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AIMS: This study aimed to investigate the association between the 'Shrunken pore syndrome' (SPS) and risk of death, 30 day rehospitalization, and health-related quality of life (QoL) in heart failure (HF) patients. SPS is characterized by a difference in renal filtration between cystatin C and creatinine, resulting in a low eGFRcystatin C /eGFRcreatinine ratio.METHODS AND RESULTS: A total of 373 patients hospitalized for HF [mean age 74.8 (±12.1) years; 118 (31.6%) women] were retrieved from the HeARt and brain failure inVESTigation trial (HARVEST-Malmo). Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas were used for estimation of glomerular filtration rate (eGFR). Presence of SPS was defined as eGFRcystatin C ≤ 60% of eGFRcreatinine . In Cox regression multivariate models, associations between SPS, risk of death (median follow-up time 1.8 years), and risk of 30 day rehospitalization were studied. Associations between SPS and impaired QoL were studied using multivariate logistic regressions. In multivariate models, SPS was associated with all-cause mortality [124 events; hazard ratio (HR) 1.99; 95% confidence interval (95% CI) 1.23-3.21; P = 0.005] and with 30 day rehospitalization (70 events; HR 1.82; CI 95% 1.04-3.18; P = 0.036). Analyses of QoL, based on a Kansas City Cardiomyopathy Questionnaire overall score < 50, revealed that SPS was associated with higher risk of low health-related QoL (odds ratios 2.15; CI 95% 1.03-4.49; P = 0.042).CONCLUSIONS: The results of this observational study show for the first time an association between SPS and poor prognosis in HF. Further studies are needed to confirm the results in HF cohorts and experimental settings to identify pathophysiological mechanisms. (Less)

Cancer metabolism is characterized by an increased utilization of fermentable fuels, such as glucose and glutamine, which support cancer cell survival by increasing resistance to both oxidative stress and the inherent immune system in humans. Dialysis has the power to shift the patient from a state dependent on glucose and glutamine to a ketogenic condition (KC) combined with low glutamine levels—thereby forcing ATP production through the Krebs cycle. By the force of dialysis, the cancer cells will be deprived of their preferred fermentable fuels, disrupting major metabolic pathways important for the ability of the cancer cells to survive. Dialysis has the potential to reduce glucose levels below physiological levels, concurrently increase blood ketone body levels and reduce glutamine levels, which may further reinforce the impact of the KC. Importantly, ketones also induce epigenetic changes imposed by histone deacetylates (HDAC) activity (Class I and Class IIa) known to play an important role in cancer metabolism. Thus, dialysis could be an impactful and safe adjuvant treatment, sensitizing cancer cells to traditional cancer treatments (TCTs), potentially making these significantly more efficient.

BACKGROUND: Wasting is a common complication of kidney failure that leads to weight loss and poor outcomes. Recent experimental data identified parathyroid hormone (PTH) as a driver of adipose tissue browning and wasting, but little is known about the relations among secondary hyperparathyroidism, weight loss, and risk of mortality in dialysis patients. METHODS: We included 42,319 chronic in-centre haemodialysis patients from the Dialysis Outcomes and Practice Patterns Study phases 2-6 (2002-2018). Linear mixed models were used to estimate the association between baseline PTH and percent weight change over 12 months, adjusting for country, demographics, comorbidities, and labs. Accelerated failure time models were used to assess 12 month weight loss as a mediator between baseline high PTH and mortality after 12 months. RESULTS: Baseline PTH was inversely associated with 12 month weight change: 12 month weight loss >5% was observed in 21%, 18%, 18%, 17%, 15%, and 14% of patients for PTH ≥600 pg/mL, 450-600, 300-450, 150-300, 50-150, and

Purpose: Conventional hemodialysis (HD) treatment has an acceptable removal of small uremic molecules, but so-called middle molecules in the range of 0.5-60 kDa are poorly cleared with HD compared to a native kidney, which may contribute to morbidity in the dialysis population. Hemodiafiltration (HDF) has a better removal of middle molecules compared to HD but is technically demanding and requires well-functioning dialysis access. The newly introduced medium cutoff (MCO) filters have been developed to enhance middle molecule clearance in HD-mode. The aim of this study was to compare reduction ratios (RRs) of molecules with different molecular weights (0.06-150 kDa) during dialysis with MCO dialyzer (used in HD-mode) compared to online-hemodiafiltration (ol-HDF) treatment with a conventional high-flux dialyzer. Patients and Methods: This is a prospective controlled single-center cross-over study, including 16 patients in Malmo, Sweden. All patients had ongoing post-dilution ol-HDF treatment before the study. The study compared reduction ratios of small-, middle-, and large-sized molecules during a single 4h dialysis treatment with post-dilution ol-HDF (Polyflux 210H) to a 4h dialysis treatment with MCO dialyzer (Theranova 500) in HDmode. Between treatments, the patients had a washout period of at least two weeks of their ordinary HDF treatment to reach their ordinary steady state. Results: Ol-HDF had significantly higher RR for cystatin C (13 kDa), compared to MCO (RR 68.1 vs 65.8, p=0.003), during a 4h dialysis treatment (mean convection volume of 24.5 L for HDF, and mean Qb of 324 mL/min for HDF and 323 mL/min for MCO). There was no significant difference in the RR for other middle molecules, or for smaller or larger molecules. Conclusion: Overall, the RRs were comparable for ol-HDF and MCO-HD. There was a slightly higher RR of cystatin C (a small middle molecule) for HDF compared to MCO but no difference in other measured molecules. (Less)

Background Serial assessment of phosphorus is currently recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, but its additional value versus a single measurement is uncertain. Methods We studied data from 17 414 HD patients in the Dialysis Outcomes and Practice Patterns Study, a prospective cohort study, and calculated the area under the curve (AUC) by multiplying the time spent with serum phosphorus >4.5 mg/dL over a 6-month run-in period by the extent to which this threshold was exceeded. We estimated the association between the monthly average AUC and cardiovascular (CV) mortality using Cox regression. We formally assessed whether AUC was a better predictor of CV mortality than other measures of phosphorus control according to the Akaike information criterion. Results Compared with the reference group of AUC = 0, the adjusted hazard ratio (HR) of CV mortality was 1.12 [95% confidence interval (CI) 0.90–1.40] for AUC > 0–0.5, 1.26 (95% CI 0.99–1.62) for AUC > 0.5–1, 1.44 (95% CI 1.11–1.86) for AUC > 1–2 and 2.03 (95% CI 1.53–2.69) for AUC > 2. The AUC was predictive of CV mortality within strata of the most recent phosphorus level and had a better model fit than other serial measures of phosphorus control (mean phosphorus, months out of target). Conclusions We conclude that worse phosphorus control over a 6-month period was strongly associated with CV mortality. The more phosphorus values do not exceed 4.5 mg/dL the better is survival. Phosphorus AUC is a better predictor of CV death than the single most recent phosphorus level, supporting with real-world data KDIGO’s recommendation of serial assessment of phosphorus to guide clinical decisions.

Glomerular filtration rate (GFR) is estimated by creatinine or cystatin C-based GFR-estimating equations. Those based upon creatinine, but not those based upon cystatin C, use "race" terms due to that different populations differ in average muscular mass, influencing the creatinine, but not the cystatin C, level. "Race" is not a biological, but a sociological term, determined by self-assesment. New international studies therefore strongly recommend use of cystatin C-based GFR-estimating equations.

Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous GFR-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterised by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules < 1kDa dominating the glomerular filtrate e.g., water, urea, creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterised by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines. This article is protected by copyright. All rights reserved.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease and renal replacement therapy worldwide. A pathophysiological hallmark of DKD is glomeru- lar basal membrane (GBM) thickening, whereas this feature is absent in minimal change disease (MCD). According to fundamental transport physiological principles, a thicker GBM will impede the diffusion of middle-molecules such as cystatin C, potentially leading to a lower estimated GFR (eGFR) from cystatin C compared to that of creatinine. Here we test the hypothesis that thickening of the glomerular filter leads to an increased diffusion length, and lower clearance, of cystatin C. Twenty- nine patients with a kidney biopsy diagnosis of either DKD (n = 17) or MCD (n = 12) were retrospectively included in the study. GBM thickness was measured at 20 sepa- rate locations in the biopsy specimen and plasma levels of cystatin C and creatinine were retrieved from health records. A modified two-pore model was used to simulate the effects of a thicker GBM on glomerular water and solute transport. The mean age of the patients was 52 years, and 38% were women. The mean eGFRcystatin C/ eGFRcreatinine-ratio was 74% in DKD compared to 98% in MCD (p < 0.001). Average GBM thickness was strongly inversely correlated to the eGFRcystatin C/eGFRcreatinine- ratio (Pearson's r = −0.61, p < 0.01). Two-pore modeling predicted a eGFRcystatin C/ eGFRcreatinine-ratio of 78% in DKD. We provide clinical and theoretical evidence sug- gesting that thickening of the glomerular filter, increasing the diffusion length of cys- tatin C, lowers the eGFRcystatin C/eGFRcreatinine-ratio in DKD. (Less)

Summary Reduced kidney function is associated with an increased fracture risk, although the relationship between an age-related decline and fractures needs further investigation. We followed kidney function and fracture risk for 10 years. A mild-moderate decline in kidney function was associated with fracture, but not in advanced age. Introduction With age, kidney function declines. Though well known that chronic kidney disease is associated with increased fracture risk, the extent to which the typical age-related decline contributes is unclear. In the OPRA cohort, a longitudinal study of older non-selected women, we investigated the association between kidney function and fracture. Methods Cystatin C–based kidney function estimates were available at age 75 (n = 981) and 80 (n = 685). Women were categorized by kidney function: normal (CKD stages 1 and 2), mild-moderate (3a), poor (3b-5), and imminent, short- and long-term fracture risk investigated. BMD measurements and kidney function for risk prediction were also evaluated; women were categorized by both reduced kidney function (stages 3–5) and osteoporosis status. Results In the short term, 2–3 years, mild-moderate kidney dysfunction was associated with the highest risk increase: osteoporotic fractures (2 years HRadj 2.21, 95% CI 1.27–3.87) and also up to 5 years (between 75 and 80 years) (HRadj 1.51, 1.04–2.18). Hip fracture risk was similarly increased. This association was not observed from age 80 nor for women with poorest kidney function. Reduced kidney function was associated with higher risk even without osteoporosis (osteoporotic fracture; HRadj 1.66, 1.08–2.54); risk increased by having both osteoporosis and reduced function (HRadj 2.53, 1.52–4.23). Conclusion Older women with mild-moderate reduction of kidney function are at increased risk of fractures, but not those with the worst function. Our findings furthermore confirm the value of osteoporosis assessment and it is possible that in this age group, age-related decline of kidney function has limited contribution compared with BMD. Electronic supplementary material The online version of this article (10.1007/s00198-019-05152-x) contains supplementary material, which is available to authorized users.

Item does not contain fulltext Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m(2) This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR

Background: Genome-wide association studies (GWAS) have identified >50 single nucleotide polymorphisms (SNP) in association with estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD) but little is known about whether the combination of these SNPs may aid in prediction of future incidence of CKD in the population. Methods: We included 2301 participants with baseline eGFR ≥60 mL/min per 1.73 m2 from the Malmö Diet and Cancer Study–Cardiovascular Cohort. The eGFR was estimated during baseline (1991–1996) and after a mean follow-up of 16.6 years using the CKD–Epidemiology Collaboration 2009 creatinine equation. We combined 53 SNPs into a genetic risk score weighted by the effect size (wGRSCKD), and examined its association with incidence of CKD stage 3A (eGFR ≤60 mL/min per 1.73 m2). Results: At follow-up, 453 study participants were defined as having CKD stage 3A. We observed a strong association between wGRSCKD and eGFR at baseline (P = 6.5 × 10−8) and at the follow-up reexamination (P = 5.0 × 10−10). The odds ratio (OR) for incidence of CKD stage 3A was 1.25 per 1 SD increment in the wGRSCKD (95% confidence interval [CI]: 1.12–1.39) adjusting for potential confounders (sex, age, body mass index [BMI], baseline eGFR, fasting glucose, systolic blood pressure (SBP), antihypertensive treatment, smoking, follow-up time). Adding wGRSCKD on the top of traditional risk factors did not improve the C-statistics (P = 0.12), but the Net Reclassification-Improvement-Index was significantly improved (cNRI = 21.3%; 95% CI: 21.2–21.4; P < 0.0001). Conclusion: wGRSCKD was associated with a 25% increased incidence of CKD per 1 SD increment. Although the wGRSCKD did not improve the prediction model beyond clinical risk factors per se, the information of genetic predisposition may aid in reclassification of individuals into correct risk direction. Keywords: CKD, eGFR, GRS, renal function

Background Circulating C3 has been associated with diabetes and hypertension, which are the leading causes of chronic kidney disease (CKD). C3 activation is considered to contribute to several renal diseases. Here we examined whether elevated C3 concentration is associated with hospitalization due to CKD in the general population, and whether this relationship is mediated by factors such as diabetes and hypertension. Methods Baseline plasma C3 was quantified in 4552 participants, without previous hospital admission due to CKD, from the Malmö Diet and Cancer cohort study. Incidence of first hospitalization due to CKD (main diagnosis) was investigated in relation to C3 levels using Cox proportional hazards regression models after a mean follow-up of 19.2 ± 4.16 years. Traditional risk factors of CKD including diabetes, blood pressure, C-reactive protein and baseline renal function were considered in adjustments and sensitivity analyses. Results During the follow-up period, 94 subjects were admitted to hospital due to CKD. After multivariate adjustment, the hazard ratios (95% confidence interval) for hospitalization from CKD across quartiles of C3 were 1.00 (reference), 1.68 (0.69, 4.13), 2.71 (1.15, 6.39), and 3.16 (1.36, 7.34) (p for trend = 0.003). Results were generally consistent across different sensitivity analyses. Conclusions These findings indicate that C3 is associated with incidence of first hospitalization due to CKD in the general population. The observed relationship cannot be entirely attributed to hyperglycemia and hypertension.

Background The kidney injury molecule-1 (KIM-1) has previously been associated with kidney function in rodents and humans. Yet its role as a predictive marker for future decline in kidney function has remained less clear. Methods At baseline (1991–1994), fasting plasma KIM-1 (p-KIM-1) was measured in 4739 participants of the population-based Malmö Diet and Cancer Study. Creatinine and cystatin C were used to calculate estimated glomerular filtration rate (eGFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Collaboration 2012 creatinine–cystatin C equation at baseline and follow-up examination (2007–2012). Incident CKD was defined as an eGFR Results During a mean follow-up time of 16.6 years, high p-KIM-1 levels were associated with a greater decline in eGFR (quartile 1 −1.36 versus quartile 4 −1.54 mL/min/1.73 m2; P Conclusion Our results show that p-KIM-1 predicts the future decline of eGFR and risk of CKD in healthy middle-aged participants. Whether p-KIM-1 can be used to prioritize preventive action that needs to be further investigated.

Introduction: Shrunken pore syndrome (SPS), originally defined by cystatin C−based estimated glomerular filtration rate (eGFRcystatin C) being less than 60% of creatinine-based estimated glomerular filtration rate (eGFRcreatinine) in the absence of extrarenal influences on the plasma levels of cystatin C or creatinine, is associated with a high increase in mortality, even in the absence of reduced glomerular filtration rate (GFR). The objective of the present study was to determine whether the proteome of patients with SPS shows differences from that of patients with normal or reduced measured GFR (mGFR) without SPS. Methods: Four patient cohorts were included: 1 cohort with normal mGFR without SPS, 1 with normal mGFR with SPS, 1 with reduced mGFR without SPS, and 1 with reduced mGFR with SPS. The plasma levels of 177 selected proteins were analyzed. Results: Differences in the levels of 30 proteins were specific for SPS; 31 differences were specific for patients with both SPS and reduced mGFR; and 27 were specific for reduced mGFR. Eighteen of the differences specific for SPS concerned proteins described as promoting, or being associated with, atherosclerosis. Twelve of the differences specific for patients with both SPS and reduced mGFR and 10 of the differences specific for reduced mGFR also concerned proteins described as promoting, or being associated with, atherosclerosis. Almost all (82 of 88) of the concentration differences represented increased levels. For SPS, but not for reduced mGFR, a correlation between protein size and increase in level was observed, with smaller proteins being associated with higher levels. Conclusion: The high mortality in shrunken pore syndrome might be caused by the accumulation of atherosclerosis-promoting proteins in this condition. Keywords: atherosclerosis, creatinine, cystatin C, GFR, kidney, mortality

Background and Aims The “Shrunken pore syndrome” is characterized by a difference in renal filtration between cystatin C and creatinine resulting in a low eGFRcystatinC/eGFRcreatinine-ratio, and studies have demonstrated a high risk for cardiovascular morbidity and mortality for patients with shrunken pore syndrome. In this observational study, we explored associations between shrunken pore syndrome and proteins implicated in cardiovascular disease and inflammation in patients with heart failure. Method Plasma samples from 300 individuals HARVEST-Malmö trial hospitalized for the diagnosis of heart failure (mean age 75 years; 30% female), were analyzed with a proximity extension assay consisting of 92 proteins, to identify proteins associated with shrunken pore syndrome. Shrunken pore syndrome was defined as eGFRcystatinC ≤60% of eGFRcreatinine. Proteins associated with shrunken pore syndrome in the initial age and sex-adjusted analyses (Bonferroni-corrected p≤ 5.4x10-4) were further adjusted for relevant covariates. Results In multivariate analyses, Shrunken pore syndrome was associated with elevated levels of six proteins; scavenger receptor cysteine-rich type 1 protein M130, tumor necrosis factor receptor 1, tumor necrosis factor receptor 2, osteoprotegerin, interleukin-2 receptor subunit alpha, and tyrosine-protein kinase receptor UFO (p Conclusion In heart failure patients, shrunken pore syndrome was independently associated with proteins linked to atherosclerosis and cell proliferation.

Background and Aims The cardiorenal syndrome was studied in heart failure (HF) patients with respect to the “Shrunken pore syndrome” (SPS) that is characterized by a difference in renal filtration between cystatin C and creatinine, resulting in a low eGFRcystatin C/eGFRcreatinine-ratio. Method 373 patients hospitalized for HF were retrieved from the HeARt and brain failure inVESTigation trial (HARVEST-Malmö). We used CKD-EPI formulas for estimated glomerular filtration rate (eGFR). Presence of SPS was defined as eGFRcystatinC ≤60% of eGFRcreatinine. In Cox regression multivariate models, associations between SPS, risk of death and risk of 30-day re-hospitalization were studied. Associations between SPS and impaired quality of life (QoL) were studied using multivariate logistic regressions. Results SPS was associated with all-cause mortality (124 events; hazard ratio (HR) 2.35; confidence interval (CI95%) 1.17-4.71; p=0.016 and with 30-day re-hospitalization (70 events; HR 1.82; CI95% 1.04-3.18; p=0.036). Analyses of QoL, based on a Kansas City Cardiomyopathy Questionnaire overall score Conclusion The results of this observational study show for the first time an association between SPS and poor prognosis in HF. Further studies are needed to confirm the results in HF cohorts and experimental settings to identify pathophysiological mechanisms.

Background and Aims Renal functional capacity is influenced by factors acting early in life, such as intrauterine environment, maturity, birth weight, length at birth, placental weight etc. Early life factors are responsible for the number of nephrons a person starts life with, and the consequence of a low nephron number is earlier kidney ageing and chronic kidney disease (CKD). Notably, most reports addressing early life factors in the context of adult kidney function use creatinine-based eGFR equations and/or albuminuria and lack longer follow-up ( Method 94 women and 494 men, born 1923-50, who participated in The Malmo Diet and Cancer (MDC) study were analyzed. Perinatal data records including birth weight (BW), birth length, head circumference, gestational age, placenta weight (PW) and mother related risk factors were collected from hospital and regional state archives. After a follow-up of 46 to 67 years study subjects underwent physical examination, blood pressure measurements and estimation of glomerular filtration rate (eGFR) using 4 different equations: Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2012 creatinine and cystatin C formula (CKD-EPI_creatinine, CKD-EPI_cystatin C), cystatin C eGFR equation based on Caucasian, Asian, pediatric, and adult cohorts (CAPA), the Lund-Malmö revised creatinine based eGFR equation (LM_rev). Urinary albumin-to-creatinine ratio (UACR) was measured in morning urine samples, albuminuria was defined as UACR ⩾3 mg/mmol. Birth weight z-scores (gender specific BWz and combined BWz) acquired by using the equation as reported by Marsal et al.(1996). Four growth mismatch phenotypes defined by combining low or high BW z-score (lowBWz or hiBWz respectively) with lower or higher body mass index at 20 years of age (lowBMI20 ir hiBMI20 respectively). Results Linear regression analysis of early life factors indicated that in females birth weight was positively associated with kidney function measured by both CAPA and CKD-EPI_cystatin C. In the whole population, birth weight adjusted for gestational age and sex, together with prematurity were independently associated to CKD-EPI_cystatin C, while BW/PW ratio was related to LM_rev. Logistic regression analysis showed that only gender specific BWz and combined BWz shared the same odds ratios for age and pulse pressure adjusted albuminuria in males (OR 0,75 (95%CI [0,58; 0,96]). While analyzing postnatal growth mismatch we found that females with hiBWz/lowBMI20 phenotype had significantly worse kidney function acquired by both cystatin C equations compared to those with lowBWz/lowBMI20 phenotype (p=0.044 for CAPA, p=0.040 for CKD-EPI_cystatin C). The logistic regression analysis revealed that hiBWz/hiBMI20 phenotype was related to lower risk of age and pulse pressure adjusted albuminuria (OR 0,35 (95%CI[0,12;0,93]) Conclusion Here we report that lower birth weight in females is associated with worse kidney function determined by cystatin C eGFR equations, while in males lower birth weight z-score is a risk factor for albuminuria in adulthood. Postnatal growth catch-up is not related to worse kidney function. We identified the protective phenotype (hiBWz/hiBMI20) for albuminuria in males and the unfavorable phenotype (hiBWz/lowBMI20) for kidney function in females. This suggests that lower birth weight and postnatal growth curve have a potential sex specific effect to kidney function and development of CKD in middle-aged Swedish subjects. Further studies are warranted to address early life factor prognostic accuracy in kidney function and outcomes prediction later in the lifetime.

Background It has been shown that individuals with obesity have a higher risk for chronic kidney disease (CKD). However, it is unclear which measure of obesity is most useful for prediction of CKD in the general population. The aim of this large prospective study was to explore the association between several anthropometric measures of obesity, i. e., body mass index (BMI), waist circumference (WC), waist circumference to height ratio (WHtR), waist-to-hip ratio (WHR), percentage of body fat (BF%), weight, height and incidence of hospitalizations due to CKD, in a population-based cohort study. Methods The ‘Malmö Diet and Cancer Study (MDCS)’ cohort in Sweden was examined during 1991 to 1996. A total of 28,449 subjects underwent measurement of anthropometric measures and blood pressure and filled out a questionnaire. Incidence of in- and outpatient hospital visits for CKD was monitored from the baseline examination over a mean follow-up of 18 years. Cox proportional hazards regression was used to explore the association between anthropometric measures and incidence of CKD, with adjustments for risk factors. Results The final study population included 26,723 subjects, 45-73 years old at baseline. Higher values of BMI, WC, WHR, WHtR and weight were associated with an increased risk of developing CKD in both men and women. Only in women, higher values of BF% was associated with higher risk of CKD. Comparing the 4th vs 1st quartile of the obesity measure, the highest hazard ratio (HR) for CKD in men was observed for BMI, HR 1.51 (95% CI: 1.18-1.94) and weight (HR 1.52 (95% CI: 1.19-1.94). For women the highest HR for CKD was observed for BF%, HR 2.01 (95% CI: 1.45-2.78). Conclusions In this large prospective study, all anthropometric measures of obesity were associated with a substantially increased incidence of CKD, except for BF% in men. Some measures were slightly more predictive for the risk of CKD than others such as BMI and weight in men and BF% in women. In clinical daily practice use of all anthropometric measures of obesity might be equally useful to assess the risk of developing CKD. This study supports the strong evidence for an association between obesity and CKD.

Background The relationship between growth differentiation factor 15 (GDF-15) and the development of chronic kidney disease (CKD) is still unclear. We sought to examine whether plasma GDF-15 was related to incident CKD and kidney function decline using a large prospective cohort study. Methods 4318 participants of the Malmö Diet and Cancer Study-Cardiovascular Cohort were examined in 1991-1994. Incidence of CKD was followed prospectively by linkage with national patient registers. Estimated glomerular filtration rate (eGFR) was available for all participants at baseline, and was re-measured in a subgroup of 2744 subjects after 16.6 ± 1.49 years. Incidence of CKD was examined in relation to GDF-15 using Cox regression analysis. Logistic regression was used to examine the association of GDF-15 with eGFR change and eGFR-based CKD. Models were carefully corrected for potential confounders including baseline eGFR, N-terminal pro-B-type natriuretic peptide, and competing risk from death. Results 165 patients developed CKD after 19.2 ± 4.04 years of follow-up. The adjusted hazard ratio (95% confidence interval, CI) for CKD in 4th versus 1st quartile of GDF-15 was 2.37 (1.33, 4.24) (p for trend 2 (95% CI, − 1.49 ~ − 0.45; p 2. Conclusions GDF-15 predicted incidence of CKD and eGFR decline in the general population, independent of a wide range of potential risk factors and competing risk of death.

PURPOSE: The "Shrunken pore syndrome" (SPS) is characterized by a difference in renal filtration between cystatin C and creatinine, resulting in a low eGFRcystatinC /eGFRcreatinine -ratio. Studies have demonstrated a high risk for cardiovascular morbidity and mortality for patients with SPS. In this discovery study, we explored associations between SPS and proteins implicated in cardiovascular disease and inflammation in patients with heart failure.EXPERIMENTAL DESIGN: Plasma samples from 300 individuals in HARVEST-Malmo trial hospitalized for the diagnosis of heart failure (mean age 74.9±11.5 years; 30.0% female), were analyzed with a proximity extension assay consisting of 92 proteins. A Bonferroni-corrected p-value of 0.05/92 = 5.4 × 10-4 was considered significant in the initial age and sex-adjusted analyses. Presence of SPS was defined as eGFRcystatinC ≤60% of eGFRcreatinine .RESULTS: SPS presented with significant associations (p < 5.4 × 10-4 ) in age and sex-adjusted logistic regressions with elevated levels of six proteins; scavenger receptor cysteine rich type 1 protein M130, tumor necrosis factor receptor 1, tumor necrosis factor receptor 2, osteoprotegerin, interleukin-2 receptor subunit alpha, and tyrosine-protein kinase receptor UFO. All proteins remained associated (p < 0.05) with SPS after multivariate adjustments.CONCLUSIONS AND CLINICAL RELEVANCE: In heart failure patients, SPS was associated with proteins linked to atherosclerosis and cell proliferation. This article is protected by copyright. All rights reserved. (Less)

BackgroundDiabetic nephropathy (DN) is a leading cause of end stage renal disease and renal replacement therapy worldwide. A pathophysiological hallmark of DN is glomerular basal membrane (GBM) thickening, whereas this feature is absent in minimal change disease. Theoretically, a thicker GBM will impede the diffusion of middle-molecules such as cystatin C, potentially leading to a lower estimated GFR (eGFR) from cystatin C compared to that of creatinine. Here we test the hypothesis that thickening of the glomerular filter leads to an increased diffusion length, and lower clearance, of cystatin C.MethodsTwenty-nine patients with a kidney biopsy diagnosis of either DN (n=17) or minimal change disease (MCD) (n=12) were retrospectively included in the study. GBM thickness was measured at 20 separate locations in the biopsy specimen and plasma levels of cystatin C and creatinine were retrieved from health records. A modified two-pore model was used to simulate the effects of a thicker GBM on glomerular water and solute transport.ResultsThe mean age of the patients was 52 years, and 38% were women. The mean eGFRcystatin C/eGFRcreatinine-ratio was 74% in DKD compared to 98% in MCD (P < 0.001). Average GBM thickness was strongly inversely correlated to the eGFRcystatin C/eGFRcreatinine-ratio (Pearson’s r=-0.61, P < 0.01). Two-pore modeling predicted a eGFRcystatin C/eGFRcreatinine-ratio of 78% in DN.ConclusionsWe provide clinical and theoretical evidence suggesting that thickening of the glomerular filter, increasing the diffusion length of cystatin C, lowers the eGFRcystatin C/eGFRcreatinine-ratio in DN.Significance statementIncreased thickness of the glomerular basement membrane (GBM) is an early structural abnormality in diabetes, and has been identified as an independent risk factor for progression to diabetic nephropathy (DN). Increased GBM thickness will increase the diffusion length of mid-sized molecules like cystatin C across the renal filter, potentially leading to increased plasma concentrations and lower estimated GFR from cystatin C. The authors show theoretically that estimated GFR from cystatin C (eGFRcystatin C) is lower than that of creatinine (eGFRcreatinine) in DN to a degree directly depending on GBM thickness. In line with theory, they provide clinical data showing a lower eGFRcystatin Cin diabetic patients with the eGFRcystatin C/eGFRcreatinine-ratio being inversely correlated to GBM thickness assessed from electron micrographs.

Background Middle Eastern immigrants to Europe represent a high risk population for type 2 diabetes. We compared prevalence of novel subgroups and assessed risk of diabetic macro- and microvascular complications between diabetes patients of Middle Eastern and European origin. Methods This study included newly diagnosed diabetes patients born in Sweden (N = 10641) or Iraq (N = 286), previously included in the All New Diabetes in Scania cohort. The study was conducted between January 2008 and August 2016. Patients were followed to April 2017. Incidence rates in diabetic macro- and microvascular complications were assessed using cox-regression adjusting for the confounding effect of age at onset, sex, anthropometrics, glomerular filtration rate (eGFR) and HbA1c. Findings In Iraqi immigrants versus native Swedes, severe insulin-deficient diabetes was almost twice as common (27.9 vs. 16.2% p

Background Increased urinary excretion of IgM and low-grade albuminuria are associated with increased risk of cardiovascular morbidity and mortality. The objective of this study was to investigate the association between urinary IgM, albuminuria, and vascular parameters reflecting arterial structure and function. Methods Subjects of the present study were from the Malmö Offspring study (MOS) cohort, and included 1531 offspring (children and grand-children) to first-generation subjects that participated in the Malmö Diet Cancer-Cardiovascular Arm study cohort. At baseline, technical measurements of arterial stiffness (carotid-femoral pulse wave velocity; c-f PWV), carotid arterial morphology, 24-h ambulatory blood pressure recordings, ankle-brachial-index (ABI), and evaluation of endothelial function (reactive hyperemia index, RHI) were performed. Urinary (U) IgM, U-albumin, and U-creatinine were measured. Multivariate adjusted logistic regression was used to test whether U-IgM excretion and increasing urinary albumin excretion were related to vascular parameters. Results Detectable U-IgM was independently associated with higher systolic blood pressure, odds ratio (OR) 1.021, 95% confidence interval (CI, 1.003–1.039), p = 0.025 and lower ABI; ABI dx: OR 0.026, 95% CI (0.002–0.381), p = 0.008, ABI sin: OR 0.040, 95% CI (0.003–0.496), p = 0.012. Low-grade albuminuria was independently associated with systolic and diastolic blood pressure, aortic blood pressure, the c-f PWV and the number of carotid intima plaques (p Conclusions In young to middle-aged, mostly healthy individuals, increased U-IgM excretion and low-grade albuminuria are associated with adverse vascular parameters. Increased U-IgM excretion may reflect subclinical peripheral atherosclerosis, whereas increased U-albumin excretion is associated with a wide range of cardiovascular abnormalities. This may reflect different pathophysiological mechanisms.