Kidney Function Decline In Patients Research Articles

Reduction of circulating methylglyoxal levels by a Mediterranean diet is associated with preserved kidney function in patients with type 2 diabetes and coronary heart disease: From the CORDIOPREV randomized controlled trial

AimAdvanced glycation end products (AGEs) play a role in kidney disease in type 2 diabetes mellitus (T2DM). However, there have been no prior controlled clinical trials examining the effects of specific diets on AGE metabolism and their impact on kidney function. Our aim was to assess whether modulating AGE metabolism resulting in reduced AGEs levels, after consumption of two healthy diets, could delay kidney function decline in patients with T2DM and coronary heart disease (CHD). MethodsT2DM patients (540 out of 1002 patients from the CORDIOPREV study), with estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2, were classified based on their baseline kidney function: normal eGFR (≥ 90 ml/min/1.73 m2), mildly decreased eGFR (60- < 90 ml/min/1.73 m2) and moderately decreased eGFR (<60 ml/min/1.73 m2). Serum AGE levels, methylglyoxal (MG) and N-carboximethyllysine (CML), and gene expression related to AGE metabolism (AGER1, RAGE, and GloxI mRNA) were measured before and after 5-years of dietary intervention (a Mediterranean diet or a low-fat diet). ResultsMediterranean diet produced a lower declined of eGFR compared to the low-fat diet only in patients with mildly decreased eGFR (P = 0.035). Moreover, Mediterranean diet was able to decrease MG levels and increase GloxI expression in normal and mildly decreased eGFR patients (all P < 0.05). One standard deviation increment of MG levels after dietary intervention resulted in a 6.8-fold (95 % CI 0.039;0.554) higher probability of eGFR decline. ConclusionOur study showed that lowering circulating AGE levels, specifically MG, after following a Mediterranean diet, might be linked to the preservation of kidney function, evidenced by a decreased decline of eGFR in T2DM patients with CHD. Patients with mildly decreased eGFR could potentially benefit more from AGE reduction in maintaining kidney function.

Higher beta-hydroxybutyrate ketone levels associated with a slower kidney function decline in ADPKD.

Dysregulated energy metabolism is a recently discovered key feature of autosomal dominant polycystic kidney disease (ADPKD). Cystic cells depend on glucose and are poorly able to use other energy sources such as ketone bodies. Raising ketone body concentration reduced disease progression in animal models of polycystic kidney diseases. Therefore, we hypothesized that higher endogenous plasma beta-hydroxybutyrate (BHB) concentrations are associated with reduced disease progression in patients with ADPKD. We analyzed data from 670 patients with ADPKD participating in the Developing Intervention Strategies to Halt Progression of ADPKD (DIPAK) cohort, a multi-center prospective observational cohort study. BHB was measured at baseline using nuclear magnetic resonance spectroscopy. Participants were excluded if they had type 2 diabetes, were using disease-modifying drugs (e.g. tolvaptan, somatostatin analogs), were not fasting or had missing BHB levels, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations. Of the participants, 61% were female, with an age of 47.3±11.8 years, a height-adjusted total kidney volume (htTKV) of 834 [interquartile range (IQR) 495-1327] mL/m and an estimated glomerular filtration rate (eGFR) of 63.3±28.9mL/min/1.73 m2. The median concentration of BHB was 94 (IQR 68-147) µmol/L. Cross-sectionally, BHB was associated neither with eGFR nor with htTKV. Longitudinally, BHB was positively associated with eGFR slope {B=0.35mL/min/1.73 m2 [95% confidence interval (CI) 0.09 to 0.61], P=.007}, but not with kidney growth. After adjustment for potential confounders, every doubling in BHB concentration was associated with an improvement in the annual rate of eGFR by 0.33mL/min/1.73 m2 (95% CI 0.09 to 0.57, P=.008). These observational analyses support the hypothesis that interventions that raise BHB concentration could reduce the rate of kidney function decline in patients with ADPKD.

Using Deep Learning to Determine Kidney Function Decline in Patients with ADPKD

Using Deep Learning to Determine Kidney Function Decline in Patients with ADPKD

Higher circulating levels of non-esterified fatty acids are associated with faster kidney function decline in post-menopausal women with type 2 diabetes: a pilot prospective study.

Currently, there is little and inconsistent evidence regarding the possible adverse effects of circulating levels of non-esterified fatty acids (NEFA) on kidney function decline in patients with type 2 diabetes mellitus (T2DM). We followed for a median of 4.6 years 85 post-menopausal women with non-insulin-treated T2DM and preserved kidney function at baseline. Serum NEFA concentrations were measured using an enzymatic colorimetric method. Glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Enrolled patients had a baseline mean eGFRCKD-EPI of 83 ± 12mL/min/1.73m2 and a median serum NEFA concentration of 662uEq/L (interquartile range 524-842uEq/L). During the follow-up period, 13 patients developed kidney function decline at follow-up (defined as an eGFRCKD-EPI decline ≥ 30% from baseline). In Cox proportional hazards regression analyses, higher serum NEFA levels were significantly associated with an increased risk of developing kidney function decline (adjusted-hazard ratio 3.67, 95% CI 1.64-8.22, p < 0.001; for each 1-SD increment, i.e., 262uEq/L), even after adjustment for waist circumference, hemoglobin A1c, C-reactive protein, HOMA-estimated insulin resistance, hypertension, dyslipidemia, microalbuminuria, baseline eGFRCKD-EPI, as well as temporal changes in HbA1c levels or the use of renin-angiotensin system inhibitors over the follow-up. The findings of this exploratory prospective study show that in post-menopausal women with T2DM and preserved kidney function at baseline, higher circulating levels of NEFA were strongly associated with a faster kidney function decline, even after adjustment for established renal risk factors and potential confounders.

Urinary Fetuin-A Fragments Predict Progressive Estimated Glomerular Filtration Rate Decline in Two Independent Type 2 Diabetes Cohorts of Different Ethnicities

Introduction: There is a great clinical need for novel markers to predict kidney function decline in patients with type 2 diabetes. We explored the potential of posttranslationally modified fetuin-A fragments in urine (uPTM-FetA) as such a marker. Methods: We included patients with type 2 diabetes from two independent, nonoverlapping prospective cohort studies. A cut-off for uPTM-FetA, measured via ELISA method, was determined using the Youden index in the primary cohort of patients with type 2 diabetes from Taiwan. Kidney endpoint was defined as an estimated glomerular filtration rate (eGFR) decline ≥30% from baseline, reaching of an eGFR <15 mL/min/1.73 m², or a need of renal replacement therapy. Prospective associations were assessed in Cox regression models. All analyses were replicated in a cohort of patients with type 2 diabetes from the Netherlands. Results: In total, 294 patients with type 2 diabetes (age 61 ± 10 years, 55% male, eGFR 88 ± 16 mL/min/1.73 m²) were included in the primary cohort. During a follow-up of median 4.6 years, 42 participants (14%) experienced the kidney endpoint. Using the defined cut-off, a high uPTM-FetA was associated with a higher risk of renal function decline (P_log-rank < 0.0001). This association was similar in subgroups depending on albuminuria. This association remained, independent of age, sex, baseline eGFR, albuminuria, HbA1c, and other potential confounders (HR: 9.94; 95% CI: 2.96–33.40; p < 0.001 in the final model). Analyses in the validation cohort (376 patients with type 2 diabetes, age 64 ± 11 years, 66% male, eGFR 76 ± 24 mL/min/1.73 m²) using the same cut-off yielded similar results. Conclusion: uPTM-FetA was independently associated with kidney function decline in patients with type 2 diabetes validated in a 2-cohort study. The significant additive predictive power of this biomarker from conventional risk factors suggests its clinical use for renal function progression in patients with type 2 diabetes.

Management of Hyperkalemia in Patients with Chronic Kidney Disease Using Renin Angiotensin Aldosterone System Inhibitors.

Use of renin-angiotensin-aldosterone system (RAAS) inhibiting medications is critical in the prevention of cardiovascular disease and kidney function decline in patients with chronic kidney disease (CKD); however, these agents can lead to hyperkalemia, an electrolyte disorder associated with risk of arrythmia, conduction disorders, and increased overall mortality. Discontinuation, or reduction of dose, of RAAS inhibitor therapy in hyperkalemic patients with CKD can lead to loss of kidney and cardiovascular protection afforded by these medications. Given the high prevalence of hyperkalemia among patients with CKD utilizing RAAS inhibitors, clear management principles are critical to minimize risk and maximize benefit when facing this clinical dilemma. Strategies to mitigate hyperkalemia that do not interfere with optimal RAAS inhibitor therapy should be prioritized when managing potassium elevation in patients with CKD. These strategies include discontinuing non-RAAS inhibitor medications known to cause hyperkalemia, correction of metabolic acidosis, and maximization of medication therapies that lower serum potassium, including diuretics and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Initiation of potassium exchange resins should also be considered to allow for sustained RAAS inhibitor utilization. An approach which employs multiple strategies concurrently is important to mitigate hyperkalemia and maintain long-term use of RAAS-inhibitors. Persistence of RAAS inhibitor use in patients with CKD is important to slow kidney function decline, delay onset of dialysis or the need for kidney transplant, and prevent adverse cardiovascular outcomes. When hyperkalemia develops among patients with CKD utilizing a RAAS inhibitor, a deliberate effort to reduce serum potassium levels using an approach that allows for continuation of maximally dosed RAAS inhibitor therapy is important. Patient education and engagement in the potassium management process is important for sustained success.

Association Between Risperidone Use and Kidney Function Decline in Patients with Schizophrenia: A Retrospective Cohort Study

PurposeSeveral D-amino acids have been shown to be protective against kidney injury in mice. Risperidone, a currently used atypical antipsychotic agent for schizophrenia, is also known to inhibit the activity of D-amino acid oxidase, which degrades certain D-amino acids. Based on the hypothesis that risperidone would prevent kidney disease progression, this study investigated the association between risperidone use and kidney function decline in patients with schizophrenia. MethodsThis retrospective cohort study included patients who were diagnosed with schizophrenia and had data available from two or more serum creatinine measurements between April 1, 2010, and March 31, 2020. Patients who used risperidone for at least 30 days were included in the risperidone group, whereas those who had no record of risperidone use were included in the control group. Cox regression models were used to evaluate the risk for 40% decline in estimated glomerular filtration rate (eGFR) in patients treated with risperidone compared to that in the control group. FindingsOverall, 212 patients used risperidone and 1468 patients had no record of risperidone use. The mean age was 55 years, 759 (45%) of the patients were male, and the mean eGFR at baseline was 88 mL/min/1.73 m2. The mean age in the risperidone group was less than that in the control group (52 vs 56 years); other baseline characteristics were comparable between the two groups. During a mean follow-up of 1.6 years, 267 patients (16%) had a 40% eGFR decline. The incidence rate of 40% eGFR decline was lower in the risperidone group than in the control group (60 vs 104 per 1000 person-years). After adjustment for baseline age, sex, and eGFR, risperidone use was associated with a decreased risk for 40% eGFR decline (hazard ratio = 0.54; 95% CI, 0.33–0.87; P = 0.01). ImplicationsRisperidone use may be associated with decreased risk for kidney function decline in patients with schizophrenia. Further studies are warranted to validate these findings.

Cardiovascular Autonomic Neuropathy and Risk of Kidney Function Decline in Type 1 and Type 2 Diabetes: Findings From the PERL and ACCORD Cohorts.

Previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among persons with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N=469) and with type 2 diabetes (T2D) from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (N=7,973). Baseline CAN was ascertained using ECG-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss ≥-5 ml/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed effect, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 (95%CI [-1.93, -0.37], P= 4.0x10-3) ml/min/1.73m2/year in PERL and 0.34 (95%CI [-0.49, -0.19], P= 6.3x10-6) ml/min/1.73m2/year in ACCORD. This translated in 2.11 (95% CI [1.23-3.63], P=6.9x10-3) and 1.39 (95% CI [1.20-1.61], P=1.1x10-5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (HR=2.60, 95%CI [1.15-5.45], p=0.02 in PERL and HR=1.54, 95%CI [1.28-1.84], P=3.8×10-6 in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help develop new therapies to prevent kidney function decline in patients with diabetes.

Effects of tolvaptan discontinuation in patients with autosomal dominant polycystic kidney disease: a post hoc pooled analysis

BackgroundTolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) who are at risk of rapid progression. Given that treatment requires commitment to long-term use, we evaluated the effects of tolvaptan discontinuation on the trajectory of ADPKD progression.MethodsThis was a post hoc analysis of pooled data from two clinical trials of tolvaptan (TEMPO 2:4 [NCT00413777] and TEMPO 3:4 [NCT00428948]), an extension trial (TEMPO 4:4 [NCT01214421]), and an observational study (OVERTURE [NCT01430494]) that enrolled patients from the other trials. Individual subject data were linked longitudinally across trials to construct analysis cohorts of subjects with a tolvaptan treatment duration > 180 days followed by an off-treatment observation period of > 180 days. For inclusion in Cohort 1, subjects were required have ≥ 2 outcome assessments during the tolvaptan treatment period and ≥ 2 assessments during the follow-up period. For Cohort 2, subjects were required to have ≥ 1 assessment during the tolvaptan treatment period and ≥ 1 assessment during the follow-up period. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). Piecewise-mixed models compared changes in eGFR or TKV in the on-treatment and post-treatment periods.ResultsIn the Cohort 1 eGFR population (n = 20), the annual rate of eGFR change (in mL/min/1.73 m2) was -3.18 on treatment and -4.33 post-treatment, a difference that was not significant (P = 0.16), whereas in Cohort 2 (n = 82), the difference between on treatment (-1.89) and post-treatment (-4.94) was significant (P < 0.001). In the Cohort 1 TKV population (n = 11), TKV increased annually by 5.18% on treatment and 11.69% post-treatment (P = 0.06). In Cohort 2 (n = 88), the annual TKV growth rates were 5.15% on treatment and 8.16% post-treatment (P = 0.001).ConclusionsAlthough limited by small sample sizes, these analyses showed directionally consistent acceleration in measures of ADPKD progression following the discontinuation of tolvaptan.

#3682 THE KETONE BODY BETA-HYDROXYBUTYRATE IS ASSOCIATED WITH BETTER KIDNEY FUNCTION OUTCOME IN PATIENTS WITH ADPKD: RESULTS OF THE DIPAK COHORT

Abstract Background and Aims A dysregulated energy metabolism is a key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD), characterized by cystic cells being dependent on glucose and poorly able to use other energy sources such as ketone bodies. Besides providing energy, ketone bodies, especially beta-hydroxybutyrate, can act as signaling metabolites and reduce inflammation and oxidative stress. In experimental studies, raising ketone body concentration reduced disease progression. Therefore, we hypothesized that higher endogenous serum beta-hydroxybutyrate concentration reduces disease progression in patients with ADPKD. Method We analyzed data from the DIPAK cohort, a prospective observational cohort study that included 670 patients with ADPKD. Beta-hydroxybutyrate was measured at baseline using nuclear magnetic resonance spectroscopy. We excluded participants with type 2 diabetes, who used disease-modifying drugs (e.g., tolvaptan, somatostatin analogs), were not fasting, or had missing beta-hydroxybutyrate, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations. Results The median concentration of beta-hydroxybutyrate was 94 (IQR 68–147) μmol/L. Of the participants, 61% were female, the mean age was 47.3 ± 11.8 years, and the mean estimated glomerular filtration rate (eGFR) was 63.3 ± 28.9 mL/min/1.73 m2. Cross-sectionally, beta-hydroxybutyrate was neither associated with eGFR nor with kidney volume. Longitudinally, beta-hydroxybutyrate was positively associated with the eGFR slope (B = 0.37 (95% CI 0.11 to 0.62), p = 0.005) but not with kidney growth. After adjustment for potential confounders, every doubling in beta-hydroxybutyrate concentration reduced the annual rate of eGFR loss by 0.34 (95% CI 0.10 to 0.58, p = 0.005) ml/min/1.73 m2. Conclusion These analyses support the hypothesis that raising the beta-hydroxybutyrate concentration, one of the ketone bodies, reduces the rate of kidney function decline in patients with ADPKD.

Predictors of decline in kidney function in the general population: a decade of follow-up from the Tehran Lipid and Glucose Study

Background and aims We aimed to assess the potential socio-demographic, clinical, and lifestyle-related risk factors for kidney function decline (KFD), defined as ≥30% estimated glomerular filtration rate (eGFR) decline, in an Iranian cohort study. Methods 7190 participants (4049 women) aged 20–90 years with 2–5 eGFR data from examinations (2001–2005 to 2015–2018) were included. Cox proportional hazard models were used to examine the association between potential risk factors and eGFR decline. Results During 11.5 years of follow-up, 1471 (889 women) participants had incident KFD with a crude incidence rate of 192.1 (182.6–202.2) per 10,000 person-year. Among the total population, older age, female gender, prehypertension, hypertension, diabetes, widowed/divorced states, higher triglycerides (TG), prevalent cardiovascular diseases (CVD), and higher baseline eGFR were significantly associated with higher, while moderate physical activity and a positive family history of diabetes were associated with lower risk of KFD (all p values <.05). Prevalent CVD in women but not men, diabetes, and hypertension among postmenopausal than premenopausal women were significant risk factors of KFD. According to the presence of chronic kidney disease (CKD) at baseline, higher eGFR decreased the risk of KFD in patients with CKD and increased KFD risk in those without CKD (all p for interactions <.05). Conclusion KFD is associated with multiple modifiable risk factors among the Iranian urban population that is affected by gender, menopausal status, and initial kidney function. Interventions targeting these factors might potentially help reduce the burden of KFD. Key messages: Menopausal status may influence the relationship between cardiometabolic risk factors and KFD; The impact of higher baseline eGFR on the risk of KFD differed between subjects with preserved kidney function and CKD patients. The interaction between gender, menopausal status, and baseline kidney function with different risk factors on KFD may help to make renal risk prediction scores to identify those in the general population at risk who may benefit from early prevention.

External Validation of the Nelson Equation for Kidney Function Decline in Patients with Acute Ischemic Stroke or Transient Ischemic Attack.

There is a close brain-kidney interaction following ischemic cerebrovascular disease. The new-onset kidney injury after stroke leads to severe neurological deficits and poor functional outcomes. We aimed to validate the Nelson equation for predicting the new-onset and long-term kidney function decline in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA). A total of 3169 patients were enrolled in the Third China National Stroke Registry, whose baseline estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2. The outcome of interest was the incident eGFR< 60 mL/min/1.73 m2 at 3 months. The prediction equation of participants with or without diabetes was validated respectively. The receiver operating characteristic curve (AUC) evaluated prediction performance. The Delong test compared the Nelson equation performance with the O'Seaghdha equation and the Chien equation. Continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were determined to evaluate the incremental effect. During the 3-mo follow-up period, among 1151 patients with diabetes, there were 31 cases (2.7%) of reduced eGFR. Meanwhile, among 2018 non-diabetic patients, there were 23 cases (1.1%) of reduced eGFR. The Nelson equation showed good discrimination and was well-calibrated in patients with diabetes (AUC 0.82, Hosmer-Lemeshow test p = 0.67) or without diabetes (AUC 0.82, Hosmer-Lemeshow test p = 0.09). The performance of the Nelson equation was superior to other equation, as increased continuous NRI (diabetic, 0.64; non-diabetic, 1.13) and IDI (diabetic, 0.10; non-diabetic, 0.13) to the Chien equation. The Nelson equation reliably predicted the risks of the new-onset and long-term kidney function decline in patients with AIS or TIA, which could help clinicians screen high-risk patients and improve clinical care.

Association of Incremental peritoneal dialysis with residual kidney function decline in patients on peritoneal dialysis: The balANZ trial.

Incremental peritoneal dialysis (PD), defined as less than Full-dose PD prescription, has several possible merits, including better preservation of residual kidney function (RKF), lower peritoneal glucose exposure and reduced risk of peritonitis. The aims of this study were to analyse the association of Incremental and Full-dose PD strategy with RKF and urine volume (UV) decline in patients commencing PD. Incident PD patients who participated in the balANZ randomised controlled trial (RCT) (2004-2010) and had at least one post-baseline RKF and UV measurement was included in this study. Patients receiving <56 L/week and ≥56 L/week of PD fluid at PD commencement were classified as Incremental and Full-dose PD, respectively. An alternative cut-point of 42 L/week was used in a sensitivity analysis. The primary and secondary outcomes were changes in measured RKF and daily UV, respectively. The study included 154 patients (mean age 57.9 ± 14.1 years, 44% female, 34% diabetic, mean follow-up 19.5 ± 6.6 months). Incremental and Full-dose PD was commenced by 45 (29.2%) and 109 (70.8%) participants, respectively. RKF declined in the Incremental group from 7.9 ± 3.2 mL/min/1.73 m2 at baseline to 3.2 ± 2.9 mL/min/1.73 m2 at 24 months (p < 0.001), and in the Full-dose PD group from 7.3 ± 2.7 mL/min/1.73 m2 at baseline to 3.4 ± 2.8 mL/min/1.73 m2 at 24 months (p < 0.001). There was no difference in the slope of RKF decline between Incremental and Full-dose PD (p = 0.78). UV declined from 1.81 ± 0.73 L/day at baseline to 0.64 ± 0.63 L/day at 24 months in the Incremental PD group (p < 0.001) and from 1.38 ± 0.61 L/day to 0.71 ± 0.46 L/day in the Full-dose PD group (p < 0.001). There was no difference in the slope of UV decline between Incremental and Full-dose PD (p = 0.18). Compared with Full-dose PD start, Incremental PD start is associated with similar declines in RKF and UV.

The Association of Intravitreal Anti-VEGF Injections With Kidney Function in Diabetic Retinopathy

To examine whether patients with diabetic retinopathy receiving intravitreal anti-VEGF injections are at increased risk of kidney function decline. Retrospective cohort study. Included 187 patients who received intravitreal anti-VEGF injections for proliferative diabetic retinopathy (PDR) and/or diabetic macular edema (DME), and 929 controls with non-PDR who did not receive injections, at a large tertiary care center in Chicago, Illinois. We queried our institutional enterprise data warehouse to identify patients with diabetic retinopathy, determined whether they received intravitreal anti-VEGF injections, and followed kidney function for all patients over time. We assessed time to sustained 40% decline in estimated glomerular filtration rate (eGFR) from baseline in patients receiving intravitreal anti-VEGF injections and compared it with controls using Kaplan-Meier and multivariable adjusted Cox proportional hazards regression models. This study included 1116 patients (565 female [50.6%]; mean [standard deviation {SD}] age, 57.3 [13.6] years; mean [SD] eGFR, 65.3 [32.1] ml/min/1.73 m2). Of these, 187 patients received ≥ 1 intravitreal anti-VEGF injection (mean [SD], 11.4 [13.1] injections) for PDR and/or DME, and 929 controls with non-PDR received no injections. Intravitreal anti-VEGF injection use was not associated with an increased risk of kidney function decline (hazard ratio [HR], 1.44; 95% confidence interval [CI], 0.97-2.15). Subgroup analyses revealed that use of intravitreal anti-VEGF injections was associated with increased risk of kidney function decline in male patients (HR, 1.87; 95% CI, 1.11-3.14) but not female patients (HR, 0.97; 95% CI, 0.50-1.89). Intravitreal anti-VEGF injection use was also associated with an increased risk of kidney function decline in patients with baseline eGFR > 30 ml/min/1.73 m2 (HR, 1.86; 95% CI, 1.15-3.01), but not in individuals with baseline eGFR ≤ 30 ml/min/1.73 m2 (HR, 0.97; 95% CI, 0.45-2.10). Among patients who received injections, receiving ≥ 12 injections was not associated with risk of kidney function decline (HR, 1.13; 95% CI, 0.52-2.49). Intravitreal anti-VEGF injections for patients with diabetic retinopathy are overall well-tolerated with respect to kidney function, but the use of intravitreal anti-VEGF injections was associated with an increased risk of kidney function decline in certain subgroups of patients. Proprietary or commercial disclosure may be found after the references.

The association of urinary epidermal growth factors with ADPKD disease severity and progression.

The epidermal growth factor receptor (EGFR) pathway is involved in kidney tissue repair and growth. Preclinical interventional data and scarce human data have suggested a role for this pathway in the pathophysiology of Autosomal Dominant Polycystic Kidney Disease (ADPKD), while other data have suggested that its activation is causally linked to repair of damaged kidney tissue. We hypothesize that urinary EGFR ligands, as a reflection of EGFR activity, are associated with kidney function decline in ADPKD in the context of tissue repair following injury, and as the disease progresses as a sign of insufficient repair. In the present study, we measured the EGFR ligands, EGF and heparin binding-EGF (HB-EGF), in 24-h urine samples of 301 ADPKD patients and 72 age- and sex matched living kidney donors to dissect the role of the EGFR pathway in ADPKD. During a median follow-up of 2.5 years, the association of urinary EGFR ligand excretion with annual change in estimated glomerular filtration rate (eGFR) and height adjusted total kidney volume (htTKV) in ADPKD patients was analyzed using mixed-models methods and the expression of three closely related EGFR family receptors in ADPKD kidney tissue was investigated by immunohistochemistry. Additionally, the effect of reducing renal mass (after kidney donation), was assessed to investigate whether urinary EGF matches this reduction and thus reflects the amount of remaining healthy kidney tissue. At baseline, urinary HB-EGF did not differ between ADPKD patients and healthy controls (p=0.6), whereas a lower urinary EGF excretion was observed in ADPKD patients (18.6 [11.8-27.8] compared to healthy controls (51.0 [34.9-65.4] µg/24h, p<0.001). Urinary EGF was positively associated with baseline eGFR (R=0.54, p<0.001) and a lower EGF was strongly associated with a more rapid GFR decline, even when adjusted for ADPKD severity markers (β = 1.96, p<0.001), whereas HB-EGF was not. Expression of the EGFR, but not other EGFR-related receptors, was observed in renal cysts but was absent in non-ADPKD kidney tissue. Finally, unilateral nephrectomy resulted in a decrease of 46.4 [-63.3 to -17.6]% in urinary EGF excretion, alongside a decrease of 35.2±7.2% in eGFR and 36.8±6.9% in mGFR, whereas maximal mGFR (measured after dopamine induced hyperperfusion) decreased by 46.1±7.8% (all p<0.001). Our data suggest that lower urinary EGF excretion may be a valuable novel predictor for kidney function decline in patients with ADPKD.

PS-BPC10-5: ASSOCIATION BETWEEN KIDNEY FUNCTION AND CIRCULATING EPHA2 IN PATIENTS WITH HYPERTENSION

Objective: We have previously demonstrated that high circulating levels of progranulin (PGRN) were negatively associated with estimated glomerular filtration rate (eGFR). PGRN binds to Ephrin type-A receptor 2 (EphA2). Recently, it has been reported that circulating EphA2 levels serve as a biomarker of kidney function decline in patients with diabetic kidney disease. Therefore, we investigated its level correlates with traditional renal measures, eGFR and ratio of proteinuria to creatinine (UPCR), in patients with hypertension. Design and method: EphA2 ELISA for human serum was developed and validated. The serum levels of EphA2 were measured in 80 patients with hypertension. The subjects were stratified according to the eGFR: normal kidney function (eGFR &gt; 60 mL/min/1.73m2, n = 16), and declined kidney function (CKD; eGFR &lt; 60 mL/min/1.73m2, n = 64). Results: Validation of the in-house EphA2 ELISA showed good recovery and linearity and no cross-reactivity with other Eph receptors. The levels of EphA2 were significantly higher in CKD group compared to normal kidney function group, and correlated significantly with eGFR (r = -0.83) and UPCR (r = 0.61). Conclusions: The high circulating EphA2 level has potential application as a clinical biomarker for presence of CKD in patients with hypertension.

Periostin as a Biomarker in the Setting of Glomerular Diseases-A Review of the Current Literature.

Chronic kidney disease (CKD) is a highly prevalent and potential progressive condition with life-threatening consequences. Glomerular diseases (glomerulopathies) are causes of CKD that are potentially amenable by specific therapies. Significant resources have been invested in the identification of novel biomarkers of CKD progression and new targets for treatment. By using experimental models of kidney diseases, periostin has been identified amongst the most represented matricellular proteins that are commonly involved in the inflammation and fibrosis that characterize progressive kidney diseases. Periostin is highly expressed during organogenesis, with scarce expression in mature healthy tissues, but it is upregulated in multiple disease settings characterized by tissue injury and remodeling. Periostin was the most highly expressed matriceal protein in both animal models and in patients with glomerulopathies. Given that periostin is readily secreted from injury sites, and the variations in its humoral levels compared to the normal state were easily detectable, its potential role as a biomarker is suggested. Moreover, periostin expression was correlated with the degree of histological damage and with kidney function decline in patients with CKD secondary to both inflammatory (IgA nephropathy) and non-inflammatory (membranous nephropathy) glomerulopathies, while also displaying variability secondary to treatment response. The scope of this review is to summarize the existing evidence that supports the role of periostin as a novel biomarker in glomerulopathies.

Associations Between Risperidone Use and Kidney Function Decline in Patients With Schizophrenia

Associations Between Risperidone Use and Kidney Function Decline in Patients With Schizophrenia

Association between cholinesterase inhibitors and kidney function decline in patients with Alzheimer’s dementia

Preclinical evidence shows that activation of the cholinergic anti-inflammatory pathway (CAP) may have direct and indirect beneficial effects on the kidney. Cholinesterase inhibitors (ChEIs) are specific Alzheimer's dementia (AD) therapies that block the action of cholinesterases and activate CAP. Here, we explored a plausible effect of ChEIs on slowing kidney function decline by comparing the risk of CKD progression among patients with newly diagnosed AD that initiated ChEI or not within 90 days. Using complete information of routine serum creatinine tests, we evaluated changes in estimated glomerular filtration rate (eGFR) and defined the outcome of chronic kidney disease (CKD) progression as the composite of an eGFR decline of over 30%, initiation of dialysis/transplant or death attributed to CKD. A secondary outcome was death. Inverse probability of treatment-weighted Cox regression was used to estimate hazard ratios. Among 11, 898 patients, 6,803 started on ChEIs and 5,095 did not. Mean age was 80 years (64% women) and the mean eGFR was 68 ml/min/1.73m2. During a median 3.0 years of follow-up, and compared to non-use, ChEI use was associated with 18% lower risk of CKD progression (1,231 events, adjusted hazard ratio 0.82; 95% confidence interval 0.71-0.96) and a 21% lower risk of death (0.79; 0.72-0.86). Results were consistent across subgroups, ChEI subclasses and after accounting for competing risks. Thus, in patients with AD undergoing routine care, use of ChEI (vs no-use) was associated with lower risk of CKD progression.

Clinical and Pathological Features of Chinese Patients with Type 2 Diabetes, Biopsy-Proven Diabetic Kidney Disease, and Rapid eGFR Decline.

ObjectiveThe rate of kidney function decline in patients with diabetic kidney disease (DKD) is known to differ. This study analyzed the clinicopathologic features and related risk factors affecting long-term renal survival in Chinese type 2 diabetic patients with rapid estimated glomerular filtration rate (eGFR) decline.MethodsIn this retrospective descriptive study, 191 DKD patients were first classified as rapid eGFR decliners and slow eGFR decliners on the basis of the median eGFR slope value (−8.0 mL/min/1.73 m2/year). In total, 96 patients with rapid eGFR decline were included in the analyses and subsequently allocated to end-stage renal disease (ESRD) and non-ESRD groups. Baseline clinicopathological data of rapid eGFR decliners were collected. Cox proportional hazard analysis was performed to calculate the hazard ratios (HRs) for progression to ESRD.ResultsDuring a median follow-up of 25 months, 52 (54.2%) rapid eGFR decliners progressed to ESRD. These 52 rapid eGFR decliners had poorer renal function, lower hemoglobin and albumin concentrations, higher total cholesterol and baseline proteinuria levels, and more severe interstitial inflammation than those who did not progress to ESRD. After adjustment for age, gender, baseline eGFR, proteinuria, hemoglobin level, serum albumin concentration, and histopathologic parameters, multivariate Cox proportional hazard analysis revealed that eGFR (HR 0.973, 95% CI 0.956–0.989) and proteinuria (HR 1.125, 95% CI 1.030–1.228) were associated with the increased risk of progression to ESRD.ConclusionHigher proteinuria and lower eGFR were independent risk factors for renal progression in Chinese patients with type 2 diabetes and rapid eGFR decline.