Endothelin receptor antagonists in diabetic and non-diabetic chronic kidney disease.

Chronic kidney disease (CKD) is one of the major causes of morbidity and mortality, affecting >800 million persons globally. While we still lack efficient, targeted therapies addressing the major underlying pathophysiologic processes in CKD, findings of several recent trials have brought about a shifting landscape of promising therapies. The endothelin system has been implicated in the pathophysiology of CKD and endothelin receptor antagonists are one class of drugs for which we have increasing evidence of efficacy in these patients. In this review we summarize the most recent findings on the safety and efficacy of endothelin receptor antagonists in diabetic and non-diabetic CKD, future directions of research and upcoming treatments.

First Characterization of ADAMTS-4 in Kidney Tissue and Plasma of Patients with Chronic Kidney Disease-A Potential Novel Diagnostic Indicator.

Background: We have previously shown that metzincin protease ADAMTS-4 accompanies renal fibrogenesis, as it appears in the blood of hemodialysis patients. Methods: Native kidney (NKB) and kidney transplant (TXCI) biopsy samples as well as plasma from patients with various stages of CKD were compared to controls. In paired analysis, 15 TXCI samples were compared with their zero-time biopsies (TX0). Tissues were evaluated and scored (interstitial fibrosis and tubular atrophy (IFTA) for NKB and Banff ci for TXCI). Immunohistochemical (IHC) staining for ADAMTS-4 and BMP-1 was performed. Plasma ADAMTS-4 was detected using ELISA. Results: ADAMTS-4 IHC expression was significantly higher in interstitial compartment (INT) of NKB and TXCI group in peritubular capillaries (PTC) and interstitial stroma (INT). Patients with higher stages of interstitial fibrosis (ci > 1 and IFTA > 1) expressed ADAMTS-4 in INT more frequently in both groups (p = 0.005; p = 0.013; respectively). In paired comparison, TXCI samples expressed ADAMTS-4 in INT and PTC more often than TX0. ADAMTS-4 plasma concentration varied significantly across CKD stages, being highest in CKD 2 and 3 compared to other groups (p = 0.0064). Hemodialysis patients had higher concentrations of ADAMTS-4 compared to peritoneal dialysis (p < 0.00001). Conclusion: ADAMTS-4 might have a significant role in CKD as a potential novel diagnostic indicator.

The Role of HLA and KIR Immunogenetics in BK Virus Infection after Kidney Transplantation.

BK virus (BKV) is a polyomavirus with high seroprevalence in the general population with an unremarkable clinical presentation in healthy people, but a potential for causing serious complications in immunosuppressed transplanted patients. Reactivation or primary infection in kidney allograft recipients may lead to allograft dysfunction and subsequent loss. Currently, there is no widely accepted specific treatment for BKV infection and reduction of immunosuppressive therapy is the mainstay therapy. Given this and the sequential appearance of viruria-viremia-nephropathy, screening and early detection are of utmost importance. There are numerous risk factors associated with BKV infection including genetic factors, among them human leukocyte antigens (HLA) and killer cell immunoglobulin-like receptors (KIR) alleles have been shown to be the strongest so far. Identification of patients at risk for BKV infection would be useful in prevention or early action to reduce morbidity and progression to frank nephropathy. Assessment of risk involving HLA ligands and KIR genotyping of recipients in the pre-transplant or early post-transplant period might be useful in clinical practice. This review summarizes current knowledge of the association between HLA, KIR and BKV infection and potential future directions of research, which might lead to optimal utilization of these genetic markers.

Interventions aimed at loneliness and fall prevention reduce frailty in elderly urban population.

Frailty is a pronounced symptom of aging associated with multiple comorbid states and adverse outcomes. The aim of this study was to evaluate the impact of 2 interventions, one based on prevention of falls and the other on prevention of loneliness, on total frailty and dimensions of frailty in urban community-dwelling elderly as well as associations with independent living.This prospective interventional study followed up 410 persons aged 75 to 95. The participants of the control and intervention groups were monitored through a public health intervention programme. The level of frailty was measured by the Tilburg Frailty Indicator (TFI) questionnaire and the factors of independent living were analyzed using validated questionnaires.After 1 year, physical frailty measured in the control group showed a statistically significant increase (r = -0.11), while in the intervention groups physical frailty did not increase (both P > .05). Psychological frailty measured after 1 year in the control group was significantly higher (r = -0.19), as well as in the group where the public health interventions to reduce loneliness were carried out (r = -0.19). Psychological frailty did not increase in the group in which public health interventions to prevent falls were carried out, and social frailty did not increase at all in the study period. The total level of frailty in the control group after 1 year was significantly increased (r = -0.19), while no increase was seen in the overall frailty in the intervention group. Multivariate analysis has shown that both interventions where independently associated with lower end frailty. Additionally, higher baseline frailty and visit to a physician in the last year were positively associated with higher end-study frailty level, while higher number of subjects in the household and higher total psychological quality of life (SF-12) were independently associated with lower end-study frailty. Only in the prevention of falls group there was no increase in restriction in the activities of daily living throughout study follow-up.Public health interventions to prevent falls and to prevent loneliness have a positive effect on the frailty and independent living of the elderly living in their own homes in an urban community.

Combined association of recipient killer cell immunoglobulin-like haplotype AA and donor HLA-C*07 gene with BK virus associated nephropathy in kidney transplant patients.

Kidney transplant recipient killer cell immunoglobulin-like receptors (KIR) genotype and HLA-C status of their donors have been separately associated with BK virus-associated nephropathy (BKVAN) and BK virus infection. Our aim was to determine whether different combinations of recipients KIR genes and donor HLA-C ligands influence the risk of BKVAN. Retrospective case-control study included 23 recipients with BKVAN and 46 recipients with persistently negative BK virus. Donor HLA-C*07 positivity was associated with lower odds for BKVAN, recipients bearing KIR haplotype AA or lacking any activating KIR genes were more frequent in BKVAN while recipient/donor combination HLA-C*07 negative/KIR AA positive was significantly associated with BKVAN. Our study complements and confirms results from several previously published studies, suggesting potential clinical usefulness.

Ruptured renal artery aneurysm in pregnancy and puerperium: literature review of 53 cases.

PURPOSE: To summarize and define the most appropriate diagnostic methods and therapeutic options for ruptured renal artery aneurysms in pregnancy based on rarely published data. METHODS: Literature searches of English-, German-, Spanish-, and Italian-language articles were performed in PubMed (1946-2018), PubMed Central (1900-2018) and Google Scholar. The search terms included renal artery aneurysm, renal artery rupture, pregnancy, puerperium, nierenarterienaneurysma, schwangerschaft, wochenbett, aneurisma de la arteria renal, el embarazo, puerperio, aneurisma dell'arteria renale and gravidanza. Additional studies were identified by reviewing reference lists of retrieved studies. RESULTS: Fifty-three cases were collected. The average maternal age was 31 ± 6 years; 71.4% were multiparous and significantly older than primiparas. The majority presented in the third trimester (62.3%), followed by second (20.7%) and the first (5.7%), while 11.3% presented postpartum. All postpartum patients presented during the first week postpartum and 50% during the first 24 h postpartum. Parity was not associated with the trimester of presentation. The left renal artery was affected slightly more frequently (58.5% vs. 41.5%). There were no differences in the affected side according to trimester of presentation, including postpartum. 25 out of 53 cases underwent ipsilateral nephrectomy (47.1%) and 18 underwent aneurysm repair or coil embolization (34.0%). There was no difference in maternal (25.8%) vs. 4 (18.1%) and fetal mortality according to the side of rupture. There were no differences in the distribution of maternal or fetal mortality frequency according to the trimester of presentation. CONCLUSIONS: The clinical presentation is easily confused with more common conditions and time to diagnosis is often delayed. Diagnostic delay is associated with high maternal and fetal mortality. Ruptured renal artery aneurysm should be included in the differential diagnosis for pregnant or peripartum patients presenting with acute and severe flank pain, especially if followed by a drop in blood pressure. Early diagnosis and immediate intervention are important for achieving better maternal and fetal outcomes. There are several methods of managing asymptomatic or ruptured renal artery aneurysm during pregnancy although no established guidelines exist.

Arterial Stiffness in Balkan Endemic Nephropathy, an Environmental Form of Aristolochic Acid Nephropathy.

Balkan endemic nephropathy (BEN), an environmental form of aristolochic acid nephropathy is characterized with later onset and milder forms of hypertension (HT). Thus, we hypothesized that arterial stiffness progresses slower in BEN patients resulting in lower CV mortality. A total of 186 hemodialysed (HD) patients (90 BEN, 96 non-BEN; 67.3 + 13.0 years) were enrolled and followed-up for 25 months. Brachial blood pressure (BP) and pulse wave velocity (PWV) were determined before mid-week dialysis. BEN patients were older (72.1 ± 37.1 vs. 62.8 ± 15.1; p < 0.001), had shorter duration of HT prior commencement of HD than non-BEN patients (36 vs. 84 months; p < 0.001). There were no differences in BP, but BEN patients were treated with less antihypertensive drugs (p < 0.01). BEN patients had lower PWV values at baseline and at the end of follow-up period despite being chronologically older (p < 0.001). Baseline PWV > 10 m/s was associated with higher risk for CV mortality (aHR 1.8 [1.4, 2.4]). In multivariate analyses BEN was predictor of lower PWV. During the follow-up period significantly less CV deaths were observed in BEN vs. on-BEN patients (12 vs. 31; p = 0.001). CV mortality adjusted for other risk factors was significantly lower in BEN group (aHR 0.2 [0.1, 0.5]). Overall BEN patients had longer mean survival time on HD (22.3 vs. 18.2 months; p < 0.001). Observed slower vascular aging (i.e., lower PWV) in BEN patients compared to other ESRD patients is related to the later onset of HT and milder stages of HT during predialytic clinical course and better control of BP and phosphate during HD.

LAPAROSCOPIC APPENDECTOMY DOES NOT INCREASE THE RATE OF NEGATIVE APPENDECTOMY along with a lower rate of perforated appendicitis - RESULTS IN 1899 PATIENTS at Zagreb UHC.

- Laparoscopic appendectomy is the method of choice of many professional societies owing to its many advantages. The question arises whether surgeons urge more easily to laparoscopic exploration due to its less invasiveness, faster recovery and adequate exploration of the entire abdominal cavity than to observation in unequivocal cases. This retrospective analysis (2009-2016) included 1899 patients undergoing laparoscopic (lap) or gridiron intra-abdominal approach treated at Zagreb University Hospital Centre. The analysis included total negative appendectomy, negative-negative appendectomy (normal appendix and no other pathology found), and negative-positive appendectomy (normal appendix but another pathology found) in children (≤16 years) and adults. There was no statistically significant difference in the rates of negative appendectomy (children) - lap vs. open (p=0.24); negative appendectomy (adults) - lap vs. open (p=0.15); negative-negative appendectomy (children) - lap vs. open (p=0.36); negative-negative appendectomy (adults) - lap vs. open (p=0.21); negative-positive appendectomy (children) - lap vs. open (p=0.53); negative-positive appendectomy (adults) - lap vs. open (p=0.56); and laparoscopy group negative appendectomy in children vs. adults (p=0.56). There was a statistically significantly higher perforation rate with the open approach in total (p<0.0001), in children (p<0.0001) and in adults (p=0.02). There was no statistically significant difference between adults and children in the perforation rate with laparoscopic approach (p=0.24) and perforation rate with open approach (p=0.29). Results confirmed that there was no statistically significant difference in the rate of negative appendectomy in all subgroups. It is concluded that laparoscopic appendectomy should be offered as the method of choice in any patient population with suspicion of acute appendicitis.

Expression of BMP-2 in Vascular Endothelial Cells of Recipient May Predict Delayed Graft Function After Renal Transplantation.

BACKGROUND/AIMS: Delayed graft function (DGF) is associated with adverse outcomes after renal transplantation. Bone morphogenetic protein-2 (BMP-2) is involved in both endothelial function and immunological events. We compared expression of BMP-2 in epigastric artery of renal transplant recipients with immediate graft function (IGF) and DGF. METHODS: 79 patients were included in this prospective study. Patients were divided in IGF group (64 patients) and DGF group (15 patients). BMP-2 expression in intima media (BMP2m) and endothelium (BMP2e) of epigastric artery was assessed by immunohistochemistry. RESULTS: Lower intensity of BMP2e staining was recorded in DGF compared to IGF. In DGF patients, 93% had no expression of BMP2e and 7% had 1st grade expression, compared to 45% and 41% in IGF group, respectively (P=0.001) (P<0.001 for no expression and P = 0.015 for 1st grade expression). Patients who had BMP2e staining positive had lower odds for DGF (OR 0.059 [0.007, 0.477]) and this remained significant even after adjustment for donor and recipient variables, cold ischemia time, and immunological matching (OR 0.038 [0.003, 0.492]). CONCLUSIONS: Our results demonstrate that BMP-2 expression in endothelial cells of epigastric arteries may predict development of DGF.

Adiponectin is not associated with blood pressure in normotensives and untreated hypertensives with normal kidney function.

The role of adiponectin in hypertension is still a matter of debate. Obtained conflicting results could be mostly explained with diversity of subjects included in different studies. Our aim was to analyze association of adiponectin with blood pressure (BP) in a group of normotensive and untreated hypertensive subjects. Participants (N=257) were selected from a random sample of 2487 subjects enrolled in an observational cross-sectional study. Subjects with diabetes and chronic kidney diseases were excluded. BP was measured using Omron M6 device following ESH/ESC guidelines. Adiponectin concentration was determined by ELISA. There were no differences in adiponectin values (mg/L) between hypertensives and normotensives (median 9.75; iqr: 7.44-17.88 vs 11.35; iqr: 7.43-12.63; P=0.17). On univariate linear regression adiponectin was not associated with systolic or diastolic BP (P>0.05). Furthermore, multivariate analysis did not show significant contribution of log-transformed adiponectin either to systolic (ß=-0.040; P=0.43) or diastolic BP (ß=0.066; P=0.33). In our group of normotensives and untreated hypertensives with normal kidney function adiponectin was not associated with BP even after adjustment for other risk factors. Our results and conclusions should not be extrapolated to subjects with other characteristics.

Arterial stiffness in atherosclerotic renovascular hypertension.

OBJECTIVE: Arterial stiffness is an independent cardiovascular risk factor. Aging, high blood pressure and increased renin-angiotensin system activity contribute to increased arterial stiffness in patients with atherosclerotic renovascular hypertension (aRVH). A literature search failed to identify any study related to this topic. Therefore, our aim was to determine the arterial stiffness in patients with aRVH and analyze whether stenting in addition to multifactorial drug therapy has beneficial effects on markers of stiffness and the clinical course. METHODS: In this 6-month longitudinal study, 37 patients with refractory hypertension and unilateral aRVH were enrolled. After stenting, all patients received multifactorial dug therapy including 80 mg of telmisartan. Arterial stiffness indices were determined using Arteriograph. The control group consisted of 44 patients with essential hypertension. RESULTS: There were no differences in brachial blood pressure values between the two groups (P > 0.05). At baseline, adjusted pulse wave velocity (PWV) was higher in aRVH patients than that of essential hypertensive patients (12.8 ±â€Š0.4 vs. 11.6 ±â€Š0.3 m/s; P = 0.029). In the aRVH group, at the end of the follow-up, a significant decrease in the aortic augmentation index (37.7 ±â€Š9.9 vs. 33.7 ±â€Š11.4; P = 0.02) without changes in PWV was observed (P > 0.05). CONCLUSION: This study is the first to show that arterial stiffness is higher in patients with refractory aRVH than in those with essential hypertension. Multifactorial therapy based on stenting and intensive medical treatment reduced central blood pressure and augmentation index. Failure to obtain PWV reduction is likely a consequence of the present irreversible structural vessel changes. Longer follow-up might enable us to resolve whether arterial stiffness indices have better predictive ability in patients with aRVH than brachial blood pressure.

The assessment of arterial stiffness in endemic (Balkan) nephropathy patients undergoing haemodialysis.

Cardiovascular (CV) complications are the most important cause of morbidity and mortality in patients with advanced chronic kidney disease (CKD). Arterial stiffness (AS) has been recognized as a strong and independent predictor for CV events in CKD. Our aim was to assess indices of AS in a group of Endemic (Balkan) Nephropathy (EN) patients undergoing haemodialysis (HD). Hypertenison was not considered an importnat feauture in earlier stages of the disease, and therefore we presumed that those patients would have lower AS. Interestingly, we found AS to be even higher in this group of EN patients. This result should be confirmed in a larger cohort of EN patients.