Dysmetabolic markers predict outcomes in autosomal dominant polycystic kidney disease.

BACKGROUND: Overweight and obesity were recently associated with a poor prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD). Whether the metabolic consequences of obesity as defined by the metabolic syndrome (MS) are also linked with disease progression remains untested. METHODS: Eligible ADPKD patients with different stages of CKD (n = 105) and 105 non-diabetic controls matched for CKD stage were enrolled in the study. Groups were evaluated at baseline for presence of MS, blood markers of metabolism, homeostasis model assessment of insulin resistance (HOMA-IR) score, and biochemical markers of inflammation (hs-CRP, IL-1ß, IL-6, TNF-α and PON-1). MS was defined according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III). Patients were followed for 12 months and progression defined as a decrease in baseline eGFR > 10%. RESULTS: MS and hypertension were more prevalent amongst ADPKD patients than in the control group. Meanwhile, markers of inflammation such as hs-CRP (3.63 [3.45-5.17] vs. 4.2 [3.45-8.99] mg/dL; p = 0.014), IL-6 (21.65 [14.1-27.49] vs. 24.9 [16.23-39.4] pg/mL; p = 0.004) and IL-1ß (21.33 [15.8-26.4] vs. 26.78 [18.22-35] pg/mL; p < 0.001) levels were all more elevated in ADPKD patients than in non-diabetic CKD subjects. In multivariate analysis having a truncating PKD1 mutation predicted (OR 1.25 [1.09-1.43]; p = 0.002) fulfilling the MS criteria. Finally, ADPKD patients fulfilling MS criteria had a significantly more rapid progression during 12 months of follow-up than did those that did not (OR 3.28 [1.09-9.87]; p = 0.035). CONCLUSIONS: Our data supports the notion that dysmetabolisms part of the ADPKD phenotype and associated with a poor outcome, especially in patients with a truncating PKD1 mutation.

Serum micro-rna profiles in patients with autosomal dominant polycystic kidney disease according to hypertension and renal function.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder with unclear disease mechanism. Currently, overt hypertension and increased renal volume are the best predictors of renal function. In this study, we assessed the usefulness of selected circulating microRNAs (miRs) to predict disease progress in a cohort with ADPKD. METHODS: Eighty ADPKD patients (44.6 ± 12.7 years, 40% female, 65% hypertensive) and 50 healthy subjects (HS; 45.4 ± 12.7, 44% female) were enrolled in the study. Serum levels of 384 miRs were determined by Biomark Real Time PCR. Groups were compared using the limma method with multiple-testing correction as proposed by Smyth (corrected p < 0.01 considered significant). RESULTS: Comparing ADPKD to HS, we found significant differences in blood levels of 18 miRs (3 more and 15 less abundant). Of these, miR-3907, miR-92a-3p, miR-25-3p and miR-21-5p all rose while miR-1587 and miR-3911 decreased as renal function declined in both cross-sectional and longitudinal analysis. Using ROC analysis, an increased baseline miR-3907 in the circulation predicted a > 10% loss of GFR over the following 12 months (cut-off >2.2 AU, sensitivity 83%, specificity 78%, area 0.872 [95% CI: 0.790-0.953, p < 0.001]). Adjusting for age and starting CKD stage using multiple binary logistic regression analysis did not abrogate the predictive value. CONCLUSION: Increased copy numbers of miR-3907 in the circulation may predict ADPKD progression and suggest pathophysiological pathways worthy of further study.

Pericardial, pleural and peritoneal involvement in a patient with primary gastric mantle cell lymphoma.

Primary gastric mantle cell lymphoma is a rare form of gastointestinal tumour. Although peritoneal carcinomatosis accompanied by malignant ascites is relatively common, mantle cell lymphoma presenting with ascites is rare. Also, effusions involving pericardial and pleural cavities are uncommon during the course of lymphomas. We report the first case in which pericardial, pleural and peritoneal effusion of a primary gastric mantle cell lymphoma.

Ratio of metastatic to examined lymph nodes is a predictor of mortality in locally advanced gastric cancer treated chemo-radiotherapy.

BACKGROUND/AIMS: To evaluate whether the ratio between the number of metastatic lymph nodes and the number of total removed lymph nodes (MLR) is related survival in patients with locally advanced (stage 3) gastric cancer treated chemo-radiotherapy. METHODOLOGY: We included 179 patients with locally advanced lymph node-positive gastric cancer treated chemo-radiotherapy within this study. The cut-off values, area under curve (AUC), sensitivity, and specificity were calculated using the receiver operating characteristic (ROC) curve technique for MLR. RESULTS: The sensitivity and specificity of MLR for mortality were 71.54% and 51.79%, respectively, when the cutoff level was accepted as the ratio ≥ 0.3. The AUC for the predictive value of MLR with regard to mortality was 0.609 (95% confidence interval [CI]: 0.533-0.681, p: 0.0135). Overall survival rates were significantly lower in patients with high MLR than in those with low MLR (15 months vs. 35 months, p: 0.002, respectively). In multivariate analysis, overall survival rates were significantly associated with MLR status (low or high). CONCLUSION: The simple and easily obtainable MLR is an independent predictor for mortality in patients with locally advanced gastric cancer even if chemo-radiotherapy, which is known to increase local control, was given.

A link between the intrarenal renin angiotensin system and hypertension in autosomal dominant polycystic kidney disease.

BACKGROUND/AIMS: Early onset of hypertension and its consequences account for the great majority of deaths in patients with autosomal dominant polycystic kidney disease (ADPKD). Renin-angiotensin system (RAS) components have been shown in ADPKD kidneys independent of systemic RAS. Thus, we examined the urinary angiotensinogen (UAGT) levels as a biomarker of intrarenal RAS status in ADPKD patients with/without hypertension and healthy subjects. METHODS: Eighty-four ADPKD patients (43 with hypertension and 41 without hypertension) and 40 healthy controls were studied cross-sectionally. Patients with glomerular filtration rate <60 ml/min were excluded from the study. Hypertension was diagnosed with ambulatory blood pressure monitoring. Urinary and plasma concentration of angiotensinogen, spot urine microprotein and creatinine (UCre) levels were recorded for each participant. RESULTS: UAGT/UCre levels were higher in hypertensive ADPKD patients (23.7 ± 8.4) compared with normotensive ADPKD patients (16.6 ± 5.2) and healthy controls (6.9 ± 3.3; p < 0.001). In univariate analysis, UAGT correlated with systolic blood pressure, diastolic blood pressure (DBP) and proteinuria. The independence of these correlations was analyzed in a regression model, and UAGT was shown to be significantly predicted by proteinuria and DBP. CONCLUSION: Intrarenal RAS activation which is monitored by UAGT levels clinically may be a harbinger of hypertension and kidney disease in ADPKD patients.

Evaluation of Fibrosis Markers: Apelin and Transforming Growth Factor-ß1 in Autosomal Dominant Polycystic Kidney Disease Patients.

Renal interstitial fibrosis is an important pathological feature of autosomal dominant polycystic kidney disease (ADPKD), which progressively develops to end-stage renal disease (ESRD). It has been shown that apelin and transforming growth factor-ß1 (TGF-ß1) play important roles in the renal fibrosis process. The aim of the present study is to evaluate the relationship of these fibrosis markers and ADPKD. Forty-five patients with ADPKD and 28 healthy controls were studied cross-sectionally. Estimated glomerular filtration rate (eGFR), apelin, TGF-ß1 were measured in all participants, using conventional methods. Apelin levels were lower (1.2 ± 0.9 ng/mL vs. 2.5 ± 1.3 ng/mL, P < 0.001), while TGF-ß1 levels were higher in the patient group according to healthy controls (466.5 ± 200.5 ng/L vs. 367.1 ± 163.45 ng/L, P = 0.031), respectively. Apelin was negatively correlated with TGF-ß1 and highly sensitive C-reactive protein (hs-CRP); and positively correlated with eGFR. In all subjects, eGFR was independently predicted by TGF-ß1 and apelin. Apelin and TGF-ß1 may be used as biomarkers of renal fibrosis that is an important pathological feature of ADPKD, which progressively develops to ESRD in ADPKD patients.

Toll-Like Receptors in the Progression of Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of chronic kidney disease. The intriguing role of innate immune system and inflammation become a target for potential therapeutic approach to slow progression. When toll-like receptors (TLRs) signaling and their receptors activate, they start a cascade of intracellular signaling that induces the production of the inflammatory cytokines and chemokines. Thus, we aim to investigate the association of TLRs between progression of ADPKD. Ninety ADPKD patients and ninety matched controls were enrolled this prospective study and were followed during 3 years. TLR-2 and TLR-4 gene polymorphisms and expressions were measured. Hypertension was diagnosed with ambulatory blood pressure monitoring. Rapid progression was defined as sustained decline in estimated glomerular filtration rate (eGFR) of more than 5 mL/min per 1.73 m2 per year. TLR-4Asp299Gly polymorphisms were significantly different between patient and control group (P < 0.05). Also, TLR-2 and TLR-4 gene expressions were significantly different between the ADPKD patients and the control subjects (P < 0.05). The expression levels of both TLR-2 and TLR-4 were found to be higher in the rapid progression groups comparing the slow progression group (P < 0.05). TLR-2 gene expression, hypertension and uric acid were found to be independent risk factors in identifying rapid progression in ADPKD patients. TLR-2 and TLR-4 gene expressions are associated with rapid progression in ADPKD patients. TLRs may play a role in the progression of ADPKD.

Pentraxin 3 as a novel bio-marker of inflammation and endothelial dysfunction in autosomal dominant polycystic kidney disease.

BACKGROUND/AIMS: Cardiovascular disease (CVD) is the main cause of mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Prior to hypertension early vascular changes and inflammation have been reported. We aimed to investigate long pentraxin 3 (PTX-3), which has been recently described as a biomarker of inflammation, and its relation with endothelial dysfunction in early ADPKD patients. METHODS: Twenty-five ADPKD patients without hypertension and 25 healthy controls were studied cross-sectionally. Hypertension was diagnosed with ambulatory blood pressure monitoring. Plasma concentrations of PTX-3 and proteinuria levels were obtained from each participant. Endothelial dysfunction was assessed using ischemia-induced forearm flow-mediated vasodilation (FMD). RESULTS: PTX-3 levels were higher in ADPKD patients compared to healthy controls (4.2 [1.2-10.1] vs. 1.4 [0.4-3.1] ng/ml, p < 0.001). Additionally, C-reactive protein (CRP) and proteinuria levels were higher in ADPKD patients than in healthy subjects. In the whole cohort, PTX-3 correlated negatively with FMD (r: -0.58, p < 0.001) and positively with proteinuria (r: 0.56, p < 0.001) and uric acid (r: 0.57, p < 0.001). In all subjects, FMD was independently predicted by PTX-3, but not by uric acid, CRP or proteinuria. CONCLUSION: PTX-3 may be a better biomarker of inflammation than CRP to predict endothelial dysfunction in normotensive ADPKD patients with well-preserved kidney function. Hence, inflammation which is demonstrated by PTX-3 may potentially be used to predict future CVD in this population.

Endothelial nitric oxide synthase gene expression is associated with hypertension in autosomal dominant polycystic kidney disease.

BACKGROUND/AIMS: Early occurrence of hypertension is the prominent feature of autosomal dominant polycystic kidney disease (ADPKD). The role of angiotensin-converting enzyme (ACE) gene polymorphism and endothelial nitric oxide synthase (eNOS) gene polymorphism in the clinical course of ADPKD is not well understood. However, data about the expression of these genes are lacking. Thus, we aimed to investigate the polymorphisms and expressions of both the ACE and eNOS genes that affect hypertension in ADPKD. METHODS: Whole blood samples were obtained from all participants. ACE and eNOS gene polymorphisms and their expressions were analyzed in 78 ADPKD patients and 30 controls. Gene expressions were assessed by quantitative real-time PCR. Twenty-four-hour blood pressure monitoring was performed for the diagnosis of hypertension in all study participants. RESULTS: eNOS expression and the estimated glomerular filtration rate were found to be significantly higher in ADPKD patients without hypertension than in those with hypertension. Each unit of increase in eNOS expression led to a 0.88-fold decrease (95% CI: 0.80-0.96) in the risk of hypertension in multiple logistic regression analysis. CONCLUSIONS: eNOS gene expression is independently predictive of hypertension in the ADPKD population. This study showed, for the first time, a novel link between eNOS gene expression and hypertension in ADPKD.