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Introduction: Soluble guanylate cyclase (sGC) stimulators and activators are known to enhance kidney function in various models of chronic kidney disease (CKD) by increasing cyclic guanosine monophosphate (cGMP). Their differential effects on CKD progression, particularly under conditions of oxidative stress, remain unexplored by direct comparative studies. Methods: We conducted a side-by-side comparison using 5/6 nephrectomized rats on a high salt diet (5/6Nx+HSD) to evaluate the efficacy of the sGC stimulator BAY 41-8543 and the sGC activator BAY 60-2770 in CKD progression. BAY 41-8543 (1 mg/kg; twice daily) and BAY 60-2770 (1 mg/kg; once daily) were administered by gavage for 11 weeks. Results: The 5/6Nx+HSD model led to increased plasma creatinine, proteinuria, and blood pressure. Both BAY 41-8543 and BAY 60-2770 significantly reduced systolic and diastolic blood pressure to a similar extent but did not improve renal function parameters. Notably, BAY 60-2770 reduced renal fibrosis, including interstitial fibrosis and glomerulosclerosis, whereas BAY 41-8543 did not. These antifibrotic effects of BAY 60-2770 were independent of blood pressure reduction. Proteomic analysis revealed that BAY 60-2770 corrected the upregulation of 9 proteins associated with apoptosis and fibrosis, including Caspase-3, MKK6 (Mitogen-Activated Protein Kinase Kinase 6), Prdx5 (Peroxiredoxin-5), in the 5/6Nx+HSD group. Discussion: In contrast, BAY 41-8543 had no significant impact on these proteins. sGC activators were more effective than sGC stimulators in reducing renal fibrosis in 5/6 nephrectomized rats on a high salt diet, and this effect was due to modulation of apoptosis-associated proteins beyond the control of blood pressure. [ABSTRACT FROM AUTHOR]

Aims: To assess the predictive value of estradiol (E2) related parameters on the incidence of gestational diabetes mellitus (GDM) in women undergoing fresh embryo transfer. Materials and methods: A Post-hoc analysis of a prospective cohort study. Results: We identified an optimal E2/follicle (E2/F) ratio threshold of 246.03 pg/ml on the day of human chorionic gonadotropin (hCG) administration. Women with an E2/F ratio exceeding this threshold had significantly lower rates of GDM (12.75% vs. 20.41%, P < 0.001) and ovarian hyperstimulation syndrome (OHSS) (11.75% vs. 15.48%, P = 0.03). Additional E2 parameters were also evaluated: baseline E2, E2 on hCG day, E2 increase, and E2 fold change. Lower GDM rates were observed in women with baseline E2 above 31.50 pg/ml (13.51% vs. 19.42%, P <0.01), E2 on hCG day above 3794.50 pg/ml (12.26% vs. 19.32%, P < 0.001), and E2 increase above 3771.50 pg/ml (12.24% vs. 19.28%, P < 0.001). There were no significant differences in OHSS rates for these additional E2 parameters. After adjusting for confounders, lower E2/F ratio (OR: 1.626, 95% CI: 1.229-2.150, P <0.01), E2 on hCG day (OR: 1.511, 95% CI: 1.133-2.016, P = 0.01), and E2 increase (OR: 1.522, 95% CI: 1.141-2.031, P <0.01) were identified as risk factors for GDM. Conclusion: This study demonstrates that an E2/F ratio over 246.03 pg/ml is significantly associated with a reduced risk of both GDM and OHSS in women undergoing fresh embryo transfer, highlighting the E2/F ratio as a superior predictive biomarker compared to other E2-related parameters. [ABSTRACT FROM AUTHOR]

Target values for 25-hydroxy vitamin D and 1,25(OH)2D or 1,25-dihydroxy vitamin D remain a topic of debate among clinicians. We analysed data collected from December 2012 to April 2020 from two cohorts. Cohort A, comprising 455,062 subjects, was used to investigate the relationship between inflammatory indicators (white blood cell [WBC] count and C-reactive protein [CRP]) and 25(OH)D/1,25(OH)2D. Cohort B, including 47,778 subjects, was used to investigate the connection between 25(OH)D/1,25(OH)2D and mineral metabolism markers (phosphate, calcium, and intact parathyroid hormone [iPTH]). Quadratic models fit best for all tested correlations, revealing U-shaped relationships between inflammatory indicators and 25(OH)D and 1,25(OH)2D. Minimal CRP and WBC counts were observed at 1,25(OH)2D levels of 60 pg/mL and at 25(OH)D levels of 32 ng/mL, as well as of 42 ng/mL, respectively. iPTH correlated inversely with both 1,25(OH)2D and 25(OH)D, while phosphate as well as calcium levels positively correlated with both vitamin D forms. Calcium-phosphate product increased sharply when 25(OH)D was more than 50 ng/mL, indicating a possible risk for vascular calcification. Multiple regression analyses confirmed that these correlations were independent of confounders. This study suggests target values for 25(OH)D between 30–50 ng/mL and for 1,25(OH)2D between 50–70 pg/mL, based particularly on their associations with inflammation but also with mineral metabolism markers. These findings contribute to the ongoing discussion around ideal levels of vitamin D but require support from independent studies with data on clinical endpoints. [ABSTRACT FROM AUTHOR]

Therapeutic measures aimed at optimising organ function prior to transplantation—whether by conditioning the donor after determination of brain death or by improving organ preservation after kidney removal—have the potential to enhance outcomes after transplantation. The particular advantage is that, unlike any optimised immunosuppressive therapy, a favourable effect can be achieved without side effects for the organ recipient. In recent years, several such measures have been tested in controlled clinical trials on large patient cohorts following kidney transplantation. Hypothermic pulsatile machine perfusion, in particular, has become the focus of interest, but interventions in the donor prior to organ removal, such as the administration of low-dose dopamine until the start of cold perfusion as an example of conditioning antioxidant therapy and therapeutic donor hypothermia in the intensive care unit after brain death confirmation, have also significantly reduced the frequency of dialysis after transplantation with far less effort and cost. With regard to benefits for graft survival, the database for all procedures is less clear and controversial. The aim of this review article is to re-evaluate the available clinical evidence from large multicentre controlled trials, which have also significantly influenced later meta-analyses, and to assess the significance for use in routine clinical practice. [ABSTRACT FROM AUTHOR]

Renal fibrosis is closely related to the prognosis of chronic kidney disease (CKD). The increase in cGMP reduces renal fibrosis. Soluble guanylate cyclase (sGC) and phosphodiesterase (PDE) are key enzymes that maintain cGMP levels. BAY 41–8543 (1 mg/kg/day) and/or BAY 73–6691 (1 mg/kg/day) were used to treat 5/6 nephrectomized rats for 13 weeks. 5/6 Nephrectomy caused an increase in cystatin C, proteinuria and glomerulosclerosis and renal interstitial fibrosis. Neither sGC stimulation nor PDE9 inhibition alone improved kidney function and morphology, whereas BAY 41–8543 in combination with BAY 73–6691 attenuated renal interstitial fibrosis. This beneficial effect could not be explained by alterations in blood pressure and the renal immune system. BAY 41–8543 in combination with BAY 73–6691 had no effect on renal macrophage, CD4 + T‐cell and CD8 + T‐cell in the late‐stage of 5/6 nephrectomy. RNA sequencing revealed BAY 41–8543 in combination with BAY 73–6691 down‐regulated the expression of fibrosis‐related genes such as Collagen Type I Alpha 1, Collagen Type III Alpha 1 Chain and Collagen Type XIV Alpha 1 Chain. sGC stimulator combined with PDE9 inhibitor attenuated renal fibrosis in 5/6 nephrectomized rats by down‐regulating fibrosis‐related gene expression. This novel approach of using low‐dose combination therapies to minimize side effects while maintaining therapeutic efficacy offers a promising strategy for the treatment of CKD. [ABSTRACT FROM AUTHOR]

Introduction: Cardiac implantable electrical devices are able to affect kidney function through hemodynamic improvements. The cardiac contractility modulation (CCM) is a device-based therapy option for patients with symptomatic chronic heart failure (HF) despite optimized medical treatment. The long-term cardiorenal interactions for CCM treated patients are yet to be described. Methods: CCM recipients (n = 187) from the Mannheim Cardiac Contractility Modulation Observational Study (MAINTAINED) were evaluated in the long-term (up to 60 months) for changes in serum creatinine, estimated glomerular filtration rate (eGFR), other surrogate markers of kidney function, and the chronic kidney disease (CKD) stage distribution. With regard to kidney function at baseline, the patients were furthermore grouped to either advanced CKD (aCKD, CKD stage ≥3, eGFR≤59 mL/min/1.73 m2, n = 107) or preserved kidney function and mild CKD (pCKD, CKD stages 1–2, eGFR≥60 mL/min/1.73 m2, n = 80). The groups were compared for differences regarding kidney function, New York Heart Association classification (NYHA), biventricular systolic function, HF hospitalizations and other parameters in the long-term (60 months). Results: CKD stage distribution remained stable during the entire follow-up (p = 0.65). An increase in serum creatinine (1.47 ± 1 vs. 1.6±1 mg/dL) with a corresponding decline of eGFR (58.2 ± 23.4 vs. 54.2 ± 24.4 mL/min/1.73 m2, both p < 0.05) were seen after 60 months but not before for the total cohort, which was only significant in pCKD patients in terms of group comparison. Mean survival (54.3 ± 1.3 vs. 55.3 ± 1.2 months, p = 0.53) was comparable in both groups. Improvements in NYHA (3.11 ± 0.46 vs. 2.94 ± 0.41–2.28 ± 0.8 vs. 1.94 ± 0.6) and LVEF (24.8 ± 7.1 vs. 22.9 ± 6.6–31.1 ± 11.4 vs. 35.5 ± 11.1%) were likewise similar after 60 months (both p < 0.05). The aCKD patients suffered from more HF hospitalizations and ventricular tachycardias during the entire follow-up period (both p < 0.05). Conclusions: The kidney function parameters and CKD stage distribution might remain stable in CCM treated HF patients in the long-term, who experience improvements in LVEF and functional status, regardless of their kidney function before. An impaired kidney function might be associated with further cardiovascular comorbidities and more advanced HF before CCM, and could be an additional risk factor of HF complications afterward. [ABSTRACT FROM AUTHOR]

The association of serum concentrations of minerals and phosphate with overall and cardiovascular mortality based on renal function is poorly understood. 3307 patients (average age 62.7 ± 10.6 years) in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study were grouped by estimated glomerular filtration rate (eGFR) into three categories: < 60, 60-89, and ≥ 90 mL/min per 1.73 m 2 , per KDIGO 2022 guidelines and were analysed using Cox regression. Low serum sodium and iron concentrations were associated with poor renal function and increased overall mortality risk, whereas higher serum zinc concentrations were associated with reduced overall and cardiovascular mortality risk. Elevated serum copper concentrations were associated with increased mortality risk across all eGFR categories. Comparing low and normal eGFR, we observed a fourfold increase in all-cause mortality risk for eGFR < 60 mL/min per 1.73 m 2 and a twofold increase for eGFR 60-89 mL/min per 1.73 m 2 , accompanied by changes in serum mineral concentrations. The optimal range of mineral and phosphate concentrations in serum was strongly related to renal function. To reduce mortality risk, it's important to regularly monitor serum mineral and phosphate concentrations as well as renal function, especially in cardiovascular patients with compromised renal function., Competing Interests: Declarations Competing interests Marcus E. Kleber and Winfried März are employed with SYNLAB Germany. The other authors do not report any conflict of interest. Informed consent Written informed consent was obtained from all participants involved in the study. Ethical statement The study was approved by the Ethics Committee of the “Landesärztekammer Rheinland-Pfalz” (837.255.97 (1394)) and conducted in accordance with the “Declaration of Helsinki.”, (© 2024. The Author(s).)

Aims: To investigate the prevalence of familial hypercholesterolaemia (FH) and compare the performance of clinical criteria and genetic testing in patients undergoing coronary angiography., Methods and Results: The prevalence of FH was determined with the Dutch Lipid Clinical Network (DLCN), US 'Make Early Diagnosis to Prevent Early Death' (US-MEDPED), Simon Broome (SB) criteria, the 'familial hypercholesterolaemia case ascertainment tool' (FAMCAT), and a clinical algorithm. Genetic screening was conducted with a custom array from Affymetrix (CARRENAL array) harbouring 944 FH mutations.The study cohort consisted of 3267 patients [78.6% with coronary artery disease (CAD)]. FH was diagnosed in 2.8%, 2.2%, 3.9%, and 7.9% using the DLCN, US-MEDPED, SB criteria, and the FAMCAT. The clinical algorithm identified the same patients as the SB criteria. Pathogenic FH mutations were found in 1.2% (1.2% in patients with CAD, 1.0% in patients without CAD). FH was more frequently diagnosed in younger patients. With genetic testing as reference, the clinical criteria achieved areas under the ROC curve [area under the curves (AUCs)] in the range of 0.56-0.68. Using only low-density lipoprotein cholesterol (LDL-C) corrected for statin intake, an AUC of 0.68 was achieved., Conclusion: FH is up to four-fold more prevalent in patients undergoing coronary angiography than in contemporary cohorts representing the general population. Different clinical criteria yield substantially different diagnosis rates, overestimating the prevalence of FH compared with genetic testing. LDL-C testing alone may be sufficient to raise the suspicion of FH, which then needs to be corroborated by genetic testing., Lay Summary: In this study, we investigated the frequency of familial hypercholesterolaemia-a common genetic condition leading to markedly elevated low-density lipoprotein (LDL) cholesterol and increased risk of atherosclerosis-in 3267 patients undergoing coronary angiography according to commonly used diagnostic scoring systems and genetic testing., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Soluble guanylate cyclase (sGC) stimulators and activators are known to enhance kidney function in various models of chronic kidney disease (CKD) by increasing cyclic guanosine monophosphate (cGMP). Their differential effects on CKD progression, particularly under conditions of oxidative stress, remain unexplored by direct comparative studies., Methods: We conducted a side-by-side comparison using 5/6 nephrectomized rats on a high salt diet (5/6Nx+HSD) to evaluate the efficacy of the sGC stimulator BAY 41-8543 and the sGC activator BAY 60-2770 in CKD progression. BAY 41-8543 (1 mg/kg; twice daily) and BAY 60-2770 (1 mg/kg; once daily) were administered by gavage for 11 weeks., Results: The 5/6Nx+HSD model led to increased plasma creatinine, proteinuria, and blood pressure. Both BAY 41-8543 and BAY 60-2770 significantly reduced systolic and diastolic blood pressure to a similar extent but did not improve renal function parameters. Notably, BAY 60-2770 reduced renal fibrosis, including interstitial fibrosis and glomerulosclerosis, whereas BAY 41-8543 did not. These antifibrotic effects of BAY 60-2770 were independent of blood pressure reduction. Proteomic analysis revealed that BAY 60-2770 corrected the upregulation of 9 proteins associated with apoptosis and fibrosis, including Caspase-3, MKK6 (Mitogen-Activated Protein Kinase Kinase 6), Prdx5 (Peroxiredoxin-5), in the 5/6Nx+HSD group., Discussion: In contrast, BAY 41-8543 had no significant impact on these proteins. sGC activators were more effective than sGC stimulators in reducing renal fibrosis in 5/6 nephrectomized rats on a high salt diet, and this effect was due to modulation of apoptosis-associated proteins beyond the control of blood pressure., Competing Interests: Authors DD and TK were employed by Boehringer Ingelheim Pharma GmbH & Co. KG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Xiong, Zeng, Delić, Gaballa, Kalk, Klein, Krämer and Hocher.)

Aims: To assess the predictive value of estradiol (E2) related parameters on the incidence of gestational diabetes mellitus (GDM) in women undergoing fresh embryo transfer., Materials and Methods: A Post-hoc analysis of a prospective cohort study., Results: We identified an optimal E2/follicle (E2/F) ratio threshold of 246.03 pg/ml on the day of human chorionic gonadotropin (hCG) administration. Women with an E2/F ratio exceeding this threshold had significantly lower rates of GDM (12.75% vs. 20.41%, P < 0.001) and ovarian hyperstimulation syndrome (OHSS) (11.75% vs. 15.48%, P = 0.03). Additional E2 parameters were also evaluated: baseline E2, E2 on hCG day, E2 increase, and E2 fold change. Lower GDM rates were observed in women with baseline E2 above 31.50 pg/ml (13.51% vs. 19.42%, P <0.01), E2 on hCG day above 3794.50 pg/ml (12.26% vs. 19.32%, P < 0.001), and E2 increase above 3771.50 pg/ml (12.24% vs. 19.28%, P < 0.001). There were no significant differences in OHSS rates for these additional E2 parameters. After adjusting for confounders, lower E2/F ratio (OR: 1.626, 95% CI: 1.229-2.150, P <0.01), E2 on hCG day (OR: 1.511, 95% CI: 1.133-2.016, P = 0.01), and E2 increase (OR: 1.522, 95% CI: 1.141-2.031, P <0.01) were identified as risk factors for GDM., Conclusion: This study demonstrates that an E2/F ratio over 246.03 pg/ml is significantly associated with a reduced risk of both GDM and OHSS in women undergoing fresh embryo transfer, highlighting the E2/F ratio as a superior predictive biomarker compared to other E2-related parameters., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Liu, Xu, Hu, Cai, Gong, Lin, Kalk, Krämer and Hocher.)

Systemic COVID-19 disease is associated with a variety of organ involvement in infected patients. A rarely reported complication is the induction of complement-mediated thrombotic microangiopathy (TMA). TMA is an extremely rare pathological condition that results in thrombosis in capillaries and small arterioles, due to an endothelial injury. It is often combined with thrombocytopenia, Coombs-negative hemolytic anemia, and end-organ damage. This case involves a patient who was admitted to our hospital for the purpose of diagnosis and treatment of acute kidney injury (AKIN 3) with severe proteinuria after a preceding SARS-CoV-2 infection. A 77-year-old male patient had COVID-19 pneumonia in January 2021 with the need of high-flow oxygen therapy in the intensive care unit. In March 2021, he was hospitalized again due to elevated serum creatinine levels and proteinuria. The patient exhibited normal vital parameters. A renal biopsy showed severe TMA. A diagnosis of COVID-19-associated TMA was made, and treatment with high-dose glucocorticoid therapy and plasma exchange was initiated. Additionally, therapy with eculizumab was established. Unfortunately, the kidney failure was initially progressive, so that hemodialysis (HD) was temporarily necessary. In May 2021, kidney function recovered to an estimated glomerular filtration rate of ~ 30 mL/min/1.73m 2 corresponding to chronic kidney disease stage 3bA3 - 4A3. COVID-19-associated TMA is an extremely rare disease. TMA may be a possible long-term complication with the risk of end-stage renal disease if not properly diagnosed and treated.

Introduction: Leptospirosis is a globally transmitted zoonotic disease caused by Leptospira spp., a highly mobile, obligate aerobic, spiral-shaped bacteria. Described first by Adolf Weil in 1886, leptospirosis in Germany is rare, leading to a delayed diagnosis due to diverse symptoms. Most cases are mild, but severe forms, like Weil's disease, cause life-threatening complications such as fever, jaundice, hemoptysis, and acute kidney injury (AKI). The aim of this work was to provide a literature review of leptospirosis with renal manifestation based on a case report., Case Presentation: We report the case of an 81-year-old male patient with initially unclear oliguric AKI, bilateral pulmonary infiltrates, and jaundice. After excluding common AKI causes, the expanded patient history suggested possible rat contact in his chicken coop. Finally, we serologically identified an infection with Leptospira spp. by positive IgM, proving that the illness was compatible with classical Weil's disease. The patient underwent temporary hemodialysis and antibiotic treatment with intravenous penicillin G for 2 weeks. Under therapy, the AKI, hyperbilirubinemia, and clinical condition of the patient improved. The patient was discharged after 2 weeks. In the following controls, slightly impaired kidney function was observed, indicating a progress of his chronic kidney disease (CKD)., Conclusion: Although leptospirosis is rare, there are some cases with a fulminant course. Impairment of renal function often correlates with severity of the disease requiring antibiotic treatment. In some cases, AKI progresses to CKD demonstrating the need to raise awareness for leptospirosis., (© 2024 S. Karger AG, Basel.)

Introduction: Periostin is a matricellular protein. Elevated serum concentrations of periostin have been reported in patients with various cardiovascular diseases, including heart failure. Patients with end-stage renal disease have a substantially increased risk for cardiovascular diseases. However, there is a lack of clinical studies to clarify the prognostic significance of systemic periostin on all-cause mortality in patients with end-stage renal disease on hemodialysis., Methods: 313 stable end-stage renal disease patients were recruited and followed for 5 years concerning all-cause mortality. At baseline, we collected blood samples and clinical data. Serum periostin concentrations were measured using a certified ELISA., Results: The optimal cut-off value for serum periostin regarding all-cause mortality, calculated through receiver operating characteristic analysis, was 777.5 pmol/L. Kaplan-Meier survival analysis using this cut-off value demonstrated that higher periostin concentrations are linked to higher all-cause mortality (log-rank test: p = 0.002). Subgroup analysis revealed that serum periostin concentrations only affected all-cause mortality in male but not in female patients (p = 0.002 in male patients and p = 0.474 in female patients). Multivariate Cox regression analyses, adjusted for confounding factors, likewise showed that elevated serum periostin concentrations were positively associated with all-cause mortality in male (p = 0.028) but not in female patients on hemodialysis (p = 0.313)., Conclusion: Baseline serum periostin is an independent risk factor for all-cause mortality in male patients with chronic renal disease on hemodialysis., (© 2024 The Author(s). Published by S. Karger AG, Basel.)