The glomerular basement membrane (GBM) is a kind of net that remains in a state of dynamic equilibrium. Heparan sulfate proteoglycans (HSPGs) are among its most important components. There are much data indicating the significance of these proteoglycans in protecting proteins such as albumins from penetrating to the urine, although some new data indicate that loss of proteoglycans does not always lead to proteinuria. Heparanase is an enzyme which cleaves beta 1,4 D: -glucuronic bonds in sugar groups of HSPGs. Thus it is supposed that heparanase may have an important role in the pathogenesis of proteinuria. Increased heparanase expression and activity in the course of many glomerular diseases was observed. The most widely documented is the significance of heparanase in the pathogenesis of diabetic nephropathy. Moreover, heparanase acts as a signaling molecule and may influence the concentrations of active growth factors in the GBM. It is being investigated whether heparanase inhibition may cause decreased proteinuria. The heparanase inhibitor PI-88 (phosphomannopentaose sulfate) was effective as an antiproteinuric drug in an experimental model of membranous nephropathy. Nevertheless, this drug is burdened by some toxicity, so further investigations should be considered.

Background Chronic Kidney Disease—Mineral and Bone Disorder (CKD-MBD) is a common complication of CKD, associated with higher mortality in dialysis patients, while its impact in non-dialysis patients remains mostly unknown. We investigated the associations between parathyroid hormone (PTH), phosphate, and calcium (and their interactions) and all-cause, cardiovascular (CV), and non-CV mortality in older non-dialysis patients with advanced CKD. Methods We used data from the European Quality study, which includes patients aged ≥65 with eGFR ≤20 ml/min/1.73 m2 from six European countries. Sequentially adjusted Cox models were used to assess the association between baseline and time-dependent CKD-MBD biomarkers and all-cause, CV, and non-CV mortality. Effect modification between biomarkers was also assessed. Results In 1294 patients, the prevalence of CKD-MBD at baseline was 94%. Both PTH (aHR 1.12, 95%CI 1.03–1.23, p 0.01) and phosphate (aHR 1.35, 95%CI 1.00–1.84, p 0.05), but not calcium (aHR 1.11, 95%CI 0.57–2.17, p 0.76), were associated with all-cause mortality. Calcium was not independently associated with mortality, but modified the effect of phosphate, with the highest mortality risk found in patients with both hypercalcemia and hyperphosphatemia. PTH level was associated with CV mortality, but not with non-CV mortality, whereas phosphate was associated with both CV and non-CV mortality in most models. Conclusions CKD-MBD is very common in older non-dialysis patients with advanced CKD. PTH and phosphate are independently associated with all-cause mortality in this population. While PTH level is only associated with CV mortality, phosphate seems to be associated with both CV and non-CV mortality.

Background Patients with chronic kidney disease (CKD) are at a higher risk of major adverse cardiovascular events (MACE) compared to the general population, but gender differences in this risk, especially in older adults, are not fully known. We aim to identify gender differences in the risk of MACE in older European CKD patients, and explore factors which may explain these differences. Methods The European Quality study (EQUAL) is a prospective study on stage 4–5 CKD patients, ≥65 years old, not on dialysis, from Germany, Italy, the Netherlands, Poland, Sweden, and the UK. Cox regression and cumulative incidence competing risk curves were used to identify gender differences in MACE risks. Mediation analysis was used to identify variables which may explain risk differences between men and women. Results 417 men out of 1 134 (37%) and 185 women out of 602 women (31%) experienced at least one MACE, over a follow-up period of 5 years. Women had an 18% lower risk of first MACE compared to men (HR: 0.82; 95% CI: 0.69–0.97; p = 0.02), which was attenuated after adjusting for pre-existing cardiometabolic comorbidities and cardiovascular risk factors. There were no significant gender differences in the risk of recurrent MACE or fatal MACE. The risk difference in MACE by gender was larger in patients aged 65–75, compared to patients over 75. Conclusions In a cohort of older adults with advanced CKD, women had lower risks of MACE. These risk differences were partially explained by pre-existing cardiometabolic comorbidities and cardiovascular risk factors.

BACKGROUND AND AIMS In the general population, men have a higher risk of major adverse cardiovascular events (MACE) compared with women, with this risk difference between men and women decreasing with increasing age. Patients with chronic kidney disease (CKD) are at a higher risk of MACE compared with the general population, but sex differences in this group, especially older adults, are not fully known. We aim to identify differences in the risk of (recurrent) MACE by sex in CKD patients over 65 years old from Europe and explore factors that may explain these differences. METHOD The European Quality study (EQUAL study) is a prospective study on stage 4–5 CKD patients not on dialysis from Germany, Italy, Poland, Sweden, the UK and the Netherlands who were ≥ 65 years old. Cox regression and cumulative incidence competing risk curves were used to calculate MACE risks. Mediation analysis was used to identify variables that may explain risk differences between men and women. RESULTS In 1136 men and 607 women, over a follow-up period of 5 years, 417 (37%) men and 185 (31%) women experienced at least one MACE, and there was a total of 1247 MACE. Men and women had 123 (14% of total MACE in men) and 54 (14% of total MACE in women) fatal MACE, respectively. The most common type of first MACE was peripheral vascular disease for men and congestive heart failure for women (Fig. 1). Accounting for the competing risk of non-MACE death, the probability of having a first MACE was 43% (95% CI: 40–47%) for men and 39% (95% CI: 34–44%) for women (Fig. 2), corresponding with a 18% lower relative risk of first MACE in women (HR: 0.82; 95% CI: 0.69–0.97; P = 0.02 ). There was no significant difference in the risk of recurrent MACE (HR: 0.91; 95% CI: 0.80–1.03; P = 0.14 ) or fatal MACE (HR: 0.84; 95% CI: 0.61–1.16; P = 0.30) between men and women. Adjusting for pre-existing comorbidities attenuated the MACE risk difference between men and women. MACE risk differences between men and women changed according to age group but not according to diabetes status. In those ≤ 75 years, women had a 25% lower risk of first MACE (HR: 0.75; 95% CI: 0.57–0.99; P = 0.04), which was 15% in those > 75 years old (HR: 0.85; 95% CI: 0.68–1.06; P = 0.14 ). The risk difference of fatal MACE between men and women differed greatly between those ≤ 75 years old (HR: 1.38; 95% CI: 0.82–2.33; P = 0.22 ) and those > 75 years (HR: 0.61; 95% CI: 0.41–0.93; P = 0.02). CONCLUSION Men had a higher probability of having a MACE over a 5-year period. Overall, women had lower risks of MACE compared with men, but risk differences between men and women changed with increasing age. Pre-existing comorbidities explained part of this risk difference.

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