A lentivirus-vectored feline erythropoietin gene therapy strategy in tissue culture and rodent models for the potential treatment of chronic renal disease-associated anemia.

OBJECTIVE: The aim of this study was to assess the efficacy and safety of a third-generation lentivirus-based vector encoding the feline erythropoietin (EPO) (feEPO) gene in vitro and in rodent models in vivo. This vector incorporates a genetic mechanism to facilitate the termination of the therapeutic effect in the event of supraphysiologic polycythemia, the herpes simplex virus thymidine kinase (HSV-TK) "suicide gene." ANIMALS: CFRK cells and replication-defective lentiviral vectors encoding feEPO were used for in vitro experiments. Eight Fischer rats were enrolled in the pilot in vivo study, 24 EPO-deficient mice were used in the initial mouse study, and 15 EPO-deficient mice were enrolled in the final mouse study. METHODS: Efficacy of a third-generation lentivirus encoding feEPO was determined in vitro using western blot assays. Subsequently, in a series of rodent experiments, animals were administered the viral vector in progressively increasing inoculation doses with serial measurements of blood packed cell volume (PCV) over time. RESULTS: We documented production of feEPO protein in transduced CRFK cells with subsequent cessation of production when treated with the HSV-TK substrate ganciclovir. In vivo, we demonstrated variably persistent elevated PCV values in treated rats and mice with eventual return to baseline values over time. CLINICAL RELEVANCE: These results provide justification for a lentiviral gene therapy approach to the treatment of nonregenerative anemia associated with chronic renal disease in cats.

Renoprotective strategies.

Kidney disease remains a condition with an increasing incidence, high morbidity and mortality associated with cardiovascular events. The incidence of end-stage renal disease is expected to increase. Despite of the technical improvement, dialysis never achieved a full clearance of the blood dialysis. Therefore, the demand for new renoprotective measures has never been greater. Here, we report new strategies for preventing renal damage.

Pros of Inpatient Sodium Glucose Cotransporter-2 Inhibitor Use.

OBJECTIVE: Sodium-glucose-cotransporter 2 (SGLT-2) inhibitors are widely used for diabetes management especially because their effects go beyond glucose control. More recently, their indications and usage have expanded to heart failure (HF) and renal dysfunction therapy in patients both with and without diabetes. Beneficial effects, especially for HF readmission, accrue very early in their treatment trajectory, and this has promoted their use in the hospital setting. Data on their safety and efficacy for inpatient use are accumulating but have lagged behind the outpatient data for their use. The objective of this counterpoint piece is to highlight areas of benefit for starting or continuing SGLT-2 inhibitors in the inpatient setting. METHODS: Discussion after literature review of available studies with a focus on HF outcomes and SGLT-2 inhibitor use. RESULTS: The benefits of starting or continuing an SGLT-2 inhibitor in the inpatient setting are well documented, mainly in HF. Similar data are not available for glucose or renal outcomes alone. Starting in the hospital allows the ability to titrate medications with similar effects, such as diabetes and HF agents, as well as reducing treatment inertia to obtain and start new medications after patients are discharged home. It is important to choose patients appropriately and hold these drugs when patients are without nutrition or on low-carbohydrate diets which can lead to diabetic ketoacidosis. CONCLUSION: In the right setting, using an SGLT-2 inhibitor in the hospital can affect multiple aspects of a patient's treatment trajectory and should be a consideration.

Associations between short-term exposure to ambient temperature and renal disease mortality in Japan during 1979-2019: A time-stratified case-crossover analysis.

Background: Previous studies have indicated that renal disease mortality is sensitive to ambient temperatures. However, most have been limited to the summer season with inconclusive evidence for changes in population vulnerability over time. Objective: This study aims to examine the association between short-term exposure to ambient temperatures and mortality due to renal diseases in Japan, and how this association varied over time. Methods: We conducted a two-stage, time-stratified case-crossover study from 1979 to 2019 across 47 prefectures of Japan. We obtained the data of daily mortality counts for all renal diseases, acute renal failure, and chronic renal disease. We fitted a conditional quasi-Poisson regression model with a distributed lag nonlinear model. A random-effects meta-analysis was applied to calculate national averages. We performed additional analyses by four subperiods, sex, and age groups. Results: We analyzed 997,590 renal mortality cases and observed a reversed J-shaped association. Lower temperatures were associated with increased mortality in all renal disease categories. The cumulative relative risks at 2.5th percentile compared to the minimum mortality temperature percentile were 1.34 (95% confidence interval [CI] = 1.29, 1.40), 1.51 (95% CI = 1.33, 1.71), and 1.33 (95% CI = 1.24, 1.43) for all renal, acute renal failure, and chronic renal disease mortality, respectively. The associations were observed in individuals of both sexes and aged 65 years and above. The associations of kidney mortality with low temperature remained consistent, while the associations with high temperature were pronounced in the past, but not in recent periods. Conclusions: Protection for individuals with impaired renal function from exposure to low temperatures during cold seasons is warranted.

Causal associations between prostate diseases, renal diseases, renal function, and erectile dysfunction risk: a 2-sample Mendelian randomization study.

Background: Previous observational studies have found a potential link between prostate disease, particularly prostate cancer (PCa), and kidney disease, specifically chronic renal disease (CKD), in relation to erectile dysfunction (ED), yet the causal relationship between these factors remains uncertain. Aim: The study sought to explore the potential causal association between prostate diseases, renal diseases, renal function, and risk of ED. Methods: In this study, 5 analytical approaches were employed to explore the causal relationships between various prostate diseases (PCa and benign prostatic hyperplasia), renal diseases (CKD, immunoglobulin A nephropathy, membranous nephropathy, nephrotic syndrome, and kidney ureter calculi), as well as 8 renal function parameters, with regard to ED. All data pertaining to exposure and outcome factors were acquired from publicly accessible genome-wide association studies. The methods used encompassed inverse variance weighting, MR-Egger, weighted median, simple mode, and weighted mode residual sum and outlier techniques. The MR-Egger intercept test was utilized to assess pleiotropy, while Cochran's Q statistic was employed to measure heterogeneity. Outcomes: We employed inverse variance weighting MR as the primary statistical method to assess the causal relationship between exposure factors and ED. Results: Genetically predicted PCa demonstrated a causal association with an elevated risk of ED (odds ratio, 1.125; 95% confidence interval, 1.066-1.186; P < .0001). However, no compelling evidence was found to support associations between genetically determined benign prostatic hyperplasia, CKD, immunoglobulin A nephropathy, membranous nephropathy, nephrotic syndrome, kidney ureter calculi, and the renal function parameters investigated, and the risk of ED. Clinical Implications: The risk of ED is considerably amplified in patients diagnosed with PCa, thereby highlighting the importance of addressing ED as a significant concern for clinicians treating individuals with PCa. Strengths and Limitations: This study's strength lies in validating the PCa-ED association using genetic analysis, while its limitation is the heterogeneity in study results. Conclusion: The results of this study suggest a potential link between PCa and a higher risk of ED.

Chronic kidney disease and left ventricular diastolic dysfunction (CKD-LVDD) alter cardiac expression of mitochondria-related genes in swine.

Cardiovascular disease and heart failure doubles in patients with chronic kidney disease (CKD), but the underlying mechanisms remain obscure. Mitochondria are central to maintaining cellular respiration and modulating cardiomyocyte function. We took advantage of our novel swine model of CKD and left ventricular diastolic dysfunction (CKD-LVDD) to investigate the expression of mitochondria-related genes and potential mechanisms regulating their expression. CKD-LVDD and normal control pigs (n=6/group, 3 males/3 females) were studied for 14 weeks. Renal and cardiac hemodynamics were quantified by multidetector-CT, echocardiography, and pressure-volume loop studies, respectively. Mitochondrial morphology (electron microscopy) and function (Oroboros) were assessed ex vivo. In randomly selected pigs (n=3/group), cardiac mRNA-, MeDIP-, and miRNA-sequencing (seq) were performed to identify mitochondria-related genes and study their pre- and post -transcriptional regulation. CKD-LVDD exhibited cardiac mitochondrial structural abnormalities and elevated mitochondrial H2O2 emission but preserved mitochondrial function. Cardiac mRNA-seq identified 862 mitochondria-related genes, of which 69 were upregulated and 33 downregulated (fold-change ≥2, false discovery rate≤0.05). Functional analysis showed that upregulated genes were primarily implicated in processes associated with oxidative stress, whereas those downregulated mainly participated in respiration and ATP synthesis. Integrated mRNA/miRNA/MeDIP-seq analysis showed that upregulated genes were modulated predominantly by miRNAs, whereas those downregulated were by miRNA and epigenetic mechanisms. CKD-LVDD alters cardiac expression of mitochondria-related genes, associated with mitochondrial structural damage but preserved respiratory function, possibly reflecting intrinsic compensatory mechanisms. Our findings may guide the development of early interventions at stages of cardiac dysfunction in which mitochondrial injury could be prevented, and the development of LVDD ameliorated.

High Ferritin and Low Total Iron-Binding Capacity in Plasma Predict All-Cause Mortality During the First 3 Years of Hemodialysis in Patients with End-Stage Chronic Kidney Disease.

Aim: To determine all-cause mortality rate and the predictive value of plasma ferritin and total iron-binding capacity (TIBC) concentrations for mortality during the first 3 years of hemodialysis in patients with end-stage chronic renal disease (ESRD). Methods: We conducted a study on 174 ESRD patients (estimated Glomerular Filtration Rate < 15 mL/min/1.73m2). The plasma TIBC level was quantified by the ELISA method in all patients at the time before hemodialysis. Based on TIBC concentration, patients were divided equally into 2 groups. Each group had 87 patients. Patients were initiated on hemodialysis, and patients who died from any cause during the first 3 years of hemodialysis were recorded. Results: The all-cause mortality rate of ESRD patients in the first 3 years of maintenance hemodialysis was 22.9%. Plasma high hs-CRP, high ferritin, and low TIBC concentrations were independent factors associated with all-cause mortality in the patients. Plasma ferritin (cut-off value = 454.2 ng/L) and TIBC (cut-off value = 39.84 µmol/L) were predictors of all-cause mortality, AUC is: 0.772; 0.723, p < 0.001. Conclusion: Plasma ferritin and TIBC were good predictors of all-cause mortality in ESRD patients during the first 3 years of hemodialysis.

Lithium induced chronic renal disease: A case report.

We present a case of lithium-induced chronic renal disease in a 69-year-old female with past medical history of hypertension, and bipolar disorder, treated with long-term lithium-causing chronic renal disease.

The 50th Anniversary of the Implementation of PL 92-603: A Major Change in the Care of Patients with End Stage Kidney Disease.

Fifty years ago, in July 1973, providing care to patients with end stage kidney disease changed dramatically with the implementation of legislation (PL 92-603) that deemed chronic renal disease to be a disability and provided coverage under Medicare for the treatment of the disease. In this article, we discuss the impact of the implementation of PL 92-603.

Computerized nailfold video-capillaroscopy in type 2 diabetes: A cross-sectional study on 102 outpatients.

BACKGROUND: Type 2 diabetes (T2D) is a chronic disease that negatively affects vascular health. A careful assessment of chronic complications, including microcirculation, is mandatory. The computerized nailfold video-capillaroscopy (CNVC) accurately examines the nailfold microvasculature, but its suitability in T2D is currently under investigation. AIMS: To describe nailfold microvasculature in T2D patients regarding the level of glucose control and chronic microvascular and macrovascular complications. METHODS: This is a cross-sectional study on 102 consecutive and unselected outpatients with T2D who had undergone CNVC examination. The examination was carried out by using an electronic video-capillaroscope with 300x magnification. Capillaroscopic appearance and capillary changes were described according to well-established parameters. Capillaroscopic parameters were compared between patients with poor glucose control (HbA1c ≥7%) and those with better glucose control (HbA1c <7%) and between patients with chronic complications and those without. Chronic complications were deduced from the anamnestic, laboratory, and instrumental data and the five-item International Index of Erectile Function (IIEF-5) questionnaire. RESULTS: Nailfold capillaries in patients with HbA1c ≥7% were thicker (p = .019) and longer (p = .021) than in those with better glucose control. Ectasias (p = .017) and microaneurysms (p = .045) were more frequently observed in patients with HbA1c ≥7.0% than those with HbA1c <7.0%. Patients with ED, compared to those without, had a lower frequency of bizarre-shaped capillaries (p = .02). Microaneurysms (p = .02) were more frequently described in patients with carotid stenosis (>20%) than those without. CONCLUSION: Relevant nailfold microvascular alterations were observed in T2D, most of which were associated with poor glycemic control, ED, and carotid stenosis. Further investigation is needed to recognize the role of CNVC in predicting the onset and evolution of chronic complications and monitoring the effectiveness of antihyperglycemic treatments on microcirculation.

From Primary Cilia and Planar Cell Polarity to Kidney Injury and Repair.

Almost every cell in the kidney, including renal tubular epithelial cells, has a primary cilium, which is a membrane-bound, hair-like structure protruding from the cellular surface. Dysfunction of primary cilia has been linked to a wide spectrum of human genetic diseases, termed ciliopathies. Planar cell polarity (PCP) refers to the coordinated alignment of cells along the cell sheet or tissue plane, a fundamental process in embryo development and organogenesis. Interestingly, there is evidence that primary cilium and PCP are interconnected. However, very limited is known about the involvement of cilia and PCP in kidney injury and repair. By using cell and mouse models, we have demonstrated a protective role of primary cilia in acute kidney injury. Mechanistically, we unveiled a reciprocal promoting relationship between cilia and autophagy in kidney tubular cells, and, accordingly, cilia may protect tubular cells by enhancing autophagy. Our recent studies further demonstrated that PCP dysfunction exaggerates acute kidney injury and may also contribute to maladaptive kidney repair after acute kidney injury. These findings provide a novel dimension to further understanding kidney injury and repair from the standpoint of cell biology.

Measurement of Ghrelin as a Marker of Appetite Dysregulation in Cats with and without Chronic Kidney Disease.

Appetite abnormalities and weight loss are important comorbidities in the treatment of chronic kidney disease (CKD) in cats. Ghrelin, a key hormone involved in the regulation of appetite and metabolism, is a potential marker of appetite dysregulation in cats with CKD. The aim of this study was to compare the plasma concentrations of acylated, desacyl, and total ghrelin in normal cats and cats with CKD. Storage methodology was investigated prior to evaluating ghrelin concentrations in normal and CKD cats to facilitate clinical sample collection. Twelve normal cats and twelve cats with CKD were enrolled. Plasma acylated and total ghrelin concentrations were measured using radioimmunoassay. Desacyl ghrelin was calculated (total ghrelin minus acylated ghrelin). Cats with CKD had significantly increased total ghrelin and calculated desacyl ghrelin concentrations in comparison to normal cats (p < 0.0001 and p = 0.0001). There was no significant difference in active ghrelin concentrations between groups. Both total ghrelin and calculated desacyl ghrelin were significantly correlated with serum creatinine concentrations (p < 0.0001, r = 0.70 and p < 0.0001, r = 0.73). Elevated plasma desacyl ghrelin concentrations in cats with CKD provides evidence for dysregulation of appetite in feline CKD.

Penile calciphylaxis with penoscrotal necrosis: A case report with literature review.

Penile calciphylaxis, also known as calcific uremic arteriolopathy is an uncommon condition of the penile vessels due to its extensive vascular network. The aim of this report is to report a very rare case of penile calciphylaxis with penoscrotal necrosis. A 54-year-old male patient presented with progressive penoscrotal necrosis within a duration of one month. He had a history of diabetes mellitus and stage 5 chronic kidney disease. Under spinal anesthesia, partial penectomy and excision of the necrotic scrotum were performed. Histopathological examination was consistent with calciphylaxis. Despite it is a rare occurrence, penile calciphylaxis should be included in the different diagnosis of any diabetic and end stage kidney disease patients who presented with penile pain.

Pattern, frequency and factors associated with inappropriate high dosing in chronic kidney disease patients at a tertiary care hospital in Pakistan.

BACKGROUND: Patients with chronic kidney diseases (CKD) are susceptible to the toxic drug effects if given unadjusted doses. Although Pakistan harbors a high burden of CKD patients, there is limited information available on the frequency, pattern and factors associated with unadjusted drug doses among CKD patients. METHODS: This cross-sectional study conducted at Sandeman Provincial Hospital, Quetta included 303 non-dialysis ambulatory CKD patients (glomerular filtration rate < 60 ml/min/1.73m2). The patients' data were collected through a purpose designed data collection form. The appropriateness of doses was checked against the renal drug handbook-2018, Kidney Disease Improving Global Outcomes guidelines, British National Formulary-2022, and manufacturer leaflets. Data were analysed by SPSS 23 and multiple binary logistic regression analysis was used to assess the factors associated with receiving inappropriate high doses. A p-value < 0.05 was considered statistically significant. RESULTS: The patients received a total of 2265 prescription lines, with a median of eight different drugs per patient (interquartile range: 6-9 drugs). A total of 34.5% (783/2265) drugs required dose adjustment. Of these, doses were not adjusted for 56.1% (440) drugs in 162 (53.4%) patients. The most common pharmacological class of drugs requiring dose adjustment were antibiotics (79.1%), followed by antidiabetics (59.2%), diuretics (57.0%), angiotensin converting enzyme inhibitors (56.9%), beta blockers (56.9%), analgesics (56.0%), angiotensin receptor blockers (55.2%), domperidone (53.9%) and antihyperlipidmics (46.1%). Patient's age of 41-60 (OR = 5.76) and > 60 years (OR = 9.49), hypertension (OR = 2.68), diabetes mellitus (OR = 3.47) and cardiovascular diseases (OR = 2.82) had statistically significant association (p-value < 0.05) with inappropriate high doses. CONCLUSION: The high frequency of inappropriate high doses suggests an important quality gap in medication dosing for patients with ND-CKD at the study site. Special attention should be paid to the drugs and patients with identified risk factors for receiving inappropriate high doses.

A Single-Center Study Using IVUS to Guide Rotational Atherectomy for Chronic Renal Disease's Calcified Coronary Artery.

Objective: To assess the effectiveness and safety of an IVUS-guided rotational atherectomy (RA) percutaneous coronary intervention (PCI) in chronic renal patients with complex coronary calcification who are at risk for contrast-related acute kidney injury (AKI). Methods: From October 2018 to October 2021, 48 patients with chronic renal disease who were receiving PCI with RA at the General Hospital of NingXia Medical University were informed for data collection for this research. They were randomly assigned to the IVUS-guided RA group and the Standard RA group, which did not use IVUS. According to a clinical expert consensus document on rotational atherectomy in China, both PCI procedures were performed. The intravascular ultrasound (IVUS) results from the study group were used to describe the morphology of the lesion and to guide the selection of burrs, balloons, and stents. IVUS and angiography were used to evaluate the outcome in the end. IVUS-guided RA PCI and Standard RA PCI groups' effects and results were contrasted. Results: There were no appreciable differences in the clinical baseline characteristics between the IVUS-guided RA PCI group and the Standard RA PCI group. The average estimated glomerular filtration rate (eGFR) of two groups was (81.42 ± 20.22 vs 82.34 ± 22.19) mL/min/1.73 m2. Most of them (45.8% vs 54.2%) was in stage 60-90 mL/min/1.73m2. When compared to the standard RA PCI group, RA in IVUS-Guided group was more performed electively (87.5% vs 58.3%; p = 0.02). The IVUS-guided RA PCI group was associated with shorter fluoroscopy time (20.6 ± 8.4 vs 36 ± 22; p<0.01) and less contrast amount (32 ±16 vs 184 ±116mL; p<0.01) than Standard-RA group. Five patients in the Standard RA PCI group developed contrast-induced nephropathy, which was 5 times than the IVUS-guided RA PCI group (20.8% VS 4.1%; p=0.19). Conclusion: In chronic renal patients with complex coronary calcification, an IVUS-guided RA PCI technique is effective and safe. It can also lower the volume of contrast and perhaps the incidence of contrast-related AKI.

Renal Transplant Patients Have a Lower Risk of Complications and Mortalities After Total Knee Arthroplasty Compared to Those on Hemodialysis: A Large National Database Study.

BACKGROUND: Total knee arthroplasty (TKA) in end-stage renal disease is associated with complications. Controversy exists whether elective TKA should be performed while patients are on hemodialysis (HD) or following renal transplant (RT). This study compares TKA outcomes in HD versus RT patients. METHODS: A national database was retrospectively reviewed using International Classification of Diseases codes to identify HD and RT patients who underwent primary TKA from 2010 to 2018. Demographics, comorbidities, and hospital factors were compared using Wald and Chi-squared tests. The primary outcome was in-hospital mortalities while secondary outcomes included quality outcomes and medical/surgical complications. Multivariate regressions were used to determine independent associations. Significance was determined with a 2-tailed P value of .05. There were 13,611 patients who underwent TKA (61.1 HD and 38.9% RT). Patients who had RT were younger, had fewer comorbidities, and more likely to have private insurance. RESULTS: The RT patients had a lower rate of mortality (odds ratio (OR) 0.23, P < .01)), complications (OR 0.63, P < .01), cardiopulmonary complications (OR 0.44, P = .02), sepsis (OR 0.22, P < .001), and blood transfusion (OR 0.35, P < .001) during the index hospitalization. This cohort was also found to have decreased length of stay (-2.0 days, P < .001), non-home discharge (OR 0.57, P < .001), and hospital cost (-$5,300, P < .001). Patients who had RT had a lower rate of readmission (OR 0.54, P < .001), periprosthetic joint infection (OR 0.50, P < .01), and surgical site infection (OR 0.37, P < .001) within 90 days. CONCLUSION: These findings suggest that HD patients are a high-risk population in TKA compared to RT patients and warrant stringent perioperative monitoring.

Percutaneous left atrial appendage closure for stroke prevention in patients with chronic renal disease.

Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia in the general population. Atrial fibrillation is associated with an increased risk of thromboembolic events, particularly stroke. Chronic kidney disease (CKD) is associated with a higher prevalence of AF and is an independent risk factor of increased mortality and stroke in AF patients. Left atrial appendage closure (LAAC) for stroke prevention plays an important role in the treatment of patients with AF and increased bleeding risk. The impact of CKD on outcomes after LAAC has not been deeply investigated. We assessed whether percutaneous LAAC is safe and feasible in CKD patients. Material and methods: Ninety-seven patients (mean age: 73.9 ±8.5 years) with AF and contraindications for oral anticoagulation (OAC) or complications under OAC underwent LAAC with the Amplatzer Cardiac Plug and the Amplatzer Amulet Occluder in an open-label observational single-center study. We classified patients as having normal to mild (KDOQI stage I-II) or moderate to severe (KDOQI stage III-V) CKD. Results: Patients with moderate to severe CKD (n = 49) had increased CHA2DS2-VASc and HAS-BLED scores and were at higher thromboembolic and bleeding risk (CHA2DS2-VASc: 4.08 ±0.79, HAS-BLED: 4.76 ±0.69) than patients with mild to moderate CKD (n = 48, CHA2DS2-VASc: 3.69 ±1.1, HAS-BLED: 4.06 ±0.66; p < 0.001 for both). In both groups, procedural and occlusion success was similar (97.9% vs. 95.9%; p = 0.479). Follow-up of 6 months and from 12 to 36 months revealed effective stroke prevention and no bleeding complication in both groups. Conclusions: In spite of a higher thromboembolic and bleeding risk in patients with severe CKD, LAAC is a safe and feasible option for stroke prevention.

The Development of Dyslipidemia in Chronic Kidney Disease and Associated Cardiovascular Damage, and the Protective Effects of Curcuminoids.

Chronic kidney disease (CKD) is a health problem that is constantly growing. This disease presents a diverse symptomatology that implies complex therapeutic management. One of its characteristic symptoms is dyslipidemia, which becomes a risk factor for developing cardiovascular diseases and increases the mortality of CKD patients. Various drugs, particularly those used for dyslipidemia, consumed in the course of CKD lead to side effects that delay the patient's recovery. Therefore, it is necessary to implement new therapies with natural compounds, such as curcuminoids (derived from the Curcuma longa plant), which can cushion the damage caused by the excessive use of medications. This manuscript aims to review the current evidence on the use of curcuminoids on dyslipidemia in CKD and CKD-induced cardiovascular disease (CVD). We first described oxidative stress, inflammation, fibrosis, and metabolic reprogramming as factors that induce dyslipidemia in CKD and their association with CVD development. We proposed the potential use of curcuminoids in CKD and their utilization in clinics to treat CKD-dyslipidemia.