Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Study of tubular transport of urate in adult polycystic kidney disease with the pyrazinamide and probenecid test

The human kidney is responsible for 2/3 to 3/4 of the excretion of the daily load of uric acid, the final product of the purine metabolism. In spite of the fact that uric acid is almost totally filtered in the glomeruli, only 10 % of the filtered quantity is excreted in the urine, because of extensive reabsorption of urate. Many factors affect the tubular transport of urate, some by increasing the tubular transport (extracellular volume increment, sodium load, hyperglycemia, ADH, contrast media, drugs e.t.c.), and others by decreasing it (organic acids, angiotensin II, norepinephrine, PTH, drugs, e.t.c.). In chronic renal failure (CRF) irrelevant of primary kidney disease, recent studies have shown that the quantity of the urate excreted per nephron is increased, mainly by a supression of postsecretory reabsorption, and also by supression of presecretory reabsorption, which is becomes more obvious in the final stages of the disease. The renal handling of urate was studied by probenecid and pyrazinamide tests, in 58 patients with adult dominant polycystic kidney disease (ADPKD), 25 with normal renal function and the rest with various degrees of chronic renal failure. The above 58 patients were compared to 21 healthy persons and 42 patients suffering from glomerulonephritis (G/N) (among them 11 with normal renal function and the rest with chronic renal failure), who served as a control group. The 21 persons with normal renal function comprised group M of controls, while the patients with ADPKD as well as those with G/N were separated into 5 groups. All groups were comparative in age, sex and creatinine clearance (except Group E where creatinine clearance was significantly higher in G/N patients). Group A with a creatinine clearance higher than 80 ml/min. Group Β with a creatinine clearance ranging from 40 to 80 ml/min. Group C with a creatinine clearance ranging from 20 to 40 ml/min. Group D with a creatinine clearance ranging from 10 to 20 ml/min and Group E with a creatinine clearance less than 10 ml/min. Upon the comparison of the results between the groups with normal renal function, the plasma urate levels did not show any significant difference between the ADPKD group and the controls (group M). However plasma urate levels were found to be significantly higher in G/N patients comparing to controls (p80 ml/min) και 42 πάσχοντες από σπειραματονεφρίτιδα, τόσο με φυσιολογική νεφρική λειτουργία όσο και με χρόνια νεφρική ανεπάρκεια. Τα 21 άτομα με φυσιολογική νεφρική λειτουργία αποτέλεσαν την ομάδα Μ των μαρτύρων. Οι ασθενείς τόσο με ΠΚΝ όσο και με Σ/Ν χωρίστηκαν σε 5 ομάδες, συγκρίσιμες ως προς την ηλικία, το φύλο και την κάθαρση κρεατινίνης από 40-80 ml/min, τη Γ με κάθαρση κρεατινίνης από 20-40 ml/min, τη Δ με κάθαρση κρεατινίνης από 10-20 ml/min, και την Ε με κάθαρση κρεατινίνης 7 mg/dl) ωστόσο παρουσιάζουν μία στατιστικώς σημαντικά μεγαλύτερη τιμή ουρικού πλάσματος, n οποία θα πρέπει να αποδοθεί στη στατιστικώς σημαντικά χαμηλότερη κάθαρση και κλασματική απέκκριση του. 2. Οι ασθενείς με ΠΚΝ και ΧΝΑ εμφανίζουν υψηλότερη κάθαρση και κλασματική απέκκριση ουρικού σε σχέση με τους πάσχοντες από Σ/Ν και ανάλογου βαθμού νεφρικής ανεπάρκειας σε όλα τα στάδια εξελίξεως, η οποία καθίσταται σημαντική στην ομάδα Γ. Το εύρημα αυτό είναι αποτέλεσμα της διαφοράς στην προεκκριτική επαναρρόφηση, η οποία είναι μεγαλύτερη στη Σ/Ν. 3. Συμπερασματικά οι ασθενείς με ΠΚΝ όταν έχουν φυσιολογική νεφρική λειτουργία δε διαφέρουν από τους φυσιολογικούς μάρτυρες, όσον αφορά τη νεφρική αποβολή του ουρικού, γι' αυτό και τα επίπεδα του πλάσματος παραμένουν φυσιολογικά. Κατά την εξέλιξη της ΠΚΝ προς το τελικό στάδιο της ΧΝΑ, τα μεν επίπεδα του ουρικού του πλάσματος είναι χαμηλότερα, η δε κάθαρση και η κλασματική του απέκκριση είναι υψηλότερες συγκρινόμενες με τους ασθενείς που πάσχουν από Σ/Ν και με ανάλογο βαθμό νεφρικής ανεπάρκειας

HIPEC for gynaecological malignancies: A last update (Review)

Advanced-stage gynaecological cancer represents a clinical entity with challenging surgical treatment in an effort to optimize prognosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) following cytoreductive surgery (CRS) has been reported as a method potentially eligible to improve prognosis. However, no definitive conclusions have yet been made on which types of cancer and which context HIPEC may actually have a beneficial impact. The present review discusses the efficacy and safety of HIPEC as a treatment option for patients with primary/recurrent ovarian, endometrial and cervix cancer, as well as peritoneal sarcomatosis. A literature search was conducted using MeSH terms for each topic in the PubMed database and supplemented with a manual search to retrieve additional articles eligible for inclusion/fulfilling the inclusion criteria. The implementation of HIPEC appears to be beneficial in terms of survival in patients with epithelial ovarian carcinoma (EOC) following neoadjuvant chemotherapy, as well as in patients with recurrent EOC. Statistical superiority is not justified by current studies regarding other gynaecological malignancies with peritoneal dissemination. Furthermore, as regards safety, HIPEC following CRS does not appear to significantly increase the mortality and morbidity rates compared to the use of CRS alone. The rationale for using HIPEC and CRS in the treatment of ovarian cancer, particularly in the neoadjuvant setting, as well as for recurrences, is adequately evidenced, with acceptable safety and post-operative complication rate profiles. Its current place in the multimodal strategy for patients with peritoneal metastases remains uncertain, however. Randomized clinical trials are warranted to further examine the use of HIPEC and establish the optimal regimen and temperature settings. The role of optimal cytoreduction and no residual disease, as well as the proper patient selection remain basic parameters for maximizing survival parameters

Combined pelvic and para-aortic is superior to only pelvic lymphadenectomy in intermediate and high-risk endometrial cancer: a systematic review and meta-analysis

BACKGROUND: Lymph node metastasis is a principal prognostic factor for the treatment of endometrial cancer. Added value of para-aortic lymphadenectomy to only pelvic lymphadenectomy for intermediate/high-risk endometrial cancer patients remains controversial. OBJECTIVE: A systematic review and meta-analysis was performed to assess the impact of combined pelvic and para-aortic lymph node dissection (PPALND) compared to only pelvic lymph node dissection (PLND) on survival outcomes of intermediate and/or high-risk patients. STUDY DESIGN: The systematic review and meta-analysis adhered to the PRISMA guidelines for meta-analyses of interventional studies. Pubmed, Scopus, EMBASE and Cochrane were searched up to April 20, 2018. Included studies were those comparing high-risk endometrial cancer patients that had performed pelvic and para-aortic lymph node dissection (PPALND) vs. only pelvic lymph node dissection (PLND) apart from standard procedure (total hysterectomy with bilateral salpingo-oophorectomy, TAHBSO). Primary outcomes of the study were overall survival and disease-free survival rates. Methodological quality of the included studies was assessed using the ROBINS-I tool. Overall quality of the evidence for the primary and secondary outcomes was evaluated as per GRADE guideline using the GRADE pro GD tool. RESULTS: There were 13 studies identified with 7349 patients included. All studies were retrospective observational as no RCTs or prospective studies adhering to inclusion criteria were retrieved. Combined pelvic and para-aortic lymphadenectomy was associated with 46% decreased risk for death (HR 0.54, 95% CI 0.35-0.83, I2 = 62.1%) and 49% decreased risk for recurrence (HR 0.51, 95% CI 0.28-0.93). It was also associated with increased 5-year OS rate (RR 1.13, 95% CI 1.04-0.24, I2 = 57.3%) and increased 5-year DFS rate (RR 1.23, 95% CI 1.14-1.31, I2 = 85.5) compared with only pelvic lymphadenectomy. CONCLUSION: Combined pelvic and para-aortic lymphadenectomy is associated with improved survival outcomes compared with only pelvic lymphadenectomy in women with intermediate/high-risk endometrial cancers. Further prospective studies should be performed.status: publishe

Combined pelvic and para-aortic is superior to only pelvic lymphadenectomy in intermediate and high-risk endometrial cancer: a systematic review and meta-analysis

Background Lymph node metastasis is a principal prognostic factor for the treatment of endometrial cancer. Added value of para-aortic lymphadenectomy to only pelvic lymphadenectomy for intermediate/high-risk endometrial cancer patients remains controversial. Objective A systematic review and meta-analysis was performed to assess the impact of combined pelvic and para-aortic lymph node dissection (PPALND) compared to only pelvic lymph node dissection (PLND) on survival outcomes of intermediate and/or high-risk patients. Study design The systematic review and meta-analysis adhered to the PRISMA guidelines for meta-analyses of interventional studies. Pubmed, Scopus, EMBASE and Cochrane were searched up to April 20, 2018. Included studies were those comparing high-risk endometrial cancer patients that had performed pelvic and para-aortic lymph node dissection (PPALND) vs. only pelvic lymph node dissection (PLND) apart from standard procedure (total hysterectomy with bilateral salpingo-oophorectomy, TAHBSO). Primary outcomes of the study were overall survival and disease-free survival rates. Methodological quality of the included studies was assessed using the ROBINS-I tool. Overall quality of the evidence for the primary and secondary outcomes was evaluated as per GRADE guideline using the GRADE pro GD tool. Results There were 13 studies identified with 7349 patients included. All studies were retrospective observational as no RCTs or prospective studies adhering to inclusion criteria were retrieved. Combined pelvic and para-aortic lymphadenectomy was associated with 46% decreased risk for death (HR 0.54, 95% CI 0.35-0.83, I-2 = 62.1%) and 49% decreased risk for recurrence (HR 0.51, 95% CI 0.28-0.93). It was also associated with increased 5-year OS rate (RR 1.13, 95% CI 1.04-0.24, I-2 = 57.3%) and increased 5-year DFS rate (RR 1.23, 95% CI 1.14-1.31, I-2 = 85.5) compared with only pelvic lymphadenectomy. Conclusion Combined pelvic and para-aortic lymphadenectomy is associated with improved survival outcomes compared with only pelvic lymphadenectomy in women with intermediate/high-risk endometrial cancers. Further prospective studies should be performed