Reduced Kidney Function Research Articles

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-<60 and <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<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 <45 mL/min/1.73m2, respectively (P for non-linearity <0.001). For any given NT-proBNP concentration, participants with eGFR <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>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 <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 <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

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.

Six months of physical inactivity is insufficient to cause chronic kidney disease in C57BL/6J mice.

Chronic kidney disease (CKD) is a progressive disorder marked by a decline in kidney function. Obesity and sedentary behavior contribute to the development of CKD, though mechanisms by which this occurs are poorly understood. This knowledge gap is worsened by the lack of a reliable murine CKD model that does not rely on injury, toxin, or gene deletion to induce a reduction in kidney function. High-fat diet (HFD) feeding alone is insufficient to cause reduced kidney function until later in life. Here, we employed a small mouse cage (SMC), a recently developed mouse model of sedentariness, to study its effect on kidney function. Wildtype C57BL/6J male mice were housed in sham or SMC housing for six months with HFD in room (22°C) or thermoneutral (30°C) conditions. Despite hyperinsulinemia induced by the SMC+HFD intervention, kidneys from these mice displayed normal glomerular filtration rate (GFR). However, the kidneys showed early signs of kidney injury, including increases in Col1a1 and NGAL transcripts, as well as fibrosis by histology, primarily in the inner medullary/papilla region. High-resolution respirometry and fluorometry experiments showed no statistically significant changes in the capacities for respiration, ATP synthesis, or electron leak. These data confirm the technical challenge in modeling human CKD. They further support the notion that obesity and a sedentary lifestyle make the kidneys more vulnerable, but additional insults are likely required for the pathogenesis of CKD.

Sex and Population-Specific 99th Percentiles of Troponin for Myocardial Infarction in the Danish Population (DANSPOT).

Sex- and population-specific 99th percentiles of high-sensitivity cardiac troponin (hs-cTn) are recommended in guidelines although the evidence for a clinical utility is sparse. The DANSPOT trial will investigate the clinical effect of sex- and population-specific 99th percentiles of cTn. We report the 99th percentiles derived from this trial and their dependency on kidney function. We used samples from healthy Danish blood donors and measured hemoglobin A1c, N-terminal pro-brain natriuretic peptide and creatinine, and calculated an estimated glomerular filtration rate (eGFR). We compared 2 cutoffs for the eGFR of healthy participants (60 vs 90 mL/min/1.73 m2). The cTn assays investigated were Siemens Atellica and Dimension Vista hs-cTnI, Abbott hs-cTnI, and Roche hs-cTnT. A total of 2287 participants were sampled, of which 71 (3.1%) were excluded due to a history of heart disease (n = 4), insufficient material (n = 7), or a screening biomarker (n = 60). Of the remaining 2216 participants, 1325 (59.8%) had an eGFR ≥90 mL/min/1.73 m2. Compared to a cutoff of 60 mL/min/1.73 m2 for eGFR, using 90 mL/min/1.73 m2 resulted in lower 99th percentiles for females; Siemens Vista (46 vs 70 ng/L), Abbott (14 vs 18 ng/L), and Roche cTnT (10 vs 13 ng/L), and decreased the number of measurements above the manufacturers' 99th percentiles for all assays. We present reference values for 4 cTn assays for eGFR cutoffs of 60 and 90 mL/min/1.73 m2. These cutoffs differ based on the eGFR threshold for inclusion indicating that any chosen cutoff is also valuable with moderately reduced kidney function.

Hyperkalemia Management with Intravenous Insulin in Patients with Reduced Kidney Function.

Background: Insufficient kidney function increases the risk of hyperkalemia and hypoglycemia, particularly in hemodialysis-dependent patients. Hypoglycemia is a common complication of insulin-based hyperkalemia treatment. This study aims to evaluate the efficacy and safety of hyperkalemia treatment in hemodialysis-dependent and -non-dependent patients and identify risk factors associated with hypoglycemia. Methods: A retrospective observational cohort study was conducted to assess the efficacy and safety of hyperkalemia treatment including patients with reduced kidney function and hyperkalemia treated with intravenous insulin. The decline rate of potassium and glucose levels were compared between hemodialysis-dependent and non-dependent patients. In addition, univariate and multivariable logistic regression analyses were performed to identify risk factors associated with hypoglycemia. Results: A total of 172 patients with hyperkalemia and reduced kidney function were included. The steepest reduction of serum potassium levels happened within the first 6 h after insulin administration, at 1.1 and 0.9 mmol/L for hemodialysis-dependent and non-dependent patients, respectively. The incidence of hypoglycemia was 18%, and no significant difference was found between cohorts. Hemodialysis-dependent patients were more likely to be readmitted within one month with hyperkalemia, while all-cause ICU admission was more likely for non-dependent patients. Older patients, and those who had heart failure or received a second dose of insulin to treat hyperkalemia, were more likely to experience hypoglycemia. Conclusions: Monitoring blood glucose levels following insulin administration is essential given the complexity of patients' factors associated with hypoglycemia resulting from hyperkalemia treatment in patients with insufficient kidney function.

Longitudinal Trajectories of Estimated Glomerular Filtration Rate in a European Population of Living Kidney Donors.

A living donor (LD) kidney transplant is the best treatment for kidney failure, but LDs safety is paramount. We sought to evaluate our LDs cohort's longitudinal changes in estimated glomerular filtration rate (eGFR). We retrospectively studied 320 LDs submitted to nephrectomy between 1998 and 2020. The primary outcome was the eGFR change until 15years (y) post-donation. Subgroup analysis considered distinct donor characteristics and kidney function reduction rate (%KFRR) post-donation [-(eGFR6months(M)-eGFRpre-donation)/eGFRpre-donation*100]. Donors had a mean age of 47.3 ± 10.5years, 71% female. Overall, LDs presented an average eGFR change 6M onward of +0.35mL/min/1.73m2/year. The period with the highest increase was 6M-2Y, with a mean eGFR change of +0.85L/min/1.73m2/year. Recovery plateaued at 10years. Normal weight donors presented significantly better recovery of eGFR +0.59mL/min/1.73m2/year, compared to obese donors -0.18L/min/1.73m2/year (p = 0.020). Noteworthy, these results only hold for the first 5years. The subgroup with a lower KFRR (<26.2%) had a significantly higher decrease in eGFR overall of -0.21mL/min/1.73m2/year compared to the groups with higher KFRR (p < 0.001). These differences only hold for 6M-2Y. Moreover, an eGFR<50mL/min/1.73m2 was a rare event, with ≤5% prevalence in the 2-15Y span, correlating with eGFR pre-donation. Our data show that eGFR recovery is significant and may last until 10years post-donation. However, some subgroups presented more ominous kidney function trajectories.

Specific antigen-based stratification of membranous nephropathy in patients after haematopoietic stem cell allotransplantation - a case series and literature review.

Nephrotic syndrome (NS) is a rare complication that can occur after haematopoietic stem cell transplantation (HSCT). In patients with membranous nephropathy (MN) who have undergone allogeneic HSCT, a new antigen called protocadherin FAT1 has been identified. Our objective is to present a case series of MN patients after HSCT with a novel antigen-based stratification. Patients who developed full-blown NS due to MN after an HSCT were enrolled in the University Hospital Centre Zagreb study. The first two patients were treated with an HSCT for acute myeloid leukaemia, and both developed NS after cessation of graft versus host disease (GVHD) prophylaxis. The first patient had reduced kidney function, while the second had completely preserved function. Kidney biopsy showed MN with only subepithelial deposits. A thorough examination revealed that there was no secondary cause of the disease. The patients achieved complete remission after undergoing immunosuppression treatment. The third patient underwent HSCT for acute lymphoblastic leukaemia. He developed both acute and chronic GVHD and also experienced avascular hip necrosis. After sixteen years, the patient developed NS with preserved kidney function. The kidney specimen showed membranous nephropathy (MN) with mesangial and subepithelial deposits. Extensive research was conducted, but no secondary cause for the MN was detected. All three cases tested negative for anti-PLA2R antibodies. Biopsy tissue samples were analysed using laser microdissection and tandem mass spectrometry of glomeruli for the detection of different specific antigens. Patients one and two tested positive for FAT1, whereas patient three tested positive for PCSK6. MN can develop at various time intervals after HSCT. Specific antigen testing can help establish the relationship between MN and HSCT. In the future, serum testing for anti-FAT1 antibodies in HSCT patients could be significant in diagnosing FAT1-associated MN, similar to how anti-PLA2R antibodies are significant in diagnosing PLA2R-associated MN.

Chronic kidney disease - alternative labels used by Australian general practitioners. A qualitative interview study.

Guidelines for terminology defining chronic kidney disease (CKD) have been in use for 20 years. Age is not currently considered in the guideline definition of CKD. In previous studies, General Practitioners (GPs) have been reluctant to give older patients the label of CKD. Our study aimed to determine what language general practitioners are using to describe or label chronic kidney disease with their older patients, and to explore the reasons for their use of alternative language. This was a descriptive qualitative interview study of Australian GPs. Twenty-seven GPs were recruited via email and interviewed regarding their management of CKD., GPs were asked what language and terminology they used when discussing a diagnosis of CKD with their older patients. "Labelling of CKD", the language that GPs use when talking about CKD with their patients, emerged as a major theme from the initial GP interviews. Sub-themes emerged, including: types of labels, alternate labels and rationale for alternate labelling. GPs used descriptions of "reduced kidney function" to explain CKD to their patients, either in parallel with the diagnosis of CKD or instead of it. GPs had concerns about the words "chronic" and "disease" and used different terminology to explain these words to patients when diagnosing them with CKD. GPs use alternative descriptions to explain mild decrease in kidney function with older patients. Alternative labels that denote level of risk to older patients, without creating unnecessary concern about normal age-related kidney function need to be explored.

Natriuretic Peptides, Kidney Function, and Clinical Outcomes in Heart Failure With Preserved Ejection Fraction

BackgroundN-terminal pro–B-type natriuretic peptides (NT-proBNPs) are guideline-recommended biomarkers for risk stratification in patients with heart failure. However, NT-proBNP levels are often elevated in chronic kidney disease, introducing uncertainty about their prognostic relevance in persons across a broad range of estimated glomerular filtration rate (eGFR). ObjectivesThe aim of this study was 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. MethodsA pooled analysis was conducted of participants with NT-proBNP and eGFR measured at baseline in the I-PRESERVE (Irbesartan in Heart Failure and Preserved Ejection Fraction), TOPCAT (Americas region) (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function), PARAGON (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction), and DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trials. The relationship between NT-proBNP and eGFR was assessed using piecewise linear regression. Using multivariable Cox and Poisson regression models, the association of NT-proBNP with outcomes across a range of eGFR was evaluated. The primary outcome was hospitalization for heart failure or cardiovascular death. ResultsAmong 14,831 participants (mean age: 72.1 years; 50.3% female; mean eGFR: 63.3 mL/min/1.73 m2, and median NT-proBNP: 840 pg/mL) followed up for a median 33.5 months, there were 3,092 primary outcomes. NT-proBNP levels increased by 9%, 8%, and 23% per 10 mL/min/1.73 m2 lower eGFR in patients with baseline eGFR ≥60, 45-<60, and <45 mL/min/1.73 m2, respectively (P for nonlinearity < 0.001). 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 for interaction = 0.42). For the same incidence of the primary outcome, NT-proBNP levels were approximately 2.5- to 3.5-fold lower in patients with eGFR <45 mL/min/1.73 m2, compared with patients with eGFR ≥60 mL/min/1.73 m2. Similar patterns were observed across all outcomes studied, including cardiovascular and noncardiovascular death. ConclusionsThe same NT-proBNP concentration predicts a substantially higher absolute risk of adverse outcomes for people with heart failure and reduced kidney function, compared with those with preserved kidney function. These data call into question proposals for higher NT-proBNP references ranges in people with CKD, and suggest that reduced kidney function per se should not be a reason to disregard higher NT-proBNP levels.

Objective Measures of Cardiometabolic Risk and Advanced Fibrosis Risk Progression in Primary Care Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease

BackgroundWe examined the association of objective measures of cardiometabolic risk with progression to a high-risk for advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) at initially low- and indeterminate-risk for advanced fibrosis. MethodsWe performed a retrospective cohort study of primary care patients with MASLD between 2012 and 2021. We evaluated patients with MASLD and low- or indeterminate-risk Fibrosis-4 Index (FIB-4) scores and followed them until the outcome of a high-risk FIB-4 (≥2.67), or the end of the study period. Exposures of interest were body mass index, systolic blood pressure, hemoglobin A1c, cholesterol, estimated glomerular filtration rate, and smoking status. Variables were categorized by the threshold for primary care therapy intensification. Unadjusted and adjusted Cox regression models were developed for the outcome of time to a high-risk FIB-4 value. ResultsThe cohort included 1347 patients with a mean follow-up of 3.6 years (SD 2.7). Of the cohort, 258 (19%) had a subsequent FIB-4 > 2.67. In the fully adjusted Cox regression models, mean systolic blood pressure ≥ 150 mm Hg (1.57; 95% confidence interval (CI) 1.02-2.41) and glomerular filtration rate ≤ 59 ml/min (hazard ratio 2.78; 95%CI 2.17-3.58) were associated with an increased hazard of a high-risk FIB-4, while receiving a statin prescription (hazard ratio 0.51; 95%CI 0.39-0.66) was associated with a lower risk. ConclusionsNearly 1 in 5 primary care patients with MASLD transitioned to a high-risk FIB-4 score during 3.6 years of follow-up, and uncontrolled blood pressure and reduced kidney function were associated with an increased hazard of a FIB-4 at high-risk for advanced fibrosis.

Sodium-Glucose Cotransporter-2 Inhibitors Use in Patients with Reduced Kidney Function Hospitalized for Fluid Overload and Heart Failure: An Observational Study.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are recommended in kidney disease and heart failure to reduce adverse clinical outcomes, but utilization can vary. To understand potential gaps in clinical practice and identify opportunities for improvement, we aimed to describe the prevalence and factors associated with SGLT2i prescription in patients with reduced kidney function hospitalized for fluid overload and/or heart failure. Single-center observational study of patients with reduced kidney function (eGFR 20-59 mL/min/1.73 m2) hospitalized for fluid overload or heart failure between January 2022 and December 2023. Data were retrieved from electronic medical records. The outcome was SGLT2i prescription at discharge. Potential variables affecting SGLT2i prescription were identified during stakeholder engagement and evaluated using multivariable logistic regression. Among 2,543 patients, the median age was 79 (71, 86) years and admission eGFR was 38.7 (28.4, 49.4) mL/min/1.73 m2. SGLT2i was prescribed to 630 (24.8%) patients at discharge. SGLT2i prescription at discharge was independently associated with cardiovascular disease (OR 1.76, 95% CI: 1.31-2.35), diabetes (OR 1.59, 95% CI: 1.19-2.14), fluid overload or heart failure as the primary discharge diagnosis (OR 1.71, 95% CI: 1.29-2.28), SGLT2i pre-hospitalization (OR 104.91, 95% CI: 63.22-174.08), RAS blocker (OR 2.1, 95% CI: 1.65-2.89), and higher eGFR (OR 1.01, 95% CI: 1.003-1.02) at discharge; but inversely associated with older age (OR 0.97, 95% CI: 0.96-0.98). SGLT2i prescription at discharge was suboptimal among patients with reduced kidney function hospitalized for fluid overload and/or heart failure, especially in older age and more severe kidney disease. Additionally, cardiovascular disease, diabetes, primary discharge diagnosis of fluid overload or heart failure, prior SGLT2i use, and concurrent RAS blocker at discharge were independently associated with SGLT2i prescription at discharge. Interventions are needed to increase clinicians' knowledge and overcome clinical inertia to increase SGLT2i use in patients with fluid overload and heart failure.

Metformin attenuates PM2.5-induced oxidative stress by inhibiting the AhR/CYP1A1 pathway in proximal renal tubular epithelial cells

The harmful effects of PM2.5 on human health, including an increased risk of chronic kidney disease (CKD), have raised a lot of attention, but the underlying mechanisms are unclear. We used the Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) to simulate the inhalation of PM2.5 in the real environment and established an animal model by exposing C57BL/6 mice to filtered air (FA) and Particulate Matter (PM2.5) for 8 weeks. PM2.5 impaired the renal function of the mice, and the renal tubules underwent destructive changes. Analysis of NHANES data showed a correlation between reduced kidney function and higher blood levels of PM2.5 components, polychlorinated biphenyls (PCBs) and dioxins, which are Aryl hydrocarbon Receptor (AhR) ligands. PM2.5 exposure induced higher levels of AhR and CYP1A1 and oxidative stress as evidenced by the higher levels of ROS, MDA, and GSSG in kidneys of mice. PM2.5 exposure led to AhR overexpression and nuclear translocation in proximal renal tubular epithelial cells. Inhibition of AhR reduced CYP1A1 expression and PM2.5-increased levels of ROS, MDA and GSSG. Our study suggested metformin can mitigate PM2.5-induced oxidative stress by inhibiting the AhR/CYP1A1 pathway. These findings illuminated the role of AhR/CYP1A1 pathway in PM2.5-induced kidney injury and the protective effect of metformin on PM2.5-induced cellular damage, offering new insights for air pollution-related renal diseases.

Causal Relationship Between Kidney Function and Cancer Risk: A Mendelian Randomization Study

Rationale & ObjectivePatients treated with kidney replacement therapy experience a 1.5 to 2-fold increased risk of cancer and cancer mortality compared to the general population. Whether this excess risk extends to people with earlier stages of chronic kidney disease is unclear. This study explored the potentially causal relationship between reduced kidney function and cancer. Study DesignTwo-sample Mendelian randomization (MR). Setting & ParticipantsGenome Wide Association Study (GWAS) summary statistics for estimated glomerular filtration rate (eGFR) (n=567,460) and urinary albuminuria (UACR) (n=127,865) from the CKDGen consortium and cancer outcomes from the UK Biobank (n=407,329). ExposureseGFR and UACR. OutcomesOverall cancer incidence, cancer-related mortality, and site-specific colorectal, lung, and urinary tract cancer incidence. Analytical ApproachUnivariable and multivariable MR were conducted for all outcomes using inverse-variance weighted methods. ResultsThe mean eGFR and median UACR were 91.4 mL/min/1.73m2 and 9.32 mg/g in the CKDGen and 90.4 mL/min/1.73m2 and 9.29 mg/g in the UK Biobank. There were 98,093 cases of cancer, 6,664 colorectal, 3584 lung, and 3,271 urinary tract. There were 15,850 cases of cancer-related death, The genetic instruments for eGFR and UACR comprised 34 and 38 variants, respectively. Genetically predicted kidney function (eGFR and UACR) was not associated with overall cancer risk or cancer death. No associations of genetically predicted eGFR and UACR with overall cancer incidence were observed; odds ratio (95%CI; p-value) of 0.88 (0.40-1.97; p=0.76) and 0.90 (0.78-1.04; p=0.16), respectively. An adjusted generalized additive model for eGFR and cancer demonstrated evidence of non-linearity. There was no evidence of a causal association between eGFR and cancer in a stratified MR. LimitationsTo avoid overlapping samples a smaller GWAS for UACR was used, reducing the strength of the instrument and potentially introducing population stratification. ConclusionsThese findings did not demonstrate a causal association of kidney function with overall cancer incidence or cancer-related death.

Cancer therapy in patients with reduced kidney function.

Chronic Kidney Disease (CKD) and cancer constitute two major public health burdens and are on the rise. Moreover, the number of patients affected simultaneously by both conditions is growing. Potential nephrotoxic effect of cancer therapies is particularly important for patients with CKD, as they are also affected by several comorbidities. Therefore, administering the right therapy at the right dose for patients with decreased kidney function can represent a daunting challenge. We review in detail the renal toxicities of anti-cancer therapies i.e. conventional chemotherapy, targeted therapy, immune checkpoint inhibitors, and radioligand therapies, issue recommendations for patient monitoring along with guidance on when to withdraw treatment and suggest dosage guidelines for select agents in advanced stage CKD. Various electrolytes disturbances can occur as the result of the administration of anti-cancer agents in the patient with decreased kidney function. These patients are prone to developing hyponatremia, hyperkalemia, and other metabolic abnormalities because of a decreased GFR. Therefore, all electrolytes, minerals and acid base status should be checked at baseline and before each administration of chemotherapeutic agents. Moreover, studies on patients on kidney replacement therapy (KRT) are very limited and only single cases or small case series are published. Therefore, clinical therapeutical decisions in cancer patients with decreased function should be made by multidisciplinary teams constituted of medical oncologists, nephrologists, and other specialists. Onconephrology is an evolving and expanding subspecialty. It is crucial to consider anticancer drug treatment in these patients and offer them a chance to be treated effectively.

Effect of Pravastatin on Kidney Function in Patients with Dyslipidemia and Type2 Diabetes Mellitus: A Multicenter Prospective Observational Study.

Several studies have reported that pravastatin can mitigate the progression of kidney disease, but limited evidence exists regarding its effects on kidney function in Asian patients. This multicenter prospective observational study aimed to assess the effect of pravastatin on kidney function in Korean patients with dyslipidemia and type2 diabetes mellitus (T2DM) in clinical practice. This 48-week prospective multicenter study included 2604 of 2997 eligible patients with dyslipidemia and T2DM who had available estimated glomerular filtration rate (eGFR) measurements. The primary endpoint was eGFR percent change at week24 from baseline. We also assessed secondary endpoints, which included percent changes in eGFR at weeks12 and 48 from baseline, as well as changes in eGFR, metabolic profiles (lipid and glycemic levels) at 12, 24, and 48weeks from baseline, and safety. We noted a significant improvement in eGFR, with mean percent changes of 2.5%, 2.5%, and 3.0% at 12, 24, and 48weeks, respectively (all adjusted p < 0.05). The eGFR percent changes significantly increased in subgroups with baseline eGFR 30-90mL/min/1.73m2, glycated hemoglobin (HbA1c) ≥ 7 at baseline, no hypertension history, T2DM duration > 5years, or previous statin therapy. Lipid profiles were improved and remained stable throughout the study, and interestingly, fasting glucose and HbA1c were improved at 24weeks. Our findings suggest that pravastatin may have potential benefits for improving eGFR in Korean patients with dyslipidemia and T2DM. This could make it a preferable treatment option for patients with reduced kidney function. NCT05107063 submitted October 27, 2021.

Proliferative glomerulonephritis with monoclonal IgG deposits in an adolescent successfully treated with daratumumab

AbstractThere is no specific treatment for proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID), a disease that is very rare in the pediatric population. We report the case of a 15-year-old boy who presented with mildly reduced kidney function and nephrotic syndrome. Kidney biopsy revealed PGNMID with monoclonal deposits of IgG3 with kappa light chain restriction. Flow cytometry showed a significant CD38 plasma cell population in the peripheral blood in the absence of other signs of hematological malignancy. The patient was treated with a 6-month course of daratumumab, a monoclonal antibody targeting CD38. There was a significant reduction in proteinuria and normalization of kidney function. Based on positive experience with adults, daratumumab should also be studied in children with PGNMID.