: Cardiovascular and renal events during a median follow-up of 12 years. Estimation of annual rate of decline in glomerular filtration rate. ANALYTICAL APPROACH: Analysis of variance, linear regression analysis, and Fine-Gray competing-risk survival analysis. RESULTS: 9 homozygous, 57 heterozygous, and 44 unaffected family members were identified. In all affected individuals, full sequence analysis of the LCAT gene revealed a mutation (c.820C>T) predicted to cause a proline to serine substitution at amino acid 274 (P274S). Homozygosity caused a complete loss of LCAT activity. Kidney biopsy findings demonstrated lipid deposition causing glomerular basement membrane thickening, mesangial expansion, and "foam-cell" infiltration of kidney tissue. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with worse kidney outcomes. Estimated glomerular filtration rate deteriorated among homozygous family members at an average annual rate of 3.56 mL/min/1.73 m2. The incidence of cardiovascular and renal complications was higher among homozygous family members compared with heterozygous and unaffected members. Mild thrombocytopenia was a common finding among homozygous participants. LIMITATIONS: The presence of cardiovascular disease was mainly based on medical history. CONCLUSIONS: The P274S LCAT mutation was found to cause FLD with renal involvement. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with a worse renal prognosis.

Dynamic changes of phenotypically different circulating tumor cells sub-populations in patients with recurrent/refractory small cell lung cancer treated with pazopanib.

The aim of the study was to investigate the effect of 2nd-line pazopanib on the different CTCs subpopulations in SCLC patients and evaluate the clinical relevance of their changes. Different CTCs subpopulations were evaluated before pazopanib initiation (n = 56 patients), after one-cycle (n = 35) and on disease progression (n = 45) by CellSearch and double immunofluorescence using anti-CKs and anti-Ki67, anti-M30 or anti-Vimentin antibodies. Before treatment, CTCs were detected in 50% of patients by CellSearch whereas 53.4%, 15.5% and 74.1% patients had CK+/Ki67+, CK+/M30+ and CK+/Vim+ CTCs, respectively. One pazopanib cycle significantly decreased the number of CTCs as detected by CellSearch (p = 0.043) as well as the number of CK+/Ki67+ (p < 0.001), CK+/M30+ (p = 0.015) and CK+/Vim+ (p < 0.001) cells. On disease progression, both the incidence and CTC numbers were significantly increased (CellSearch, p = 0.027; CK+/Ki67+, p < 0.001; CK+/M30+, p = 0.001 and CK+/Vim+, p < 0.001). In multivariate analysis, the detection of CK+/Vim+ CTCs after one treatment cycle (HR: 7.9, 95% CI: 2.9-21.8; p < 0.001) and CTCs number on disease progression, as assessed by CellSearch, (HR: 2.0, 95% CI: 1.0-6.0; p = 0.005) were emerged as independent factors associated with decreased OS. In conclusion, pazopanib can eliminate different CTC subpopulations in patients with relapsed SCLC. The analysis of CTCs could be used as a dynamic biomarker of treatment efficacy.

Renal artery stenting for atherosclerotic renal artery stenosis identified in patients with coronary artery disease: Does captopril renal scintigraphy predict outcomes?

The authors evaluated the effectiveness of percutaneous renal revascularization (PRR) with stenting for the treatment of atherosclerotic renal artery stenosis (ARAS) in patients with coronary artery disease and the usefulness of captopril renal scintigraphy for predicting clinical outcomes after PRR. Sixty-four consecutive patients, referred for evaluation of suspected ARAS, after coronary angiography, underwent baseline captopril renal scintigraphy followed by renal angiography. Forty-four patients (68.7%) were diagnosed with a significant ARAS≥ 60% and were treated with PRR plus medical therapy. Twenty-four months after PRR, 86.4% and 73.3% of patients showed a hypertension and renal benefit, respectively. Captopril renal scintigraphy positivity had moderate sensitivity and high specificity in predicting a hypertension and renal benefit. In patients with ARAS≥ 70%, the sensitivity and specificity were 100% for both a hypertension and renal benefit.PRR for ARAS conferred a substantial benefit in patients with a high coronary artery disease burden. Captopril renal scintigraphy was highly accurate in predicting clinical outcomes.

Phenotypic characterization of circulating tumor cells in the peripheral blood of patients with small cell lung cancer.

BACKGROUND: To evaluate the phenotypic heterogeneity of circulating tumor cells (CTCs) based on the expression of proliferative, apoptotic and Epithelial-to-Mesenchymal Transmission (EMT) markers during front-line treatment in patients with small cell lung cancer (SCLC) and to evaluate their clinical relevance. METHODS: CTCs from 108 chemotherapy-naïve patients with SCLC were analyzed by double immunofluorescence staining using anti-Ki67, anti-M30, anti-Vimentin along with anti-CKs antibodies. In 83 patients CTCs were also enumerated using the CellSearch. RESULTS: Sequential samples were available from 76 and 48 patients after one-treatment cycle and on disease progression (PD), respectively, for immunofluorescence and from 50 and 36 patients after one-cycle and on PD, respectively, for CellSearch. At baseline, 60.2% of the patients had detectable CTCs by either method. Both proliferative (CK67+) and non-proliferative (Ki67-), apoptotic (M30+) and non-apoptotic (M30-) as well as EMT (Vim+) CTCs were present in the same patient. Among 22 patients without detectable CTCs by CellSearch, CK+/Ki67+ and CK+/Vim+ CTCs could be detected in 6 (27.3%) and 6 (27.3%) patients, respectively. One-chemotherapy cycle reduced both the incidence of detection (p<0.001) and the absolute number (p<0.001) of CTCs; conversely, on PD both the incidence of detection and the number of CTCs were significantly increased (p = 0.002 and p = 0.04, respectively). Multivariate analysis revealed that the increased number of Vim+ CTCs at baseline and of non-apoptotic CTCs on PD could be emerged as independent prognostic factors associated with decreased OS(p = 0.009 and p = 0.023, respectively). CONCLUSIONS: CK+/Ki67+, CK+/M30+ and CK+/Vim+ CTCs represent distinct subpopulations of CTCs in patients with SCLC, can be detected even in the absence of detectable CTCs by CellSearch; CK+/Ki67+ and CK+/Vim+ CTCs are associated with unfavorable clinical outcome.

TTF-1- and/or CD56-positive Circulating Tumor Cells in patients with small cell lung cancer (SCLC).

The aim of the study was to evaluate the phenotypic CTCs heterogeneity (TTF-1+ and/or CD56+) in SCLC patients and correlate it with the CellSearch. Peripheral blood was obtained from 108 consecutive patients. CTCs were detected by CellSearch and double-immunofluorescence using anti-CD45, anti-TTF-1 and anti-CD56 antibodies. Before chemotherapy TTF-1+/CD45-, CD56+/CD45- and TTF-1+/CD56+ CTCs were detected in 66(61.1%), 55(50.9%) and 46(42.6%) patients, respectively; 60.2% of patients were CellSearch+. Among the 22 patients with 0 CTCs/7.5 ml on CellSearch, TTF-1+/CD45-, CD56+/CD45- and TTF-1+/CD56+ CTCs were detected in 8(36.4%), 6(27.3) and 6(27.3%) patients, respectively; no CK+/EpCAM+ or TTF1+/EpCAM+ CTCs were detected in these patients. One-chemotherapy cycle decreased both the number of positive patients (p < 0.001) and their CTC number (p < 0.001), irrespectively of their phenotype and the detection method. The incidence and number of the different CTC subpopulations on PD, was significantly increased at their baseline levels. Multivariate analysis revealed that the increased number of CTCs at baseline and on PD were significantly associated with decreased PFS (p = 0.048) and OS (p = 0.041), respectively. There is an important CTC heterogeneity in such patients according to the expression of TTF-1 and CD56 which could detect EpCAM- CTC subpopulations and, thus, undetectable by CellSearch. These CTC subpopulations are dynamically correlated with treatment efficacy and disease-progression.

A phase II trial evaluating the clinical and immunologic response of HLA-A2(+) non-small cell lung cancer patients vaccinated with an hTERT cryptic peptide.

OBJECTIVES: The immunological and clinical responses of patients with NSCLC treated, in the context of an expanded action program, with the cryptic hTERT-targeting Vx-001 vaccine are presented. MATERIALS AND METHODS: Forty-six HLA-A*0201-positive patients with advanced NSCLC and residual (n=27) or progressive (n=19) disease following front-line treatment received two subcutaneous injections of the optimized TERT572Y peptide followed by four injections of the native TERT572 peptide, every 3 weeks. Peptide-specific immune responses were monitored by enzyme-linked immunosorbent spot assay at baseline, and after the 2nd and the 6th vaccinations. Thirty-eight HLA-A*0201-positive matched patients were used as historical controls. RESULTS: Twenty-three patients (50%) completed the vaccination protocol and 87% received at least two administrations. Twelve patients (26%) without disease progression after the 6th vaccination received boost vaccinations. Three (7%) patients achieved a partial response and 13 (28%) disease stabilization. The disease control rate was significantly higher in patients with non-squamous histology compared to those with squamous-cell histology [n=14 (45%) versus n=2 (13%); p=0.03]. The median progression-free survival (PFS) and overall survival (OS) was 3.8 (range, 0.7-99.4) and 19.8 months (range, 0.7-99.4), respectively. Patients who developed immune response had a numerically higher PFS compared to those who failed to mount any (6.7 versus 2.7 months; p=0.090). However, the median OS for the immune-responders was significantly prolonged compared to non-responders (40.0 versus 9.2 months, respectively; p=0.02). Toxicity was