Lyanne M. Kieneker

Urinary Potassium Excretion and Risk of Developing Hypertension The Prevention of Renal and Vascular End-Stage Disease Study

Previous prospective cohort studies on the association between potassium intake and risk of hypertension have almost exclusively relied on self-reported dietary data, whereas repeated 24-hour urine excretions, as estimate of dietary uptake, may provide a more objective and quantitative estimate of this association. Risk of hypertension (defined as blood pressure ≥140/90 mm Hg or initiation of blood pressure–lowering drugs) was prospectively studied in 5511 normotensive subjects aged 28 to 75 years not using blood pressure–lowering drugs at baseline of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Potassium excretion was measured in two 24-hour urine specimens at baseline (1997–1998) and midway during follow-up (2001–2003). Baseline median potassium excretion was 70 mmol/24 h (interquartile range, 57–85 mmol/24 h), which corresponds to a dietary potassium intake of ≈91 mmol/24 h. During a median follow-up of 7.6 years (interquartile range, 5.0–9.3 years), 1172 subjects developed hypertension. The lowest sex-specific tertile of potassium excretion (men: <68 mmol/24 h; women: <58 mmol/24 h) had an increased risk of hypertension after multivariable adjustment (hazard ratio, 1.20; 95% confidence interval, 1.05–1.37), compared with the upper 2 tertiles ( P nonlinearity=0.008). The proportion of hypertension attributable to low potassium excretion was 6.2% (95% confidence interval, 1.7%–10.9%). No association was found between the sodium to potassium excretion ratio and risk of hypertension after multivariable adjustment. Low urinary potassium excretion was associated with an increased risk of developing hypertension. Dietary strategies to increase potassium intake to the recommended level of 90 mmol/d may have the potential to reduce the incidence of hypertension. # Novelty and Significance {#article-title-43}Previous prospective cohort studies on the association between potassium intake and risk of hypertension have almost exclusively relied on self-reported dietary data, whereas repeated 24-hour urine excretions, as estimate of dietary uptake, may provide a more objective and quantitative estimate of this association. Risk of hypertension (defined as blood pressure ≥140/90 mm Hg or initiation of blood pressure–lowering drugs) was prospectively studied in 5511 normotensive subjects aged 28 to 75 years not using blood pressure–lowering drugs at baseline of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Potassium excretion was measured in two 24-hour urine specimens at baseline (1997–1998) and midway during follow-up (2001–2003). Baseline median potassium excretion was 70 mmol/24 h (interquartile range, 57–85 mmol/24 h), which corresponds to a dietary potassium intake of ≈91 mmol/24 h. During a median follow-up of 7.6 years (interquartile range, 5.0–9.3 years), 1172 subjects developed hypertension. The lowest sex-specific tertile of potassium excretion (men: <68 mmol/24 h; women: <58 mmol/24 h) had an increased risk of hypertension after multivariable adjustment (hazard ratio, 1.20; 95% confidence interval, 1.05–1.37), compared with the upper 2 tertiles (Pnonlinearity=0.008). The proportion of hypertension attributable to low potassium excretion was 6.2% (95% confidence interval, 1.7%–10.9%). No association was found between the sodium to potassium excretion ratio and risk of hypertension after multivariable adjustment. Low urinary potassium excretion was associated with an increased risk of developing hypertension. Dietary strategies to increase potassium intake to the recommended level of 90 mmol/d may have the potential to reduce the incidence of hypertension.

Low potassium excretion but not high sodium excretion is associated with increased risk of developing chronic kidney disease

It is unclear whether sodium and potassium intake is relevant to the development of chronic kidney disease (CKD) in the general population. Our aim was to examine the associations of urinary sodium (UNaV) and potassium excretion (UKV), as estimates of intake, with risk of developing CKD in a population-based cohort. We studied 5315 individuals free of CKD at baseline of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women aged 28 to 75 years. UNaV and UKV were measured in two 24-hour urine specimens at baseline (1997-1998) and midway during follow-up (2001-2003). CKD was defined as de novo development of eGFR under 60 ml/min per 1.73 m(2) or albuminuria over 30 mg/24 hours, or both. Baseline UNaV and UKV were 135 mmol/24 hours (interquartile range: 106-169 mmol/24 hours) and 70 mmol/24 hours (interquartile range, 57-85 mmol/24 hours), respectively. During a median follow-up of 10.3 years, 872 patients developed CKD. After multivariable adjustment for important covariables, no association was observed between UNaV and risk of CKD (hazard ratio per 50 mmol/24 hours [1 SD] increment, 0.97; 95% confidence interval, 0.89-1.06). Each 21 mmol/24 hours (1 SD) decrement in UKV was significantly associated with a 16% higher risk of developing CKD (multivariable-adjusted hazard ratio, 1.16; 95% confidence interval, 1.06-1.28). Thus, low UKV, and not high UNaV, was associated with an increased risk of developing CKD in a population-based cohort with normal kidney function.

Urinary potassium excretion and risk of cardiovascular events

BACKGROUND Observational studies on dietary potassium and risk of cardiovascular disease (CVD) have reported weak-to-modest inverse associations. Long-term prospective studies with multiple 24-h urinary samples for accurate estimation of habitual potassium intake, however, are scarce. OBJECTIVE We examined the association between urinary potassium excretion and risk of blood pressure-related cardiovascular outcomes. DESIGN We studied 7795 subjects free of cardiovascular events at baseline in the Prevention of Renal and Vascular End-stage Disease study, a prospective, observational cohort with oversampling of subjects with albuminuria at baseline. Main cardiovascular outcomes were CVD [including ischemic heart disease (IHD), stroke, and vascular interventions], IHD, stroke, and new-onset heart failure (HF). Potassium excretion was measured in two 24-h urine specimens at the start of the study (1997-1998) and midway through follow-up (2001-2003). RESULTS Baseline median urinary potassium excretion was 70 mmol/24 h (IQR: 56-84 mmol/24 h). During a median follow-up of 10.5 y (IQR: 9.9-10.8 y), a total of 641 CVD, 465 IHD, 172 stroke, and 265 HF events occurred. After adjustment for age and sex, inverse associations were observed between potassium excretion and risk [HR per each 26-mmol/24-h (1-g/d) increase; 95% CI] of CVD (0.87; 0.78, 0.97) and IHD (0.86; 0.75, 0.97), as well as nonsignificant inverse associations for risk of stroke (0.85; 0.68, 1.06) and HF (0.94; 0.80, 1.10). After further adjustment for body mass index, smoking, alcohol consumption, education, and urinary sodium and magnesium excretion, urinary potassium excretion was not statistically significantly associated with risk (multivariable-adjusted HR per 1-g/d increment; 95% CI) of CVD (0.96; 0.85, 1.09), IHD (0.90; 0.81, 1.04), stroke (1.09; 0.86, 1.39), or HF (0.99; 0.83, 1.18). No associations were observed between the sodium-to-potassium excretion ratio and risk of CVD, IHD, stroke, or HF. CONCLUSION In this cohort with oversampling of subjects with albuminuria at baseline, urinary potassium excretion was not independently associated with a lower risk of cardiovascular events.

Incident type 2 diabetes is associated with HDL, but not with its anti-oxidant constituent - paraoxonase-1: The prospective cohort PREVEND study

OBJECTIVE High-density lipoprotein cholesterol (HDL-C) is an established risk marker for cardiovascular disease and consistently associated with type 2 diabetes risk. Serum paraoxonase-1 (PON-1) - an anti-oxidant constituent of HDL - is inversely associated with cardiovascular disease risk, but its relationship with incident type 2 diabetes is uncertain. We aimed to investigate the prospective association between PON-1 and type 2 diabetes risk. METHODS PON-1 was measured as its arylesterase activity at baseline in the Prevention of Renal and Vascular End-stage Disease (PREVEND) prospective study of 5947 predominantly Caucasian participants aged 28-75years with no pre-existing diabetes, that recorded 500 type 2 diabetes cases during a median follow-up of 11.2years. RESULTS Serum PON-1 was positively correlated with HDL-C (r=0.17; P<0.001). In analyses adjusted for conventional diabetes risk factors, the hazard ratio (95% CI) for type 2 diabetes per 1 standard deviation increase in PON-1 was 1.07 (0.98 to 1.18; P=0.13), which remained non-significant (1.02 (0.93 to 1.12) P=0.65) after additional adjustment for potential confounders. The association was unchanged on further adjustment for HDL-C (1.05 (0.96 to 1.15; P=0.29). However, in subsidiary analyses in the same set of participants, serum HDL-C concentration was inversely and independently associated with risk of type 2 diabetes. CONCLUSIONS Incident type 2 diabetes is associated with HDL cholesterol but not with its anti-oxidant constituent - PON-1 - in a large cohort of apparently healthy men and women. The current data question the importance of PON-1 activity for the development of diabetes.

Plasma Proenkephalin and Poor Long-Term Outcome in Renal Transplant Recipients

Background Proenkephalin (pro-ENK), a stable and reliable surrogate marker for unstable enkephalins, was found to be associated with acute kidney injury and chronic renal failure in previous studies. We aimed to investigate whether pro-ENK is linked to chronic kidney injury and poor long-term outcome in renal transplant recipients (RTR). Methods We included 664 stable RTR and 95 healthy kidney donors. Pro-ENK was measured in plasma with a double monoclonal sandwich immunoassay. Graft failure was defined as return to dialysis therapy or retransplantation. Results Median pro-ENK was 110 pmol/L (interquartile range [IQR], 85-148 pmol/L) in RTR and 48 pmol/L (IQR, 42-55 pmol/L) in kidney donors. Pro-ENK was correlated with estimated glomerular filtration rate (GFR) (rs = −0.80, P < 0.001) in RTR and with measured GFR (rs = −0.74, P < 0.001) in kidney donors. During a median follow-up of 3.1 years (IQR, 2.7-3.9 years), 45 RTR developed graft failure and 76 died. Pro-ENK was positively associated with risk (hazard ratio [HR] per standard deviation increment of the logarithm of pro-ENK; 95% confidence interval [CI]) of graft failure (HR, 4.80; 95% CI, 3.55-6.48) and mortality (HR, 1.50; 95% CI, 1.22-1.85). After adjustment of age, sex, and estimated GFR, the association of pro-ENK with graft failure remained significant (HR, 2.36; 95% CI, 1.37-4.06), whereas no significant association of pro-ENK with risk of all-cause mortality was observed (HR, 1.34; 95% CI, 0.90-2.09). Conclusions Plasma pro-ENK is associated with kidney function as reflected by correlations with measured GFR in both RTR and kidney donors. In addition, pro-ENK was independently associated with increased risk of graft failure in RTR. Pro-ENK may aid in identification of RTR at risk for late graft failure.

Plasma potassium, diuretic use and risk of developing chronic kidney disease in a predominantly White population

Objective Both hypokalemia and hyperkalemia are associated with disease progression in patients with chronic kidney disease (CKD). It is unclear whether similar associations are present in the general population. Our aim was to examine the association of plasma potassium with risk of developing CKD and the role of diuretics in this association in a population-based cohort. Research design and methods We studied 5,130 subjects free of CKD at baseline of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women aged 28–75 years. Hypokalemia was defined as plasma potassium <3.5 mmol/L, and hyperkalemia as plasma potassium ≥5.0 mmol/L. Risk of CKD was defined as de novo development of eGFR <60 ml/min/1.73m2 and/or albuminuria >30 mg/24h. Results Mean baseline plasma potassium was 4.4±0.3 mmol/L. The prevalences of hypokalemia and hyperkalemia were 0.5% and 3.8%, respectively; 3.0% of the subjects used diuretics. During a median follow-up of 10.3 years (interquartile range: 6.3–11.4 years), 753 subjects developed CKD. The potassium-CKD association was modified by diuretic use (Pinteraction = 0.02). Both hypokalemia without (HR, 7.74, 95% CI, 3.43–17.48) or with diuretic use (HR, 4.32, 95% CI, 1.77–10.51) were associated with an increased CKD risk as compared to plasma potassium 4.0–4.4 mmol/L without diuretic use. Plasma potassium concentrations ≥3.5 mmol/L were associated with an increased CKD risk among subjects using diuretics (Ptrend = 0.01) but not among subjects not using diuretics (Ptrend = 0.74). Conclusion In this population-based cohort, hypokalemia was associated with an increased CKD risk, regardless of diuretic use. In the absence of hypokalemia, plasma potassium was not associated with an increased CKD risk, except among subjects using diuretics.

Urinary Potassium Excretion and Risk of Developing Hypertension

Previous prospective cohort studies on the association between potassium intake and risk of hypertension have almost exclusively relied on self-reported dietary data, whereas repeated 24-hour urine excretions, as estimate of dietary uptake, may provide a more objective and quantitative estimate of this association. Risk of hypertension (defined as blood pressure ≥140/90 mm Hg or initiation of blood pressure–lowering drugs) was prospectively studied in 5511 normotensive subjects aged 28 to 75 years not using blood pressure–lowering drugs at baseline of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Potassium excretion was measured in two 24-hour urine specimens at baseline (1997–1998) and midway during follow-up (2001–2003). Baseline median potassium excretion was 70 mmol/24 h (interquartile range, 57–85 mmol/24 h), which corresponds to a dietary potassium intake of ≈91 mmol/24 h. During a median follow-up of 7.6 years (interquartile range, 5.0–9.3 years), 1172 subjects developed hypertension. The lowest sex-specific tertile of potassium excretion (men: <68 mmol/24 h; women: <58 mmol/24 h) had an increased risk of hypertension after multivariable adjustment (hazard ratio, 1.20; 95% confidence interval, 1.05–1.37), compared with the upper 2 tertiles ( P nonlinearity=0.008). The proportion of hypertension attributable to low potassium excretion was 6.2% (95% confidence interval, 1.7%–10.9%). No association was found between the sodium to potassium excretion ratio and risk of hypertension after multivariable adjustment. Low urinary potassium excretion was associated with an increased risk of developing hypertension. Dietary strategies to increase potassium intake to the recommended level of 90 mmol/d may have the potential to reduce the incidence of hypertension. # Novelty and Significance {#article-title-43}Previous prospective cohort studies on the association between potassium intake and risk of hypertension have almost exclusively relied on self-reported dietary data, whereas repeated 24-hour urine excretions, as estimate of dietary uptake, may provide a more objective and quantitative estimate of this association. Risk of hypertension (defined as blood pressure ≥140/90 mm Hg or initiation of blood pressure–lowering drugs) was prospectively studied in 5511 normotensive subjects aged 28 to 75 years not using blood pressure–lowering drugs at baseline of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Potassium excretion was measured in two 24-hour urine specimens at baseline (1997–1998) and midway during follow-up (2001–2003). Baseline median potassium excretion was 70 mmol/24 h (interquartile range, 57–85 mmol/24 h), which corresponds to a dietary potassium intake of ≈91 mmol/24 h. During a median follow-up of 7.6 years (interquartile range, 5.0–9.3 years), 1172 subjects developed hypertension. The lowest sex-specific tertile of potassium excretion (men: <68 mmol/24 h; women: <58 mmol/24 h) had an increased risk of hypertension after multivariable adjustment (hazard ratio, 1.20; 95% confidence interval, 1.05–1.37), compared with the upper 2 tertiles (Pnonlinearity=0.008). The proportion of hypertension attributable to low potassium excretion was 6.2% (95% confidence interval, 1.7%–10.9%). No association was found between the sodium to potassium excretion ratio and risk of hypertension after multivariable adjustment. Low urinary potassium excretion was associated with an increased risk of developing hypertension. Dietary strategies to increase potassium intake to the recommended level of 90 mmol/d may have the potential to reduce the incidence of hypertension.

The Failing Heart Stimulates Tumor Growth by Circulating Factors

Background: Heart failure (HF) survival has improved, and nowadays, many patients with HF die of noncardiac causes, including cancer. Our aim was to investigate whether a causal relationship exists between HF and the development of cancer. Methods: HF was induced by inflicting large anterior myocardial infarction in APCmin mice, which are prone to developing precancerous intestinal tumors, and tumor growth was measured. In addition, to rule out hemodynamic impairment, a heterotopic heart transplantation model was used in which an infarcted or sham-operated heart was transplanted into a recipient mouse while the native heart was left in situ. After 6 weeks, tumor number, volume, and proliferation were quantified. Candidate secreted proteins were selected because they were previously associated both with (colon) tumor growth and with myocardial production in post–myocardial infarction proteomic studies. Myocardial gene expression levels of these selected candidates were analyzed, as well as their proliferative effects on HT-29 (colon cancer) cells. We validated these candidates by measuring them in plasma of healthy subjects and patients with HF. Finally, we associated the relation between cardiac specific and inflammatory biomarkers and new-onset cancer in a large, prospective general population cohort. Results: The presence of failing hearts, both native and heterotopically transplanted, resulted in significantly increased intestinal tumor load of 2.4-fold in APCmin mice (all P<0.0001). The severity of left ventricular dysfunction and fibrotic scar strongly correlated with tumor growth (P=0.002 and P=0.016, respectively). We identified several proteins (including serpinA3 and A1, fibronectin, ceruloplasmin, and paraoxonase 1) that were elevated in human patients with chronic HF (n=101) compared with healthy subjects (n=180; P<0.001). Functionally, serpinA3 resulted in marked proliferation effects in human colon cancer (HT-29) cells, associated with Akt-S6 phosphorylation. Finally, elevated cardiac and inflammation biomarkers in apparently healthy humans (n=8319) were predictive of new-onset cancer (n=1124) independently of risk factors for cancer (age, smoking status, and body mass index). Conclusions: We demonstrate that the presence of HF is associated with enhanced tumor growth and that this is independent of hemodynamic impairment and could be caused by cardiac excreted factors. A diagnosis of HF may therefore be considered a risk factor for incident cancer.

Circulating Total Bilirubin and Future Risk of Hypertension in the General Population: The Prevention of Renal and Vascular End-Stage Disease (PREVEND) Prospective Study and a Mendelian Randomization Approach

Background Circulating total bilirubin is known to be inversely and independently associated with future risk of cardiovascular disease. However, the relationship of circulating total bilirubin with incident hypertension is uncertain. We aimed to assess the association of total bilirubin with future hypertension risk and supplemented this with a Mendelian randomization approach to investigate any causal relevance to the association. Methods and Results Plasma total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End‐Stage Disease) prospective study of 3989 men and women without hypertension. Hazard ratios (95% confidence intervals) of total bilirubin with incident hypertension were assessed. New‐onset hypertension was recorded in 1206 participants during a median follow‐up of 10.7 years. Baseline total bilirubin was approximately log‐linearly associated with hypertension risk. Age‐ and sex‐adjusted hazard ratio for hypertension per 1‐SD increase in loge total bilirubin was 0.86 (0.81–0.92; P<0.001), which was attenuated to 0.94 (0.88–0.99; P=0.040) after further adjustment for established risk factors and other potential confounders. The association was marginally significant on further adjustment for high‐sensitivity C‐reactive protein (0.94; 0.88–1.00; P=0.067). A genetic variant at the UGT1A1*28 locus consistently shown to be strongly associated with circulating bilirubin levels—rs6742078—was not significantly associated with blood pressure or hypertension (P>0.05 for all), arguing against a strong causal association of circulating bilirubin with blood pressure. Conclusions The weak and inverse association of circulating total bilirubin with future hypertension risk may be driven by biases such as unmeasured confounding and/or reverse causation. Further evaluation is warranted.

Plasma N-terminal Prosomatostatin and Risk of Incident Cardiovascular Disease and All-Cause Mortality in a Prospective Observational Cohort: the PREVEND Study

BACKGROUND Somatostatin is a component of the well-known insulin-like growth factor-1/growth hormone (GH) longevity axis. There is observational evidence that increased GH is associated with an increased risk of cardiovascular disease (CVD). We aimed to investigate the potential association of plasma N-terminal fragment prosomatostatin (NT-proSST) with incident CVD and all-cause mortality in apparently healthy adults. METHODS We studied 8134 participants without history of CVD (aged 28-75 years; women, 52.6%) from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study in Groningen, the Netherlands. Plasma NT-proSST was measured in baseline samples. Outcomes were incidence of CVD and all-cause mortality. RESULTS In cross-sectional analyses, NT-proSST [mean (SD), 384.0 (169.3) pmol/L] was positively associated with male sex and age (both P < 0.001). During a median follow-up of 10.5 (Q1-Q3: 9.9-10.8) years, 708 (8.7%) participants developed CVD and 517 (6.4%) participants died. In univariable analyses, NT-proSST was associated with an increased risk of incident CVD and all-cause mortality (both P < 0.001). In multivariable analyses, these associations were independent of the Framingham risk factors, with hazard ratios (95% CI) per doubling of NT-proSST of 1.17 (1.03-1.34; P = 0.02) for incident CVD and of 1.28 (1.09-1.49; P = 0.002) for all-cause mortality. Addition of NT-proSST to the updated Framingham Risk Score improved reclassification (integrated discrimination improvement (P < 0.001); net reclassification improvement was 2.5% (P = 0.04)). CONCLUSIONS Plasma NT-proSST is positively associated with increased risk of future CVD and all-cause mortality, partly independent of traditional CVD risk factors. Further research is needed to address the nature of associations.