Severe Renal Impairment Research Articles

Pharmacokinetics and Safety of Imeglimin in Japanese Patients With Impaired Renal Function.

Imeglimin is a diabetic drug excreted mainly in the urine; therefore, the impact of renal impairment on its pharmacokinetics (PK) is of interest. We assessed the PK and safety of imeglimin in Japanese patients with impaired renal function. This was an uncontrolled, open-label, single-dose, phase 1 study. Participants were classified into 4 groups by their estimated glomerular filtration rate (mL/min/1.73m2 ) as follows: ≥90, normal renal function; and 60 to <90, mild; 30 to <60, moderate; and 15 to <30, severe renal impairment. All participants received imeglimin 1000 mg except those with severe renal impairment, who received imeglimin 500 mg. PK parameters were estimated using noncompartmental analysis, and those after multiple administrations were projected using a noncompartmental superposition method. In total, 24 Japanese participants (6 in each group) were enrolled and completed the study. The mean plasma imeglimin concentration reached the maximum at 2-4 hours after administration and then rapidly decreased. The geometric mean maximum observed plasma concentration and area under the plasma concentration-time curve values were higher in the impaired renal function groups versus normal renal function group. Most imeglimin was excreted in urine by 24 hours after administration. Renal clearance decreased with decreasing renal function. Projected maximum observed plasma concentration and area under the plasma concentration-time curve over the dosing interval after multiple dosing were greater in the renal impairment groups versus normal renal function group. No adverse events were observed. Considering increased plasma exposure along with decreased renal clearance, dose adjustment is required in patients with moderate and severe renal impairment with estimated glomerular filtration rate of 15 to <45 mL/min/1.73 m2 .

Zero‐contrast IVUS‐guided complex PCI in a patient with NSTE‐ACS and severe renal impairment

A 76-year-old male with severe comorbidities and multiple cardiovascular risk factors including stage IV chronic kidney disease presents with non-ST-elevation myocardial infarction. An ultra-low contrast invasive coronary angiography using the DyeVert system and iso-osmolar contrast agent revealed a multivessel disease with heavy calcifications involving the left main stem and its bifurcation requiring a complex percutaneous coronary intervention. Because of the high risk of contrast-induced acute kidney injury, a zero-contrast intervention was performed using intravascular ultrasound guidance and dedicated stenting techniques with optimal imaging, clinical, and renal outcomes. Zero-contrast policies can be safely implemented even in complex clinical scenarios but at least two orthogonal angiographic projections should always be acquired to rule out distal complications.

Leveraging Prior Healthy Participant Pharmacokinetic Data to Evaluate the Impact of Renal and Hepatic Impairment on Ritlecitinib Pharmacokinetics

Ritlecitinib is a selective, covalent, irreversible inhibitor of Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinases. Pharmacokinetics and safety of ritlecitinib in participants with hepatic (Study 1) or renal (Study 2) impairment were to be characterized from two phase I studies. Due to a study pause caused by the COVID-19 pandemic, the study 2 healthy participant (HP) cohort was not recruited; however, the demography of the severe renal impairment cohort closely matched the study 1 HP cohort. We present results from each study and two innovative approaches to utilizing available HP data as reference data for study 2: a statistical approach using analysis of variance and an in silico simulation of an HP cohort created using a population pharmacokinetics (POPPK) model derived from several ritlecitinib studies. For study 1, the observed area under the curve for 24-h dosing interval and maximum plasma concentration for HPs and their observed geometric mean ratios (participants with moderate hepatic impairment vs HPs) were within 90% prediction intervals from the POPPK simulation-based approach, thereby validating the latter approach. When applied to study 2, both the statistical and POPPK simulation approaches demonstrated that patients with renal impairment would not require ritlecitinib dose modification. In both phase I studies, ritlecitinib was generally safe and well tolerated. These analyses represent a new methodology for generating reference HP cohorts in special population studies for drugs in development with well-characterized pharmacokinetics in HPs and adequate POPPK models.Trial RegistrationClinicalTrials.gov NCT04037865, NCT04016077, NCT02309827, NCT02684760, and NCT02969044.Graphical

Olaparib in an ovarian cancer patient with end-stage renal disease and hemodialysis

PurposeFor patients with severe renal impairment (CrCl ≤ 30 ml/min) or end-stage renal disease (ESRD), olaparib intake is not recommended as the pharmacokinetics and safety of olaparib have not been evaluated in this patient group. Therefore, this valuable patient group is generally excluded from poly(ADP-ribose) polymerase inhibitor (PARPi) therapy. Here we report the pharmacokinetics (PK), efficacy, safety and tolerability of olaparib capsules 200 mg BID in a patient with recurrent epithelial ovarian cancer (EOC) and ESRD requiring hemodialysis.MethodsBlood and dialysate samples of the patient were collected on a dialysis and non-dialysis day. Olaparib total plasma concentrations were determined through high-performance liquid chromatography with tandem mass spectrometric detection. Actual scheduled sample times were used in the PK analysis to determine multiple dose PK parameters at steady state.ResultsMaximum concentration was achieved 1.5 h after drug administration on non- dialysis and after 1 h on dialysis day. The steady-state trough concentration and the maximal plasma concentration were similar on dialysis and non- dialysis day. On non-dialysis day, the AUCss was 30% higher (24.0 µg.h/mL vs. 16.9 µg.h/ml) than on dialysis day. The plasma clearance CLss/F was lower on non-dialysis day. Olaparib was not detectable in the dialysate samples.ConclusionA total dose of olaparib 200 mg BID capsule formulation was well tolerated by our patient with ESRD and hemodialysis. Moreover, this maintenance therapy led to 16 months of progression free survival. Further trials on PARPi therapy in patients with hemodialysis are warranted.

The Association Between Baseline Hepatic or Renal Function and Clinical Outcomes for Patients With Non-Small Cell Lung Cancer Treated With a PD-1/PD-L1 Blocking Antibody Using Real-World and Trial Data.

Clinical trials have demonstrated the benefit of PD-1/PD-L1 blocking antibodies for the treatment of patients with advanced non-small cell lung cancer (NSCLC) in defined patient populations that often exclude patients with moderate or severe hepatic or renal impairment. We assessed the association between overall survival (OS) and baseline organ function in patients with advanced NSCLC treated with PD-1/PD-L1 blocking antibodies in real-world data (RWD; patient-level data from electronic health records) and pooled clinical trial data submitted to the US Food and Drug Administration (FDA). The Kaplan-Meier estimator was used to estimate OS in different subgroups based on organ function. Unadjusted and adjusted Cox proportional hazards models were used to estimate the association between OS and organ function. In this hypothesis-generating study, baseline renal impairment did not appear to be associated with OS, while patients with baseline liver impairment had shorter OS. RWD provided information on a broader range of renal and hepatic function than was evaluated in clinical trials and hold promise to complement trial data in better understanding populations not represented in clinical trials.

Mitochondrial DNA copy number in peripheral blood of IgA nephropathy: a cross-sectional study

Mitochondrial DNA (mtDNA) copy number (CN) is a biomarker of mitochondrial function and has been reported associated with kidney disease. However, its association with IgA nephropathy (IgAN), the most common cause of glomerulonephritis (GN), has not been evaluated. We included 664 patients with biopsy-proven IgAN and measured mtDNA-CN in peripheral blood by multiplexed real-time quantitative polymerase chain reaction (RT-qPCR). We examined the associations between mtDNA-CN and clinical variables and found that patients with higher mtDNA-CN had higher estimated glomerular filtration rate (eGFR) (r = 0.1009, p = .0092) and lower serum creatinine (SCr), blood urea nitrogen (BUN), and uric acid (UA) (r=−0.1101, −0.1023, −0.07806, respectively, all p values <.05). In terms of pathological injury, mtDNA-CN was higher in patients with less mesangial hypercellularity (p = .0385, M0 vs. M1 score by Oxford classification). Multivariable logistic regression analyses also showed that mtDNA-CN was lower for patients with moderate to severe renal impairment (defined as eGFR < 60 mL/min/1.73 m2) vs. mild renal impairment, with the odds ratio of 0.757 (95% confidence interval: 0.579–0.990, p = .042). In conclusion, mtDNA-CN was correlated with better renal function and less pathological injury in patients with IgAN, proposing that systemic mitochondrial dysfunction may be involved in or reflect the development of IgAN.

Deep-learning approach to automate the segmentation of aorta in non-contrast CTs.

Segmentation of vascular structures in preoperative computed tomography (CT) is a preliminary step for computer-assisted endovascular navigation. It is a challenging issue when contrast medium enhancement is reduced or impossible, as in the case of endovascular abdominal aneurysm repair for patients with severe renal impairment. In non-contrast-enhanced CTs, the segmentation tasks are currently hampered by the problems of low contrast, similar topological form, and size imbalance. To tackle these problems, we propose a novel fully automatic approach based on convolutional neural network. The proposed method is implemented by fusing the features from different dimensions by three kinds of mechanisms, i.e., channel concatenation, dense connection, and spatial interpolation. The fusion mechanisms are regarded as the enhancement of features in non-contrast CTs where the boundary of aorta is ambiguous. All of the networks are validated by three-fold cross-validation on our dataset of non-contrast CTs, which contains 5749 slices in total from 30 individual patients. Our methods achieve a Dice score of 88.7% as the overall performance, which is better than the results reported in the related works. The analysis indicates that our methods yield a competitive performance by overcoming the above-mentioned problems in most general cases. Further, experiments on our non-contrast CTs demonstrate the superiority of the proposed methods, especially in low-contrast, similar-shaped, and extreme-sized cases.

Long-Term Safety, Clinical and Immunological Outcomes in Primary Membranous Nephropathy with Severe Renal Impairment Treated with Cyclophosphamide and Steroid-Based Regimen

Introduction and Aims: Therapy of primary membranous nephropathy (PMN) with progressive advanced kidney dysfunction is challenging with limited literature and no clear therapeutic strategies. This is due to the scant evidence of effectiveness and uncertainty around the risk-benefit profile of immunosuppression (ImS) when eGFR is less than 30 mL/min. We aimed to determine long-term clinical outcomes in patients with PMN and severe renal impairment treated with combined cyclophosphamide and steroids. Methods: The study is a single-center retrospective longitudinal cohort study. All patients (between 2004 and 2019) with biopsy confirmed PMN who initiated combination therapy with steroids and cyclophosphamide and had an eGFR of ≤30 mL/min/1.73 m² at the time of initiation of therapy were included for analysis. Clinical and laboratory parameters including anti-PLA₂R-Ab were monitored as per standard clinical guidance. Primary outcome was achievement of partial remission. Secondary outcomes included immunological remission, need for renal replacement therapy, and adverse effects. Results: Eighteen patients with median age of 68 (IQR 58–73) years and 5:1 M:F ratio received the combination therapy when eGFR was ≤30 mL/min/1.73 m² (CKD-EPI). At time of ImS, median eGFR and uPCR were 23 (IQR 18–27) mL/min/1.73 m² and 8.4 (IQR 6.9–10.7) g/g, respectively. Median follow-up was for 67 (IQR 27–80) months. 16 patients (89%) achieved partial remission and 7 (39%) achieved complete remission. eGFR increased by 7 mL/min/1.73 m² (27%) after 1 year of starting ImS treatment and 12 mL/min/1.73 m² at end of follow-up. Two patients (11%) developed end-stage renal disease needing renal replacement therapy. 67% achieved both immunological and clinical remission. At the end of the follow-up period, 2 (11%) patients required hospitalization secondary to infections, 4 (22%) patients developed cancer and 4 patients died (22%). Conclusion: Combination therapy with cyclophosphamide and steroids is effective in achieving partial remission and improving renal function in PMN with advanced renal dysfunction. Prospective controlled studies are required to provide further evidence to rationalize treatment and improve outcomes in such patients.

Pharmacokinetics, Safety, and Tolerability of Glepaglutide, a Long-Acting GLP-2 Analog, in Subjects with Renal Impairment.

Glepaglutide is a novel, ready-to-use, long-acting, glucagon-like peptide-2 (GLP-2) analog intended for the treatment of patients with short bowel syndrome (SBS). This study investigated the impact of renal function on the pharmacokinetics and safety of glepaglutide. In this 3-site, non-randomized, open-label study, 16 subjects were enrolled: 4 with severe renal impairment (eGFR 15 to < 30mL/min/1.73m2), 4with end stage renal disease (ESRD) not on dialysis (eGFR < 15mL/min/1.73m2), and 8 matching controls with normal renal function (eGFR ≥ 90mL/min/1.73m2). Blood samples were collected over a 14-day period following a single subcutaneous (SC) dose of glepaglutide 10mg. Safety and tolerability were assessed throughout the study. The primary pharmacokinetic parameters were area under the curve between dosing and 168h (AUC0-168h) and the maximum plasma concentration (Cmax). There was no clinically relevant difference between subjects with severe renal impairment/ESRD and normal renal function with respect to total exposure (AUC0-168h) and peak plasma concentrations (Cmax) of glepaglutide following a single SC dose. A single SC dose of glepaglutide 10mg appeared safe and well tolerated in subjects with normal renal function and subjects with severe renal impairment or ESRD. No serious adverse events were reported, and no safety issues were identified. No difference in glepaglutide pharmacokinetics was seen between renal impaired and normal subjects. Based on this trial, dose adjustment appears not to be warranted in SBS patients with renal impairment. The trial is registered at http://www. gov (NCT04178447) and has the EudraCT number: 2019-001466-15.

Justifying Ribociclib Dose in Patients with Advanced Breast Cancer with Renal Impairment Based on PK, Safety, and Efficacy Data: An Innovative Approach Integrating Data from a Dedicated Renal Impairment Study and Oncology Clinical Trials.

Renal impairment is common in patients with cancer and can alter the PK and thus the safety and efficacy of drugs. We assessed the impact of renal impairment during treatment with ribociclib, a cyclin-dependent kinase 4/6 inhibitor, and determined dose recommendations for patients with advanced breast cancer with renal impairment. A comprehensive assessment integrating pharmacokinetic, safety, and efficacy data from a phase I dedicated renal impairment study in non-cancer subjects and six phase I-III trials in patients with cancer was performed. Ribociclib showed higher pharmacokinetic exposure in subjects with renal impairment than those with normal renal function following a single 400-mg dose in the dedicated renal impairment study. However, in patient trials, both single-dose and steady‑state ribociclib exposure was comparable between patients with cancer with mild/moderate renal impairment and those with normal renal function following the recommended starting dose of 600 mg. Model-predicted steady‑state exposure in patients with advanced breast cancer was also similar across the renal function groups. Progression-free survival was similar and safety profiles were generally consistent across the renal cohorts (normal/mild/moderate) in patients with advanced breast cancer, with low-grade and manageable adverse events, demonstrating a positive benefit-risk profile. From the collective evidence and considering a real-world clinical setting, no dose adjustment is recommended for patients with mild/moderate renal impairment, whereas a reduced dose is recommended for patients with severe renal impairment. This report presented a holistic and innovative strategy to determine dose in patients with renal impairment and demonstrated the effectiveness of integrating the data of both a clinical pharmacology study and patient trials to justify doses in patients with renal impairment. Clinicaltrials.gov identifiers: NCT02431481, NCT01958021, NCT02422615, NCT02278120, NCT01237236, NCT01898845, NCT01872260.

Pharmacokinetic and dose-finding study of osimertinib in patients with impaired renal function and low body weight.

The safety of osimertinib is limited in patients with severe or moderate renal impairment, or low body weight. This study aimed to investigate the safety, pharmacokinetics (PK) and recommended dose (RD) of osimertinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with impaired renal function and low body weight. Thirty-one eligible patients were enrolled and allocated into four cohorts: A, normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 mL/min/1.73 m2 ) and normal body weight (≥45 kg); B, moderate renal impairment (eGFR=30-50 mL/min/1.73 m2 ); C, low body weight (<45 kg); and D, severe renal impairment (eGFR <30 mL/min/1.73 m2 or undergoing dialysis). PK parameters and safety were evaluated with a starting dose of 80 mg osimertinib administered orally once daily in cohorts A, B, and C and 40 mg once daily in cohort D. The PK parameters in cohorts A, B, and C were found to be similar. No dose-limiting toxicity was observed, and the RD was determined to be 80 mg once daily in patients with moderate renal function and low body weight. Four serious adverse events, acneiform rash, diarrhea, QTc prolongation, and interstitial lung disease, were noted. Although the PK parameters of osimertinib were similar across all cohorts, toxicity occurred more frequently in patients with impaired renal function and low body weight. Clinicians should prescribe osimertinib with caution in NSCLC patients with impaired renal function and low body weight.

Management of Locally Advanced Unresectable or Metastatic Urothelial Carcinoma: Expert Opinion from an Indian Panel via Delphi Consensus Method

Introduction Currently, there are no guidelines for the management of locally advanced unresectable or metastatic urothelial carcinoma (mUC) from an Indian perspective. There is a lack of consensus on the utility of treatment options in first-line (1L) and second-line (2L) settings, especially in cisplatin- and platinum-unfit mUC patient subgroups. Objective This articles aims to develop evidence-based practical consensus recommendations for the management of mUC in Indian settings. Methods Modified Delphi consensus methodology was considered to arrive at a consensus. An expert scientific committee of 15 medical oncologists from India constituted the panel. Twelve clinically relevant questions were grouped into five categories for presentation and discussion: (1) cisplatin and platinum ineligibility criteria; (2) programmed death ligand 1 and fibroblast growth factor receptor (FGFR) testing in mUC patients; (3) treatment options in 1L settings; (4) role of switch maintenance; and (5) treatment options in 2L. Statements that reached high (≥ 80%) and moderate (60–79%) levels of consensus in the first round (electronic survey) did not undergo the second Delphi round. The questions that received a low level of consensus (&lt; 60%) were discussed during the virtual meeting. Results Renal impairment (creatinine clearance [CrCl] &lt; 60 mL/min) and New York Heart Association class 3 heart failure are important assessment criteria for determining cisplatin ineligibility. Patients are unfit for any platinum-based chemotherapy in case of Eastern Cooperative Oncology Group performance status&gt; 3 or severe renal impairment (CrCl &lt; 30 mL/min). Gemcitabine and platinum with cisplatin over carboplatin were preferred in 1L settings. In patients unfit for cisplatin-based regimens, carboplatin–gemcitabine chemotherapy was preferred over immunotherapy (atezolizumab or pembrolizumab). Selected patients who are platinum ineligible may be considered for immunotherapy. Post-induction chemotherapy, those who do not progress may be strongly considered for avelumab maintenance. Experts recommended erdafitinib in FGFR-positive mUC patients in 2L settings. In FGFR-negative patients, immunotherapy (pembrolizumab, nivolumab, or avelumab) may be preferred over chemotherapy (paclitaxel, docetaxel, or vinflunine). Enfortumab vedotin and sacituzumab govitecan may be considered for further lines of therapy. Conclusion Expert panel consensus will offer expert guidance to oncologists/clinicians on the management of mUC in Indian settings. Key Points

Evaluating the impact of co-administered drug and disease on ripretinib exposure: A physiologically-based pharmacokinetic modeling approach

Ripretinib, as an oral kinase inhibitor, has been approved to treat advanced gastrointestinal stromal tumors (GIST) and is often used in combination with other drugs to slow disease progression, thus potential drug-drug Interactions (DDIs) and drug-disease interactions (DDZIs) have received much attention. To guide clinical rational drug use, this study assessed the effect of co-administered drugs and diseases on ripretinib exposure. Simcyp® Simulator was used to develop the physiologically-based pharmacokinetic (PBPK) model of ripretinib, which was validated and refined with clinical data. We then examined the impact of several CYP3A4 inhibitors and inducers as well as different diseases on ripretinib exposure using the validated model. In the DDI simulation, moderate CYP3A4 inhibitors and inducers changed the exposure of ripretinib by 1.25–2 fold. In hepatic impairment (HI), the simulation showed that ripretinib's AUC increased by 32%, 100%, and 152% for Child-Pugh A, B, and C classification while Cmax increased by 2%, 10%, and 15%, respectively. In renal impairment (RI), the model-simulated AUC in moderate and severe RIs increased by 27% and 20%. In conclusion, PBPK models demonstrated quantitative prediction of ripretinib's pharmacokinetic changes under varying conditions that might be useful for its rational use.

The first study on urinary loss of iron and transferrin in association with proteinuria in dogs with chronic kidney disease.

Anemia is an important factor in surviving chronic kidney disease (CKD). Anemia in CKD is associated with various factors, such as inadequate production of erythropoietin and the availability of iron and its binding protein. Reduced total iron-binding capacity (TIBC) and iron concentrations may be related to their urinary loss along with proteinuria. This study aimed to determine the urinary loss of iron and transferrin (TF) in relation to the degree of proteinuria. The study was performed on 37 dogs with CKD. Dogs were divided according to the severity of proteinuria into two groups based on the mean of urinary protein-creatinine (UPC) ratio into UPC ratio <4 and UPC ratio >4. The hematocrit (HCT), blood chemistries, plasma iron, plasma TF, UPC ratio, urinary iron per creatinine ratio (U-Iron/CR), and urinary TF per creatinine ratio (U-TF/CR) were evaluated. Anemia was associated with the severity of renal impairment as demonstrated by reduction of HCT when staging of CKD was higher. Dogs with UPC ratio >4 had higher urinary loss of both U-Iron/CR (p < 0.01) and U-TF/CR (p < 0.001) with lower plasma TIBC (p < 0.001). The UPC ratio was positively correlated with both U-Iron/CR (r = 0.710, p < 0.001) and U-TF/CR (r = 0.730, p < 0.001) but negatively with TIBC (r = -0.462, p < 0.01). Proteinuria was associated with urinary loss of both iron and TF which may contribute to anemia in CKD.

Safety and efficacy of autologous stem cell transplantation in dialysis-dependent myeloma patients-The DIADEM study from the chronic malignancies working party of the EBMT.

The role of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in the treatment of myeloma (MM) patients with severe and/or dialysis-dependent renal impairment remains uncertain. We report on the outcomes of 110 patients (median age 57 years) who had become dialysis-dependent pre-ASCT and who underwent a first ASCT between 1997 and 2017. Sixty-three (57%) patients had light chain MM. All patients required dialysis (94% hemodialysis and 6% peritoneal). Forty-four of 71 (62%) patients received bortezomib-based induction regimens and 42 (39%) patients had achieved at least a very good partial response (VGPR) pre-ASCT. Melphalan dosing was as follows: ≤140 mg/m2 (82%), and >140 mg/m2 (18%). The median PFS after ASCT was 35 months (95% CI: 21.5-42.2) and the median OS 102 months (95% CI: 70.4-129.1). At 1, 2, and 5 years after ASCT, 8% (95% CI 3-14%), 13% (6-20%), and 20% (12-29%) of patients, respectively, had achieved dialysis independence. In multivariate analyses of OS and PFS including age at ASCT, response at ASCT, and year of ASCT, younger age at ASCT and better response at ASCT (CR/VGPR/PR vs. MR/SD/progression) were significantly associated with better OS and PFS.

Population pharmacokinetic model-based dosing proposal for ampicillin prophylaxis in cardiac surgery patients with cardiopulmonary bypass

The aim of this study was to describe and quantify pharmacokinetics of ampicillin used prophylactically in cardiac surgery both with and without cardiopulmonary bypass (CPB) using population pharmacokinetic analysis in order to propose an optimal dosing strategy. Adult patients undergoing cardiac surgery and treated with prophylactic dose of 2 g ampicillin were enrolled to this prospective study. Blood samples were collected according to the study protocol and ampicillin plasma concentrations were measured using HPLC/UV system. A three-stage population pharmacokinetic model using nonlinear mixed-effects modelling approach was developed. Totally 273 blood samples obtained from 20 patients undergoing cardiac surgery with the use of the CPB and 20 patients without CPB use were analyzed. Two-comparmental model best fits ampicillin concentration-time data. Mean ± SD body weight-normalized ampicillin central and peripheral volume of distribution was 0.12 ± 0.02 L/kg and 0.15 ± 0.03 L/kg, respectively, while mean ± SD ampicillin clearance in typical patient with eGFR of 1.5 mL/s/1.73 m2 was 1.17 ± 0.05 L/h. The use of CPB did not significantly affect the pharmacokinetics of ampicillin. When administering 2 g of ampicillin before surgery, an additional dose should be administered to reach the PK/PD target of fT > MIC = 50% if the operation lasts longer than 430 min in patients with moderate to severe renal impairment, 320 min in patients with mild renal impairment, 220 min in patients with normal renal function status or 140 min in patients with an augmented renal clearance.

Quanduzhong capsules for the treatment of grade 1 hypertension patients with low-to-moderate risk: A multicenter, randomized, double-blind, placebo-controlled clinical trial.

Background: Duzhong [DZ (Eucommia ulmoides Oliv.)] is regarded as a traditional Chinese medicine with a history dating back more than 2000years. This herb is considered a nourishing herb in China and is commonly used as a tonic to strengthen muscles and bones, nourish the kidneys and liver, and soothe miscarriages. Moreover, there is evidence that DZ is capable of regulating blood pressure (BP), and several compounds isolated from DZ have been shown to have a BP-lowering effect. Quanduzhong capsules contain an extract of DZ [Eucommia ulmoides Oliv. (Eucommiaceae; Eucommiae cortex)] that is effective in treating hypertension. This multicenter, randomized, double-blind, placebo-controlled clinical trial sought to evaluate the clinical efficacy of Quanduzhong capsules in the treatment of low-to-moderate risk grade 1 hypertension patients. Materials and methods: A total of 60 patients from 3 centers with documented low-to-moderate risk grade 1 hypertension were randomly assigned in a 1:1 ratio to the test group or the control group. After a 1week lead-in period using sham Quanduzhong capsules, all patients who met the entry criteria (29 cases in the test group and 29 cases in the control group) entered the 4week test period. The test group took Quanduzhong capsules, and the control group continued to take sham Quanduzhong capsules. The primary endpoints [24-h mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) determined via 24-h ambulatory blood pressure monitoring (ABPM); office SBP and DBP] and secondary endpoints [mean arterial pressure; mean pulse; daytime mean SBP and DBP; nocturnal mean SBP and DBP; SBP and DBP load; area under the blood pressure (BP) curve; morning peak BP; early morning SBP and DBP; smoothness index of SBP and DBP; 24h BP mean coefficient of variation (CV); percentage of patients with circadian restoration in ABPM; home BP; quality of life evaluated by WHO Quality of Life-BREF questionnaire; grading and quantitative evaluation of hypertension symptoms; values of plasmatic renin activity, angiotensin II, aldosterone, β-2 microglobulin and homocysteine] were assessed following the treatment. Drug-related adverse events and adverse drug reactions were also compared. Results: After a 4week test period, a significant difference in the DBP CV between the two groups was observed (-2.49 ± 4.32 vs. 0.76 ± 4.3; p < .05). Moreover, the mean office SBP change was -7.62 ± 9.32mmHg, and the mean DBP change was -4.66 ± 6.03 (p < .05). Among the three subjects with abnormal homocysteine levels in the test group, homocysteine levels decreased by 6.23 ± 9.15μmol/L after treatment. No differences were observed between the two groups in any other indicators. After 4weeks of treatment, there were no significant differences between the groups in terms of safety indicators (p > .05). No abnormal vital signs (except BP) or severe liver or renal function impairment were observed during the treatment periods; in addition, adverse events and drug reactions were mild. Conclusion: Treatment with Quanduzhong capsules reduced office SBP and DBP as well as DBP CV determined by 24-h ambulatory BP monitoring in patients with grade 1 hypertension at low-to-moderate risk. Clinical Trial Registration: https://www.chictr.org.cn/showproj.aspx?proj=32531, identifier ChiCTR1900021699.

Parathyroid Carcinoma Mimicking Multiple Myeloma: A Tale of Refractory Hypercalcemia

Primary hyperparathyroidism yields various symptoms, including hypercalcemia, pathological fracture, and renal impairment. Parathyroid carcinoma is the rarest cause of primary hyperparathyroidism, accounting for <1% of the cases. We reported a case of a 46-year-old male with closed fractures at the humerus and femur. Further findings revealed severe refractory hypercalcemia, renal impairment, anemia, and bone lytic lesion (CRAB). No palpable cervical mass was identified. Surprisingly, the serum protein electrophoresis was normal, and urinary Bence-Jones protein was negative along with normal bone marrow aspiration. Hence, multiple myeloma was unlikely. The intact parathyroid hormone level was very high, along with a suspicious nodule on the left thyroid lobe (TIRADS 4). Total thyroidectomy and total parathyroidectomy were performed. The post-surgical pathological examination confirmed the diagnosis of parathyroid carcinoma. After the surgery, the patient was in stable condition with normal intact parathyroid hormone and serum calcium levels. In this case, primary hyperparathyroidism was caused by parathyroid carcinoma with “CRAB” symptoms, mimicking multiple myeloma. Primary hyperparathyroidism should be considered in the patient with refractory hypercalcemia.

Baseline eGFR, albuminuria and renal outcomes in patients with SGLT2 inhibitor treatment: an updated meta-analysis.

To elucidate the association between baseline renal characteristics and the disparities in renal outcomes among patients with SGLT2i treatment. Pubmed, Medline, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov were searched from inception to November 2022. Event-driven randomized controlled trials of SGLT2i with reports of renal outcomes were included. Sensitivity analyses of prespecified eGFR and UACR subgroups were conducted. Generally, compared with placebo, the use of SGLT2i was associated with improved renal prognosis (HR = 0.64, 95%CI 0.59-0.70). The magnitude of risk reductions in composite renal outcomes between SGLT2i versus placebo was comparable among different eGFR stratifications (normal renal function: HR = 0.49, 95%CI 0.31-0.79; mild renal impairment: HR = 0.57, 95%CI 0.48-0.68; moderate renal impairment: HR = 0.70, 95%CI 0.63-0.78; severe renal impairment: HR = 0.72, 95%CI 0.62-0.84; P for subgroup difference = 0.09). However, renal benefits seemd to be more prominent in normal to mildly increased albuminuria stratum (HR = 0.51, 95%CI 0.39-0.66) and severely increased albuminuria stratum (HR = 0.57, 95%CI 0.47-0.68), when compared with moderately increased albuminuria stratum (HR = 0.79, 95%CI 0.65-0.96; P for subgroup difference = 0.01). Generally, the use of SGLT2i was consistently associated with decreased risk of renal events in all prespecified eGFR and albuminuria spectrums, even in patients with substantial renal impairment. The renal benefits of SGLT2i seemed to be independent of baseline eGFR, while the risk reduction in renal events was more profound among patients with mildly increased albuminuria or severely increased albuminuria.

Clinical Characteristics and Prognosis of Diabetic Foot Ulcers Patients of Different Renal Function Statuses

To explore the clinical characteristics and the prognosis of diabetic foot ulcers (DFU) inpatients of different renal function statuses. A retrospective analysis of 962 inpatients with DFU was conducted. The patients were divided into three groups according to their renal function statuses, and the clinical characteristics of the three groups were compared to identify differences. In addition, the patients were followed up in outpatient clinics or by telephone and their prognostic status and risk factors for death were analyzed. Analysis of the clinical characteristics showed that, compared with diabetic patients with normal renal function or mild renal function impairment, diabetic patients with moderate and severe renal function impairment had a longer course of disease ( P<0.001). Patients with foot ulcers of Wagner grade 4 predominates the moderate and severe renal function impairment groups ( P<0.05). Patients in the moderate and severe renal function impairment groups had a relatively higher proportion of comorbidities, including hypertension, coronary heart disease, and peripheral arterial disease ( P<0.05). These patients had relatively lower levels of glycosylated hemoglobin and hemoglobin (all P<0.05) and relatively higher levels of neutrophil ratio and procalcitonin (all P<0.05). Of the two groups, patients in the moderate renal function impairment group were older ( P<0.001) and had lower ankle-brachial index ( P<0.001). The severe renal function impairment group had a higher proportion of patients with foot ulcers of Wagner grades 3 and 5 (all P<0.05). For the purpose of conducting prognostic analysis, 748 patients were followed up in outpatient clinics or by telephone for a median length of 41 months. Among them, 239 died. The all-cause mortality was 31.9%, and the mortality in the three groups was 25.8%, 46.2% ( P<0.001), and 59.4% ( P<0.001), respectively. The survival rate of patients in the moderate and severe renal function impairment groups was significantly lower than those in the normal renal function and mild renal function impairment groups ( P<0.001). Univariate Cox regression analysis showed that age, concomitant coronary heart disease and peripheral arterial disease, degree of renal function impairment, and foot ulcers of Wagner grade 4 and 5 were associated with all-cause deaths. Furthermore, multivariate Cox regression analysis showed that moderate and severe renal function impairment was an independent risk factor for all-cause deaths in DFU patients ( P<0.001). As renal function impairment worsens, patients with DFU present clinical characteristics of greater complexity, higher risks of cardiovascular events, and higher mortality. It is essential to prevent kidney damage and foot ulcers, to pay attention to the cardiovascular risks of DFU patients with moderate and severe renal function impairment, and to reduce mortality.