Renal Tolerability Research Articles

The reduced function allele SLCO1B1 c.521T>C is of no practical relevance for the renal graft function over the first post-transplant year in patients treated with mycophenolic acid.

It is unclear whether renal transplant recipients treated with mycophenolic acid (MPA) who carry the reduced-function allele at polymorphism SLCO1B1 c.521T>C differ from their wild-type peers regarding renal outcomes and tolerability. We aimed to estimate the effect of this polymorphism on the graft function (estimated glomerular filtration rate, eGFR) over the first 12 post-transplant months in patients on MPA-based maintenance immunosuppression. In a 12-month observational cohort study, consecutive adult patients were repeatedly assessed for eGFR. The SLCO1B1 c.521C>T variant allele carriers (exposed) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and eGFR trajectory was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation. The adjusted eGFR slopes from day 1 to day 28 (daily), and from day 28 to day 365 (monthly) were practically identical in exposed (n = 86) and control (n = 168) patients [geometric means ratios (GMR) = 0.99, 95% confidence interval (CI) = 0.92-1.06 and GMR = 0.98, 0.94-1.01, respectively]. The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in exposed and controls [rate ratios (RR) = 0.94, 0.49-1.84 and RR = 1.08, 0.74-1.58, respectively]. The pharmacokinetic analysis did not signal meaningful differences regarding exposure to MPA, overall (exposed n = 23, control n = 45), if cotreated with cyclosporine (n = 17 vs. n = 26) or with tacrolimus (n = 8 vs. n = 17). In patients treated with MPA, variant allele SLCO1B1 c.521T>C appears of no practical relevance regarding the 12-month renal graft function, MPA safety and exposure to MPA at early steady-state.

#5214 RENAL TOLERABILITY OF SGLT-2 INHIBITORS COMBINING WITH RENIN-ANGIOTENSIN SYSTEM BLOCKERS AND MINERALOCORTICOID RECEPTOR ANTAGONISTS IN CKD

Abstract Background and aims Recently the sodium glucose cotransporter-2 (SGLT-2) inhibitors combining with angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor II blocker (ARBs) or angiotensin-receptor neprilysin inhibitor (ARNI)) and mineralocorticoid receptor antagonist (MRA) ((triple therapy (TT)), would help prevent further progression of renal and cardiovascular (CV) endpoints including progression of end-stage kidney disease (ESKD). The degree to which data on TT initiation and discontinuation in cronic kidney disease (CKD) patients can be generalized to patients in real-world practice is unclear. Aims to evaluate renal tolerability to the TT at target doses as well as clinical incidents and dosage adjustments. To analyze the risk factors for TT discontinuation. Method A retrospective cohort study was carried out in patients ≥18 years old with chronic kidney disease (CKD) treated with TT in Rey Juan Carlos Hospital between January 2019 to December 2022. The collected clinical data included age, gender, associated morbidities, serum creatinine (Scr), estimated glomerular filtration rate (eGFR), potassium, sodium levels, dose adjustments before administration of TT and in the first year of follow up. Multivariate logistic models were performed to evaluate the risk factors to dosage adjusted and discontinuation of TT. Results Among 104 patients treated with TT were included. Medium age was 69 years old (range, 37-91). Most of them were men, 78% (81). The main cause to initiate TT was cardiorenal syndrome 59% (61). Before to initiate TT, in 35% patients the treatment was adjusted. The main modification was reduced or discontinuation of diuretics (loop or thiazide) therapy 23% (24/104). In the first year of follow up, in 69 patients (66%) it was necessary dosage adjustments, being the reduced of MRA (spironolactone and eplerenone) the main modification treatment 38% (26/69). The major cause of dose adjustment was developed of acute kidney injury (AKI) in 43 patients (41%). According to KDIGO criteria, 38 patients (88%) reached stage 1; 4 patients (9%) stage 2 and 1 case (2%) stage 3. The independent risk factor associated with dosage adjustment were AKI development (OR: 28.57; 95% CI 6.04-134.4; P = 0.0001) adjusted by sex and age. Despite the dosage adjustment and titers, in 29 patients (28%) TT was discontinued in a median time of 4 months (IQR 2–11) after its initiation. The risk factor associated with TT discontinuation were AKI developed (P = 0,003) and eGFR at the 12 months of follow up (P = 0,01). There were no significant excess risks of symptomatic hypotension, volume depletion, and hyperkalemia after a year of follow up. Conclusions The renal tolerability of use to triple therapy in chronic kidney disease appears to be low. The AKI development was the main risk factor of dosage adjustment and discontinuation of TT. Its necessary to clarify which is the best way to maximizing renal tolerability in this complex groups of patients. The use of early combination therapy requires careful assessment. Its important to find strategies to guide clinicians about the steps and challenges to improving overall use of triple therapy tolerability and dosage adjustment.

Ketoprofen lysine salt has a better gastrointestinal and renal tolerability than ketoprofen acid: A comparative tolerability study in the Beagle dog

Due to the widespread use of non-steroidal anti-inflammatory drugs (NSAIDs), the incidence of NSAID-associated adverse events has increased exponentially over the past decades. Ketoprofen (ketoprofen acid, KA) is a widely used NSAID and, like with other NSAIDs, its use can be associated with adverse effects that especially involve the gastrointestinal tract and the kidney. The salification of KA with L-lysine has led to the synthesis of ketoprofen lysine salt (KLS), which is characterized by higher solubility and a more rapid gastrointestinal absorption compared to KA. Previous studies have reported that KLS has also an increased gastric tolerance in vitro, and this is due to the inhibition of lipid peroxidation and reactive oxygen species scavenging effects of L-lysine. Here, we report in vivo tolerability/toxicity studies that were conducted prior seeking KLS marketing authorization, in which we compared KLS and KA safety profile, focusing in particular on the evaluation of the gastrointestinal and renal tolerability of the drugs administered orally to dogs. Our results demonstrate that KLS has an increased in vivo gastrointestinal tolerability compared to KA and show, for the first time, that KLS has also increased in vivo renal tolerability compared to KA, thus supporting the concept that L-lysine may counteract NSAID-induced oxidative stress-mediated gastrointestinal and renal injury.

Efficacy and Renal Tolerability of Ultrafiltration in Acute Decompensated Heart Failure: A Meta-analysis and Systematic Review of 19 Randomized Controlled Trials

Background: Acute decompensated heart failure (ADHF) is a life-threatening and costly disease. Controversy remains regarding the efficacy and renal tolerability of ultrafiltration for treating ADHF. We therefore performed this meta-analysis to evaluate this clinical issue. Methods: A search of PubMed, EMBASE, and the Cochrane database of controlled trials was performed from inception to March 2021 for relevant randomized controlled trials. The quality of the included trials and outcomes was evaluated with the use of the risk of bias assessment tool and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, respectively. The risk ratio and the standardized mean difference (SMD) or weighted mean difference (WMD) were computed and pooled with fixed-effects or random-effects models. Results: This meta-analysis included 19 studies involving 1281 patients. Ultrafiltration was superior to the control treatments for weight loss (WMD 1.24 kg, 95% confidence interval [CI] 0.38–2.09 kg, P=0.004) and fluid removal (WMD 1.55 L, 95% CI 0.51–2.59 l, P=0.003) and was associated with a significant increase in serum creatinine level compared with the control treatments (SMD 0.15 mg/dL, 95% CI 0.00–0.30 mg/dL, P=0.04). However, no significant effects were found for serum N-terminal prohormone of brain natriuretic peptide level, length of hospital stay, all-cause mortality, or all-cause rehospitalization in the ultrafiltration group. Conclusions: The use of ultrafiltration in patients with ADHF is superior to the use of the control treatments for weight loss and fluid removal, but has adverse renal effects and lacks significant effects on long-term prognosis, indicating that this approach to decongestion in ADHF patients is efficient for fluid management but less safe renally.

Penicillin versus anti-staphylococcal beta-lactams for penicillin-susceptible Staphylococcus aureus blood stream infections: a retrospective cohort study.

The objective of the study is to assess the efficacy and tolerability of penicillins compared to anti-staphylococcal beta-lactams for treatment of penicillin-susceptible Staphylococcus aureus bloodstream infections (PSSA BSI). A retrospective cohort study was conducted of 140 sequential PSSA BSI presenting to a local health district (90 cases included). Penicillin susceptibility was confirmed by disc diffusion, Vitek® and Nitrocefin beta-lactamase methods. Clinical information regarding comorbidities and infection complexity was recorded. Antibiotic choice, dosage and duration were reviewed. Outcomes were compared according to the definitive treatment with either penicillin or ASBLs. The primary outcome was 30-day mortality. Secondary outcomes included renal injury, microbiological relapse and treatment tolerability. Ninety patients met inclusion criteria and were included in subsequent analysis. Of PSSA BSI, 69% were community acquired. Eighty-two percent had complex PSSA infections. The average duration of bacteraemia was 2.8days (SD = 1.8days). Sixty-six patients received definitive penicillin treatment, with a mean of 3.5days of empiric antibiotics prior to penicillin. Twenty-four patients received definitive ASBL treatment (11 cefazolin, 13 flucloxacillin). There was no difference in 30-day mortality between groups (p = 1). There was no difference in renal injury (p > 0.5), hospital length of stay (p = 0.59) or microbiological relapse within 1year (p = 0.17). Penicillin treatment was well tolerated. Our data supports penicillin as a suitable and well-tolerated alternative to ASBL in managing complex PSSA BSI.

Anfotericina B liposomal: farmacología clínica, farmacocinética y farmacodinamia

Liposomal amphotericin B is a lipid formulation of the antifungal drug amphotericin B with some distinguishing characteristics in its pharmacological behavior that entail some clinical differences of great interest. The significant improvement in the systemic and renal tolerability is one of them. This fact is related to the great stability of the liposome, promoted by its negative charge, the presence of cholesterol and the remarkable thermo-stability of the remaining lipids that compose it. In this situation, amphotericin B seems to be released from the liposome not spontaneously but when the liposome binds to the ergosterol in the fungal cell membrane. For this reason, there is almost no free amphotericin B in plasma or tissues, although it seems that its availability is greater when there is fungal infection. As a consequence, when the pharmacokinetic behavior is studied, the concentration and availability of liposomal amphotericin B are very high, and its volume of distribution is reduced in comparison with the other formulations.

Single Ascending Dose Study to Assess Pharmacokinetic Linearity, Safety, and Tolerability of Trimetazidine - Modified Release in Healthy Human Subjects.

This study assessed the linearity of pharmacokinetics (PK) of trimetazidine (TMZ) modified-release tablets (indicated in adults as an add-on therapy for stable angina pectoris) and measured its renal elimination, safety, and tolerability in healthy subjects. This was a randomized, open-label, single-ascending dose study in healthy subjects. Subjects were administered with a single dose of 35, 70, or 105 mg TMZ-modified release tablets (six subjects each). Pharmacokinetic evaluations and safety analysis were performed before the first dose and till 48 h post-first dose. Following administration of 35, 70, and 105 mg TMZ-modified release; the Cmax (mean±SD) was 79.32 (±23.08), 153.17 (±23.08), and 199.67 (±23.08) ng/mL, the Tmax was 5.42 (±0.49), 4.51 (±1.27), and 4.57 (±0.96) h, t1/2 was 7.75 (±1.62), 6.40 (±1.23), and 6.50 (±1.18) h, AUC(0-inf) was 1116.89 (±378.35), 1838.39 (±284.50), and 2504.84 (±348.35) ng.h/mL, CLR was 13.70 (±2.24), 14.80 (±5.91), and 19.58 (±6.24) L·h-1 and CL/F was 33.69 (±8.51), 38.85 (±6.15), and 42.74 (±7.10) L·h-1, respectively. Slope estimates for AUC(0-inf), AUC(0-t), and Cmax were less than 1. Corresponding 95% CI of the slope for the AUC parameters excluded 1, indicating that the deviation from dose-proportionality was statistically significant. Corresponding 95% CI of the slope for Cmax included 1, indicating that the less than dose-proportional increase in Cmax was not statistically significant. No significant adverse events were observed. Substantial deviation from a dose-proportional increase in AUC(0-inf) and AUC(0-t) suggested a non-linear PK for TMZ-modified release. Single dose of TMZ-modified release was well tolerated and safe.

Strength in Amalgamation: Newer Combination Agents for HIV and Implications for Practice

Antiretroviral (ART) therapy for the treatment of human immunodeficiency virus (HIV) infection has undergone significant changes over the past 30 years. Many single-tablet regimens (STRs), including newer fixed-dose combination (FDC) tablets, are available, offering patients several options for choosing a treatment regimen that works best for them. Given these changes, patients are more likely to adhere to treatment, achieve better clinical outcomes, and experience both fewer side effects and drug-drug interactions. Newer STRs include dolutegravir (DTG)/lamivudine (3TC)/abacavir (ABC) (Triumeq; Viiv Healthcare, Research Triangle Park, NC), rilpivirine (RPV)/emtricitabine (FTC)/tenofovir alafenamide (TAF) (Odefsey; Gilead, Foster City, CA), RPV/FTC/tenofovir disoproxil fumarate (TDF) (Complera; Gilead), elvitegravir (EVG)/cobicistat (COBI)/FTC/TDF (Stribild; Gilead), and EVG/COBI/FTC/TAF (Genvoya; Gilead). Recently approved FDCs, such as atazanavir (ATV)/COBI (Evotaz; Bristol-Myers Squibb, Princeton, NJ), darunavir (DRV)/COBI (Prezcobix; Janssen Products, Titusville NJ), and FTC/TAF (Descovy; Gilead), are also now available. The Department of Health and Human Services treatment guidelines for HIV recommend many of these integrase strand transfer inhibitor (INSTI) STRs as a preferred choice for initiation of treatment in both ART-naive and -experienced patients because they offer comparably faster rates of virologic suppression, reduced rates of resistance development (especially with DTG), and overall better adherence than protease inhibitors or NNRTIs. Numerous phase 3 clinical trials support these recommendations including several switch or simplification clinical trials. Notably, the novel pharmacokinetic booster COBI, with its water soluble properties, has enabled the development and coformulation of a few of these STRs and FDCs. Also, a newer tenofovir salt formulation, TAF, has an advantageous pharmacokinetic profile, contributing to better overall renal and bone tolerability compared with TDF. Further simplification regimens comprising dual ART therapies are currently being explored. This review provides an overview of the clinical efficacy and safety data for these coformulated agents, highlighting the relative impact on comparative adverse events, assessing the potential for experiencing fewer drug-drug interactions, and discussing the clinical implications regarding adherence to treatment.

P075 Efficacy and safety of switching to EVG/COBI/FTC/TAF in virologically suppressed women

IntroductionElvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate(E/C/F/TDF) demonstrated superior efficacy when compared with atazanavir boosted by ritonavir(ATV/r+F/TDF) in 575 treatment naïve women at Week(W) 48. We now report the safety and efficacy of subsequent switching to E/C/F/tenofovir alafenamide(TAF) versus remaining on ATV/r+F/TDF.MethodsAfter completing the initial randomised, blinded 48-week trial,women on ATV/r+F/TDF were randomised 3:1 to receive open label E/C/F/TAF versus remaining on their current regimen. Viral suppression by FDA snapshot analysis, pre-defined bone and renal safety and tolerability endpoints 48 weeks after switch are reported. Women who become pregnant while on study are given the option to continue study drug.Results212 HIV-infected, virologically suppressed women were randomised(E/C/F/TAF n=159, ATV/r+F/TDF n=53). Virologic suppression(<50c/mL) was maintained in 94.3% on E/C/F/TAF vs 86.8% on ATV/r+F/TDF with virologic failure in 1.9%, 3.8%, respectively. More women on E/C/F/TAF achieved <20c/mL at W48 compared with ATV/r+F/TDF (84.9% versus 71.7%p=0.041). No treatment emergent resistance was detected in either group. Mean% increase in BMD was higher in the TAF group for both lumbar spine and total hip. Multiple markers of renal safety were improved for participants randomised to TAF. No cases of proximal renal tubulopathy were reported. Nineteen women became pregnant during the switch study 13 E/C/F/TAF, 6 ATV/r+F/TDF,3 normal infants have been delivered in each group to date.DiscussionThese data demonstrate that women who switch to an integrase inhibitor+TAF-based regimen maintain high levels of virologic suppression with improvement in BMD and renal function biomarkers compared with those remaining on their ATV/r+TDF-based regimen.

Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III-rationale, trial design and baseline data.

BackgroundPatients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis.MethodsUK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor–neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin–angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD.ResultsBetween November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol.ConclusionsUK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD.

Two-year Single-Center Real-Life Data of Tenofovir Disoproxil Fumarate Treatment for Chronic Hepatitis B Patients in Taiwan

Aim: Chronic infection with hepatitis B virus (CHB) is a worldwide disease. The aim of this study was to evaluate the treatment efficacy and renal tolerability of Tenofovir disoproxil fumarate (TDF) in patients with CHB. Method: Data from patients were retrospectively collected from January 2012 to September 2014. The inclusion criteria included CHB, serum HBV DNA > 2000 IU/ml, high serum alanine aminotransferase (ALT), and persistent use of TDF for at least one year. The exclusion criteria included HCV or HIV coinfection. The therapeutic efficacy was recorded at screening and every 6 months thereafter. Results: Among all 100 enrolled subjects, 28 and 24 patients were HBe-positive and treatment-experienced, respectively. The 2-year biochemical response (ALT less than 40 U/L) was 95% to 100%, virologic response (HBV DNA < 20 IU/ml) was 86% to 98%, and serologic response (HBeAg seroloss) was 33%. No cases with HBsAg clearance were detectable. No significant difference existed between treatment-naive and -experienced patients, but those with positive HBe had a poor virological response compared with the negative HBe group (P=0.043). There was no significant change in renal function. Conclusion: TDF treatment was considered as a efficient, safe and well tolerated therapy to CHB individuals.

Direct inhibition of plasmatic renin activity with aliskiren: a promising but under-investigated therapeutic option for non-diabetic glomerulonephritis.

Non-diabetic glomerulonephritis is a frequent cause of end-stage renal disease. The use of renin-angiotensin-aldosterone system blockers is a fundamental therapeutic approach. However, converting enzyme inhibitors (ACE-is) and angiotensin receptor blockers do not always achieve the desired target of proteinuria. The induction of the prorenin and renin up-regulation is a possible explanation. Aliskiren is the first drug acting as direct inhibitor of plasmatic renin activity, also able to interfere with the prorenin and renin profibrotic escape. We aimed at reviewing the literature for the assessment of potential efficacy and safety of aliskiren in the treatment of non-diabetic glomerulonephritis. The data on this topic are limited; however, we concluded for a possible usefulness of aliskiren. The renal safety profile appears potentially acceptable in non-diabetic patients although extreme carefulness, particularly with respect to long-term renal and cardiovascular tolerability, is recommended.

Gemcitabine plus split-dose cisplatin could be a promising alternative to gemcitabine plus carboplatin for cisplatin-unfit patients with advanced urothelial carcinoma.

Cisplatin-based chemotherapies are standard treatment regimens of advanced urothelial cell carcinoma. But a significant proportion of patients are unsuitable for cisplatin due to impaired renal function. Carboplatin-based regimens such as gemcitabine and carboplatin regimen (GCb) were applied due to less nephrotoxicity and side effects in these patients. However, it is known that clinical outcome of carboplatin-based regimens was unsatisfactory compared to cisplatin-based regimens. We compared the nephrotoxicity and response to treatment between GCb and gemcitabine plus split-dose cisplatin regimen (GC-S). GC-S consists of cisplatin 35mg/m(2) given on day 1, 2 and gemcitabine 1000mg/m(2) on day 1, 8 every 3weeks. GCb consists of carboplatin (AUC 4.5) on day 1 and gemcitabine 1000mg/m(2) on day 1, 8 every 3weeks. Patient demographics, serum creatinine and calculated GFR, adverse events, and radiologic response were retrospectively reviewed. Forty-four patients with advanced urothelial carcinoma treated with GCb (n=22) or GC-S (n=22) in our institution. There was no difference at deterioration of serum creatinine or GFR between GCb and GC-S (p=0.442, p=0.345). For patients who had GFR<60mL/min/1.73m(2) subgroup, similar results were produced (p=0.292, p=0.186). In addition, GC-S (68.4%) showed improved response compared to GCb (31.6%) (p=0.023). Both treatments were well tolerated, and there were no unexpected serious adverse events. Based on preserved renal function, favorable response, and tolerability, GC-S could be a promising alternative to GCb for cisplatin-unfit patients with advanced urothelial carcinoma.

Everolimus-based calcineurin-inhibitor sparing regimens for kidney transplant recipients: a systematic review and meta-analysis.

Calcineurin inhibitors (CNI) associated nephrotoxicity remains a risk factor for long-term graft dysfunction after renal transplantation. Everolimus is a mammalian target of rapamycin inhibitor and exhibits synergistic immunosuppressive activity with CNI to permit CNI-reduction. We conducted a systematic review to compare the efficacy of everolimus-based CNI sparing and standard CNI regimens in renal transplantation recipients. We searched PubMed and Web of Science databases to identify relevant randomized controlled trials. Glomerular filtration rate (GFR), biopsy-proven acute rejection (BPAR), death or graft loss and incidence of adverse events were the major estimates of renal function, efficacy, and tolerability of the two regimens. Seven studies providing data for 2,067 patients were included. Six of the seven studies used cyclosporine as the CNI. The patients were divided into two groups: everolimus-based CNI sparing (elimination and minimization) group and standard CNI group. Everolimus-based regimen was associated with increased GFR [P = 0.02; weighted mean difference (WMD) 4.83 mL/min], decreased serum creatinine (P = 0.004; WMD -9.94 μmol/L) and no more death or graft loss [P = 0.72; relative risk (RR) 1.07]. CNI-minimization was not associated with increased BPAR (P = 0.25; RR 0.85) while CNI-elimination was associated with more BPAR Grade 1 (P < 0.00001; RR 4.20). Use of everolimus reduced the risk of CMV infection (P = 0.0002; RR 0.47). There was a higher risk of discontinuation of everolimus (P < 0.00001; RR 1.69) and non-fatal adverse events (P < 0.00001; RR 1.73) in patients on the everolimus based CNI sparing regimens. Everolimus-based CNI sparing regimen could optimize long-term graft function without leading to more death or graft loss. Although CNI elimination was associated with higher risk of BPAR, everolimus use with CNI minimization did not increase the risk of acute rejections. Use of everolimus was associated with reduction in the incidence of CMV infection, but there was a higher risk of discontinuation of this drug and other non-fatal adverse events.

Angiotensin II Contributes to Diabetic Renal Dysfunction in Rodents and Humans via Notch1/Snail Pathway

In nondiabetic rat models of renal disease, angiotensin II (Ang II) perpetuates podocyte injury and promotes progression to end-stage kidney disease. Herein, we wanted to explore the role of Ang II in diabetic nephropathy by a translational approach spanning from in vitro to in vivo rat and human studies, and to dissect the intracellular pathways involved. In isolated perfused rat kidneys and in cultured human podocytes, Ang II down-regulated nephrin expression via Notch1 activation and nuclear translocation of Snail. Hairy enhancer of split-1 was a Notch1-downstream gene effector that activated Snail in cultured podocytes. In vitro changes of the Snail/nephrin axis were similar to those in renal biopsy specimens of Zucker diabetic fatty rats and patients with advanced diabetic nephropathy, and were normalized by pharmacological inhibition of the renin-angiotensin system. Collectively, the present studies provide evidence that Ang II plays a relevant role in perpetuating glomerular injury in experimental and human diabetic nephropathy via persistent activation of Notch1 and Snail signaling in podocytes, eventually resulting in down-regulation of nephrin expression, the integrity of which is crucial for the glomerular filtration barrier.

Renal tolerability of iopromide and iodixanol in 562 renally impaired patients undergoing cardiac catheterisation: the DIRECT study

This multi-centre, randomised, double-blind study compared the nephrotoxicity of low-osmolar, low-viscous iopromide and iso-osmolar, high-viscous iodixanol in Chinese patients with moderate renal dysfunction, after coronary angiography or percutaneous coronary intervention (PCI). The primary endpoint was contrast-induced nephropathy (CIN) on day 3, defined as a post-dose increase in serum creatinine (SCr) of ≥50% from baseline. All patients were rigorously hydrated from six hours before intervention. In 562 evaluable patients (of 592 recruited), the contrast volume, presence of diabetes mellitus, mean baseline SCr and estimated glomerular filtration rate (eGFR) were comparable between the iopromide- and iodixanol-treated groups. SCr increases of ≥50% occurred in 1/278 (0.4%) of patients after iopromide and 1/284 (0.3%) after iodixanol. Incidences in the secondary endpoints were the following: SCr increases of ≥0.5 mg/dL, 1.4% and 0.7%, respectively; SCr increases of ≥25%, 5.4% and 2.8%; eGFR decreases of ≥25%, 3.6% and 2.5%. Only one patient showed renal failure, one week after dosing with iodixanol. All differences were statistically insignificant, in the overall collective group and in the subgroup with diabetes (n=170). With rigorous hydration, the CIN incidence was very low in patients with moderate renal dysfunction who underwent coronary angiography or PCI. No difference in nephrotoxicity was found between iopromide and iodixanol.

Renal uptake and tolerability of a 2′-O-methoxyethyl modified antisense oligonucleotide (ISIS 113715) in monkey

The primary target organ for uptake of systemically administered phosphorothioate oligonucleotides is the kidney cortex and the proximal tubular epithelium in particular. To determine the effect of oligonucleotide uptake on renal function, a detailed renal physiology study was performed in cynomolgus monkeys treated with 10–40mg/kg/week ISIS 113715 for 4 weeks. The concentrations of oligonucleotide in the kidney cortex ranged from 1400 to 2600μg/g. These concentrations were associated with histologic changes in proximal tubular epithelial cells that ranged from the appearance of cytoplasmic basophilic granules to atrophic and degenerative changes at higher concentrations. However, there were no renal functional abnormalities as determined by the typical measurements of blood urea nitrogen, serum creatinine, creatinine clearance, or urine specific gravity. Nor were there changes in glomerular filtration rate, or renal blood flow. Specific urinary markers of tubular epithelial cell damage, such as N-acetyl-glucosaminidase, and α-glutathione-s-transferase were not affected. Tubular function was further evaluated by monitoring the urinary excretion of amino acids, β2-microglobulin, or glucose. Renal function was challenged by administering a glucose load and by examining concentrating ability after a 4-h water deprivation. Neither challenge produced any evidence of change in renal function. The only change observed was a low incidence of increased urine protein/creatinine ratio in monkeys treated with ≥40mg/kg/week which was rapidly reversible. Collectively, these data indicate that ISIS 113715-uptake by the proximal tubular epithelium has little or no effect on renal function at concentrations of 2600μg/g.

Zoledronic acid to prevent bone loss in Chinese men receiving androgen deprivation therapy for prostate cancer

To explore the bone mineral density (BMD) preservation effect of zoledronic acid and its renal safety and tolerability in Chinese patients with prostate cancer on androgen deprivation therapy (ADT). Overall 26 prostate cancer patients with ADT were given zoledronic acid 4 mg by a 15-min i.v. infusion every 3 months for up to 12 months. Assessment was made at baseline and at 3, 6, 9 and 12 months. Dual-energy X-ray absorptiometry was used to measure the BMD of the lumbar spine and the femoral neck at baseline and 12 months. A total of 23 of 26 recruited patients completed the study. Seven patients had bone metastases. The overall mean increase in BMD (T-score) of the lumbar spine and femoral head from baseline to follow up at 12 months was significant (-2.32 ± 0.98 to -2.03 ± 1.08, P = 0.02 and -1.77 ± 0.72 to -1.63 ± 0.76, P = 0.01, respectively). In subgroup analyses, significant BMD improvement was observed independent of the status of bone metastasis and the means of ADT. Zoledronic acid had no adverse effect on renal function. Adverse events related to zoledronic acid were minimal. Zoledronic acid administered every 3 months significantly increased BMD in prostate cancer patients receiving ADT. It had a satisfactory adverse event profile and imposed minimal risk on patients' renal function.

5069 Ibandronate in clinical practice: renal safety and tolerability in patients with metastatic breast cancer

Bisphosphonates are highly effective inhibitors of bone resorption. This class of agents includes alendronate, etidronate, pamidronate, ibandronate, risedronate, clodronate, tiludronate, and zoledronate, which are variously used as the free acid or as the sodium salts. They are used extensively in the treatment and prophylaxis of bone loss due to glucocorticoid treatment, post-menopausal estrogen loss, or to malignant disease, and in treating hypercalcemia of malignancy and Paget's disease of bone. The drugs are analogs of pyrophosphate, which was shown many years ago to inhibit calcium phosphate dissolution in vitro, but which had no useful effect in vivo …

NSAIDs, prostaglandins and the neonatal kidney

Renal prostaglandins, particularly PGE2, play a homeostatic role in the immature kidney through their hemodynamic and tubular effects, and this role may be crucial under conditions of renal stress.Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in the neonatal period to treat or prevent patent ductus arteriosus (PDA) in preterm infants. The nephrotoxic effects induced by NSAIDs result from the inhibition of renal cyclooxygenase activity and prostaglandin synthesis. NSAID-induced prostaglandin inhibition may result in renal hypoperfusion and acute renal failure which are clinically relevant, but usually reversible, adverse effects in the newborn.Currently, ibuprofen appears to be the therapeutic option of choice in the preterm newborn with PDA because of its better renal tolerability compared to other NSAIDs. Nevertheless, the use of this drug is not free from adverse renal effects, particularly in circumstances when renal prostaglandin activation is maximal.The implementation of measures to prevent or minimise nephrotoxicity and close monitoring of renal function are mandatory in the newborn treated with NSAIDs. The measurement of urinary PGE2 may represent a non-invasive and sensitive tool to evaluate renal function, and thus should be implemented in the clinical management of newborns exposed to nephrotoxic insults.