Ten-Year Outcomes in Patients Undergoing Simultaneous Coronary and Renal Angiography-Does Renal Artery Stenosis Matter?

Background: We aimed to characterize the population of consecutive patients undergoing coronary angiography with simultaneous renal artery angiography and assess prognostic factors at a 10 year follow-up. Methods: The KORONEF study was a prospective, single-center, observational, and descriptive study with 492 patients included. We analyzed several baseline demographics, clinical and periprocedural characteristics, and laboratory data, and we assessed the results of coronary angiography and renal artery angiography. Results: The study population consisted of 37.2% women, and the mean age was 64.4 ± 9.9 years (min. 30 years, max. 89 years). Angiography revealed significant renal artery stenosis (RAS) in 35 (7.1%) patients. Among patients with significant RAS (≥50%), we observed more women (57.1% vs. 35.7%, p = 0.011), and patients were older (69.1 ± 10.4 years vs. 64.0 ± 9.7 years, p = 0.005). In the whole population, all-cause death was reported in 29.9% of patients, myocardial infarction (MI) rate-in 11.8%, and stroke-in 4.9%. In the multivariable analysis, independent predictors of death were age 65-75 years (HR 2.88), age > 75 years (HR 8.07), diabetes (HR 1.59), previous MI (HR 1.64), chronic kidney disease (HR 2.22), unstable angina (HR 0.37), and left ventricular ejection fraction > 60% (HR 0.43). Conclusions: Over a 10 year follow-up, the all-cause death rate was 29.9%, showing no statistically significant differences between patients with and without significant RAS.

Ubiquitin-Specific Protease 18 in Chronic Kidney Disease-Another Emerging Biomarker to Consider?

Ubiquitin-specific protease 18 (USP18) is a protein recognized for its dual enzymatic and non-enzymatic nature. It is involved in many physiological processes like the cell cycle and cell signaling. It also suppresses heart muscle remodeling upon an increase in the afterload. The role of USP18 in kidney pathology remains unknown. The objective of the study was to assess the relationship between serum and urine USP18 levels, the factors contributing to cardiovascular risk, and the markers of kidney disease activity at different stages of chronic kidney disease (CKD). One hundred participants, aged between 24 and 85 years (mean 53.1 ± 17.1 years), were included. Five groups (n = 20 each) were recruited according to their renal status (healthy individuals, patients with proteinuric glomerulonephritis, patients with non-proteinuric CKD, patients who were treated with hemodialysis, and kidney transplant recipients). The measurements of serum and urine USP18 levels were performed using ELISA. The median serum USP18 level was the highest in healthy participants (1143.0 pg/mL) and kidney transplant recipients (856.6 pg/mL), whereas, in individuals with different forms of CKD, it fitted within the range of 402.1-471.9 pg/mL. Urinary USP18 reached the highest level in the group of CKD patients not yet on dialysis (303.3 pg/mL). Only in this group did it correlate with serum creatinine and urea concentrations. Our results suggest the inhibition of cardioprotective USP18 signaling when kidney function is impaired. Moreover, an increased level of urinary USP18 may indicate chronic tubular damage.

Prevalence and Management of Chronic Pain, Including Neuropathic Pain, in Dialysis Patients with End-Stage Renal Disease.

BACKGROUND Chronic kidney disease (CKD) is a growing global health concern. Chronic pain, as a common symptom of CKD, particularly among patients with end-stage renal disease (ESRD), is influenced by complications, dialysis procedures, and comorbidities. We aimed to evaluate chronic pain and probable neuropathic pain in 96 dialysis patients with ESRD using the Douleur Neuropathique 4 (DN4) questionnaire. MATERIAL AND METHODS A total of 96 patients from a single dialysis center were enrolled for the purpose of this study. ESRD was caused by diseases causing kidney damage, such as diabetes. The average duration of maintenance dialysis was 4.6±5.67 years. Comorbidities, functional and mental assessment, and pharmacological treatment data were collected using a questionnaire. The satisfaction with life scale was also used. Chronic pain was defined as lasting more than 3 months. The DN4 was used to determine the neuropathic component of pain. RESULTS Chronic pain was observed in 63.5% of the study participants, with 47.5% of them reporting the presence of neuropathic pain accompanied by a neuropathic component. Significantly more patients with chronic pain reported mood disorders and reduced life satisfaction, but there was no difference in their activities of daily living-assessed functional status or duration of dialysis. Patients experiencing chronic pain received non-steroidal anti-inflammatory drugs, paracetamol, and opioids. CONCLUSIONS Chronic pain, especially with a neuropathic component, is highly prevalent in patients with CKD, and its treatment remains ineffective. Undiagnosed components of pain can contribute to underdiagnosis and inadequate therapy. Further studies and staff education are needed to address this important issue.

Kidneys in heart failure: Impact of flozins.

Chronic kidney disease (CKD) and heart failure (HF) represent two modern diseases of civilization and are closely related. According to the concept of cardio-renal and reno-cardiac syndromes, most patients with CKD are affected by cardiovascular disease (CVD), and CVD (including HF) is one of the factors not only promoting progression of established CKD but also triggering its onset and development. Treatment of CVD and HF in CKD patients remains challenging since CKD patients are characterized by extremely diverse and strongly expressed risk profiles, and the data from well-designed clinical trials addressing this population are scarce. Nevertheless, it seems that most of the drugs used in the treatment of CVD and HF (including beta-blockers, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blocking agents, mineralocorticosteroid receptor antagonists, and sacubitril/valsartan) are of similar efficacy in patients with glomerular filtration rate (GFR) ranging between 45 and 60 ml/min/1.73 m² (although higher prevalence of side effects may limit their use). The data on cardiovascular (CV) drug efficacy in patients with lower GFR values (i.e. below 30-45 ml/min/1.73 m²) remain limited. In this review, we focused on the efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the treatment of CVD and HF in CKD patients with or without diabetes. SGLT2i are clearly cardioprotective in a wide spectrum of estimated GFR although the data for HF patients with respect to urine albumin-creatinine ratio (UACR) are scarce, and for those with significantly reduced estimated GFR are still not available or not convincing, even after completion of large-scale high-quality major cardiovascular outcome trials (CVOT) in type 2 diabetes mellitus (T2DM) or trials with flozins in CKD and HF.

The Role of Sclerostin in Rheumatic Diseases: A Review.

Systemic connective tissue disorders constitute a heterogenous group of autoimmune diseases with the potential to affect a range of organs. Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune inflammatory disease affecting the joints. Systemic lupus erythematosus (SLE) may manifest with multiple system involvement as a result of inflammatory response to autoantibodies. Spondyloarthropathies (SpAs) such as ankylosing spondylitis (AS) or psoriatic arthritis (PsA) are diseases characterised by the inflammation of spinal joints, paraspinal tissues, peripheral joints and enthesitis as well as inflammatory changes in many other systems and organs. Physiologically, sclerostin helps to maintain balance in bone tissue metabolism through the Wnt/ß-catenin pathway, which represents a major intracellular signalling pathway. This review article aims to present the current knowledge on the role of sclerostin in the Wnt/ß-catenin pathway and its correlation with clinical data from RA, SLE, AS and PsA patients.

Pharmacological Nephroprotection in Non-Diabetic Chronic Kidney Disease-Clinical Practice Position Statement of the Polish Society of Nephrology.

Chronic kidney disease (CKD) is a modern epidemic worldwide. Introducing renin-angiotensin system (RAS) inhibitors (i.e., ACEi or ARB) not only as blood-pressure-lowering agents, but also as nephroprotective drugs with antiproteinuric potential was a milestone in the therapy of CKD. For decades, this treatment remained the only proven strategy to slow down CKD progression. This situation changed some years ago primarily due to the introduction of drugs designed to treat diabetes that turned into nephroprotective strategies not only in diabetic kidney disease, but also in CKD unrelated to diabetes. In addition, several drugs emerged that precisely target the pathogenetic mechanisms of particular kidney diseases. Finally, the role of metabolic acidosis in CKD progression (and not only the sequelae of CKD) came to light. In this review, we aim to comprehensively discuss all relevant therapies that slow down the progression of non-diabetic kidney disease, including the lowering of blood pressure, through the nephroprotective effects of ACEi/ARB and spironolactone independent from BP lowering, as well as the role of sodium-glucose co-transporter type 2 inhibitors, acidosis correction and disease-specific treatment strategies. We also briefly address the therapies that attempt to slow down the progression of CKD, which did not confirm this effect. We are convinced that our in-depth review with practical statements on multiple aspects of treatment offered to non-diabetic CKD fills the existing gap in the available literature. We believe that it may help clinicians who take care of CKD patients in their practice. Finally, we propose the strategy that should be implemented in most non-diabetic CKD patients to prevent disease progression.

Patterns of Dickkopf-3 Serum and Urine Levels at Different Stages of Chronic Kidney Disease.

Dickkopf 3 (Dkk3) is a WNT/ß-catenin signaling pathway regulator secreted by tubular epithelial cells upon the influence of different stressors. Recently Dkk3 was described as a biomarker of tubular cell injury and a tool that may estimate the risk of chronic kidney disease (CKD) progression. The data about Dkk3 concentrations at particular stages of CKD are lacking. The aim of this study was to measure serum and urine Dkk3 levels in patients with different 'renal status' and evaluate its role as a biomarker of renal damage. One hundred individuals, aged between 24 and 85 years (mean 53.1 ± 17.1), were enrolled in the study. Five groups of 20 subjects each were recruited based on their kidney function. Serum and urine Dkk3 levels were measured by ELISA. The highest median urinary Dkk3 normalized to urinary creatinine was found in patients with established CKD (7051 pg/mg). It was two times higher in renal transplant patients (5705 pg/mg) than in healthy individuals (2654 pg/mg) and the glomerulonephritis group (2470 pg/mg). Urinary Dkk3 was associated with serum creatinine in participants with established CKD and following transplantation. Our results confirm the potential role of Dkk3 as a biomarker of an ongoing renal injury.

The influence of SGLT2 inhibitors on oxidative stress in heart failure and chronic kidney disease in patients with type 2 diabetes.

There is increasing interest in sodium-glucose cotransporter 2 inhibitors (SGLT2i) as not only a new oral glucose-lowering drug class but also one with cardio- and nephroprotective potential. Understanding the underlying mechanisms is therefore of great interest, and postulated benefits have included increased natriuresis, lower blood pressure, increased haematocrit, enhanced cardiac fatty acid utilization, reduced low-grade inflammation, and decreased oxidative stress. In particular, redox homeostasis seems to be crucial in the pathogenesis of heart and kidney disease in diabetes, and there is accumulating evidence that SGLT2i have beneficial effects in this perspective. In this review, we aimed to summarize the potential mechanisms of the influence of SGLT2i on oxidative stress parameters in animal and human studies, with a special focus on heart failure and chronic kidney disease in diabetes mellitus.

Relationship of vitamin D deficiency with cardiovascular disease and glycemic control in patients with type 2 diabetes mellitus: the Silesia Diabetes-Heart Project.

INTRODUCTION: Vitamin D (VD) has a pleiotropic effect on many health­related aspects, yet the results of studies regarding vitamin D deficiency (VDD) and both glycemic control and cardiovascular disease (CVD) are conflicting. OBJECTIVE: The aim of this work was to determine the prevalence of VDD and its associations with CVD and glycemic control among patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: This was an observational study in T2DM patients recruited at the diabetology clinic in Zabrze, Poland (April-September 2019 and April-September 2020). The presence of CVD was determined based on medical records. Blood biochemical parameters, densitometry, and carotid artery ultrasound examination were performed. Control of diabetes was assessed based on glycated hemoglobin A1c (HbA1c) levels. A serum VD level below 20 ng/ml was considered as VDD. RESULTS: The prevalence of VDD in 197 patients was 36%. CVD was evident in 27% of the patients with VDD and in 33% of the patients with VD within the normal range (vitamin D sufficiency [VDS]) (P = 0.34). The difference between the groups regarding diabetes control was insignificant (P = 0.05), as for the VDD patients the median value (interquartile range) of HbA1c was 7.5% (6.93%-7.9%), and for VDS patients it was 7.5% (6.56%-7.5%). The VDD patients were more often treated with sodium­glucose cotransporter­2 inhibitors (SGLT­2is) (44% vs 25%; P = 0.01). CONCLUSIONS: About one­third of the patients showed VDD. The VDD and VDS groups did not differ in terms of CVD occurrence and the difference in glycemic control was insignificant. The patients with VDD were more often treated with SGLT­2is, which requires further investigation.

Diabetic Peripheral Neuropathy is Associated With Diabetic Kidney Disease and Cardiovascular Disease: The Silesia Diabetes-Heart Project.

Microvascular complications of diabetes seem to be clustered and put patients at higher risk of developing cardiovascular disease (CVD). This was a questionnaire-based study designed to screen for the presence of diabetic peripheral neuropathy (DPN), defined as the score in the Michigan Neuropathy Screening Instrument (MNSI) above 2, and to evaluate its association with other complication of diabetes, including CVD. There were 184 patients included into the study. The prevalence of DPN in the study group was 37.5%. The regression model analysis revealed that the presence of DPN was significantly associated with the presence of diabetic kidney disease (DKD) (P = 0.0034;) and patient's age (P < 0.0001). Thirty-four patients (49.3%) with MNSI score >2 were diagnosed with CVD in comparison to 24 (20.1%) subjects with MNSI score ≤ 2 (P = 0.00006). In case of having one diabetes complication diagnosed, it is important to screen for others, including macrovascular ones.

A Stepwise Screening Protocol for Multiple Myeloma.

BACKGROUND: Monoclonal gammopathies and multiple myeloma should be screened in the primary care setting. METHODS: The screening strategy consisted of an initial interview supported with the analysis of basic laboratory test results and the increasing laboratory workload in the following steps was developed based on characteristics of patients with multiple myeloma. RESULTS: The developed 3-step screening protocol includes evaluation of myeloma-related bone disease, two renal function markers, and three hematologic markers. In the second step, the erythrocyte sedimentation rate (ESR) and the level of C-reactive protein (CRP) were cross-tabulated to identify persons qualifying for confirmation of the presence of monoclonal component. Patients with diagnosed monoclonal gammopathy should be referred to a specialized center to confirm the diagnosis. The screening protocol testing identified 900 patients with increased ESR and normal level of CRP and 94 of them (10.4%) had positive immunofixation. CONCLUSIONS: The proposed screening strategy resulted in an efficient diagnosis of monoclonal gammopathy. The stepwise approach rationalized the diagnostic workload and cost of screening. The protocol would support primary care physicians, standardizing the knowledge about the clinical manifestation of multiple myeloma and the method of evaluation of symptoms and diagnostic test results.

Inhibitors of sodium-glucose transport protein 2: A new multidirectional therapeutic option for heart failure patients.

Several mechanisms have been suggested to explain positive cardiovascular effects observed in studies with sodium-glucose co-transporter 2 (SGLT2) inhibitors. The reduction in glucose reabsorption in proximal tubuli induced by SGLT2 inhibitors increases urinary glucose and sodium excretion resulting in increased osmotic diuresis and consequently in decreased plasma volume, followed by reduced preload. In addition, the hemodynamic effects of SGLT2 inhibition were observed in both hyper and euglycemic patients. Due to the complex and multidirectional effects induced by SGLT2 inhibitors, this originally antidiabetic group of drugs has been successfully used to treat patients with heart failure as well as for subjects with chronic kidney disease. Moreover, their therapeutic potential seems to be even broader than the indications studied to date.

SARS-CoV-2 mRNA Vaccine-Induced Cellular and Humoral Immunity in Hemodialysis Patients.

BACKGROUND/AIMS: Chronic kidney disease CKD patients on intermittent hemodialysis IHD are exposed to SARS-CoV-2 infection and carry a risk of developing severe symptoms. The aim of this study was to evaluate the humoral and cellular immunity induced by two doses of mRNA vaccines, the Pfizer-BioNTech (Comirnaty) COVID-19 Vaccine and the Moderna (mRNA-1273) COVID-19 vaccine. PATIENTS AND METHODS: The study included 281 patients from five dialysis centers in northern Poland. Within 2 weeks prior to the first dose of the vaccine, a blood sample was collected for an evaluation of SARS-CoV-2 antibodies. Thirty to forty-five days after the second dose of the vaccine, a blood sample was taken to evaluate humoral and cellular response. RESULTS: Patients with stage 5 CKD on IHD were characterized by a considerable SARS-CoV-2 vaccine-induced seroconversion rate. The strongest factors influencing the antibodies AB level after vaccination were a pre-vaccination history of SARS-CoV-2 infection, age, the neutrophil-to-lymphocyte ratio NLR, neutrophil absolute count, and the hemoglobin level. Cellular immunity was higher in patients with a pre-vaccination history of SARS-CoV-2 infection. Cellular immunity depended on the albumin level. Positive cellular response to vaccination was a positive factor reducing all-cause mortality, except for COVID-19 mortality (no such deaths were reported during our follow-up). Cellular immunity and humoral immunity were positively mutually dependent. High levels of albumin and hemoglobin, low neutrophil count, and a reduced NLR, translated into better response to vaccination. CONCLUSIONS: Patients with stage 5 CKD on IHD were characterized by a considerable SARS-CoV-2 vaccine-induced seroconversion rate and a good rate of cellular immunity. The factors that change with exacerbating inflammation and malnutrition (albumin, hemoglobin, neutrophil count, the NLR) affected the efficacy of the vaccination.

Serum WNT4 protein as an indicator of chronic glomerulonephritis but not a marker of inflammatory cell infiltration and fibrosis: A preliminary study.

BACKGROUND: The WNT signaling pathway contributes to renal fibrosis, which is a hallmark of chronic kidney disease (CKD). Serum concentration of WNT4 could be used to monitor the kidney disease; however, no data have yet been published on the subject. OBJECTIVES: This study measures WNT4 protein in serum of CKD patients depending on the stage, type of nephropathy, the non-nephrotic (NNP) or nephrotic proteinuria (NP), inflammatory cell infiltration in kidney parenchyma (IIKP), interstitial fibrosis in biopsy and serum creatinine. We also evaluated the usefulness of the serum WNT4 as a marker of fibrosis and IIKP. MATERIAL AND METHODS: The WNT4 protein level in serum of CKD patients and healthy individuals was measured using enzyme-linked immunoassay (ELISA). Patients' blood biochemical profiles and kidney biopsies were evaluated with common laboratory methods. RESULTS: The serum level of WNT4 protein was higher in CKD patients (i) regardless of the underlying etiology and at early stages of disease; (ii) with lupus nephritis and Immunoglobulin A (IgA) nephropathy; (iii) without or with a small area of IIKP; and (iv) with a small area covered with fibrosis. No difference was observed between NNP and NP patients. The utility of serum WNT4 as a marker of IIKP and fibrosis was not confirmed. Negative correlations with total and low-density lipoprotein (LDL)-cholesterol were found in CKD and IIKP patients. In patients with serum WNT4 above the median value, serum creatinine was higher. However, no correlation between serum WNT4 and creatinine level was found. CONCLUSIONS: The observed increase in serum WNT4 protein in the early stages of CKD and in patients diagnosed with immune-mediated glomerular disease may suggest that WNT4 may act as a mediator of inflammation. A certain association with the dysregulation of serum lipid metabolism can also be suspected. Serum WNT4 protein may be considered as the indicator of chronic glomerulonephritis, but not a diagnostic marker of IIKP and fibrosis.

Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists.

The incidence of type 2 diabetes (T2D) has been increasing worldwide, and diabetic kidney disease (DKD) remains one of the leading long-term complications of T2D. Several lines of evidence indicate that glucose-lowering agents prevent the onset and progression of DKD in its early stages but are of limited efficacy in later stages of DKD. However, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor (GLP-1R) agonists were shown to exert nephroprotective effects in patients with established DKD, i.e., those who had a reduced glomerular filtration rate. These effects cannot be solely attributed to the improved metabolic control of diabetes. In our review, we attempted to discuss the interactions of both groups of agents with inflammation and oxidative stress­the key pathways contributing to organ damage in the course of diabetes. SGLT2i and GLP-1R agonists attenuate inflammation and oxidative stress in experimental in vitro and in vivo models of DKD in several ways. In addition, we have described experiments showing the same protective mechanisms as found in DKD in non-diabetic kidney injury models as well as in some tissues and organs other than the kidney. The interaction between both drug groups, inflammation and oxidative stress appears to have a universal mechanism of organ protection in diabetes and other diseases.

FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy.

Background: Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data. Methods: A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR). Results: Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters. Conclusions: Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G.

Influence of SGLT2 Inhibitor Treatment on Urine Antioxidant Status in Type 2 Diabetic Patients: A Pilot Study.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been recognized as potent antioxidant agents. Since SGLT2i are nephroprotective drugs, we aimed to examine the urine antioxidant status in patients with type 2 diabetes mellitus (T2DM). One hundred and one subjects participated in this study, including 37 T2DM patients treated with SGLT2i, 31 T2DM patients not using SGLT2i, and 33 healthy individuals serving as a control group. Total antioxidant capacity (TAC), superoxide dismutase (SOD), manganese superoxide dismutase (MnSOD), free thiol groups (R-SH, sulfhydryl groups), and catalase (CAT) activity, as well as glucose concentration, were assessed in the urine of all participants. Urine SOD and MnSOD activity were significantly higher among T2DM patients treated with SGLT2i than T2DM patients without SGLT2i treatment (p = 0.009 and p = 0.003, respectively) and to the healthy controls (p = 0.002 and p = 0.001, respectively). TAC was significantly lower in patients with T2DM treated with SGLT2i when compared to those not treated and healthy subjects (p = 0.036 and p = 0.019, respectively). It could be hypothesized that the mechanism by which SGLT2i provides nephroprotective effects involves improvement of the SOD antioxidant activity. However, lower TAC might impose higher OS (oxidative stress), and elevation of SOD activity might be a compensatory mechanism.