Cardiovascular safety of current and emerging drugs to treat anaemia in chronic kidney disease: a safety review.

INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) are the standard of treatment for anemia in chronic kidney disease. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) are small molecules that stimulate endogenous erythropoietin synthesis. AREAS COVERED: The cardiovascular safety of ESAs and HIF-PHIs. We performed a PubMed search using several key words, including anemia, chronic kidney disease, safety, erythropoiesis stimulating agents, HIF-PH inhibitors. EXPERT OPINION: ESAs are well-tolerated drugs with a long history of use; there are safety concerns, especially when targeting high hemoglobin levels. HIF-PHIs have comparable efficacy to ESAs in correcting anemia. Contrary to expectations, randomized phase 3 clinical trials have shown that overall HIF-PHIs were non-inferior to ESA or placebo with respect to the risk of cardiovascular endpoints. In addition, some phase 3 trials raised potential safety concerns regarding cardiovascular and thrombotic events, particularly in non-dialysis patients.Today, HIF-PHIs represent an additional treatment option for anemia in patients with chronic kidney disease. This has made the management of anemia in CKD more complex and heterogeneous. A better understanding of the mechanisms causing hypo-responsiveness to ESAs, combined with an individualized approach that balances ESAs, HIF-PHIs and iron doses, could increase the benefits while reducing the risks.

Prevalence and clinical correlates of hyperkalemia in stable kidney transplant recipients.

Although hyperkalemia (HK) is often associated with adverse clinical outcomes in renal patients, few studies are available in the setting of kidney transplantation. Therefore, we evaluated prevalence and clinical correlates of HK in stable kidney transplant recipients (KTRs) on standard of care immunosuppressive therapy. We studied 160 stable KTRs (post-transplant vintage 46.6 ± 16.6 months), most of whom (96.2%) on calcineurin inhibitor (CNI)-based immunosuppressive therapy. HK was defined as plasma potassium levels above 5 mEq/L, confirmed in two consecutive samples. Office blood pressure was measured, and renal graft function was expressed by estimated glomerular filtration rate (eGFR), calculated according to the CKD-EPI formula. HK prevalence was 8.8%, and plasma K above 5.5 mEq/L was found in 2.5% of all KTRs. In the univariate logistic regression analysis HK was significantly associated with serum urea concentration (OR 1.03, 95% CI 1.01-1.05 for each 1 mg/dL increase), tCO2 (OR 0.77, 95% CI 0.66-0.90 for each 1 mmol/L increase), the presence of arterial hypertension (OR 4.01, 95% CI 1.3-12.64), the use of RAAS inhibitors (OR 5.26, 95% CI 1.6-17.7), and eGFR less than 30 ml/min/1.73 m2 (OR 7.51, 95% CI 2.37-23.77). By multivariable backward stepwise regression analysis, the presence of metabolic acidosis (OR 0.83, 95% CI 0.69-0.99, P = 0.04), arterial hypertension (OR 4.65 95% CI 1.01-17.46 P = 0.03), and to be administered RAAS inhibitors (OR 6.11, 95% CI 1.03-25.96 P = 0.03) remained significantly associated with HK. We conclude that in stable KTRs the prevalence of HK is about 9%, slightly lower than previously reported. Moreover, it is not associated with eGFR, but with metabolic acidosis, arterial hypertension, and the use of RAAS inhibitors.

Everolimus for BKV nephropathy in kidney transplant recipients: a prospective, controlled study.

There is no specific therapy for polyoma BK virus nephropathy (BKVN) in kidney transplant recipients, a condition associated with poor outcomes. Everolimus showed promising antiviral effects, but data from prospective studies are limited. Therefore, we converted ten consecutive kidney transplant recipients with biopsy-proven BKVN from standard exposure Calcineurin inhibitors and Mycophenolate to Everolimus and reduced exposure Calcineurin inhibitors. Ten patients not administered Everolimus, on reduced exposure Calcineurin inhibitor and halved MPA doses served as controls. All kidney transplant recipients continued steroid therapy. Each patient underwent kidney graft biopsy, BKV replication by PCR, and de novo DSA determination. During a 3-year follow-up no graft loss occurred in kidney transplant recipients on Everolimus but it was observed in 5/10 controls (P = 0.032). eGFR improved on Everolimus and worsened in controls (between group difference + 25.6 ml/min/1.73 m2, 95% CI 10.5-40.7, P = 0.002). BKV replication declined in the Everolimus group alone (from 6.4 ± 0.8 to 3.6 ± 1.6 Log 10 genomic copies, P = 0.0001), and we found a significant inverse relationship between eGFR and BKV genomic copy changes (P = 0.022). Average Calcineurin inhibitors trough levels did not differ between the two study groups during follow-up. By multivariable Cox regression analysis, Everolimus treatment resulted the only significant predictor of survival free of a combined endpoint of graft loss and 57% eGFR reduction (P = 0.02). Kidney transplant recipients on Everolimus had a higher survival free of adverse graft outcome (log-rank test, P = 0.009). In conclusion an Everolimus-based immunosuppressive protocol with minimization of Calcineurin inhibitors and antimetabolite discontinuation effectively treated BKVN in kidney transplant recipients.

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 (>0.3 g/24 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 ± 2.7 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 = 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 = 0.003), together with more severe graft dysfunction at biopsy (HR 6.41, 95% CI 2.57-16; P < 0.001). We conclude that grade 3 CD68+ interstitial infiltration is associated with increased risk of subsequent graft loss independent of other factors.

Cardiac valve calcification and use of anticoagulants: Preliminary observation of a potentially modifiable risk factor.

AIMS: Direct oral anticoagulant (DOAC) has been recently introduced in the clinical practice. Rather than interfering with vitamin K-dependent posttranscriptional modification of various proteins, DOACs selectively inhibit factors involved in the coagulation cascade. In particular, in contrast with Warfarin, Rivaroxabn does not interfere with activation of matrix Gla Protein (MGP), a potent vascular calcification Inhibitor. We herein sought to investigate the impact of Rivaroxaban and Warfarin on cardiac valve calcifications in a cohort of moderate-to advanced CKD patients. METHODS AND RESULTS: This is a multicenter, observational, retrospective, longitudinal study. Consecutive CKD stage 3b - 4 (according to KDIGO guidelines) patients from 8 cardiologic outpatient clinics were enrolled between May 2015 and October 2017. All patients received anticoagulation (100 Warfarin vs 247 Rivaroxaban) as part of their non-valvular atrial fibrillation management. Cardiac valve calcification was evaluated via standard trans-thoracic echocardiogram. 347 patients (mean age: 66 years; mean eGFR: 37 ml/min/1.73 m2) were studied. Over a mean follow-up period of 16 months, Rivaroxaban compared to Warfarin reduced both mitral and aortic valve calcifications (p < 0.001) independently of the degree of calcifications at baseline and potential confounders. Notably, Rivaroxaban use was also associated with a significant reduction in C reactive protein (CRP) (p < 0.001) during follow-up. CONCLUSION: This study generates the hypothesis that the use of Rivaroxaban associates with a reduction of cardiac valve calcification deposition and progression as compared to Warfarin, in a cohort of CKD stage 3b-4 patients. Future endeavors are needed to confirm and to establish the mechanisms responsible for these findings.

[mTOR inhibitors in kidney transplantation].

A changing paradigm of treatment of kidney transplant recipients is a new, wider approach to immunosuppression, which should take into account both antiviral and anticancer effects, in addition to cardiovascular protection. Recent observations suggest that the early introduction of mammalian target of rapamycin inhibitors (mTORi) in association with low dose CNI may offer many of these effects. The present manuscript summarizes benefits and contraindications of combinations with mTORi in kidney transplant immunosuppressive strategies.

Controversial issues in CKD clinical practice: position statement of the CKD-treatment working group of the Italian Society of Nephrology.

This position paper of the study group "Conservative treatment of Chronic Kidney Disease-CKD" of the Italian Society of Nephrology addresses major practical, unresolved, issues related to the conservative treatment of chronic renal disease. Specifically, controversial topics from everyday clinical nephrology practice which cannot find a clear, definitive answer in the current literature or in nephrology guidelines are discussed. The paper reports the point of view of the study group. Concise and practical advice is given on several common issues: renal biopsy in diabetes; dual blockade of the renin-angiotensin-aldosterone system (RAAS); management of iron deficiency; low protein diet; dietary salt intake; bicarbonate supplementation; treatment of obesity; the choice of conservative therapy vs. dialysis. For each topic synthetic statements, guideline-style, are reported.

Effect of early conversion from CNI to sirolimus on outcomes in kidney transplant recipients with allograft dysfunction.

BACKGROUND: Studies evaluating the effect of conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) in renal transplant recipients (RTRs) have shown conflicting results, and only few short-term uncontrolled studies are available in patients with chronic allograft dysfunction. This is the first controlled study to evaluate long-term survival and both renal and cardiac outcomes in nondiabetic RTRs with allograft dysfunction who were converted from CNI to SRL. METHODS: We evaluated 13 RTRs with biopsy-proven allograft dysfunction who underwent early conversion from CNI to SRL, and 26 controls with normal graft function taking CNI. All continued both steroids and mycophenolate mofetil. SRL was titrated to trough levels of 4-8 ng/mL. Outcome measures included 3-year event-free survival, acute rejection rate and 3-year changes in Modification of Diet in Renal Disease (MDRD) Study equation estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMi) as assessed by echocardiography. RESULTS: Compared with controls, patients on SRL showed better 3-year event-free survival (p=0.024; log-rank test), significant eGFR increase (+5.5 ± 8.9 vs, -6.4 ± 14.7 ml/min per 1.73 m2, p=0.011), LVMi regression (-9.0 ± 7.6 g/m(2.7) vs. 1.0 ± 10.1 g/m(2.7), p=0.0038) and similar acute rejection rate. Three-year change in eGFR was the only significant predictor of event-free survival by Cox regression analysis (hazard ratio = 0.96; 95% confidence interval, 0.93-0.99; p=0.017), whereas SRL was the strongest predictor of both eGFR increase (beta coefficient, 0.342; p=0.01) and LVM reduction (beta coefficient, -0.609; p=0.0001) by multivariate regression analysis. CONCLUSIONS: Conversion from CNI to SRL in RTRs with allograft dysfunction proved to be associated with better survival, improved renal graft function and regression of cardiac hypertrophy.

Association of arterial hypertension with renal target organ damage in kidney transplant recipients: the predictive role of ambulatory blood pressure monitoring.

BACKGROUND: Although arterial hypertension is a powerful predictor of graft failure, only few studies have evaluated 24-hr blood pressure (BP) profile in renal transplant recipients (RTRs). METHODS: We performed ambulatory blood pressure monitoring (ABPM) in 94 RTRs (65 men; age 28-71 years) with 1-year functioning grafts. Serum biochemical parameters, daily proteinuria, and transplantation-related data were evaluated in all subjects. RESULTS: ABPM showed that only 5% of RTRs were normotensives (BP<130/80 mm Hg) and identified 29% of patients with nocturnal hypertension. A strong, direct correlation was shown between each set of both systolic BP and diastolic BP measured by ABPM and serum creatinine, daily proteinuria, and serum triglycerides (P at least <0.025 for each). Serum creatinine immediately after transplantation and 1-yr asleep diastolic BP were the only significant predictors of 1-yr creatinine (P<0.0001; r=0.49), whereas awake systolic BP was the only predictor of daily proteinuria (r=0.39; P=0.005) by multiple regression analysis. CONCLUSIONS: BP assessed by ABPM proved to be a stronger predictor of renal graft damage than traditional immunologic factors. ABPM improved the diagnostic accuracy of arterial hypertension in RTRs and was the only effective tool in disclosing the association of BP with 1-year renal transplant outcome.

Effect of sirolimus on left ventricular hypertrophy in kidney transplant recipients: a 1-year nonrandomized controlled trial.

BACKGROUND: Left ventricular hypertrophy (LVH) after renal transplantation may be affected by immunosuppressive therapy. STUDY DESIGN: Nonrandomized controlled trial evaluating the effect of sirolimus (SRL) on LVH of renal transplant recipients (RTRs). SETTING & PARTICIPANTS: 13 RTRs without diabetes who had received a single-kidney transplant from a deceased donor with chronic allograft dysfunction and biopsy-proven allograft nephropathy who were converted from calcineurin-inhibitor (CNI) to SRL treatment; 26 controls matched for age and year of transplantation who were not converted from CNI to SRL treatment. INTERVENTION: Conversion from CNI to SRL therapy. OUTCOMES & MEASUREMENTS: Left ventricular mass determination by using echocardiography at baseline and again 1 year later. Blood pressure (BP), hemoglobin level, serum creatinine level, uric acid level, lipid levels, trough levels of immunosuppressive drugs, and daily proteinuria were assessed at least twice monthly. Conventional antihypertensive therapy was used to achieve BP of 130/80 mm Hg or less. RESULTS: The study population included 26 men and 13 women (age, 25 to 66 years). Changes in BP were similar in the 2 groups (between-group difference, -4 +/- 5 mm Hg; P = 0.5 for systolic BP; -2 +/- 3; P = 0.6 for diastolic BP), whereas left ventricular mass significantly decreased in the SRL group alone (between-group difference, 8.6 +/- 2.4 g/m(2.7); P < 0.001) because of a decrease in both the interventricular septum and left ventricular posterior wall. LVH regressed in 12 of 13 patients on SRL therapy and 10 of 26 controls (P = 0.002). LIMITATIONS: Nonrandomized design. Single-center study with small sample size. CONCLUSIONS: Conversion from CNI to SRL therapy may regress LVH in RTRs regardless of BP changes, mainly by decreasing left ventricular wall thickness, thus suggesting nonhemodynamic-effect mechanisms of SRL on left ventricular mass.

Bone disease in long-term renal transplant recipients with severe osteopenia: a cross-sectional study.

BACKGROUND: Fracture is a disabling clinical outcome after transplantation, but there is little histopathological information on long-term renal recipients with severe osteopenia. METHODS: Twenty kidney recipients (8.3+/-1.9 years after transplantation), 13 males and 7 females (five postmenopausal) with nearly normal renal function, affected by severe osteopenia (T-score: males= -4.9+/-0.28; females= -5.08+/-0.47) underwent bone biopsy and morphometric X-ray absorptiometry to evaluate vertebral fractures. RESULTS: Histopathological diagnosis was osteoporosis-osteopenia in seven patients, osteitis fibrosa in six, prevalent osteomalacic lesion in six, and "normal" bone in one patient. Significant increases in osteoid volume (OV/BV), osteoid surface, osteoblastic surface (ObS/BS) and osteoid thickness were observed. OV/BV and Obs/BS ratios were inversely correlated to cumulative doses of MPRED (r2=0.85 P<.0001 for both ratios), whereas age, sex, time after transplantation, iPTH levels, and cumulative cyclosporine A dose were not related to osteoblastic indices. Osteoclast surface was slightly increased. Widened mineralization lag times were observed, with normalcy of the bone formation rate. Half of the patients showed fractured vertebrae. No differences in T scores were found when patients were subdivided into groups "with" or "without" vertebral fractures. A higher prevalence of fractures was observed in patients with osteoporosis-osteopenia compared to other osteopathies (P<0.02). No relationships between bone volume versus T-scores were observed. CONCLUSIONS: In long-term renal transplant recipients, severe osteopenia does not predict osteoporosis alone. The main abnormality we found was an increase in osteoblastic activity with a slight mineralization defect. The heterogeneous bone illness we observed would suggest performing bone biopsy in these patients.