Natural history of non-functioning pituitary microadenomas: results from the UK non-functioning pituitary adenoma consortium.

OBJECTIVE: The optimal approach to the surveillance of non-functioning pituitary microadenomas (micro-NFPAs) is not clearly established. Our aim was to generate evidence on the natural history of micro-NFPAs to support patient care. DESIGN: Multi-centre, retrospective, cohort study involving 23 endocrine departments (UK NFPA consortium). METHODS: Clinical, imaging, and hormonal data of micro-NFPA cases between January, 1, 2008 and December, 21, 2021 were analysed. RESULTS: Data for 459 patients were retrieved [median age at detection 44 years (IQR 31-57)-152 males/307 females]. Four hundred and nineteen patients had more than two magnetic resonance imagings (MRIs) [median imaging monitoring 3.5 years (IQR 1.71-6.1)]. One case developed apoplexy. Cumulative probability of micro-NFPA growth was 7.8% (95% CI, 4.9%-8.1%) and 14.5% (95% CI, 10.2%-18.8%) at 3 and 5 years, respectively, and of reduction 14.1% (95% CI, 10.4%-17.8%) and 21.3% (95% CI, 16.4%-26.2%) at 3 and 5 years, respectively. Median tumour enlargement was 2 mm (IQR 1-3) and 49% of micro-NFPAs that grew became macroadenomas (nearly all >5 mm at detection). Eight (1.9%) patients received surgery (only one had visual compromise with surgery required >3 years after micro-NFPA detection). Sex, age, and size at baseline were not predictors of enlargement/reduction. At the time of detection, 7.2%, 1.7%, and 1.5% patients had secondary hypogonadism, hypothyroidism, and hypoadrenalism, respectively. Two (0.6%) developed hypopituitarism during follow-up (after progression to macroadenoma). CONCLUSIONS: Probability of micro-NFPA growth is low, and the development of new hypopituitarism is rare. Delaying the first follow-up MRI to 3 years and avoiding hormonal re-evaluation in the absence of tumour growth or clinical manifestations is a safe approach for micro-NFPA surveillance.

Coronary Artery Calcification as a Marker for Coronary Artery Stenosis: Comparing Kidney Failure to the General Population.

RATIONALE & OBJECTIVE: The presence of calcified plaques in the coronary arteries is associated with cardiovascular mortality and is a hallmark of chronic kidney failure, but it is unclear whether this is associated with the same degree of coronary artery stenosis as in patients without kidney disease. We compared the relationship of coronary artery calcification (CAC) and stenosis between dialysis patients and patients without chronic kidney disease (CKD). STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 127 dialysis patients and 447 patients without CKD with cardiovascular risk factors underwent cardiac computed tomography (CT), consisting of non-contrast-enhanced CT and CT angiography. CAC score and degree of coronary artery stenosis were assessed by independent readers. PREDICTOR: Dialysis treatment. OUTCOME: Association between calcification and stenosis. ANALYTICAL APPROACH: Logistic regression to determine the association between CAC score and the presence of stenosis in a matched cohort and, in the full cohort, testing for the interaction of dialysis status with this relationship. RESULTS: 112 patients were matched from each cohort, totaling 224 patients, using propensity scores for dialysis, balancing numerous cardiovascular risk factors. Median CAC score was 210 (IQR, 19-859) in dialysis patients and 58 (IQR, 0-254) in patients without CKD; 35% of dialysis patients and 36% of patients without CKD had coronary artery stenosis ≥ 50%. Per each 100-unit higher CAC score, the matched dialysis cohort had significantly lower ORs for stenosis than the non-CKD cohort, 0.67 (95% CI, 0.52-0.83) for stenosis ≥ 50% and 0.75 (95% CI, 0.62-0.90) for stenosis ≥ 70%. LIMITATIONS: No comparison with the gold standard fractional flow reserve. CONCLUSIONS: Dialysis patients have higher risk for coronary artery stenosis with higher CAC scores, but this risk is comparatively lower than in patients without CKD with similar CAC scores. In dialysis patients, a high CAC score can easily be found without significant stenosis. Our data enable "translation" of degree of calcification to the probability of coronary stenosis in dialysis patients.

Progression of coronary artery calcification in conventional hemodialysis, nocturnal hemodialysis, and kidney transplantation.

INTRODUCTION: Cardiovascular disease is the leading cause of death in end-stage renal disease (ESRD) and is strongly associated with vascular calcification. An important driver of vascular calcification is high phosphate levels, but these become lower when patients initiate nocturnal hemodialysis or receive a kidney transplant. However, it is unknown whether nocturnal hemodialysis or kidney transplantation mitigate vascular calcification. Therefore, we compared progression of coronary artery calcification (CAC) between patients treated with conventional hemodialysis, nocturnal hemodialysis, and kidney transplant recipients. METHODS: We measured CAC annually up to 3 years in 114 patients with ESRD that were transplantation candidates: 32 that continued conventional hemodialysis, 34 that initiated nocturnal hemodialysis (≥4x 8 hours/week), and 48 that received a kidney transplant. We compared CAC progression between groups as the difference in square root transformed volume scores per year (ΔCAC SQRV) using linear mixed models. Reference category was conventional hemodialysis. RESULTS: The mean age of the study population was 53 ±13 years, 75 (66%) were male, and median dialysis duration was 28 (IQR 12-56) months. Median CAC score at enrollment was 171 (IQR 10-647), which did not differ significantly between treatment groups (P = 0.83). Compared to conventional hemodialysis, CAC progression was non-significantly different in nocturnal hemodialysis -0.10 (95% CI -0.77 to 0.57) and kidney transplantation -0.33 (95% CI -0.96 to 0.29) in adjusted models. CONCLUSIONS: Nocturnal hemodialysis and kidney transplantation are not associated with significantly less CAC progression compared to conventional hemodialysis during up to 3 years follow-up. Further studies are needed to confirm these findings, to determine which type of calcification is measured with CAC in end-stage renal disease, and whether that reflects cardiovascular risk.

Survival of patients treated with extended-hours haemodialysis in Europe: an analysis of the ERA-EDTA Registry.

BACKGROUND: Previous US studies have indicated that haemodialysis with ≥6-h sessions [extended-hours haemodialysis (EHD)] may improve patient survival. However, patient characteristics and treatment practices vary between the USA and Europe. We therefore investigated the effect of EHD three times weekly on survival compared with conventional haemodialysis (CHD) among European patients. METHODS: We included patients who were treated with haemodialysis between 2010 and 2017 from eight countries providing data to the European Renal Association-European Dialysis and Transplant Association Registry. Haemodialysis session duration and frequency were recorded once every year or at every change of haemodialysis prescription and were categorized into three groups: CHD (three times weekly, 3.5-4 h/treatment), EHD (three times weekly, ≥6 h/treatment) or other. In the primary analyses we attributed death to the treatment at the time of death and in secondary analyses to EHD if ever initiated. We compared mortality risk for EHD to CHD with causal inference from marginal structural models, using Cox proportional hazards models weighted for the inverse probability of treatment and censoring and adjusted for potential confounders. RESULTS: From a total of 142 460 patients, 1338 patients were ever treated with EHD (three times, 7.1 ± 0.8 h/week) and 89 819 patients were treated exclusively with CHD (three times, 3.9 ± 0.2 h/week). Crude mortality rates were 6.0 and 13.5/100 person-years. In the primary analyses, patients treated with EHD had an adjusted hazard ratio (HR) of 0.73 [95% confidence interval (CI) 0.62-0.85] compared with patients treated with CHD. When we attributed all deaths to EHD after initiation, the HR for EHD was comparable to the primary analyses [HR 0.80 (95% CI 0.71-0.90)]. CONCLUSIONS: EHD is associated with better survival in European patients treated with haemodialysis three times weekly.

Coronary Artery Calcification in Hemodialysis and Peritoneal Dialysis.

BACKGROUND: Vascular calcification is seen in most patients on dialysis and is strongly associated with cardiovascular mortality. Vascular calcification is promoted by phosphate, which generally reaches higher levels in hemodialysis than in peritoneal dialysis. However, whether vascular calcification develops less in peritoneal dialysis than in hemodialysis is currently unknown. Therefore, we compared coronary artery calcification (CAC), its progression, and calcification biomarkers between patients on hemodialysis and peritoneal dialysis. METHODS: We measured CAC in 134 patients who had been treated exclusively with hemodialysis (n = 94) or peritoneal dialysis (n = 40) and were transplantation candidates. In 57 of them (34 on hemodialysis and 23 on peritoneal dialysis), we also measured CAC progression annually up to 3 years and the inactive species of desphospho-uncarboxylated matrix Gla protein (dp-ucMGP), fetuin-A, osteoprotegerin. We compared CAC cross-sectionally with Tobit regression. CAC progression was compared in 2 ways: with linear mixed models as the difference in square root transformed volume score per year (ΔCAC SQRV) and with Tobit mixed models. We adjusted for potential confounders. RESULTS: In the cross-sectional cohort, CAC volume scores were 92 mm3 in hemodialysis and 492 mm3 in peritoneal dialysis (adjusted difference 436 mm3; 95% CI -47 to 919; p = 0.08). In the longitudinal cohort, peritoneal dialysis was associated with significantly more CAC progression defined as ΔCAC SQRV (adjusted difference 1.20; 95% CI 0.09 to 2.31; p = 0.03), but not with Tobit mixed models (adjusted difference in CAC score increase per year 106 mm3; 95% CI -140 to 352; p = 0.40). Peritoneal dialysis was associated with higher osteoprotegerin (adjusted p = 0.02) but not with dp-ucMGP or fetuin-A. CONCLUSIONS: Peritoneal dialysis is not associated with less CAC or CAC progression than hemodialysis, and perhaps with even more progression. This indicates that vascular calcification does not develop less in peritoneal dialysis than in hemodialysis.

Health-related quality of life compared between kidney transplantation and nocturnal hemodialysis.

BACKGROUND: Health-related quality of life (HRQOL) is an important outcome measure in patients with end-stage renal disease. HRQOL is assumed to improve with kidney transplantation and also with nocturnal hemodialysis compared to conventional hemodialysis. However, there is no evidence regarding HRQOL to support the optimal treatment choice for patients on nocturnal hemodialysis who hesitate opting for transplantation. We therefore compared HRQOL between patients who were treated with kidney transplantation or nocturnal hemodialysis for one year. METHODS: We assessed HQROL using the Kidney Disease Quality of Life-Short Form questionnaire in a cross-sectional sample of patients who were treated with kidney transplantation (n = 41) or nocturnal hemodialysis (n = 31) for one year. All patients on nocturnal hemodialysis were transplantation candidates. Using linear regression, we compared HRQOL between kidney transplantation and nocturnal hemodialysis, and adjusted for age, sex, dialysis duration, cardiovascular disease, and presence of residual urine production. RESULTS: At one year follow-up, mean age of the study population was 54 ±13 years, and median dialysis duration was 3.2 (IQR 2.1-5.0) years. Kidney transplantation was associated with significantly higher HRQOL on the domain "effects" compared to nocturnal hemodialysis (adjusted difference 12.0 points, 95% CI 3.9; 20.1). There were potentially clinically relevant differences between kidney transplantation and nocturnal hemodialysis on the domains "burden" (adjusted difference 11.1 points, 95% CI -2.6; 24.8), "social support" (adjusted difference 6.2, 95% CI -6.6; 19.1), and the physical composite score (adjusted difference 3.0, 95% CI -2.0; 8.1), but these were not significant. CONCLUSIONS: After kidney transplantation, HRQOL is especially higher on the domain "effects of kidney disease" compared to nocturnal hemodialysis. This can be useful when counseling patients on nocturnal hemodialysis who may opt for transplantation.

The role of kidney transplantation and phosphate binder use in vitamin K status.

BACKGROUND: Cardiovascular disease is the leading cause of death in end-stage renal disease and is strongly associated with vascular calcification. Both kidney transplantation and phosphate binders may lower the risk of vascular calcification. Vascular calcification is actively inhibited by vitamin-K-dependent matrix γ-carboxyglutamic acid protein (MGP). Whether kidney transplantation or phosphate binders affect vitamin K status is unknown. Therefore, we studied the influence of kidney transplantation and phosphate binder use on vitamin K status. METHODS: We measured plasma desphospho-uncarboxylated MGP (dp-ucMGP), a marker reflecting low vitamin K status, in a cross-sectional study of patients on hemodialysis (n = 82), peritoneal dialysis (n = 31) or who recently received a kidney transplantation (n = 36). By medication inventory, we assessed phosphate binder use. With linear regression, we assessed the influence of kidney transplantation and phosphate binder use on natural-log-transformed dp-ucMGP, adjusting for potential confounders. RESULTS: Mean age of patients was 52±13 years; 102 (68%) were male. Dp-ucMGP levels were significantly lower in kidney transplant recipients (median 689 pmol/L) compared to patients on dialysis (median 1537 pmol/L, p<0.001). Eighty-nine patients on dialysis used phosphate binders. Using any phosphate binder was not associated with dp-ucMGP levels (median 1637 pmol/L, p = 0.09) compared to no phosphate binders (median 1142 pmol/L). Twenty-six patients used sevelamer monotherapy, which was associated with higher dp-ucMGP levels (median 1740 pmol/L, p = 0.04) after adjusting for age, sex and vitamin K antagonist use. CONCLUSIONS: Recent kidney transplantation is associated with lower dp-ucMGP levels suggesting improved vitamin K status after transplantation. Sevelamer monotherapy is associated with higher dp-ucMGP levels suggesting worsening of vitamin K status. Both findings warrant more attention to vitamin K status in patients on dialysis, as vitamin K is necessary for protection against vascular calcification.

Is progression of coronary artery calcification influenced by modality of renal replacement therapy? A systematic review.

BACKGROUND: Progression of coronary artery calcification is an important marker for cardiovascular morbidity in end-stage renal disease patients. Therefore, we reviewed the evidence on coronary artery calcification progression in different renal replacement therapies. METHODS: MEDLINE (PubMed), Embase and TRIP databases were searched from 1999 - 2016. Additionally, bibliographies were searched by hand and citation tracking of key publications was performed. Prospective studies were included that examined coronary artery calcification with two or more multislice computed tomography scans ≥6 months apart in patients 18-75 years old receiving any renal replacement therapy, including kidney transplantation. Reporting of separate scores for different modalities was required. Two researchers extracted data independently with pilot-tested forms and assessed the risk of bias using a validated tool. RESULTS: We identified 29 eligible studies that assessed coronary artery calcification progression in end-stage renal disease patients, of which 19 studies evaluated haemodialysis and 8 kidney transplantation. Evidence on progression in peritoneal dialysis (three studies) and nocturnal haemodialysis (one study) was limited. Meta-analysis was not possible due to diverse reporting methods of coronary artery calcification scores and definitions of progression. Median coronary artery calcification scores were considerably higher in haemodialysis cohorts at baseline, presumably due to a generally higher age and dialysis vintage. Median coronary artery calcification progressed universally. Visual inspection suggested the least progression in kidney transplant recipients. CONCLUSIONS: There is insufficient evidence to compare the influence of renal replacement therapies on coronary artery calcification progression. We advocate the adoption of a standardized reporting method of coronary artery calcification progression.

Long-term clinical parameters after switching to nocturnal haemodialysis: a Dutch propensity-score-matched cohort study comparing patients on nocturnal haemodialysis with patients on three-times-a-week haemodialysis/haemodiafiltration.

OBJECTIVES: Nocturnal haemodialysis (NHD), characterised by 8-hour sessions ≥3 times a week, is known to improve clinical parameters in the short term compared with conventional-schedule haemodialysis (HD), generally 3×3.5-4 hours a week. We studied long-term effects of NHD and used patients on conventional HD/haemodiafiltration (HDF) as controls. DESIGN: Four-year prospective follow-up of patients who switched to NHD; we compared patients with patients on HD/HDF using propensity score matching. SETTING: 28 Dutch dialysis centres. PARTICIPANTS: We included 159 patients starting with NHD any time since 2004, aged 56.7±12.9 years, with median dialysis vintage 2.3 (0.9-5.1) years. We propensity-score matched 100 patients on NHD to 100 on HD/HDF. PRIMARY AND SECONDARY OUTCOME MEASURES: Control of hypertension (predialysis blood pressure, number of antihypertensives), phosphate (phosphate, number of phosphate binders), nutritional status and inflammation (albumin, C reactive protein and postdialysis weight) and anaemia (erythropoiesis-stimulating agent (ESA) resistance). RESULTS: Switching to NHD was associated with a non-significant reduction of antihypertensives compared with HD/HDF (OR <2 types 2.17, 95% CI 0.86 to 5.50, P=0.11); and a prolonged lower need for phosphate binders (OR <2 types 1.83, 95% CI 1.10 to 3.03, P=0.02). NHD was not associated with significant changes in blood pressure or phosphate. NHD was associated with significantly higher albumin over time compared with HD/HDF (0.70 g/L/year, 95% CI 0.10 to 1.30, P=0.02). ESA resistance decreased significantly in NHD compared with HD/HDF, resulting in a 33% lower ESA dose in the long term. CONCLUSIONS: After switching to NHD, the lower need for antihypertensives, phosphate binders and ESA persists for at least 4 years. These sustained improvements in NHD contrast significantly with the course of these parameters during continued treatment with conventional-schedule HD and HDF. NHD provides an optimal form of dialysis, also suitable for patients expected to have a long waiting time for transplantation or those convicted to indefinite dialysis.