Else van den Berg

Calcification Propensity and Survival among Renal Transplant Recipients

Calciprotein particle maturation time (T50) in serum is a novel measure of individual blood calcification propensity. To determine the clinical relevance of T50 in renal transplantation, baseline serum T50 was measured in a longitudinal cohort of 699 stable renal transplant recipients and the associations of T50 with mortality and graft failure were analyzed over a median follow-up of 3.1 years. Predictive value of T50 was assessed for patient survival with reference to traditional (Framingham) risk factors and the calcium-phosphate product. Serum magnesium, bicarbonate, albumin, and phosphate levels were the main determinants of T50, which was independent of renal function and dialysis vintage before transplant. During follow-up, 81 (12%) patients died, of which 38 (47%) died from cardiovascular causes. Furthermore, 45 (6%) patients developed graft failure. In fully adjusted models, lower T50 values were independently associated with increased all-cause mortality (hazard ratio, 1.43; 95% confidence interval, 1.11 to 1.85; P=0.006 per SD decrease) and increased cardiovascular mortality (hazard ratio, 1.55; 95% confidence interval, 1.04 to 2.29; P=0.03 per SD decrease). In addition to age, sex, and eGFR, T50 improved prognostication for all-cause mortality, whereas traditional risk factors or calcium-phosphate product did not. Lower T50 was also associated with increased graft failure risk. The associations of T50 with mortality and graft failure were confirmed in an independent replication cohort. In conclusion, reduced serum T50 was associated with increased risk of all-cause mortality, cardiovascular mortality, and graft failure and, of all tested parameters, displayed the strongest association with all-cause mortality in these transplant recipients.

Sodium intake and blood pressure in renal transplant recipients

BACKGROUNDnHypertension is common among renal transplant recipients (RTR) and a risk factor for graft failure and mortality. Sodium intake is a well-established determinant of blood pressure (BP) in the general population. However, data in RTR are limited. International guidelines recommend a maximum daily sodium intake of 70 mmol. We investigated sodium intake in RTR as compared to healthy controls and its association with BP.nnnMETHODSnWe included 660 RTR (age 53 ± 13 years, 58% male) and 201 healthy controls (age 54 ± 11 years, 46% male). Sodium intake was assessed from 24-h urine collections. The morning after completion of urine collection, BP was measured according to a strict protocol.nnnRESULTSnUrinary sodium excretion was 156 ± 62 mmol/24 h in RTR and 195 ± 75 in controls (difference: P < 0.001), and 95% of RTR had a urinary sodium excretion >70 mmol/24 h. Systolic BP (SBP) and diastolic BP (DBP) were 136 ± 18 and 82 ± 11 mmHg, respectively. Sodium intake was positively associated with SBP (β = 0.042 mmHg/mmol/24 h, P = 0.002) and DBP (β = 0.023 mmHg/mmol/24 h, P = 0.007), independent of potential confounders.nnnCONCLUSIONSnAlthough RTR had a lower sodium intake than healthy controls, their intake still exceeded current guidelines. Reduction of sodium intake to recommended amounts could reduce SBP by 4-5 mmHg. Better control of sodium intake may help to prevent graft failure and mortality due to hypertension among RTR.

Urinary Sulfur Metabolites Associate with a Favorable Cardiovascular Risk Profile and Survival Benefit in Renal Transplant Recipients

In post-transplant conditions, sulfur may be protective by intermediate conversion to hydrogen sulfide and thiosulfate. However, sulfate, the end product of sulfur-containing amino acids (SAAs), contributes to metabolic acid load and may adversely influence acid-base homeostasis. We investigated the association of urinary sulfur metabolites with cardiometabolic parameters in renal transplant recipients (RTRs) and analyzed their predictive capacity for mortality. We studied urinary sulfate and thiosulfate excretion in 24-hour urine samples from 707 RTRs at a median 5.4 years (interquartile range, 1.9 to 12.2) after transplantation as well as from 110 controls. Diet was assessed for SAA content and various risk factors were measured. Urinary sulfate was similar, whereas thiosulfate was higher in RTRs versus controls. SAA intake was lower in RTRs compared with controls and correlated with sulfate but not thiosulfate excretion. Sulfate beneficially associated with eGFR, net acid excretion, systolic BP, high-sensitivity C-reactive protein, N-terminal probrain natriuretic peptide, and proteinuria (all P≤0.01). Thiosulfate beneficially associated with eGFR, serum acidity, high-sensitivity C-reactive protein, and N-terminal probrain natriuretic peptide (all P≤0.001). During a median 27 months (interquartile range, 22-36) of follow-up, 47 RTRs died. After adjustment for age, sex, and eGFR, hazard ratios for mortality were 0.87 (95% confidence interval, 0.82 to 0.92; P<0.001) for urinary sulfate and 0.60 (95% confidence interval, 0.41 to 0.59; P=0.01) for thiosulfate. Thus, despite the association of urinary sulfate with metabolic acid load, urinary sulfate and thiosulfate beneficially associated with survival in RTRs, possibly by influencing cardiovascular parameters. Intervention studies with exogenous sulfur are warranted to elucidate mechanisms underlying these promising associations in RTRs.

Vitamin K Intake and Plasma Desphospho-Uncarboxylated Matrix Gla-Protein Levels in Kidney Transplant Recipients

Vitamin K is essential for activation of γ-carboxyglutamate (Gla)-proteins including the vascular calcification inhibitor matrix Gla-protein (MGP). Insufficient vitamin K intake leads to production of uncarboxylated, mostly inactive proteins and contributes to an increased cardiovascular risk. In kidney transplant recipients, cardiovascular risk is high but vitamin K intake and status have not been defined. We investigated dietary vitamin K intake, vascular vitamin K status and its determinants in kidney transplant recipients. We estimated vitamin K intake in a cohort of kidney transplant recipients (nu200a=u200a60) with stable renal function (creatinine clearance 61 [42–77] (median [interquartile range]) ml/min), who were 75 [35–188] months after transplantation, using three-day food records and food frequency questionnaires. Vascular vitamin K status was assessed by measuring plasma desphospho-uncarboxylated MGP (dp-ucMGP). Total vitamin K intake was below the recommended level in 50% of patients. Lower vitamin K intake was associated with less consumption of green vegetables (33 vs 40 g/d, pu200a=u200a0.06) and increased dp-ucMGP levels (621 vs 852 pmol/L, p<0.05). Accordingly, dp-ucMGP levels were elevated (>500 pmol/L) in 80% of patients. Multivariate regression identified creatinine clearance, coumarin use, body mass index, high sensitivity-CRP and sodium excretion as independent determinants of dp-ucMGP levels. In a considerable part of the kidney transplant population, vitamin K intake is too low for maximal carboxylation of vascular MGP. The high dp-ucMGP levels may result in an increased risk for arterial calcification. Whether increasing vitamin K intake may have health benefits for kidney transplant recipients should be addressed by future studies.

Dietary Acid Load and Metabolic Acidosis in Renal Transplant Recipients

BACKGROUND AND OBJECTIVESnAcidosis is prevalent among renal transplant recipients (RTRs) and adversely affects cardiometabolic processes. Factors contributing to acidosis are graft dysfunction and immunosuppressive drugs. Little is known about the potential influence of diet on acidosis in RTRs. This study examined the association of metabolic acid load with acidosis and with cardiovascular risk factors in RTRs and aimed to identify dietary factors associated with acidosis. DESIGN, PARTICIPANTS, SETTING, & MEASUREMENTS: 707 RTRs were included. Metabolic acid load was assessed by measuring 24-hour urinary net acid excretion (NAE; i.e., titratable acid + ammonium - bicarbonate). Acidosis was defined as serum [HCO(3)(-)] < 24 mmol/L. BP and insulin resistance, reflected by hemoglobin A1c, were among cardiovascular risk factors. Diet was assessed with food-frequency questionnaires. Linear regression analysis was applied to investigate association between NAE and acidosis and between dietary factors and acidosis.nnnRESULTSnMean age ± SD was 53 ± 13 years; 57% of patients were male. Acidosis was present in 31% of RTRs. NAE was associated with acidosis (serum HCO(3)(-): β=-0.61; serum pH: β=-0.010; both P<0.001). Patients with high intake of animal protein (i.e., from meat, cheese, and fish) and low intake of fruits and vegetables had significantly lower serum HCO(3)(-) and serum pH. No associations were observed between NAE and cardiovascular risk factors, such as hypertension and insulin resistance.nnnCONCLUSIONSnIn addition to conventional factors contributing to acidosis, diet might influence acid-base homeostasis in RTRs. Higher intake of fruits and vegetables and lower animal protein intake is associated with less acidosis in RTRs.

Sodium thiosulfate attenuates angiotensin II-induced hypertension, proteinuria and renal damage.

Hypertension and proteinuria are important mediators of renal damage. Despite therapeutic interventions, the number of patients with end stage renal disease steadily increases. Hydrogen sulfide (H(2)S) is an endogenously produced gasotransmitter with vasodilatory, anti-inflammatory and antioxidant properties. These beneficial characteristics make H(2)S an attractive candidate for pharmacological use in hypertensive renal disease. We investigated the protective properties of H(2)S in angiotensin II (Ang II)-induced hypertensive renal disease in rats. Treatment with the H(2)S donor NaHS and major H(2)S metabolite sodium thiosulfate (STS) during three weeks of Ang II infusion reduced hypertension, proteinuria, oxidative stress and renal functional and structural deterioration. In an ex vivo isolated perfused kidney setup, NaHS, but not STS, reduced intrarenal pressure. The effect of NaHS could partially be explained by its activation of the ATP-sensitive potassium channels. In conclusion, treatment with H(2)S attenuates Ang II-associated functional and structural renal deterioration, suggesting that intervention in H(2)S production pathways has potential therapeutic benefit and might be a valuable addition to the already existing antihypertensive and renoprotective therapies.

Kidney function and plasma copeptin levels in healthy kidney donors and autosomal dominant polycystic kidney disease patients.

BACKGROUND AND OBJECTIVESnPlasma copeptin, a marker of arginine vasopressin, is elevated in patients with autosomal dominant polycystic kidney disease and predicts disease progression. It is unknown whether elevated copeptin levels result from decreased kidney clearance or as compensation for impaired concentrating capacity. Data from patients with autosomal dominant polycystic kidney disease and healthy kidney donors before and after donation were used, because after donation, overall GFR decreases with a functionally normal kidney.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnData were obtained between October of 2008 and January of 2012 from healthy kidney donors who visited the institution for routine measurements predonation and postdonation and patients with autosomal dominant polycystic kidney disease who visited the institution for kidney function measurement. Plasma copeptin levels were measured using a sandwich immunoassay, GFR was measured as (125)I-iothalamate clearance, and urine concentrating capacity was measured as urine-to-plasma ratio of urea. In patients with autosomal dominant polycystic kidney disease, total kidney volume was measured with magnetic resonance imaging.nnnRESULTSnPatients with autosomal dominant polycystic kidney disease (n=122, age=40 years, men=56%) had significantly higher copeptin levels (median=6.8 pmol/L; interquartile range=3.4-15.7 pmol/L) compared with donors (n=134, age=52 years, men=49%) both predonation and postdonation (median=3.8 pmol/L; interquartile range=2.8-6.3 pmol/L; P<0.001; median=4.4 pmol/L; interquartile range=3.6-6.1 pmol/L; P<0.001). In donors, copeptin levels did not change after donation, despite a significant fall in GFR (from 105 ± 17 to 66 ± 10; P<0.001). Copeptin and GFR were significantly associated in patients with autosomal dominant polycystic kidney disease (β=-0.45, P<0.001) but not in donors. In patients with autosomal dominant polycystic kidney disease, GFR and total kidney volume were both associated significantly with urine-to-plasma ratio of urea (β=0.84, P<0.001; β=-0.51, P<0.001, respectively).nnnCONCLUSIONSnOn the basis of the finding in donors that kidney clearance is not a main determinant of plasma copeptin levels, it was hypothesized that, in patients with autosomal dominant polycystic kidney disease, kidney damage and associated impaired urine concentration capacity determine copeptin levels.

Plasma ADMA associates with all-cause mortality in renal transplant recipients

Asymmetric dimethylarginine (ADMA) is a key endogenous inhibitor of endothelial NO synthase that affects endothelial function, blood pressure and vascular remodeling. Increased plasma levels of ADMA are associated with worse outcome from cardiovascular disease. Due to endothelial dysfunction before and after kidney transplantation, renal transplant recipients (RTR) are at high risk for the alleged deleterious effects of ADMA. We investigated the associations of ADMA levels with all-cause mortality and graft failure in RTR. Plasma ADMA levels were determined in 686 stable outpatient RTR (57xa0% male, 53xa0±xa013xa0years), with a functioning graft for ≥1xa0year. Determinants of ADMA were evaluated with multivariate linear regression models. Associations between ADMA and mortality were assessed using multivariable Cox regression analyses. The strongest associations with plasma ADMA in the multivariable analyses were male gender, donor age, parathyroid hormone, NT-pro-BNP and use of calcium supplements. During a median follow-up of 3.1 [2.7–3.9] years, 79 (12xa0%) patients died and 45 (7xa0%) patients developed graft failure. ADMA was associated with increased all-cause mortality [HR 1.52 (95xa0% CI 1.26–1.83] per SD increase, Pxa0<xa00.001], whereby associations remained upon adjustment for confounders. ADMA was associated with graft failure [HR 1.41 (1.08–1.83) per SD increase, Pxa0=xa00.01]; however, upon addition of eGFR significance was lost. High levels of plasma ADMA are associated with increased mortality in RTR. Our findings connect disturbed NO metabolism with patient survival after kidney transplantation.

High urinary homoarginine excretion is associated with low rates of all-cause mortality and graft failure in renal transplant recipients

Renal transplant recipients (RTR) have an increased cardiovascular risk profile. Low levels of circulating homoarginine (hArg) are a novel risk factor for mortality and the progression of atherosclerosis. The kidney is known as a major source of hArg, suggesting that urinary excretion of hArg (UhArg) might be associated with mortality and graft failure in RTR. hArg was quantified by mass spectrometry in 24-h urine samples of 704 RTR (functioning graft ≥1xa0year) and 103 healthy subjects. UhArg determinants were identified with multivariable linear regression models. Associations of UhArg with all-cause mortality and graft failure were assessed using multivariable Cox regression analyses. UhArg excretion was significantly lower in RTR compared to healthy controls [1.62 (1.09–2.61) vs. 2.46 (1.65–4.06)xa0µmol/24xa0h, Pxa0<xa00.001]. In multivariable linear regression models, body surface area, diastolic blood pressure, eGFR, pre-emptive transplantation, serum albumin, albuminuria, urinary excretion of urea and uric acid and use of sirolimus were positively associated with UhArg, while donor age and serum phosphate were inversely associated (model R2xa0=xa00.43). During follow-up for 3.1 (2.7–3.9) years, 83 (12xa0%) patients died and 45 (7xa0%) developed graft failure. UhArg was inversely associated with all-cause mortality [hazard risk (HR) 0.52 (95xa0% CI 0.40–0.66), Pxa0<xa00.001] and graft failure [HR 0.58 (0.42–0.81), Pxa0=xa00.001]. These associations remained independent of potential confounders. High UhArg levels are associated with reduced all-cause mortality and graft failure in RTR. Kidney-derived hArg is likely to be of particular importance for proper maintenance of cardiovascular and renal systems.

Integrated Assessment of Pharmacological and Nutritional Cardiovascular Risk Management: Blood Pressure Control in the DIAbetes and LifEstyle Cohort Twente (DIALECT)

Cardiovascular risk management is an integral part of treatment in Type 2 Diabetes Mellitus (T2DM), and requires pharmacological as well as nutritional management. We hypothesize that a systematic assessment of both pharmacological and nutritional management can identify targets for the improvement of treatment quality. Therefore, we analysed blood pressure (BP) management in the DIAbetes and LifEstyle Cohort Twente (DIALECT). DIALECT is an observational cohort from routine diabetes care, performed at the ZGT Hospital (Almelo and Hengelo, The Netherlands). BP was measured for 15 min with one minute intervals. Sodium and potassium intake was derived from 24-hour urinary excretion. We determined the adherence to pharmacological and non-pharmacological guidelines in patients with BP on target (BP-OT) and BP not on target (BP-NOT). In total, 450 patients were included from August 2009 until January 2016. The mean age was 63 ± 9 years, and the majority was male (58%). In total, 53% had BP-OT. In those with BP-NOT, pharmacological management was suboptimal (zero to two antihypertensive drugs) in 62% of patients, and nutritional guideline adherence was suboptimal in 100% of patients (only 8% had a sodium intake on target, 66% had a potassium intake on target, 3% had a sodium-to-potassium ratio on target, and body mass index was <30 kg/m2 in 35%). These data show pharmacological undertreatment and a low adherence to nutritional guidelines. Uncontrolled BP is common in T2DM, and our data show a window of opportunity for improving BP control, especially in nutritional management. To improve treatment quality, we advocate to incorporate the integrated monitoring of nutritional management in quality improvement cycles in routine care.