Growth hormones in chronic kidney disease

Several hormonal systems are disrupted in chronic kidney disease (CKD) and disturbances of the growth hormone axis could contribute to increased morbidity and mortality through effects on cardiovascular health, energy metabolism and inflammation. The overall aim of this thesis was to increase knowledge about hormonal alterations and their consequences in CKD, focusing on cardiovascular disease (CVD), mortality and the growth hormone axis in end-stage renal disease. We tested cross-sectional associations between different growth hormones and known risk factors for CVD. We also analyzed longitudinal associations between blood hormone levels and outcomes. In addition we studied potassium disturbances in a large healthcare-based cohort.

Paper I was a cohort study of insulin-like growth factor 1 (IGF-1) levels and mortality in patients starting hemodialysis. We found that patients with IGF-1 levels in the lowest tertile were more often female, had lower creatinine, lower serum albumin and higher degree of inflammation. Low IGF-1 levels were associated with increased mortality and this association remained when adjusted for age, sex and comorbid conditions [diabetes mellitus (DM), CVD, heart failure]. Our results show that low IGF-1 levels at dialysis initiation are associated with increased mortality.

Paper II was a cohort study of incident dialysis patients investigating pregnancy-associated plasma protein-A (PAPP-A) in relation to mortality and CVD. We also tested whether body composition, DM or inflammation would act as effect modifiers on this association. Higher PAPP-A levels showed a moderate association with mortality when adjusted for cardiovascular risk factors and body composition but when also including high-sensitivity C-reactive protein (hs-CRP) the association was weakened. In survival analysis, interactions with PAPP-A were found for hs-CRP, DM and fat tissue index. This indicates that higher PAPP-A levels in patients starting dialysis are associated with increased mortality, and that this association is modulated by inflammation, DM and body composition.

In paper III we describe incidence and determinants of hyperkalemia and hypokalemia in a large healthcare based cohort including adult individuals from Stockholm accessing healthcare in 2009. Estimated glomerular filtration rate (eGFR) was included as a measure of kidney function. During three years follow-up, 13.6% had at least one episode of hypokalemia. Hyperkalemia of any degree of severity was detected in 7%. Frequency of potassium testing was naturally associated with dyskalaemia risk. In adjusted analysis, lower hyperkalemia risk was seen in women and in loop/thiazide diuretics users while hyperkalemia risk was higher in older age, lower eGFR, diabetes, heart failure and use of renin-angiotensin-aldosterone system inhibitors. Women, those of younger age, with higher eGFR or use of diuretics had higher risk of hypokalemia.

In paper IV, we investigated PAPP-A levels and mortality in prevalent HD patients and sought specifically to test our previous exploratory findings that inflammation and DM modulated the effect of PAPP-A on mortality. Higher PAPP-A was associated with increased mortality both in univariable analysis and when adjusted for confounders and cardiovascular risk factors. An interaction between PAPP-A and DM was found, implying greater prognostic utility of PAPP-A in patients with DM.

In paper V, we hypothesized that combining a function measurement of muscle strength (handgrip strength, HGS) with a biochemical nutritional marker (plasma IGF-1 levels) would have a stronger association to mortality in CKD than either marker alone. Patients in the low IGF-1 and low HGS category had increased mortality rate compared to the other categories and this association was robust when adjusted for Framingham’s CVD risk score, CVD, malnutrition, smoking, hs-CRP, albumin and lean body mass index. The predictive utility of IGF-1 was somewhat enhanced but still weak in the low HGS group. Our results indicate that low HGS predicts higher mortality risk in CKD and that adding IGF-1 levels may marginally improve risk prediction in the low HGS group.

List of scientific papers

I. Nilsson E, Carrero JJ, Heimbürger O, Hellberg O, Lindholm B, Stenvinkel P. A cohort study of insulin-like growth factor 1 and mortality in haemodialysis patients. Clin Kidney J. 2016; 9: 148–52.
https://doi.org/10.1093/ckj/sfv118

II. Nilsson E, Cao Y, Lindholm B, Ohyama A, Carrero JJ, Qureshi, Stenvinkel P. Pregnancy-associated plasma protein-A predicts survival in end-stage renal disease-confounding and modifying effects of cardiovascular disease, body composition and inflammation. Nephrol Dial Transplant. 2017; 32: 1776.
https://doi.org/10.1093/ndt/gfx215

III. Nilsson E, Gasparini A, Ärnlöv J, Xu H, Henriksson KM, Coresh J, Grams ME, Carrero JJ. Incidence and determinants of hyperkalemia and hypokalemia in a large healthcare system. Int J Cardiol. 2017; 245: 277–84.
https://doi.org/10.1016/j.ijcard.2017.07.035

IV. Nilsson E, Rudholm T, Stenvinkel P, Ärnlöv J. Pregnancy-associated plasma protein A and mortality in haemodialysis. Eur J Clin Invest. 2018; e12959.
https://doi.org/10.1111/eci.12959

V. Chen Z, Nilsson E, Lindholm B, Heimbürger O, Barany P, Stenvinkel P, Chen J, Qureshi AR. Low plasma insulin-like growth factor-1 associates with increased mortality in chronic kidney disease patients with reduced muscle strength. [Manuscript]