Change in GFR over time in the Oxford Renal Cohort Study

Background: Decline in kidney function can result in adverse health outcomes. The OxREN study has detailed baseline assessments from 884 participants ≥60 years. Aim: To determine the proportion of participants with decline in estimated glomerular filtration rate (eGFR), identify determinants of decline and determine proportions with chronic kidney disease (CKD) remission. Design and setting: Observational cohort study in UK primary care. Methods: Data were used from baseline and annual follow-up assessments to monitor change in kidney function. Rapid eGFR decline was defined as eGFR decrease >5 ml/min/1.73m2/year, improvement as eGFR increase >5ml/min/1.73m2/year and remission in those with CKD at baseline and eGFR>60 ml/min/1.73m2 during follow-up. Cox proportional hazard models were used to identify factors associated with eGFR decline. Results: In 686 participants with a median follow-up of 2.1 years, 164 (24%) evidenced rapid GFR decline, 185 (27%) experienced eGFR improvement and 82 of 394 (21%) meeting CKD stage 1-4 at baseline experienced remission. In the multivariable analysis, smoking status, higher systolic blood pressure and being known to have CKD at cohort entry were associated with rapid GFR decline. Those with CKD stage 3 at baseline were less likely to exhibit GFR decline compared with normal kidney function. Conclusions: This study established that 24% of people evidenced rapid GFR decline whereas 21% evidenced remission of CKD. People at risk of rapid GFR decline may benefit from closer monitoring and appropriate treatment to minimise risks of adverse outcomes, though only a small proportion meet the NICE criteria for referral to secondary care.

Impact of Tacrolimus Daily Dose Limitation in Renal Transplant Recipients Expressing CYP3A5: A Retrospective Study

The pharmacokinetic variability of tacrolimus can be partly explained by CYP3A5 activity. Our objective was to evaluate a tacrolimus sparing policy on renal graft outcome according to CYP3A5 6986A>G genetic polymorphism. This retrospective study included 1114 recipients with a median follow-up of 6.3 years. Genotyping of the 6986A>G allelic variant corresponding to CYP3A5*3 was systematically performed. One year after transplantation, tacrolimus blood trough concentration (C0) target range was 5–7 ng/mL. However, daily dose was capped to 0.10 mg/kg/day regardless of the CYP3A5 genotype. A total 208 CYP3A5*1/- patients were included. Despite a higher daily dose, CYP3A5*1/- recipients exhibited lower C0 during follow-up (p < 0.01). Multivariate analysis did not show any significant influence of CYP3A5*1/- genotype (HR = 0.70, 0.46–1.07, p = 0.10) on patient-graft survival. Glomerular Filtration Rate (GFR) decline was significantly lower for the CYP3A5*1/- group (p = 0.02). The CYP3A5*1/- genotype did not significantly impact the risk of biopsy-proven acute rejection (BPAR) (HR = 1.01, 0.68–1.49, p = 0.97) despite significantly lower C0. Based on our experience, a strategy of tacrolimus capping is associated with a better GFR evolution in CYP3A5*1/- recipients without any significant increase of BPAR incidence. Our study raised some issues about specific therapeutic tacrolimus C0 targets for CYP3A5*1/- patients and suggests to set up randomized control studies in this specific population.

Serum matrix metalloproteinase 7 and accelerated glomerular filtration rate decline in a general non-diabetic population

Background Age-related reduction of glomerular filtration rate (GFR) is a major contributor to the global chronic kidney disease (CKD) epidemic. We investigated whether baseline serum levels of the pro-fibrotic matrix metalloproteinase 2 (MMP2), MMP7 and their inhibitor, tissue inhibitor of metalloproteinase 1 (TIMP1), which mediates fibrosis development in aging animals, were associated with GFR decline in a general non-diabetic population. Methods In the Renal Iohexol Clearance Survey, we measured GFR using iohexol clearance in 1627 subjects aged 50–64 years without self-reported diabetes, kidney or cardiovascular disease. After a median of 5.6 years, 1324 had follow-up GFR measurements. Using linear mixed models and logistic regression analyses, we evaluated the association of MMP7, MMP2 and TIMP1 with the mean GFR decline rate, risk of accelerated GFR decline (defined as subjects with the 10% steepest GFR slopes: ≥1.8 mL/min/1.73 m2/year) and incident CKD [GFR &lt;60 mL/min/1.73 m2 and/or urinary albumin to creatinine ratio (ACR) ≥3.0 mg/mmol]. Results Higher MMP7 levels (per standard deviation increase of MMP7) were associated with steeper GFR decline rates [−0.23 mL/min/1.73 m2/year (95% confidence interval −0.34 to −0.12)] and increased risk of accelerated GFR decline and incident CKD [odds ratios 1.58 (1.30–1.93) and 1.45 (1.05–2.01), respectively, in a model adjusted for age, sex, baseline GFR, ACR and cardiovascular risk factors]. MMP2 and TIMP1 showed no association with GFR decline or incident CKD. Conclusions The pro-fibrotic biomarker MMP7, but not MMP2 or TIMP1, is associated with increased risk of accelerated GFR decline and incident CKD in middle-aged persons from the general population.

Cilastatin Ameliorates Rhabdomyolysis-Induced Acute Kidney Injury in Mice

Background Rhabdomyolysis, the destruction of skeletal muscle, is a significant cause of acute kidney injury (AKI) and death in the context of natural disaster and armed conflict. Rhabdomyolysis may also initiate chronic kidney disease (CKD). Development of specific pharmacologic therapy is desirable because supportive care is nearly impossible in austere environments. Myoglobin, the principal cause of rhabdomyolysis-related AKI, undergoes megalin-mediated endocytosis in proximal tubule cells, a process that specifically injures these cells. Methods To investigate whether megalin is protective in a mouse model of rhabdomyolysis-induced AKI, we used male C57BL/6 mice and mice (14-32 weeks old) with proximal tubule-specific deletion of megalin. We used a well-characterized rhabdomyolysis model, injection of 50% glycerol in normal saline preceded by water deprivation. Results Inducible proximal tubule-specific deletion of megalin was highly protective in this mouse model of rhabdomyolysis-induced AKI. The megalin knockout mice demonstrated preserved glomerular filtration rate (GFR), reduced proximal tubule injury (as indicated by kidney injury molecule-1), and reduced renal apoptosis 24 hours after injury. These effects were accompanied by increased urinary myoglobin clearance. Unlike littermate controls, the megalin-deficient mice also did not develop progressive GFR decline and persistent new proteinuria. Administration of the pharmacologic megalin inhibitor cilastatin to wild-type mice recapitulated the renoprotective effects of megalin deletion. This cilastatin-mediated renoprotective effect was dependent on megalin. Cilastatin administration caused selective proteinuria and inhibition of tubular myoglobin uptake similar to that caused by megalin deletion. Conclusions We conclude that megalin plays a critical role in rhabdomyolysis-induced AKI, and megalin interference and inhibition ameliorate rhabdomyolysis-induced AKI. Further investigation of megalin inhibition may inform translational investigation of a novel potential therapy.

Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes

<b>Objectives:</b> Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D. <p><b>Research Design and Methods: </b>In a Case-Control study, 817 T1D patients from 3 large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m²/year decline in estimated glomerular filtration rate (eGFR) while Control was defined as <1 mL/min/1.73 m²/year decline over a minimum 4-year follow up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform. </p> <p><b>Results: </b>At individual lipids, free fatty-acid (FFA)20:2 was directly, and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min. A multi-lipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved C-statistic of clinical model from 0.816 to 0.841 (p=0.039). Observations were confirmed in the validation subset. </p> <p><b>Conclusion: </b>Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at sn1 carbon of the phospholipids’ glycerol backbone as independent predictor of rapid GFR decline in T1D. </p>

Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes

<b>Objectives:</b> Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D. <p><b>Research Design and Methods: </b>In a Case-Control study, 817 T1D patients from 3 large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m²/year decline in estimated glomerular filtration rate (eGFR) while Control was defined as <1 mL/min/1.73 m²/year decline over a minimum 4-year follow up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform. </p> <p><b>Results: </b>At individual lipids, free fatty-acid (FFA)20:2 was directly, and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min. A multi-lipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved C-statistic of clinical model from 0.816 to 0.841 (p=0.039). Observations were confirmed in the validation subset. </p> <p><b>Conclusion: </b>Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at sn1 carbon of the phospholipids’ glycerol backbone as independent predictor of rapid GFR decline in T1D. </p>

SYmptom-Based STratification of DiabEtes Mellitus by Renal Function Decline (SYSTEM): A Retrospective Cohort Study and Modeling Assessment

Background: Previous UK Biobank studies showed that symptoms and physical measurements had excellent prediction on long-term clinical outcomes in general population. Symptoms and signs could intuitively and non-invasively predict and monitor disease progression, especially for telemedicine, but related research is limited in diabetes and renal medicine.Methods: This retrospective cohort study aimed to evaluate the predictive power of a symptom-based stratification framework and individual symptoms for diabetes. Three hundred two adult diabetic patients were consecutively sampled from outpatient clinics in Hong Kong for prospective symptom assessment. Demographics and longitudinal measures of biochemical parameters were retrospectively extracted from linked medical records. The association between estimated glomerular filtration rate (GFR) (independent variable) and biochemistry, epidemiological factors, and individual symptoms was assessed by mixed regression analyses. A symptom-based stratification framework of diabetes using symptom clusters was formulated by Delphi consensus method. Akaike information criterion (AIC) and Bayesian information criterion (BIC) were compared between statistical models with different combinations of biochemical, epidemiological, and symptom variables.Results: In the 4.2-year follow-up period, baseline presentation of edema (−1.8 ml/min/1.73m2, 95%CI: −2.5 to −1.2, p &lt; 0.001), epigastric bloating (−0.8 ml/min/1.73m2, 95%CI: −1.4 to −0.2, p = 0.014) and alternating dry and loose stool (−1.1 ml/min/1.73m2, 95%CI: −1.9 to −0.4, p = 0.004) were independently associated with faster annual GFR decline. Eleven symptom clusters were identified from literature, stratifying diabetes predominantly by gastrointestinal phenotypes. Using symptom clusters synchronized by Delphi consensus as the independent variable in statistical models reduced complexity and improved explanatory power when compared to using individual symptoms. Symptom-biologic-epidemiologic combined model had the lowest AIC (4,478 vs. 5,824 vs. 4,966 vs. 7,926) and BIC (4,597 vs. 5,870 vs. 5,065 vs. 8,026) compared to the symptom, symptom-epidemiologic and biologic-epidemiologic models, respectively. Patients co-presenting with a constellation of fatigue, malaise, dry mouth, and dry throat were independently associated with faster annual GFR decline (−1.1 ml/min/1.73m2, 95%CI: −1.9 to −0.2, p = 0.011).Conclusions: Add-on symptom-based diagnosis improves the predictive power on renal function decline among diabetic patients based on key biochemical and epidemiological factors. Dynamic change of symptoms should be considered in clinical practice and research design.