Effects of Tolvaptan on Oxidative Stress in ADPKD: A Molecular Biological Approach

Autosomal dominant polycystic disease (ADPKD) is the most frequent monogenic kidney disease. It causes progressive renal failure, endothelial dysfunction, and hypertension, all of which are strictly linked to oxidative stress (OxSt). Treatment with tolvaptan is known to slow the renal deterioration rate, but not all the molecular mechanisms involved in this effect are well-established. We evaluated the OxSt state in untreated ADPKD patients compared to that in tolvaptan-treated ADPKD patients and healthy subjects. OxSt was assessed in nine patients for each group in terms of mononuclear cell p22phox protein expression, NADPH oxidase key subunit, MYPT-1 phosphorylation state, marker of Rho kinase activity (Western blot) and heme oxygenase (HO)-1, induced and protective against OxSt (ELISA). p22phox protein expression was higher in untreated ADPKD patients compared to treated patients and controls: 1.42 ± 0.11 vs. 0.86 ± 0.15 d.u., p = 0.015, vs. 0.53 ± 0.11 d.u., p < 0.001, respectively. The same was observed for phosphorylated MYPT-1: 0.96 ± 0.28 vs. 0.68 ± 0.09 d.u., p = 0.013 and vs. 0.47 ± 0.13 d.u., p < 0.001, respectively, while the HO-1 expression of untreated patients was significantly lower compared to that of treated patients and controls: 5.33 ± 3.34 vs. 2.08 ± 0.79 ng/mL, p = 0.012, vs. 1.97 ± 1.22 ng/mL, p = 0.012, respectively. Tolvaptan-treated ADPKD patients have reduced OxSt levels compared to untreated patients. This effect may contribute to the slowing of renal function loss observed with tolvaptan treatment.

Risk stratification for renal deterioration in the neurogenic bladder patient: Should it be a prerequisite for patient selection in video-urodynamic studies?

Objective: The aim of this retrospective review is to determine whether risk stratification for renal deterioration in neuro-urology patients is supported by urodynamic findings in terms of bladder safety and whether urodynamic findings affect bladder management in this patient group. The primary endpoints are to determine any statistically significant differences between the high and low risk for renal deterioration groups in terms of urodynamic findings regarding bladder safety, and the frequency of changes in bladder management following video-urodynamics (VUDs). Methods: VUDs, which were performed between March 2015 and March 2021 in view of neurogenic lower urinary tract dysfunction, were included in the study. These were divided into those performed in patients with high risk and those in patients with low risk for renal deterioration categories according to criteria specified in the National Institute of Clinical Excellence (NICE) Urinary Incontinence in Neurological Disease guidelines. The two groups were then statistically compared in terms of urodynamic parameters for bladder safety and changes in management thereafter. Results: In total, 69 VUDs were included, 49.3% were classified as having been performed in high risk for renal deterioration patients, and 50.7% as low risk. 50% of those in the former group were found to have an unsafe bladder versus 31.4% in the latter group ( p = 0.12). Meanwhile, 65.2% of VUDs resulted in a change in bladder management, with no difference in change in management frequency between the two risk stratification groups ( p = 0.36). Conclusion: The lack of statistically significant difference in urodynamic bladder safety findings and change in frequency of bladder management for the low and high risk for renal deterioration categories in this cohort bring into question the need for risk stratification in the clinical decision to perform VUDs in the neurogenic bladder patient. Level of evidence: 2c

Rituximab in glomerular diseases: a case series and narrative review

Introduction: The use of Rituximab (RTX) in glomerular diseases (GD) has increased in the past years, although it is still only used in a small fraction of patients. Methods: A single center retrospective study of adult patients with membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), lupus nephritis (LN), and vasculitis treated with RTX as first or second-line therapy was conducted at our center from 2010 to 2020. Results: We identified 19 patients; 36.8% had MN and 25.0% each had FSGS, LN, and vasculitis. RTX was first-line therapy in 26.3% of patients and in 73.7% it was second-line therapy. Mean follow-up time was 7.7 ± 7.2 years. In MN, 2 patients (28.6%) had complete remission (CR), 2 patients (28.6%) had partial remission (PR), and 3 patients (42.9%) had no response (NR). In FSGS, 2 patients (50.0%) presented CR, 1 patient (25.0%) had no response, and 1 patient had renal deterioration. Two patients (50.0%) had a LN class IV with a CR after RTX, 1 patient with LN class IIIC/V had no response, and 1 patient with LN class II had renal deterioration. In vasculitis, 3 patients (75.0%) presented CR and 1 patient had PR. Infusion reactions were present in 2 patients (10.5%) and one patient had multiple infectious complications. Conclusions: The efficacy of RTX in treating different types of immune-mediated GD has been demonstrated with different response rates, but an overall safe profile. In our case series, the results are also encouraging. Longitudinal studies are needed to better understand the effect of RTX in GD.

Impact on clinical outcome of segmental vs diffuse parenchymal thinning in infants with prenatal urinary tract dilation

Objective: To determine the difference in renal function and rate of surgical intervention between neonates with diffuse and segmental parenchymal thinning. Materials and Methods: First postnatal ultrasonography images of neonates with prenatal urinary tract dilation were evaluated and measurements taken. Neonates with parenchymal thinning were categorised into segmental and diffuse parenchymal thinning groups using the medullary to intermedullary ratio. A statistical correlation of differential renal function and rate of surgical intervention between the two groups was calculated and evaluated using an independent t-test and Kaplan-Meier curve with Log-rank test, respectively. Results: Of the 20 neonates, 10 had segmental parenchymal thinning, while the other 10 had diffuse parenchymal thinning. Mean differential renal function was 49.3% in the segmental parenchymal thinning group compared to 45.8% in the diffuse group (p = 0.400). Five patients (50%) from the segmental parenchymal thinning group underwent pyeloplasty in comparison to seven patients (70%) from the diffuse group (p = 0.430) Conclusion: There were no significant differences in renal function or rate of surgical intervention between neonates with segmental parenchymal thinning and diffuse parenchymal thinning. Neonates with segmental parenchymal thinning need to be monitored as closely as those with diffuse parenchymal thinning for early detection of renal deterioration and to identify potential need for surgical intervention.

Providing Several Skills to Treat Complex Infectious Stones of Solitary Kidney in a Patient Failed to Undergo Percutaneous Nephrolithotomy: A Case Report

Conservative treatment is closely associated with renal deterioration for patients with renal staghorn stones. It is well-recognized that percutaneous nephrolithotomy (PCNL) is recommended as the first-line treatment of renal stones larger than 2 cm due to its higher stone clearance and cost-effectiveness when compared with other treatment alternatives, such as shockwave lithotripsy and flexible ureteroscopy (FURS). Besides, our findings indicated that miniaturized PCNL could be served as an alternative to PCNL with a higher stone-free rate and a lower hemorrhage risk. Despite the higher cost-effectiveness of PCNL, the management of staghorn stones are still controversial in some special situations, such as a solitary kidney. Herein, we present a case with complex infectious stones of a right-sided solitary kidney, complaining of persistent pain in the right waist. The rarity of this case is that it is difficult to encounter these cotton-like staghorn stones which are clinically resistant to holmium laser lithotripsy, and the particularity is that the patient with solitary kidney failed to undergo PCNL. We found that the combination of intermittently high-frequency oscillation and flexible ureteroscopy forceps might contribute to treat the complex infectious stones in a patient with solitary kidney. Our surgical experience might be beneficial to such patients undergoing flexible ureteroscopy in clinical practice.

Abstract 15: The Cardio-renal Effects Of Il-33 Treatment In Myocardial Infarction-induced Kidney Damage

Introduction: Interleukin (IL)-33 is a nuclear alarmin released upon tissue damage and initiating a signaling cascade by binding to its cell membrane receptor ST2. Accumulating evidence shows that the IL-33/ST2 axis mediates both inflammatory and repair responses in different models of kidney diseases, suggesting a Janus-like effect that varies within disease context and progression. This study aimed to investigate the effect of IL-33 administration on acute kidney damage at 4 and 7 days post-MI in mice. Methods: MI was induced by ligating the left anterior descending coronary artery, followed by IL-33 (1μg/day)/vehicle (PBS) treatment for 4 and 7 consecutive days. Cardiac systolic function was assessed, and kidneys were subjected to histological and molecular analysis. Results: IL-33 had no significant effect on cardiac hemodynamic parameters at 4 days but significantly decreased the left ventricular ejection fraction (20 ± 1 vs 9.8 ± 2, P<0.01) at 7 days post-MI. In the kidneys, reduced glomerular retraction (0.57 ± 0.09 vs 0.24 ± 0.06, P < 0.05) was observed at day 4 post-MI only, along with a decrease in the protein expression of αSMA (2.89 ± 0.33 vs 0.43 ± 0.13, P < 0.001) and collagen 3 (1.96 ± 0.78 vs 0.34 ± 0.14, P < 0.05). Conversely, increased protein levels of αSMA (0.86 ± 0.42 vs 21.5 ± 2.53, P < 0.0001) and collagen 3 (0.33 ± 0.08 vs 1.71 ± 0.22, P<0.01) were observed at day 7 post-MI. Total renal fibrosis increased to levels comparable to the MI vehicle group at day 4 and 7 post-MI. The mRNA expression of the apoptotic BAX/BCL2 ratio (1.05 ± 0.09 vs 0.36 ± 0.23, P < 0.05) decreased only at day 4 post-MI, whereas an increase in the mRNA levels of the DNA repair enzyme PARP-1 (1.37 ± 0.06 vs 2.05 ± 0.4, P<0.05) was observed at day 7 post-MI. A marked increase in the mRNA expression of Sirtuin 3 (1.87 ± 0.57 vs 11.72 ± 4.24, P < 0.05) and in total renal NAD levels (386.75 ± 40.52 vs 706.36 ± 66.09, P < 0.05) was observed at day 4 post-MI. Conclusion: Collectively, our findings suggest that although IL-33 treatment improves renal homeostasis 4 days post-MI, this protection is offset by day 7 post-MI through enhanced renal morphological and molecular alterations. The observed renal deterioration between day 4 and day 7 post-MI correlate with aggravated cardiac dysfunction.

Direct Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation: A Real-World Experience from a Single Spanish Regional Hospital

The aim is to evaluate a program for direct oral anticoagulants (DOACs) management in nonvalvular atrial fibrillation (NVAF) patients, according to patient profiles, appropriateness of dosing, patterns of crossover, effectiveness and safety. This is an observational and longitudinal retrospective study in a cohort of patients attended in daily clinical practice in a single regional hospital in Spain with a systematic follow-up plan for up to 3 years for patients initiating dabigatran, rivaroxaban or apixaban between JAN/2012-DEC/2016. We analyzed 490 episodes of treatment (apixaban 2.5 mg: 9.4%, apixaban 5 mg: 21.4%, dabigatran 75 mg: 0.6%, dabigatran 110 mg: 12,4%, dabigatran 150 mg: 19.8%, rivaroxaban 15 mg: 17.8% and rivaroxaban 20 mg: 18.6%) in 445 patients. 13.6% of patients on dabigatran, 9.7% on rivaroxaban, and 3.9% on apixaban, switched to other DOACs or changed dosing. Apixaban was the most frequent DOAC switched to. The most frequent reasons for switching were toxicity (23.8%), bleeding (21.4%) and renal deterioration (16.7%). Inappropriateness of dose was found in 23.8% of episodes. Patients taking apixaban 2.5 mg were older, had higher CHA2DS2VASc score and lower creatinine clearance. Patients taking dabigatran 150 mg and rivaroxaban 20 mg were younger, had lower CHA2DS2VASc and higher creatinine clearance. Rates of stroke/transient ischemic attack (TIA) were 1.64/0.54 events/100 patients-years, while rates of major, clinically relevant non-major (CRNM) bleeding and intracranial bleeding where 2.4, 5, and 0.5 events/100 patients-years. Gastrointestinal and genitourinary bleeding were the most common type of bleeding events (BE). On multivariable analysis, prior stroke (RR: 4.2; CI: 1.5-11.8; p=0.006) and age (RR: 1.2; CI: 1.1-1.4; p=0.006) were independent predictors of stroke/TIA. Concurrent platelet inhibitors (RR: 7.1; CI: 2.3-21.8; p=0.001), male gender (RR: 2.1; CI: 1.2-3.7; p=0.0012) and age (RR: 1.1; CI: 1.02-1.13; p=0.005) were independent predictors of BE. This study complements the scant data available on the use of DOACs in NVAF patients in Spain, confirming a good safety and effectiveness profile

Comment on Kobroob et al. Effectiveness of N-Acetylcysteine in the Treatment of Renal Deterioration Caused by Long-Term Exposure to Bisphenol A. Biomolecules 2021, 11, 655

Bisphenol A (BPA: 2,2-bis-(4-hydroxyphenyl)-propane) is an industrial chemical that is widely used in the production of epoxy resins and polycarbonate for food containers and plastic bottles [...]

Proton Pump Inhibitor and Tacrolimus Uses are Associated With Hypomagnesemia in Connective Tissue Disease: a Potential Link With Renal Dysfunction and Recurrent Infection

Background: Low levels of serum magnesium perturb renal tubular cell function and lymphocytes, resulting in renal deterioration and an imbalance in mononuclear cells. This study investigated the mechanism and influence of hypomagnesemia in patients with connective tissue disease.Methods: We retrospectively evaluated patients with connective tissue disease and available serum magnesium data who visited Keio University Hospital in 2019. Patients were divided into two groups: those with (serum magnesium &lt; 1.8 mg/dl) and those without hypomagnesemia; their rates of hospitalization for severe infection and cumulative renal deterioration were compared. Patients’ fractions of lymphocytes and natural killer and dendritic cell subsets, as measured by fluorescence-activated cell sorting (FACS) analysis, were also compared.Results: Among 284 patients, hypomagnesemia was detected in 63 (22.2%). Multivariate analysis revealed that the use of proton pump inhibitors [odds ratio (OR), 1.48; p = 0.01] and tacrolimus (OR, 6.14; p &lt; 0.01) was independently associated with hypomagnesemia. In addition, the renal deterioration rate was significantly higher in tacrolimus and/or proton pump inhibitor users with hypomagnesemia (p = 0.01). The hospitalization rate for severe infection was also higher in patients with hypomagnesemia (p = 0.04). FACS analysis showed lower CD8+ T cell, CD19+ B cell, natural killer cell, and dendritic cell counts in patients with hypomagnesemia (p = 0.03, p = 0.02, p = 0.02, and p = 0.03, respectively).Conclusion: The use of tacrolimus and proton pump inhibitors may be associated with hypomagnesemia and lead to poor renal outcomes and severe infection in patients with connective tissue disease.