Reduced Kidney Function Research Articles

Prevalence and factors linked to renal involvement in prediabetes patients across Europe in the ePREDICE trial

This sub-analysis of the ePREDICE trial, investigated the prevalence and determinants of renal complications, specifically glomerular hyperfiltration, albuminuria, and reduced kidney function, in individuals with prediabetes (PD). The cohort consisted of 967 participants from diverse backgrounds across seven countries. The kidney function was evaluated using the MDRD-4 equation, and the influence of various clinical and demographic factors on renal involvement was assessed by multivariable regression models. Additionally, insulinogenic and disposition indices were examined. Overall, the prevalence of renal abnormalities in this PD cohort was 9.2% (n = 89). Key findings included the detection of hyperfiltration in 20 (2%) individuals, albuminuria in 45 (4.7%), and CKD stage G3a in 29 (3%). Hyperfiltration was inversely correlated with age and height, while albuminuria showed a significant direct association with the disposition index (DI). Age and waist circumference were significantly and directly associated with estimated glomerular filtration rate (eGFR). The ePREDICE study highlights critical factors that affect renal involvement in PD individuals, revealing complex interactions among various parameters. These findings further emphasize the necessity for the search of early kidney abnormalities in people with PD especially in those in older age groups and with a large waist circumference.

Trial eligibility, treatment patterns and outcome for venetoclax-based therapy in AML: a prospective cohort study.

Venetoclax (Ven) plus hypomethylating agents are considered standard-of-care for patients with acute myeloid leukemia (AML) judged ineligible for intensive chemotherapy (IC). Real-world studies complement clinical trials, since patterns of patient selection, treatment-exposure and post-remission management may vary. This prospective observational multi-center study included 209 newly diagnosed IC-ineligible patients with a median age 75 years (interquartile range, 71-81 years). A high proportion of patients had secondary AML (53.7%), adverse-risk disease (35.3%), and complex karyotype (15.5%). At a median follow-up of 22.5 months (range 0.1-43), median overall-survival (mOS) was 11.7 months (95% Confidence Interval [CI] 9.9,15.4). Composite complete remission (CRc) was achieved in 65.2% (CR 44.4%; CRi 20.8%). Of responding patients, 21.1% underwent stem-cell transplantation. When stratified based on VIALE-A original eligibility criteria, mOS was 17.8 months for patients meeting eligibility criteria and 10.7 months for patients who did not (p=0.027). AML ontogeny (p=0.024), reduced kidney function (p=0.001), Charlson co-morbidity index (CCI; p=0.0017), ELN-risk (p=0.01) and body-mass index (p=0.0298) were significantly associated with OS. Multivariant Cox-regression analysis confirmed independent association of OS with AML ontogeny (p=0.012), CCI (p=0.033) and ELN-risk (p=0.019). Patients enrolled in the latter half of the study period demonstrated improved OS compared to those enrolled earlier (p=0.026). This prospective observational study highlights outcomes of patient subgroups, including those excluded from registration trials. (clinicaltrials.gov: #NCT03987958).

Levistolide a Attenuates Acute Kidney Injury in Mice by Inhibiting the TLR-4/NF-κB Pathway.

Acute kidney injury (AKI) is characterized by a significant reduction in kidney function and the accumulation of metabolites such as Creatinine (CRE) and Blood Urea Nitrogen (BUN). Levistolide A (LA), an active component of Ligusticum chuanxiong, offers multiple therapeutic benefits, including cardiovascular and neuroprotection, antitumor and analgesic effects, as well as anti-inflammatory, antioxidant, antifibrotic, and proapoptotic actions. However, the underlying mechanism of LA in treating AKI has not been fully elucidated. In this study, we established a glycerol-induced AKI model in mice to evaluate the protective effects of LA. Renal function was assessed by measuring levels of CRE and BUN. Histological analyses were performed to evaluate kidney tissue damage. Additionally, oxidative stress markers, apoptosis indicators, inflammatory cell infiltration, and inflammatory mediator levels were assessed. The involvement of the TLR-4/NF-κB signaling pathway was investigated through molecular assays. LA treatment significantly ameliorated glycerol-induced AKI in mice, evidenced by reduced levels of CRE and BUN. Histological examination revealed decreased renal tissue damage in LA-treated groups. LA exerted antioxidant effects by increasing the levels of Glutathione (GSH) and Superoxide Dismutase (SOD), while reducing Reactive Oxygen Species (ROS) accumulation. Apoptosis in renal tissues was attenuated, as indicated by decreased caspase-3 activation. Furthermore, LA reduced the infiltration of inflammatory cells and the release of inflammatory mediators such as TNF-α and IL-6. Mechanistically, LA suppressed the inflammatory response by inhibiting the TLR-4/NF-κB signaling pathway, as demonstrated by reduced NF-κB activation and decreased expression of TLR-4. Levistolide A mitigates acute kidney injury through its antioxidative properties and modulation of the TLR-4/NF-κB signaling pathway. These findings provide valuable insights into the therapeutic potential of LA for AKI treatment and lay the groundwork for further mechanistic studies.

Development and evaluation of a kidney health questionnaire and estimates of chronic kidney disease prevalence in the Cooperative Health Research in South Tyrol (CHRIS) study.

Kidney diseases are a public health burden but are poorly investigated in the general population. In light of inadequate survey tools, we developed a novel questionnaire for use in population-based studies, to retrospectively assess kidney diseases. The questionnaire covered general kidney diseases, reduced kidney function, and renal surgeries. It was administered between 2011 and 2018 to 11,684 participants (median age = 45 years) of the Cooperative Health Research in South Tyrol (CHRIS) study. Fasting estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) were measured. By factor analysis we contextualized the questionnaire content with respect to thebiochemical measurements. We estimated overall and sex-stratified prevalence of kidney diseases, including possible CKD, calibrating them to the general target population via relative sampling weights. Population-representative prevalence of glomerulonephritis, pyelonephritis, and congenital kidney diseases was 1.0%, 3.0%, and 0.2%, respectively, with corresponding odds ratios for females versus males of 1.4 (95% confidence interval: 1.0, 2.0), 8.7 (6.2, 12.3), and 0.7 (0.3, 1.6), respectively. Prevalence of kidney dysfunction (eGFR < 60mL/min/1.73m2 or UACR > 30mg/g) was 8.59%, while prevalence of self-reported CKD was 0.69%, indicating 95.3% oflack of disease awareness, with a similar figure in people with diabetes or hypertension. Overall, 15.76% of the population was affected by a kidney disease of any kind. In the Val Venosta/Vinschgau alpine district, CKD prevalence aligned with Western European estimates. Kidney health questionnaire implementation in population studies is feasible and valuable to assess CKD awareness, which we found to be dramatically low.

Pregnancy-related acute kidney injury leads to hypertension, reduced kidney function and cognitive impairment in postpartum rats.

Women with hypertensive disorders of pregnancy such as HELLP (hemolysis, elevated liver enzyme, low platelet) Syndrome are affected by acute kidney injury during pregnancy (PR-AKI) at higher rates than women without hypertension. Both hypertensive disorders of pregnancy and Acute Kidney Injury (AKI) outside the context of pregnancy have been associated with an increased risk of developing Chronic Kidney Disease (CKD) and cognitive impairment. In our current study, we set out to determine if PR-AKI led to the development of CKD and impaired cognition in the postpartum period and if HELLP syndrome exacerbates the impairments. Using timed-pregnant Sprague Dawley rats, on gestational day (GD) 12, mini-osmotic pumps infusing anti-angiogenic factors were surgically placed in the intraperitoneal cavity to induce HELLP. On GD18, AKI was induced via bilateral renal reperfusion ischemia surgery. Mean arterial pressure and birth outcomes were used to assess the global effects of AKI, and liver enzymes were used to assess HELLP. CKD was assessed by measuring glomerular filtration rate (GFR), urinary output, and renal fibrosis. Anxiety-like behaviors, object recognition memory, spatial memory, and avoidance memory were assessed via behavioral experiments. HELLP + AKI rats demonstrated more evidence of renal injury, hypertension, and behavioral deficits compared to normal pregnant animals. In addition, AKI had a negative impact on birth outcomes and maternal survival. HELLP + AKI together led to evidence of persistent hypertension, progressive renal dysfunction, and cognitive impairment, which were exacerbated compared to AKI or HELLP alone. These findings suggest that PR-AKI in the presence of a hypertensive disorder of pregnancy, such as HELLP, leads to the development of CKD, cognitive dysfunction, and hypertension.

Association between urinary heavy metal/trace element concentrations and kidney function: a prospective study

Abstract Background Chronic kidney disease (CKD) is an important public health problem. Although cross-sectional studies have identified many heavy metals/trace elements associated with reduced kidney function, prospective studies are needed to determine the pathogenic role of these elements in the development and progression of CKD. Methods To explore the association between baseline urinary heavy metal/trace element concentrations and long-term impaired kidney function (IKF)/CKD, as well as the incidence of rapid decline in kidney function in a population-based exploratory prospective study, we mean age 51.9 years at baseline) whose urinary trace elements concentrations have been determined by inductively coupled plasma mass spectrometry (ICP-MS). IKF was defined by a reduced estimated glomerular filtration rate (eGFR) between 60-90 mL/min/1.73 m2, and CKD was defined as an eGFR&amp;lt;60 mL/min/1.73 m2. Rapid eGFR decline was defined as a decrease≥3 mL/min/1.73 m2 /year. Results Over a mean follow-up of 12.5 years, 123 participants (2.6%) experienced rapid decline in kidney function, and 1455 (31.7%) developed IKF or CKD. After adjusting for covariates including baseline eGFR, we found that urinary vanadium (HR=1.07, 1.03-1.12), cobalt (HR=1.69, 1.21-2.37), nickel (HR=1.19, 1.08-1.3), copper (HR=1.03, 1.01-1.06), selenium (HR=1.33, 1.02-1.73), molybdenum (HR=1.48, 1.2-1.82) and iodine (HR=1.1, 1.02-1.2) were associated with an increased risk of new incident IKF or CKD cases during the follow-up. Also, urinary copper (OR=1.12, 1.04-1.21), silver (OR=1.83, 1-3.35), molybdenum (OR=1.02, 1.01-1.04) and cadmium (OR=1.05, 1.01-1.09) were associated with an increased risk of rapid eGFR decline. Conclusion In the general population, several urinary heavy metals/trace elements are associated with a rapid decline in kidney function or new cases of IKF/CKD.

Effects of iopromide contrast agents on kidney iNOS expression and tubular histopathology alterations

Contrast-induced acute kidney injury is a common complication marked by reduced kidney function within 48 hours of contrast administration. The aim of this study was to evaluate renal function, anatomy, and molecular changes at 24 hours, 48 hours, and 72 hours post-iodinated contrast media (ICM) administration. This true-experimental study used a post-test-only control group design. Rats underwent unilateral nephrectomy, followed by intravenous injection of ICM using iopromide 370 mg iodine/mL per rat at a dose of 231 mg iodine, and were then divided into four groups: control (C), rats terminated at 24 hours after iopromide administration (E24), rats terminated at 48 hours after iopromide administration (E48), and rats terminated at 72 hours (E72) after iopromide administration, with eight rats per group. Renal function (BUN and SCr levels) remained unchanged after 24, 48, and 72 hours of iopromide administration. Iopromide increased renal tubular damage, as shown by higher histopathological scores for loss of brush border and tubular necrosis, except for proteinaceous casts, where histopathological scores increase especially within the first 24 hours and decrease after 72 hours. Iopromide significantly altered iNOS expression in the glomerulus at 24 and 48 hours, and iNOS expression was decreased after 72 hours. iNOS expression in the intrarenal vascular and tubules was unaffected by iopromide administration. In conclusion, this study found no changes in renal function parameters, improvement in proteinaceous casts, and increased iNOS expression in the glomerulus, offering new insights into the effects of contrast on kidneys.

Clinical Pharmacokinetics and Safety of Remdesivir in Phase I Participants with Varying Degrees of Renal Impairment.

Remdesivir is a nucleotide analog prodrug approved for the treatment of COVID-19. This study evaluated the pharmacokinetics and safety of remdesivir and its metabolites (GS-704277 and GS-441524) in participants with varying degrees of renal impairment. Results of this phase I study, along with those of a phase III study, contributed to an extension of indication for remdesivir in the USA and Europe for use in patients with COVID-19 with all stages of renal impairment, including those on dialysis, with no dose adjustment. This phase I, open-label, parallel-group study enrolled participants who had mild (n=12), moderate (n = 11), or severe (n = 10) renal impairment or kidney failure (n = 6 with dialysis, n = 4 without dialysis). Healthy matched controls were enrolled as reference. Remdesivir was given as single intravenous doses of 100 mg (mild and moderate renal impairment), 40 mg (severe renal impairment, kidney failure predialysis), and 20 mg (kidney failure postdialysis and without dialysis). Plasma pharmacokinetics of remdesivir were not affected by mild, moderate, or severe renal impairment or kidney failure. Geometric least squares mean ratios ranged from 0.8 to 1.2 for remdesivir area under the plasma concentration-time curve (AUC). GS-704277 AUC was up to 2.8-fold higher and GS-441524 AUC up to 7.9-fold higher in participants with renal impairment. Adverse events and laboratory abnormalities were consistent with the existing safety profile for remdesivir. Observed pharmacokinetics for remdesivir and its metabolites in participants with renal impairment aligned with expected changes based on known routes of elimination. Remdesivir was generally safe and well tolerated in participants with renal impairment, and no new safety concerns were identified. These results, along with those from the phase III study in patients with COVID-19 with severely reduced kidney function, support the use of remdesivir in patients with any degree of renal impairment with no dose adjustments. EudraCT no. 2020-003441-10; 9 July 2020.

Correlation of early contrast-enhanced ultrasound parameters with postoperative graft function and at six months after kidney transplantation

Abstract Purpose We analyzed which contrast-enhanced ultrasound (CEUS) parameters are associated with reduced kidney function in the early postoperative period and are prognostic for kidney function six months after transplantation. Materials and Methods This prospective observational study included 74 patients in whom quantitative CEUS analysis and Doppler ultrasound were performed early after kidney transplantation (10±6 days). For each region of interest (ROI) the time-to-peak intensity (TTP) and the respective delta between ROIs within interlobar artery, cortex, and medulla were compared. Results were correlated with kidney function at the time of imaging and six months later. Results Patients with an eGFR&lt;30 ml/min at the time of investigation had significantly slower cortical enhancement with a longer cortical TTP (cTTP: 16.1±0.9 vs. 11.7±0.7 sec, p&lt;0.001), as well as a significant delay between the arterial and cortical phases (c–a), as shown in longer ∆TTP (c–a): 8.2±0.9 vs. 4.2 ± 0.5 sec, p&lt;0.001. There was a significant negative correlation between cTTP and eGFR with a correlation coefficient of −0.37 (p&lt;0.001), as well as between ∆TTP (c–a) and eGFR with a correlation coefficient of −0.40 (p&lt;0.001). Reduced kidney function after 6 months correlated significantly with the findings of the initial CEUS examination (p=0.005, correlation coefficient −0.39). Conclusion CEUS revealed significant differences in temporal enhancement dynamics in patients with reduced kidney function after transplantation. Quantitative CEUS might therefore be able to depict graft function regarding microvascular damage and be of prognostic value regarding long-term renal outcomes.

Untangling the Exposure-Response Relationship of Allopurinol in the Setting of Chronic Kidney Disease and Diuretic Use: Implications for Dosing.

Allopurinol dose reduction proportional to creatinine clearance (CLcr) results in suboptimal urate lowering in patients with gout. Similarly, diuretic therapy reduces oxypurinol clearance but is unexpectedly associated with the need for higher allopurinol doses to achieve the serum urate target (<0.36 mmol/L). The authors aimed to clarify the relationship between oxypurinol exposure and urate-lowering response in patients with gout at different stages of chronic kidney disease and those taking diuretics to determine the implications for maintenance dose selection. Oxypurinol and urate data from 5 clinical studies were available. Model-derived steady-state oxypurinol areas under the concentration-time curves (AUCss0-tau) were estimated using a Bayesian methodology. The observed response metrics included the percentage reduction in urate from baseline and achievement of the target urate level. Exposure-response was explored graphically and using logistic regression. In addition, the influence of chronic kidney disease and diuretic use on the allopurinol dose and oxypurinol AUCss0-tau requirements to achieve the serum urate target were explored. Data from 258 patients with gout taking allopurinol representing 1288 paired steady-state oxypurinol and serum urate measurements were available. Higher oxypurinol exposure seems to be required for urate-lowering response normalization and achieve the serum urate target in individuals with reduced kidney function and those taking diuretics. However, allopurinol dose requirements were reduced by 2-fold at the extremes of kidney function and unchanged in those taking or not taking diuretics. A lower allopurinol maintenance dose was required in patients with reduced kidney function (CLcr <30 mL/min), but this was not proportional to CLcr. Diuretic therapy did not influence allopurinol dose requirements.

Intestinal transport of organic food compounds and drugs: A scoping review on the alterations observed in chronic kidney disease

Background and aimsAround 850 million people worldwide are affected by chronic kidney disease (CKD). Patients with CKD often develop malnutrition and sarcopenia and changes in the pharmacokinetics of drugs. A reduced kidney function partially explains the prolonged half-life of certain drugs due to decreased renal clearance, which leads to an increased risk of adverse effects. While the intestine plays a fundamental role in this context, a systematic review of the effects of CKD on intestinal transport is lacking. We aimed to systematically summarize all the available evidence on intestinal transport of organic food components (carbohydrates/sugar, proteins/amino acids, fats, vitamins) and drugs (including drug transporters) in chronic kidney disease. MethodsWe conducted a systematic search of all the articles published until the 1st of April 2024, on five databases i.e. Embase, PubMed, Web of Science Core Collection, Cochrane Library, and Scopus. This systematic review was registered on the Open Science Framework (OSF) (osf.io/5e6wb) and was carried out according to the PRISMA 2020 guidelines. ResultsFrom 9205 articles identified, 68 met the inclusion criteria. Absorption of organic food compounds seems to be altered, in general, and reduced for vitamins. The expression of intestinal efflux drug transporters may be altered in CKD. ConclusionsDespite alterations in intestinal transport is suggested to be altered in CKD, the lack of recent studies, the paucity of human data and the heterogeneity of the methodologies used underscore the need for more research on the effect of CKD and uremia on intestinal transport.

Clinicopathologic, Proteomic and Outcome Characteristics of Renal Apolipoprotein C-II Amyloidosis: A Case Series

Amyloidosis derived from apolipoprotein C-II (AApoCII) is a recently discovered, rare form of amyloidosis. Data on clinical presentations and natural history are very limited. This study defines the clinicopathologic, proteomic and outcome characteristics of renal AApoCII. Case series. Twenty-five renal AApoCII cases were identified from the Mayo Clinic Tissue Proteomics Laboratory archives from January 2008 through January 2024. All patients were White, 19 were ≥65 years old at diagnosis, and 18 were female. Seven had a family history of CKD. Patients presented with proteinuria (median 3.3 g/day) and reduced kidney function (n=16, median creatinine 1.6 mg/dl). No patient had clinical evidence of other organ involvement by amyloidosis or features of monogenic hypertriglyceridemia. Histologically, amyloid deposits were often weakly positive for Congo red and involved glomeruli in all cases (with a nodular pattern in 22), whereas extraglomerular involvement was less common and generally mild. Proteomic analysis revealed abundant spectra for Apo C-II and for all 3 amyloid signature proteins (Apo E, Apo A-IV and SAP) in all cases, and detected an Apo C-II variant in 14 (K19T [p.Lys41Thr] in 12 and E47V [p.Glu69Val] in 2). Among 22 patients with follow-up available, there were 12 ESKD events and 2 deaths without ESKD during an average (SE) follow up of 75.5 (12.5) months. Retrospective design, small sample size, APOC2 gene sequencing performed in a smaller subset. AApoCII mostly affects the kidney, and manifests in the elderly with proteinuria and CKD. A minority of these patients had a family history of kidney disease. Kidney failure occurred in about half, whereas overall survival was more favorable.

Burosumab (Crysvita)

Canada’s Drug Agency recommends that Crysvita be reimbursed by public drug plans for the treatment of X-linked hypophosphatemia (XLH) in adult patients if certain conditions are met. The previous recommendation for Crysvita when initiated in pediatric patients who are at least 1 year of age and in whom epiphyseal closure has not yet occurred, continues to apply to those patients. Crysvita should only be covered to treat patients aged 18 years or older who have a diagnosis of XLH supported by classic clinical features of adult XLH and a confirmed PHEX gene variant, and who have not previously received it. Patients should also have a specific threshold for kidney function or reduced kidney function if it is confirmed not to be due to nephrocalcinosis, bone pain that is caused by XLH or osteomalacia, and have not had a sufficient response to conventional therapy (therapy with active vitamin D and oral phosphate). If a PHEX gene variant is not confirmed, XLH diagnosis can be confirmed with a serum intact fibroblast growth factor 23 (FGF23) level by a Kainos assay. Crysvita should only be reimbursed if it is prescribed by a physician who works in a comprehensive team of health care providers experienced in the diagnosis and management of XLH and if the cost of Crysvita is reduced. Reimbursement may be renewed on an annual basis for patients who do not meet any of the discontinuation criteria, which are the development of hyperparathyroidism, nephrocalcinosis, fasting hypophosphatemia, or fractures or pseudofractures based on X-ray.

Natriuretic peptides, kidney function and clinical outcomes in heart failure with mildly reduced or preserved ejection fraction: pooled data from the I-PRESERVE, TOPCAT, PARAGON and DELIVER trials

Abstract Background The prognostic utility of N-terminal pro-B-type (NT-proBNP) in patients with heart failure and chronic kidney disease (CKD) is incompletely understood since elevations in NT-proBNP could be related either to decreased clearance by the kidney or to increased severity of structural heart disease. Purpose We sought to assess the association of NT-proBNP with cardiovascular and mortality outcomes in patients with heart failure and mildly reduced or preserved ejection fraction, stratified by baseline kidney function. Methods We conducted a pooled analysis of individual participants with NT-proBNP and estimated glomerular filtration rate (eGFR) measured at baseline in the I-PRESERVE, TOPCAT (Americas region), PARAGON and DELIVER trials. We evaluated the relationship between NT-proBNP and kidney function using piecewise linear regression. Using multivariable Cox and Poisson regression models, we assessed the association of NT-proBNP with clinical outcomes across different levels of eGFR (≥60, 45-&amp;lt;60 and &amp;lt;45 mL/min/1.73m2). The primary outcome was hospitalisation for heart failure or cardiovascular death. Results Among 14,831 participants (mean age 72.1 years, 50.3% female, mean eGFR 63.3 mL/min/1.73m2 and median NT-proBNP 840 pg/mL) followed for a median 33.5 months, there were 3,092 primary outcomes, 2,184 heart failure hospitalisations, 1,465 cardiovascular and 1,049 non-cardiovascular deaths. Participants in lower eGFR categories were more likely to be older, female, and have atrial fibrillation and diabetes (all p&amp;lt;0.001). NT-proBNP levels increased by 9%, 8%, and 23% per 10 mL/min/1.73m2 lower eGFR in patients with baseline eGFR ≥60, 45-60, and &amp;lt;45 mL/min/1.73m2, respectively (P for non-linearity &amp;lt;0.001). For any given NT-proBNP concentration, participants with eGFR &amp;lt;45 mL/min/1.73m2 were at highest risk (Figure 1). Each doubling in NT-proBNP was associated with a 37% relative increase in the primary outcome (HR 1.37, 95% CI 1.34-1.41), consistent across different eGFR categories (P-interaction=0.42). Association between NT-proBNP and other clinical outcomes were also consistent across different levels of kidney function (all P-interaction&amp;gt;0.3; Figure 1). Equivalent risk for the primary outcome was apparent at NT-proBNP levels approximately 2.5- to 3.5-fold lower in patients eGFR &amp;lt;45 mL/min/1.73m2, compared to those with eGFR ≥60 mL/min/1.73m2. (Figure 2). Conclusion NTproBNP is a potent predictor of risk in patients with heart failure with mildly reduced or preserved ejection fraction across the spectrum of kidney function. However, in patients with reduced kidney function, lower NT-proBNP levels confer absolute risk of cardiovascular outcomes similar to substantially higher NT-proBNP levels in patients with normal kidney function. Accordingly, interpretation of NTproBNP levels should vary according to kidney function, particularly in those with eGFR &amp;lt;45 mL/min/1.73m2.

Incident HFpEF and time-dependent changes in markers of LVDD severity in women and men with pre-clinical LVDD

Abstract Background Over time, left ventricular diastolic dysfunction (LVDD) can progress towards heart failure with preserved ejection fraction (HFpEF). Yet, the identification of those at high risk of progression is challenging, and guidance on follow-up or preventive treatment is lacking. Purpose To study the incidence of HFpEF and changes over time in markers of LVDD severity in women and men with pre-clinical LVDD. In addition, we evaluate whether blood pressure and kidney function affect progression of LVDD. Methods We reinvited 146 participants from the HELPFul study (58% women and 42% men) with pre-clinical LVDD after a median follow-up of 4.3 [IQR: 3.9-4.7] years (Figure 1). The follow-up measurements were similar to baseline and encompassed a structured interview, physical examination, blood draw, electrocardiogram and (exercise) echocardiography. We determined HFpEF incidence and report changes over time in cardiovascular risk factors as well as echocardiographic characteristics and biomarkers of LVDD. Additionally, we studied whether changes in blood pressure and kidney function affected LVDD progression using generalized mixed models. LVDD progression was defined as an increase in plasma NT-proBNP levels and HFA-PEFF major functional and morphological abnormalities. All analyses were performed for women and men combined as well as stratified by sex. Results Fifteen (10%) of the 146 participants developed HF of whom 13 had HFpEF (9 women and 4 men) during follow-up. Over time, systolic and diastolic blood pressure levels remained stable while mean kidney function (eGFR) declined from 89±14 to 81±17 mL/min/1.73m2. Median NT-proBNP plasma levels increased from 71 [IQR: 44, 120] to 100 [IQR: 51, 157] pg/mL. The prevalence of major functional abnormalities according to the HFA-PEFF score increased from 84 to 91%, while the prevalence of morphological abnormalities increased from 25% to 39% (Figure 2). A higher systolic blood pressure in women and a higher diastolic blood pressure in men was associated with an increase in NT-proBNP plasma levels over time. Additionally, lower eGFR levels were related to increased NT-proBNP plasma levels over time in both men and women. There was a significant rise in the prevalence of major functional and morphological abnormalities with time, but blood pressure and kidney function did not affect this change over time. Conclusions A small proportion of women and men with preclinical LVDD developed incident HF over a 5-year follow-up period. High blood pressure and reduced kidney function were associated with increased levels of NT-proBNP over time. This highlights the need to further explore cardiorenal protection as a method to prevent HFpEF.Study design and HF outcomesLongitudinal changes in LVDD markers

The Impact of Primary Renal Diagnosis on Prognosis and the Varying Predictive Power of Albuminuria in the NURTuRE-CKD Study

Plain Language SummaryChronic kidney disease (CKD) is a broad term that describes a reduction in kidney function. However, there are several underlying causes of CKD. Using the NURTuRE-CKD study, we explore how the individual causes of CKD affect the risk of disease progression and how some of the tests we do are more accurate in predicting kidney failure (KF) in some causes of CKD rather than others. We found that a person’s type of kidney disease can significantly impact their risk of KF and death. For example, people with DKD or certain genetic conditions had a higher risk of KF, while those with other types, like tubulointerstitial disease, had a lower risk. Albuminuria, which measures the amount of a protein called albumin in the urine, is commonly used to predict kidney disease progression. However, we found that its effectiveness varies depending on the type of kidney disease. It was most helpful in predicting outcomes for people with vasculitis and DKD but added little value for those with genetic kidney diseases. In conclusion, recognizing the specific type of kidney disease is crucial for accurate risk assessment and effective treatment planning in CKD. This study highlights the importance of a tailored approach to managing kidney disease based on the primary diagnosis.

Antiproteinuric Effect and Transient Reduction in Kidney Function of Calcineurin Inhibitors in Hispanic Patients with Lupus Nephritis

Antiproteinuric Effect and Transient Reduction in Kidney Function of Calcineurin Inhibitors in Hispanic Patients with Lupus Nephritis

Presence and Progression of Changes in Bone Mass, Bone Quality, and Vascular Calcifications in Patients with Moderate to Advanced Reduction in Kidney Function

Presence and Progression of Changes in Bone Mass, Bone Quality, and Vascular Calcifications in Patients with Moderate to Advanced Reduction in Kidney Function

Kir4.1/Kir5.1 Channel Inhibition Acutely Ameliorates Hyperkalemia in Male Rats with Reduced Kidney Function

Kir4.1/Kir5.1 Channel Inhibition Acutely Ameliorates Hyperkalemia in Male Rats with Reduced Kidney Function

Mapping biological influences on the human plasma proteome beyond the genome

Broad-capture proteomic platforms now enable simultaneous assessment of thousands of plasma proteins, but most of these are not actively secreted and their origins are largely unknown. Here we integrate genomic with deep phenomic information to identify modifiable and non-modifiable factors associated with 4,775 plasma proteins in ~8,000 mostly healthy individuals. We create a data-driven map of biological influences on the human plasma proteome and demonstrate segregation of proteins into clusters based on major explanatory factors. For over a third (N = 1,575) of protein targets, joint genetic and non-genetic factors explain 10–77% of the variation in plasma (median 19.88%, interquartile range 14.01–31.09%), independent of technical factors (median 2.48%, interquartile range 0.78–6.41%). Together with genetically anchored causal inference methods, our map highlights potential causal associations between modifiable risk factors and plasma proteins for hundreds of protein–disease associations, for example, COL6A3, which possibly mediates the association between reduced kidney function and cardiovascular disease. We provide a map of biological and technical influences on the human plasma proteome to help contextualize findings from proteomic studies.