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Alterations of fibroblast growth factor 23 (FGF-23) and Klotho levels are considered to be the earliest biochemical abnormality of chronic kidney disease – mineral and bone disease (CKDMBD) syndrome. Moreover, emerging data suggests that the dysregulated FGF-23 and Klotho axis has many effects on the cardiovascular (CV) system and contributes significantly to the increased CV morbidity and mortality rates of CKD patients. This review examines recent evidence on the role of FGF-23 and Klotho in the development and progression of CV complications of uremia namely cardiac hypertrophy, uremic cardiomyopathy, and atherosclerotic and arteriosclerotic vascular lesions. Moreover, the available evidence on their associations with adverse clinical outcomes are summarized. Undoubtedly, more studies are needed to further elucidate the effects of FGF-23 and Klotho on the heart and vessels and to gain insights into their prognostic value as CV risk factors. Finally, large prospective studies are required to test the hypothesis that modification of their levels would have a favourable impact on the unacceptably high mortality rates of these patient populations.

Background Sclerostin and Dickkopf-related protein-1 (Dkk-1) proteins are inhibitors of the canonical Wnt/β-catenin bone pathway. Sclerostin but not Dkk-1 is associated with increased arterial stiffness. This study examined the prognostic significance of sclerostin and Dkk-1 levels for cardiovascular outcomes and mortality in haemodialysis (HD) patients. Methods Serum sclerostin and Dkk-1 levels were measured with enzyme-linked immunosorbent assay in 80 HD patients that were followed-up for a median of 45 months. Factors that could interfere with the association of sclerostin and Dkk-1 with outcomes [including carotid–femoral pulse wave velocity (PWV), parathyroid hormone (PTH), calcium–phosphate product and others] were assessed at baseline. The primary endpoint was a combination of all-cause death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, hospitalization for decompensated heart failure and new-onset atrial fibrillation. Secondary endpoints included cardiovascular and all-cause mortality. Results Cumulative freedom from the primary endpoint was significantly lower for higher tertiles of sclerostin (77.8, 69.2 and 40.7%; Tertiles 1–3, respectively; log-rank P = 0.004). The risk for the primary outcome gradually increased for higher sclerostin tertiles [Tertile 3: hazard ratio (HR) = 3.847, 95% confidence interval (CI) 1.502–9.851]. No significant association was evident between sclerostin and all-cause mortality, whereas higher sclerostin levels presented a trend towards higher risk for cardiovascular mortality. Dkk-1 levels exhibited no association with the risk of the primary or secondary endpoints. In stepwise Cox regression modelled analysis, sclerostin levels were associated with the primary outcome, independently of PTH, calcium–phosphate product, serum albumin, C-reactive protein and PWV levels (HR = 2.921, 95% CI 1.401–6.090; P = 0.004). Conclusions High sclerostin levels are associated with lower cumulative freedom and higher risk for a composite endpoint of cardiovascular events and mortality. Dkk-1 exhibited no association with the future risk of adverse outcomes.

Background: The use of single RAS-blockade is currently the recommended first-line treatment for proteinuric diabetic or non-diabetic nephropathy, as these agents were repeatedly shown in studies with hard renal outcomes to retard the progression of renal injury. However, CKD will continue to progress on optimum single RAS-blockade, and other options to ameliorate renal injury were explored. Dual RAS-blockade was associated with an increased risk of adverse-events with no apparent benefits and, therefore, is currently abandoned. : Based on the phenomenon of aldosterone escape and the well-documented harmful effects of aldosterone on renal tissue, several randomized trials have studied the effects of a MRA in diabetic and non-diabetic nephropathy. Method: This is a review of the literature in relevance to data evaluating the effect of MRA on renal outcomes. Results: Studies with spironolactone and eplerenone added to single RAS-blockade showed that these agents are associated with greater reductions in urine albumin or protein excretion compared to either placebo or dual RASblockade. However, studies with these agents on hard renal outcomes are currently missing and the reasonable skepticism of physicians on the real-world incidence of hyperkalemia in CKD patients are limiting their use. A non-steroidal MRA, finerenone, has also great potency in decreasing albuminuria in diabetic nephropathy with possibly lower rates of hyperkalemia. Two multi-center clinical trials examining the effect of finerenone on hard cardiovascular and renal outcomes are currently ongoing. Conclusion: MRAs are able to reduce albuminuria and proteinuria on top of single RAS-blockade in patients with proteinuric CKD. Ongoing clinical trials are expected to clarify whether such an effect is accompanied by delay in CKD progression.

BACKGROUND In renal transplant patients receiving immunosuppression, a significant increase in alkaline phosphatase (ALP) might be indicative of liver or bone diseases caused by many factors. In infancy and early childhood, a transient and therefore benign increase in ALP often has been described, usually during a course of infectious disease. Rarely, transient hyperphosphatasemia occurs in adults. We herein present 2 cases of transient hyperphosphatasemia in an adolescent and an adult renal transplant recipient, respectively. CASE REPORT In the first case, a 17-year-old adolescent presented with an ALP value up to 2451 U/L, reporting no symptoms. In the second case, a 56-year-old woman with a second well-functioning kidney transplant presented with an ALP value up to 1532 U/L, without symptoms. In both cases, the biochemical profile and ultrasound study were negative for liver disease while no viral or other type of infection was detected. Bone scanning was within normal range and parathyroid hormone was also normal. However, bone ALP was measured at 8.9 and 11.9 times, respectively, above reference values. ALP electrophoresis had a characteristic pattern with involvement of both liver and bone-specific isoforms. About 6 weeks after their peak, ALP values gradually returned to normal range. CONCLUSION Benign transient hyperphosphatasemia, although rare, should be considered in the differential diagnosis of isolated ALP increase, even in adult patients with kidney transplant. Electrophoresis of ALP could narrow the diagnostic procedure in cases when neither liver nor bone disease is clinically apparent.

Background Erectile dysfunction (ED) is an under-recognized clinical entity in men with end-stage renal disease (ESRD), and studies on renal transplant recipients, patients on dialysis, and patients starting dialysis report different prevalence rates and severity of ED among these groups. Aim To determine the prevalence and severity of ED in patients with ESRD, assessed with the International Index of Erectile Function-15 and International Index of Erectile Function-5. Methods We performed a systematic review and meta-analysis of observational studies assessing the prevalence of ED in ESRD individuals. (PROSPERO ID: CRD42020182680). Records were identified by search in MEDLINE, Scopus, and CENTRAL databases and sources of gray literature until July 2020. We conducted a random-effects meta-analysis of proportions (double arcsine transformation). Outcomes We included 94 studies with 110 patient group entries and a total of 10,320 ESRD male individuals with a mean age of 48.8 ± 14.25 years. Results Overall, 7,253 patients experienced ED. We estimated an overall pooled ED prevalence of 71% (95% CI: 67–74%, I2 = 92%). In the subgroup analyses, the pooled prevalence was 59% (95% CI: 53–64%, I2 = 92%) among renal transplant recipients, 79% (95% CI: 75–82%, I2 = 86%) in patients on hemodialysis, 71% (95% CI: 58–83%, I2 = 86%) in patients on peritoneal dialysis, and 82% (95% CI: 75–88%, I2 = 0%) in patients with ESRD starting dialysis. The prevalence of the severity of ED was also estimated. Further assessment of heterogeneity was conducted via sensitivity analysis, cumulative meta-analysis, and meta-regression of significant risk factors. Clinical translation Despite its high prevalence in patients with ESRD, ED constitutes an underestimated and taboo subject in this group. Therefore, arousing clinical concern among healthcare providers involved in ESRD management is more than necessary to screen and treat ED in patients receiving renal replacement therapy. Strengths & Limitations We estimated ED solely for ESRD, included the largest number of patients compared with previous studies and estimated ED prevalence as per severity and renal replacement therapy subgroups. Contrary, because we restricted our eligibility criteria to the International Index of Erectile Function, some studies assessing ED prevalence with other validated tools were not included in this meta-analysis. Moreover, the levels of heterogeneity among studies remained high after sensitivity and meta-regression analyses, and for some moderators, the results of the meta-regression might have been underpowered. Conclusions ED is highly prevalent in patients with ESRD irrespective of the type of renal replacement therapy, thereby warranting clinical attention. Pyrgidis N, Mykoniatis I, Nigdelis MP, et al. Prevalence of Erectile Dysfunction in Patients With End-Stage Renal Disease: A Systematic Review and Meta-Analysis. J Sex Med 2021;18:113–120.

Background and Aims Arterial stiffness is associated with increased risk for target-organ damage, cardiovascular events and overall mortality in the general population, patients with diabetes mellitus and patients with chronic kidney disease (CKD) of all stages. This is the first study to evaluate in comparison arterial stiffness and arterial wave reflections in diabetic and non-diabetic patients with CKD. Method This study included 48 diabetic and 48 non-diabetic adult patients (>18 years) with CKD (eGFR: Results Office systolic and diastolic blood pressure was similar between diabetic and non-diabetic subjects with CKD in total and across CKD stages. Office brachial pulse pressure (PP) was significantly lower in non-diabetics (49.00±8.0 vs 52.67±8.7 mmHg, p= 0.034). Office PWV was marginally higher in diabetics compared with non-diabetics (10.89±2.0 vs 10.06±2.2 m/sec, p=0.056). In CKD stages 2 and 4, no significant difference in PWV between the two groups was noted, but PWV was higher for diabetics in CKD stages 3a (11.28±1.4 vs 9.83±1.5 m/sec, p=0.023) and 3b (11.13±1.9 vs 9.46±1.2 m/sec, p=0.016). Heart-rate-adjusted augmentation index [AIx(HR75)] was higher in diabetic compared with non-diabetic subjects only in CKD stage 4 (32.08±4.2 vs 25.92±6.6%, p=0.013). Conclusion Diabetic CKD patients present higher arterial stiffness than non-diabetic counterparts. The additional contribution of diabetes towards increased arterial stiffness is more prominent in patients with moderately impaired renal function (CKD stage 3a and 3b), whereas at stage 4, PWV was increased independent of diabetes presence.

Background and Aims Tregs regulate immune responses and maintain self-tolerance, while Natural Killer cells (NK) are cytotoxic lymphocytes critical for both adaptive and innate immunity. The presence of chronic kidney disease (CKD) is often characterized by disturbances in immune responses, including dysregulation between tolerance and cytotoxicity. Aim of the present study was to evaluate the influence of CKD on the Tregs (CD4+CD25+FoxP3+) and NK cells, as well as the effect of hemodialysis (HD) and peritoneal dialysis (PD) on these subtypes. Method A total of 40 CKD Stage V patients and 15 healthy volunteer subjects were recruited into our study. Peripheral Tregs and NK cells were isolated from whole blood samples using flow cytometry, and the results were compared to those of age and gender matched controls. The immunologic profile of CKD patients was repeated 6 months after HD initiation (n=20) and PD (n=20) in order to investigate the effect of different dialysis methods. Results Patients with CKD had significantly reduced populations of CD4+CD25+ FoxP3+ Tregs (47.5± 28.8 vs 71.5±24.7) p=0.01, while there was no difference in NK cells between patients and controls (16.4±8.1% vs. 13.4±9.1%), p=NS, respectively. There were no differences between patients started on HD or PD in terms of clinical and laboratory parameters. Frequencies and total numbers of Tregs were significantly reduced after 6 months of HD, from 7.6±2.1% to 5.2±2.3%, p=0.009, and from 53.6±26K/μL to 36.9±19K/μL, p=0.02, respectively, while showed no differences on PD patients, from 5.3±3.3% to 5.6±2%, p=NS and 33.2±27K/μL to 45.6±28K/μL, p=NS, respectively. NK cells were increased in HD patients, not reaching statistical significance (245±156K/μL to 261±128K/μL). Frequencies of NK cells were positively correlated with CRP (r=0.56, p=0.009) and Intimal media thickness (IMT) (r=0.48, p=0.03) Conclusion The results of our study show that initiation of hemodialysis (HD) seems to reduce the expression of CD4+CD25+FoxP3+ T cells while peritoneal dialysis (PD) doesn’t seem affect this cell population. The immune alterations observed in hemodialysis patients may have a clinical impact on chronic inflammation and atheromatosis.

Background and Aims Sclerostin and Dickkopf-1 (Dkk-1) protein are inhibitors of the canonical Wnt/β-catenin bone pathway. Sclerostin but not Dkk-1 is associated with increased arterial stiffness. This study examined the prognostic significance of serum sclerostin and Dickkopf-related protein-1 (Dkk-1) levels for cardiovascular outcomes and mortality in hemodialysis patients. Method Serum sclerostin and Dkk-1 levels were measured with ELISA in 80 hemodialysis patients that were followed-up for a median of 45 months. Several factors that could interfere in the association of sclerostin and Dkk-1 with outcomes (including carotid-femoral pulse-wave-velocity (PWV), parathyroid hormone, calcium-phospate product and others) were assessed at baseline The primary end-point was a combination of all-cause death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, hospitalization for decompensated heart failure and new-onset atrial fibrillation. Secondary end-points included cardiovascular and all-cause mortality. Results Cumulative freedom from the primary endpoint was significantly lower for higher tertiles of sclerostin (77.8%, 69.2%, and 40.7% for tertiles 1 to 3 respectively; log-rank-p=0.004). The corresponding risk for the primary outcome was gradually increasing for higher tertiles of sclerostin (Tertile 3: HR: 3.847, 95%CI: 1.502-9.851). No significant association was evident between sclerostin and all-cause mortality, whereas higher sclerostin levels presented a trend towards higher risk for cardiovascular mortality. Dkk-1 levels exhibited no association with the risk of the primary or the secondary endpoints. In stepwise Cox regression modeled analysis, sclerostin levels were associated with the primary outcome, independently of PTH, calcium-phosphate product, serum albumin, CRP and PWV levels (HR: 2.921, 95%CI: 1.401–6.090; p=0.004). Conclusion High serum sclerostin levels are associated with lower cumulative freedom and higher risk for a composite cardiovascular endpoint but not for all-cause mortality. Dkk-1 protein exhibited no association with the future risk of cardiovascular events.

Background and Aims Αlterations in endothelial function and capillary circulation have been associated with increased cardiovascular events and overall mortality. Both diabetes mellitus (DM) and chronic kidney disease (CKD) have been associated with microcirculatory damage. Nailfold video-capillaroscory can provide a thorough assessment of capillary density and microcirculation changes. This is the first study examining in comparison microcirculatory function parameters in diabetic and non-diabetic patients with CKD. Method We included 48 diabetic and 48 non-diabetic adult patients (>18 years) with CKD (eGFR: Results Baseline demographic, anthropometric and laboratory characteristics were similar between patients with and without diabetes in total and in CKD stages. Overall, no significant differences at baseline capillary density were observed between groups; however diabetic patients presented significantly lower capillary density during reactive hyperemia (36.3±3.8 vs 38.3±4.3 capillaries/mm2, p=0.022) and at venous congestion (37.8±4.0 vs 39.8±4.2 capillaries/mm2, p=0.015). When stratified according to CKD stages, the between-group differences in parameters of interest were not significant in stages 2, 3a and 4. In stage 3b, capillary density was significantly lower in diabetic compared to non-diabetic subjects at baseline (31.1±2.8 vs 33.4±3.4 capillaries/mm2, p=0.044), during postocclusive hyperemia (36.8±2.7 vs 40.0±4.3 capillaries/mm2, p=0.037) and venous congestion (38.3±2.8 vs 41.5±3.5 capillaries/mm2, p=0.022). Conclusion Capillary density during postocclusive reactive hyperemia and after venous congestion is lower in diabetic compared to non-diabetic CKD patients, a finding indicative that diabetes is an additional factor contributing to microcirculatory functional impairment in CKD. These differences are more prominent in CKD stage 3b, and less prominent in earlier and later stages.

Cardiovascular disease is the main cause of mortality in chronic kidney disease (CKD). Endothelial dysfunction and capillary rarefaction are established cardiovascular risk factors. Nailfold video capillaroscopy provides a thorough assessment of capillary density and functional reserve. This study aimed to examine possible differences in structural and functional capillary density in CKD stages 2–4 with nailfold video capillaroscopy. Ninety-six CKD patients, divided into four equally sized groups according to CKD stage (2, 3a, 3b, 4), underwent nailfold video capillaroscopy, during which capillary density was measured at baseline, after 4-min arterial occlusion and after 2-min venous occlusion. Arterial stiffness and wave parameters were measured with applanation tonometry and common carotid intima-media thickness (ccIMT) with ultrasound. Baseline capillary density showed a progressive reduction with advancing CKD stages (stage 2: 32.6 ± 2.8, stage 3a: 31.2 ± 3.8, stage 3b: 32.5 ± 3.3, stage 4: 28.5 ± 3.1, p = 0.011). Similar reductions were observed during postocclusive hyperemia (39.4 ± 3.0, 37.6 ± 4.2, 38.4 ± 3.8, and 33.8 ± 3.3, respectively; p = 0.021) and after venous congestion (41.1 ± 3.1, 39.0 ± 4.4, 39.9 ± 3.5, and 35.2 ± 3.4; p = 0.032). Office PWV and ccIMT showed nonsignificant increasing trends with advancing CKD. In multivariate analysis, eGFR showed a positive association (per ml/min increase; β: 0.053, 95% CI: 0.004–0.101), whereas diabetes (β: −1.706, 95% CI: −3.176 to −0.236) and parathyroid hormone (PTH) (per pg/ml increase; β: −0.022, 95% CI: −0.036 to −0.008) had negative associations with postocclusive capillary density. Both structural and functional capillary density progressively decrease with advancing CKD stages. Apart from reduced eGFR, diabetes and increased PTH levels are independently associated with this reduction. This capillary rarefaction may largely contribute to the increased cardiovascular risk of CKD patients.

Background There is lack of evidence-based optimization of the protocol for low-intensity shockwave therapy for erectile dysfunction. Furthermore, the safety and efficacy of repeating shockwave therapy have not been explored. Aim To compare the efficacy and safety of 6 and 12 treatment sessions within a 6-week treatment period and investigate the effect of repeat treatment after a 6-month period in a 2-phase study. Methods Patients with vasculogenic erectile dysfunction that responded to phosphodiesterase type 5 inhibitors were randomized into 2 groups: low-intensity shockwave therapy sessions once (group A, n = 21) or twice (group B, n = 21) per week for 6 consecutive weeks (phase 1). Patients who completed 6-month follow-up were offered 6 additional sessions (phase 2); group A received 2 sessions per week and group B received 1 session per week. Patients were followed for 6 months. Outcomes International Index for Erectile Function erectile function domain (IIEF-EF) score, minimally clinical important differences (MCIDs), Sexual Encounter Profile question 3 (SEP3) score, and triplex ultrasonographic parameters. Results In phase 1, groups A and B showed improvement in IIEF-EF score, MCID, SEP3 score, and mean peak systolic velocity compared with baseline. MCIDs were achieved in 62% of group A and 71% of group B, and the percentage of yes responses to SEP3 was 47% in group A and 65% in group B (P = .02). Mean peak systolic velocity at baseline and at 3-month follow-up were 29.5 and 33.4 cm/s for group A and 29.6 and 35.4 cm/s for group B (P = .06). In phase 2, group A showed a greater increase in the percentage of yes responses to SEP3 (group A = +14.9; group B = +0.3). When the impact of the total number of sessions received was examined, MCIDs in IIEF-EF score from baseline were achieved in 62%, 74%, and 83% of patients after 6, 12, and 18 sessions, respectively. No treatment-related side effects were reported. Clinical Implications The total number of low-intensity shockwave therapy sessions affects the efficacy of erectile dysfunction treatment. Retreating patients after 6 months could further improve erectile function without side effects. 12 sessions can be delivered within 6 weeks without a 3-week break period. Strengths and Limitations This study lacked a sham-controlled arm. However, all patients were randomized to different groups, and baseline characteristics were similar between groups. Also, all patients were confirmed by triplex ultrasonography to have arterial insufficiency. Conclusion Patients can benefit more in sexual performance from 12 sessions twice per week compared with 6 sessions once a week. Shockwave therapy can be repeated up to a total of 18 sessions.

Background: Short-term blood pressure (BP) variability (BPV) is associated with increased cardiovascular risk in hemodialysis. Patients with intradialytic hypertension have high risk of adverse outcomes. Whether BPV is increased in these patients is not clear. The purpose of this study was to compare short-term BPV in patients with and without intradialytic hypertension. Methods: Forty-one patients with and 82 patients without intradialytic hypertension (intradialytic SBP rise ≥10 mm Hg to > 150 mm Hg) matched in a 1: 2 ratio for age, sex, and hemodialysis vintage were included. All subjects underwent 48-h ambulatory BP monitoring during a regular hemodialysis and the subsequent interdialytic interval. Brachial and aortic BPV were calculated with validated formulas and compared between the 2 groups during the 48-h and the 44-h periods and during the 2 daytime and nighttime periods respectively. Results: During 48-h or 44-h periods and daytime or nighttime, brachial SBP/DBP and aortic SBP/DBP were significantly higher in cases than in controls. All brachial SBP/DBP BPV indexes [SD, weighted SD (wSD), coefficient-of-variation (CV) and average-real-variability (ARV)] were not significantly different between groups during the 48- or 44-h periods (48-h: SBP-ARV 11.59 ± 3.05 vs. 11.70 ± 2.68, p = 0.844, DBP-ARV: 8.60 ± 1.90 vs. 8.90 ± 1.63, p = 0.357). Analysis stratified by day or night between days 1 and 2 revealed, in general, similar results. No significant differences in dipping pattern were observed between groups. Analysis of aortic BPV had similar findings. Conclusions: BPV is similar between those with and without intradialytic hypertension. However, those with intradialytic hypertension have a sustained increase in systolic and diastolic BP during the entire interdialytic interval.

Objective:Short-term BP variability (BPV) is associated with increased cardiovascular risk in hemodialysis. Patients with intradialytic hypertension have high risk of adverse outcomes and increased BPV may be an involved mechanism. This is the first study comparing short-term BPV in patients with an

The impact of energy flux density (EFD) used on low-intensity shockwave therapy (LiST) for erectile dysfunction (ED) has not been explored. Our aim was to compare EFD 0.05 versus 0.10 mJ/mm2 regarding efficacy and safety of 12-treatment sessions when applied two or three times per week. Ninety-seven patients with vasculogenic ED, PDE5 inhibitors users were randomized into four groups, to receive 12 LiST sessions. Group A (n = 24) : two sessions per week, EFD 0.05 mJ/mm2; Group B (n = 24): three sessions per week, EFD 0.05 mJ/mm2; Group C (n = 24): two sessions per week, EFD 0.10 mJ/mm2; Group D (n = 25): three sessions per week, EFD 0.10 mJ/mm2. International Index for Erectile Function—Erectile Function domain (IIEF-EF), Minimally clinical important differences (MCID), sexual encounter profile, and triplex ultrasonography parameters were used to asses erectile function. Eighty-nine patients completed the 6-month follow-up (FU). All four groups improved in mean IIEF-EF score, average SEP3 “Yes” response rates at 6-month FU visit compared with baseline (p