Impaired Left Ventricular Global Longitudinal Strain among Patients with Chronic Kidney Disease and End-Stage Renal Disease and Renal Transplant Recipients

Background: Although heart failure is the most prevalent cardiovascular disease associated with adverse outcome in chronic kidney disease (CKD) and after kidney transplantation, left ventricular (LV) systolic function is often preserved in renal patients. The aim of this study was to evaluate global longitudinal strain (GLS), which is reportedly a more accurate tool for detecting subclinical LV systolic dysfunction, in patients with various degrees of renal function impairment, including kidney transplant recipients (KTRs). Methods: This prospective study evaluated demographic, clinical, and ultrasound data, including the assessment of LV GLS and mitral E peak velocity and averaged ratio of mitral to myocardial early velocities (E/e'), of 70 consecutive renal patients (20 with stage 2-4 CKD, 25 with end-stage renal disease on hemodialysis [HD], and 25 KTRs). All patients had an LV ejection fraction 6550% and no history of heart failure or coronary artery disease. We used multivariable logistic analysis to assess the risk of compromised GLS. One hundred and twenty control subjects with or without hypertension served as controls. Results: A compromised GLS <-18% was shown in 55% of patients with stage 2-4 CKD, 60% of HD patients, and 28% of KTRs, while it was 32% in hypertensive controls and 12% in non-hypertensive controls (p < 0.0001). Patients with HD had higher systolic pressure and a significantly greater prevalence of increased LV mass and diastolic dysfunction. In renal patients, E/e' (p = 0.025), and LV mass index (p = 0.063) were independent predictors of compromised GLS at logistic regression analysis. E/e', systolic artery pressure, and LV mass also exhibited the greatest areas under the curve on receiver operating characteristic analysis to identify a compromised GLS. Conclusions: Renal disease proved to be associated with early and subclinical impairment of LV systolic function, which persists after starting dialysis and even in spite of successful kidney transplantation. An increased E/e' resulted to be the most powerful independent predictor of abnormal GLS

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

[The therapeutic management and economic burden of patients with chronic kidney disease non-dialysis-dependent with anemia and ESA treated: findings from a real-world study in Italy]

Background. L’obiettivo dell’analisi real-world è stato valutare le caratteristiche dei pazienti con insufficienza renale cronica non dipendente da dialisi (IRC-NDD) con anemia e trattati con agenti stimolanti l’eritropoiesi (ESA), analizzarne la farmaco-utilizzazione e il carico economico in pratica clinica italiana. Metodi. È stata eseguita un’analisi retrospettiva basata su database amministrativi e di laboratorio riguardanti circa 1,5 milioni di assistibili. Sono stati identificati pazienti adulti con record identificanti l’IRC-NDD stadio 3a-5 e anemia nel periodo 2014-2016. Sono stati inclusi i pazienti eleggibili agli ESA (presenza di ≥ 2 valori di Hb &lt; 11 g/dL in 6 mesi) attualmente trattati. Risultati. Dei 101.143 pazienti IRC-NDD identificati, 40.020 presentavano anemia. Complessivamente, 25.360 pazienti anemici erano eleggibili al trattamento con ESA e 3.238 (12,8%) attualmente in trattamento sono stati inclusi. L’età media era di 76,9 anni, il 51,1% era di sesso maschile. Le comorbilità più frequentemente riscontrate riguardavano l’ipertensione (&gt; 90% in ogni stadio), il diabete (37,8- 43,2%) e le patologie cardiovascolari (20,5-28,9%). L’aderenza agli ESA è stata osservata nel 47,9% dei pazienti, con una tendenza decrescente dal 65,8% (stadio 3a) al 35% (stadio 5). Una quota consistente di pazienti non presentava visite nefrologiche durante i 2 anni di follow-up. La voce di costo maggiormente impattante era quella relativa ai farmaci (€4.391), seguita dai ricoveri per tutte le cause (€3.591) e dagli esami di laboratorio (€1.460). Conclusioni. I risultati hanno evidenziato un’aderenza non ottimale agli ESA, con un trend di sotto utilizzo di queste terapie nella gestione dell’anemia nell’IRC-NDD. Inoltre, l’analisi ha mostrato un elevato carico economico per i pazienti anemici IRC-NDD.Background. This real-world study aimed to provide insights on the characteristics, drug utilization, and economic burden of chronic kidney disease non-dialysis-dependent (NDD-CKD) patients with anemia prescribed Erythropoiesis Stimulating Agents (ESA) in Italian clinical practice settings. Methods. A retrospective analysis was performed based on administrative and laboratory databases covering around 1.5 million subjects across Italy. Adult patients with a record for NDD-CKD stage 3a-5 and anemia during 2014-2016 were identified. Eligibility to ESA was defined as the presence of ≥ 2 records of Hb &lt; 11 g/dL over 6 months, and patients eligible and currently treated with ESA were included. Results. Overall, 101,143 NDD-CKD patients were screened for inclusion, of which 40,020 were anemic. A total of 25,360 anemic patients were eligible to ESA treatment and 3,238 (12.8%) were prescribed ESA and included. The mean age was 76.9 years and 51.1% was male. More frequently observed comorbidities were hypertension (over 90% in each stage), followed by diabetes (37.8-43.2%) and cardiovascular condition (20.5-28.9%). Adherence to ESA was observed in 47.9% of patients, with a downward trend while progressing across stages (from 65.8% stage 3a to 35% stage 5). A consistent proportion of patients did not have nephrology visits during the 2 years of follow-up. Costs were mainly due to all drugs (€4,391) followed by all-cause hospitalization (€3,591) and laboratory tests (€1,460). Conclusions. Findings from the study highlight an under-use of ESA in the management of anemia in NDD-CKD as well as a sub-optimal adherence to ESA and showed a great economic burden for anemic NDD-CKD patients

Pt(IV) complexes based on cyclohexanediamines and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid: synthesis, characterization, cell penetration properties and antitumor activity

The Pt(iv) complexes based on (SP-4-2)-dichlorido(cyclohexane-1,4-diamine)platinum(ii) (kiteplatin) and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid (POA) were investigated. Since POA contains a chiral carbon, all the possible Pt(iv) isomers were prepared and characterized, and their antiproliferative activity on six cancer cell lines was compared with that of the corresponding Pt(iv) complexes containing the cyclohexane-1R,2R-diamine equatorial ligand. To justify the very good antiproliferative activity (nanomolar IC50), the polarity, lipophilicity, permeability, and cell accumulation of the complexes were studied. Overall, the two series of Pt(iv) complexes showed similar cell penetration properties, being significantly better than that of the Pt(ii) reference compounds. Finally, a representative compound of the whole set of complexes (i.e., that based on cyclohexane-1R,2R-diamine and racemic POA) was tested in vivo on mice bearing Lewis lung carcinoma, showing good tumor growth inhibition with negligible body weight loss

Host–guest inclusion systems of Pt(IV)-bis(benzoato) anticancer drug candidates and cyclodextrins

Two small series of Pt(IV) complexes of the general formula cis,cis,trans-[PtA2Cl2L2] (A = 2 NH3, series 1, or cyclohexane-1R,2R-diamine, dach, series 2, L = aromatic carboxylate of different chain length, i.e. –OCO(CH2)nC6H5, n = 0 (a), 1 (b), and 2 (c)) were synthesized and fully characterized, including X-ray structure analysis of one of them. The antiproliferative activity of the complexes was evaluated against a panel of eight human cancer cell lines, proving to be at the nanomolar level for the platinum-sensitive A2780 and at the sub-micromolar level for the chemoresistant mesothelioma cell lines. In contrast with Pt(IV) complexes bearing aliphatic carboxylates, whose antiproliferative potency increases with the number of carbon atoms, a clear structure–activity relationship cannot be drawn in the bis(benzoato) series. The inclusion reaction with cyclodextrins (CDs), a widely accepted approach for drug formulation, was performed in order to obtain adducts able to bypass the limitations imposed by the low water solubility of bis(benzoato) complexes. Phase-solubility tests demonstrated that b-CD was able to efficiently solubilize only the very active prototype [Pt(NH3)2Cl2(C6H5COO)2] 1a. Two methods were used to prepare the host–guest inclusion systems (i.e., simple solubilization at room temperature of 1a in solution containing excess of b-CD or thermal reaction with subsequent isolation of a solid adduct) and the resulting adducts were tested for cytotoxicity against the cancer cell lines. The presence of b-CD in solution did not decrease the remarkable antitumor activity of 1a, whereas the solid-state inclusion system underwent extensive aggregation, proving to be detrimental for Pt accumulation in the cells and, therefore, overall cytotoxicity

Early interstitial macrophage infiltration with mild dysfunction is associated with subsequent kidney graft loss

Macrophage infiltration is associated with unfavorable kidney graft outcome in protocol biopsies, but few studies have evaluated its impact on clinical practice. We therefore prospectively evaluated 37 kidney transplant recipients (KTRs) who underwent kidney biopsy due to slight increases in serum creatinine, or mild proteinuria (&gt;0.3&nbsp;g/24&nbsp;hr), in the first post-transplant year. Banff score, CD68+count (score 0-3) by immunohistochemistry, and 1-year DSA were assessed. DGF was reported in 10 (27%) patients, 6 (16%) had normal biopsy, 7 (19%) borderline lesions, 13 (35%) IFTA, and 11 (30%) other lesions. Fifteen KTRs had grade 3 CD68+ infiltration, and 47% developed de novo DSA. During a 6.2&nbsp;\ub1&nbsp;2.7&nbsp;year follow-up, four patients (11%) suffered from biopsy-proven T-cell rejection, 17 KTRs (46%) lost their graft (12 in the grade 3 CD68+group). Graft survival was lower in KTRs with grade 3 CD68+ infiltration (P&nbsp;=&nbsp;0.0074; log-rank test). Grade 3 CD68+ infiltrate was an independent predictor of graft loss (HR 5.41, 95% CI 1.74-16.8; P&nbsp;=&nbsp;0.003), together with more severe graft dysfunction at biopsy (HR 6.41, 95% CI 2.57-16; P&nbsp;&lt;&nbsp;0.001). We conclude that grade 3 CD68+interstitial infiltration is associated with increased risk of subsequent graft loss independent of other factors