Decline In GFR Research Articles

GFR decline and prior dysuria among Nicaraguan sugarcane workers

BACKGROUND AND AIM: Nicaraguan sugarcane workers have an elevated prevalence of chronic kidney disease of unknown origin, referred to as Mesoamerican Nephropathy (MeN). Work in the sugarcane industry involves exposure to climatic heat and strenuous physical labor, suspected contributors to the development of MeN. These same factors may increase the risk of dysuria, thought due to crystalluria, which in other disease states has been associated with acute kidney injury. In a longitudinal study of sugarcane workers, we examined whether experiencing dysuria was associated with subsequent reduced kidney function. METHODS: At a sugarcane company in Nicaragua, we abstracted employment and medical records for 190 male workers (1997–2010). Dates worked, jobs held, and medical data were collected. Estimated glomerular filtration rate (eGFR) was categorized as a binary outcome, first analyzed as 90 (includes mild and moderate eGFR reduction) and then analyzed as 60 (focused on moderate eGFR reduction) mL/min/1.73m2. To examine the association between prior dysuria diagnosis (ever/never) and reduced eGFR, logistic regression based on generalized estimating equations for repeated events was used to estimate the odds ratio (OR) and the 95% confidence interval (CI), controlling for age, cumulative harvest seasons worked, proportion seasons worked as cane cutter, and period of the harvest season. RESULTS:A total of 1,676 eGFR measurements were available for 190 workers. There were 134 workers with at least one dysuria diagnosis, and 72% of eGFR measures were preceded by a dysuria diagnosis. eGFR 90 [adjusted OR=2.27 (95% CI 1.40, 3,67)] and eGFR 60 [adjusted OR=3.87 (95% CI 1.81, 8.25)] were both associated with having a prior dysuria episode. CONCLUSIONS:Experiencing dysuria was associated with an increased risk of reduced eGFR. These findings suggest that crystalluria may contribute to subsequent transient changes in kidney function, though more research is warranted. KEYWORDS: Temperature, Occupational Epidemiology, Cardiovascular diseases, International collaboration, Climate

English

BACKGROUND Chronic kidney disease (CKD) includes a spectrum of different pathophysiology processes associated with abnormal kidney function, and a progressive decline in GFR. Progression of CKD is associated with having a number of complications, including thyroid dysfunction, dyslipidaemia, and cardiovascular diseases. METHODS The present study was conducted among 60 CKD patients (cases) and 60 healthy controls to compare their thyroid and lipid profile, who attended the Department of Medicine in SGRDIMSR, Sri Amritsar from January 2019 to December 2020.These 60 CKD patients were grouped as group A. Group A was further divided into various stages as per KIDGO staging according to GFR. 60 healthy individuals were taken as controls and were kept as Group B. Demographic features (age and sex) and medical history of diabetes mellitus, hypertension were noted and blood samples (5mL) were analysed for blood urea, serum creatinine, free triiodothyronine (T3), free thyroxine (T4), thyroid stimulating hormone (TSH), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), very low density lipoprotein (VLDL) and triglycerides. RESULTS Thyroid dysfunction was observed in patients of CKD, the most common being overt hypothyroidism (56.6 %) followed by subclinical hypothyroidism (16.6 %), low T3 (15 %), and hyperthyroidism (1.6 %). Hypercholesterolemia, low HDL, elevated LDL, VLDL and triglyceride levels were observed in 74.9 %, 85.0 %, 38.3 %, 41.6 % and 76.6 % patients, respectively. Patients with CKD with 5 had significantly higher risk of having thyroid dysfunction and dyslipidaemia as compared to patients with stage 3 and 4. CONCLUSIONS Thyroid dysfunction and dyslipidaemia were common in patients with CKD. Prevalence of hypothyroidism, dyslipidaemia increases with progression of CKD. Hence early detection of thyroid dysfunction and dyslipidaemia is imperative to improve mortality and morbidity of CKD patients. KEYWORDS Chronic Kidney Disease, Dyslipidaemia, Thyroid Dysfunction

The change of renal functions after nonvitamin K oral anticoagulants in patients with atrial fibrillation.

Oral anticoagulants decreased stroke and mortality in atrial fibrillation patients. There have been cumulative data suggesting that some oral anticoagulants may exert favorable renal outcomes.The aim of this study is to evaluate the renal outcomes in patients with atrial fibrillation who took oral anticoagulant.Methods:A Retrospective cohort study using hospital electronic database. Serum creatinine and GFR were collected at baseline and at 1 and 2 years.Results:Authors identified 734 patients with non-valvular AF who took oral anticoagulants. At the end of 2-year, the cumulative risk of significant GFR decline (eGFR drop > 30%) was 10.94% in warfarin group and 9.69% in NOACs group.The incidence rate of significant eGFR decline were comparable between NOACs and warfarin group which were 4.82 and 5.34 per 100-patient year respectively(HR 1.01 CI 0.62–1.66 , p- value 0.964).However, the adjusted mean eGFR change per year was significantly lower in NOAC group, especially rivaroxaban (coefficient 7.83 ,CI 4.44 11.22 , p-value < 0.001) and dabigatran (coefficient 6.22 ,CI 2.67–9.77 , p-value = 0.001) at 2 years.Conclusions:Significant GFR decline was not uncommon in non-valvular AF patients who received anticoagulant. Among these, the proportion of patients who had significant eGFR decline(>30%) were comparable between NOACs and warfarin at 2 years. However, there is a significantly less mean eGFR decline per year in patients who receive NOACs, notably with dabigatran and rivaroxaban, than those who receive warfarin.The findings of this study should be interpreted in the context of patients included in this study.

Association Between Kidney Function Decline and Baseline TNFR Levels or Change Ratio in TNFR by Febuxostat Chiefly in Non-diabetic CKD Patients With Asymptomatic Hyperuricemia

Background: The levels of circulating tumor necrosis factor receptor (TNFR) 1 and 2 help predict the future decline of estimated glomerular filtration rate (eGFR) chiefly in patients with diabetes. It has been recently reported that the change ratio in TNFR1 by SGLT2 inhibitor treatment is also related with future GFR decline in patients with diabetes. The aims of this study are to investigate the association between baseline TNFR levels and early change in TNFR levels by the non-purine selective xanthine oxidase inhibitor, febuxostat, and future eGFR decline chiefly in chronic kidney disease (CKD) patients without diabetes.Methods: We conducted a post-hoc analysis of the FEATHER study on patients with asymptomatic hyperuricemia and CKD stage 3, who were randomly assigned febuxostat 40 mg/day or matched placebo. This analysis included 426 patients in whom baseline stored samples were available. Serum TNFR levels at baseline were measured using enzyme-linked immunosorbent assay. Those levels were also measured using 12-week stored samples from 197 randomly selected patients.Results: Compared with placebo, short-term febuxostat treatment significantly decreased the median percent change from baseline in serum uric acid (−45.05, 95% CI −48.90 to −41.24 mg/dL), TNFR1 (1.10, 95% CI−2.25 to 4.40), and TNFR2 (1.66, 95% CI −1.72 to 4.93), but not TNFR levels. Over a median follow-up of 105 weeks, 30 patients (7.0%) experienced 30% eGFR decline from baseline. In the Cox multivariate model, high levels of baseline TNFR predicted a 30% eGFR decline, even after adjusting for age, sex, systolic blood pressure, high sensitivity C-reactive protein, uric acid, and presence or absence of febuxostat treatment and diabetes, in addition to baseline albumin to creatinine ratio and eGFR.Conclusion: Early change in circulating TNFR levels failed to predict future eGFR decline; however, regardless of febuxostat treatment, the elevated baseline level of TNFR was a strong predictor of 30% eGFR decline even in chiefly non-diabetic CKD patients with asymptomatic hyperuricemia.

The Association of Posttraumatic Stress Disorder With Longitudinal Change in Glomerular Filtration Rate in World Trade Center Responders.

High levels of psychological distress increase the risk of a wide range of medical diseases. In this study, we investigated the association between posttraumatic stress disorder (PTSD) and kidney disease. World Trade Center (WTC) responders were included if they had two or more measures of estimated glomerular filtration rate (eGFR). The PTSD Checklist (PCL) was used to define no PTSD (PCL < 40), "mild" PTSD (40 ≤ PCL <50), and "severe" PTSD (PCL ≥50). Subtypes of PTSD by symptom clusters were analyzed. Multinomial logistic regression was used to estimate the association of PTSD with two GFR change outcomes (decline or increase) compared with the stable GFR outcome. In 2266 participants, the mean age was 53.1 years, 8.2% were female, and 89.1% were White. Individuals with PTSD (n = 373; 16.5%) did not differ in mean baseline GFR from individuals without PTSD (89.73 versus 90.56 mL min-1 1.73 m-2; p = .29). During a 2.01-year mean follow-up, a mean GFR decline of -1.51 mL min-1 1.73 m-2 per year was noted. In multivariable-adjusted models, PTSD was associated with GFR decline (adjusted relative risk [aRR] = 1.74 [1.32-2.30], p < .001) compared with stable GFR, with "hyperarousal" symptoms showing the strongest association (aRR =2.11 [1.40-3.19]; p < .001). Dose-response effects were evident when comparing mild with severe PTSD and comparing PTSD with versus without depression. PTSD was also associated with GFR rise (aRR = 1.47 [1.10-1.97], p < .009). The association between PTSD and GFR change was stronger in participants older than 50 years. PTSD may be a novel risk factor for exaggerated longitudinal GFR change in young, healthy adults. These findings need to be validated in other cohorts.

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

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. In a case-control study, 817 patients with T1D from three large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m2 per year decline in estimated glomerular filtration rate (eGFR), while control was defined as <1 mL/min/1.73 m2 per year decline over a minimum 4-year follow-up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform. 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/1.73 m2. A multilipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved the C-statistic of the clinical model from 0.816 to 0.841 (P = 0.039). Observations were confirmed in the validation subset. Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at the sn1 carbon of the phospholipids' glycerol backbone as an independent predictor of rapid GFR decline in T1D.

Low-Intensity Shockwave Therapy (LI-ESWT) in Diabetic Kidney Disease: Results from an Open-Label Interventional Clinical Trial.

PurposeTreatment with low-intensity shockwave therapy (LI-ESWT) is associated with angiogenesis and is suggested as a treatment for different types of vascular diseases. It was hypothesized that LI-ESWT improves the renal filtration barrier and halts the progression of GFR decline in diabetic kidney disease (DKD) potentially through VEGF and NO formation. We present the first data on LI-ESWT in human DKD.MethodsThe study was designed as an interventional, prospective, one-arm, Phase 1 study. We investigated change in GFR and albuminuria in 28 patients with DKD treated with six sessions of LI-ESWT over three weeks. The patients were followed for six months. Urine excretion of kidney injury markers, vascular endothelial growth factor (VEGF) and nitric oxide metabolites (NOx) was studied after LI-ESWT.ResultsThere were no significant changes in GFR and albuminuria up to six months after LI-ESWT compared to baseline. Urine VEGF was transiently reduced one month after LI-ESWT, but there were no other significant changes in urine VEGF or NOx after LI-ESWT. Secondary analysis showed that NOx increased after LI-ESWT in patients who had low levels of NOx at baseline. Kidney injury marker trefoil factor 3 (TFF3) increased acutely after the first session of LI-ESWT indicating transient endothelial repair. Other markers of kidney injury were stable in relation to LI-ESWT.ConclusionLI-ESWT treatment did not significantly improve kidney function and albumin excretion. It is concluded that LI-ESWT is not harmful. A randomized blinded study should be performed to clarify whether adjunctive treatment with LI-ESWT is superior to standard treatment of DKD.

Empagliflozin Inhibits Proximal Tubule NHE3 Activity, Preserves GFR, and Restores Euvolemia in Nondiabetic Rats with Induced Heart Failure.

SGLT2 inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. Experiments with nondiabetic HF rats tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) inhibits proximal tubule (PT) NHE3 activity and improves renal salt and water handling. Male Wistar rats were subjected to myocardial infarction or sham operation. After 4 weeks, rats that developed HF and sham rats were treated with EMPA or untreated for an additional 4 weeks. Immunoblotting and quantitative RT-PCR evaluated SGLT2 and NHE3 expression. Stationary in vivo microperfusion measured PT NHE3 activity. EMPA-treated HF rats displayed lower serum B-type natriuretic peptide levels and lower right ventricle and lung weight to tibia length than untreated HF rats. Upon saline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment prevented GFR decline and renal atrophy in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 protein and mRNA abundance were upregulated in the PT of HF rats. Prevention of HF progression by EMPA is associated with reduced PT NHE3 activity, restoration of euvolemia, and preservation of renal mass. Moreover, dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF.

Applying Logistic Regression to Predict Diabetic Nephropathy Based on Some Clinical and Paraclinical Characteristics of Type 2 Diabetic Patients

Applying Logistic Regression to Predict Diabetic Nephropathy Based on Some Clinical and Paraclinical Characteristics of Type 2 Diabetic Patients

Comparison of Glomerular Filtration Rate Estimated by Three Methods in a Pakistani Community Cohort

Background: Estimated glomerular filtration rate (eGFR) has always been considered a better and more accurate method to assess kidney function as compared to serum creatinine. Various equations such as the Cockroft-Gault equation corrected for surface area (CG-CRTD), the four-variable Modification of Diet in Renal Disease equation (MDRD) and 2009 Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) have been derived to estimate GFR. In the South Asian region, the CKD-EPI equation has not been validated or compared with other equations. This study compares eGFR in a Pakistani community cohort calculated by all three equations.&#x0D; Results: Serum creatinine was measured using Kinetic Colorimetric Assay in alkaline medium for 461 individuals age 15 and above. Less than half of the participants (47% by CG-CRTD, 40% by MDRD, 52% by CKD-EPI) had eGFR ³90 ml/min per 1.73 m2 and for participants with eGFR ³120 ml/min per 1.73 m2 , the percentages were even lower (15%, 12%, and 22% respectively). All the equations were linearly associated with each other, but the error estimation depicted that majority of the individual differences were ≥5 and ≤-5, and very few were within ±1 indicating less degree of agreement between the formulas. Age was significantly but negatively correlated with all the three formulas in their classification of patients as per eGFR Conclusion: Our study found that the values of estimated GFR are on lower side for Pakistanis as compared to the western population. The equations available for estimation of GFR even though associated linearly with each other have significant individual differences. Thirdly, using eGFR to classify CKD should have a better consideration of physiological age-related decline in GFR. All of these findings necessitate having an adequately funded randomized study measuring true GFR of this population and at the same time validating eGFR equations to find the normal GFR ranges of South Asians.

Patterns of recombinant growth hormone therapy use and growth responses among children with chronic kidney disease.

Recombinant growth hormone (rGH) is an efficacious therapy for growth failure in children with chronic kidney disease (CKD). We described rGH use and estimated its relationship with growth and kidney function in the Chronic Kidney Disease in Children (CKiD) cohort. Participants included those with growth failure, prevalent rGH users, and rGH initiators who did not meet growth failure criteria. Among those with growth failure, height z scores and GFR were compared between rGH initiators and non-initiators across 42 months. Inverse probability weights accounted for differences in baseline variables in weighted linear regressions. Among 148 children with growth failure and no previous rGH therapy, 42 (28%) initiated rGH therapy. Of the initiators, average age was 8.9 years, height z score was 2.50 standard deviations (SDs) (0.6th percentile), and GFR was 44 ml/min/1.73m2. They were compared to 106 children with growth failure who never initiated therapy (8.8 years, -2.33 SDs, and 51 ml/min/1.73m2). At 30 and 42 months after rGH, height increased +0.26 (95%CI: -0.11, +0.62) and +0.35 (95%CI: -0.17, +0.87) SDs, respectively, relative to those who did not initiate rGH. rGH was not associated with GFR. Participants with growth failure receiving rGH experienced significant growth, although this was attenuated relative to RCTs, and were more likely to have higher household income and lower GFR. A substantial number of participants, predominantly boys, without diagnosed growth failure received rGH and had the highest achieved height relative to mid-parental height. Since rGH was not associated with accelerated GFR decline, increasing rGH use in this population is warranted.

204-OR: ADA Presidents’ Select Abstract: Cardiovascular Autonomic Neuropathy Is Associated with Rapid Kidney Function Decline in Type 2 Diabetes: Findings from the ACCORD Trial

Cardiovascular autonomic neuropathy (CAN) has been shown to predict progressive kidney function decline among persons with type 1 diabetes. We aimed to determine whether CAN has a similar effect on kidney function decline in type 2 diabetes (T2D). To this end, we investigated the association between measures of CAN obtained at baseline and GFR decline during a 5-year follow-up among T2D participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. CAN was defined as ECG-derived heart rate variability indices being below the 5th percentile of the normal distribution (standard deviation of all normal-to-normal R-R intervals [SDNN] &amp;lt;8.2 ms and root mean square of successive differences between normal-to-normal R-R intervals [rMSSD] &amp;lt;8.0 ms). eGFR slopes were estimated by linear regression among participants with ≥3 eGFR measurements during follow up. Of the 6,805 ACCORD participants who had valid measures of CAN and eGFR slope, 1,327 (19.5%) had evidence of CAN at baseline. CAN independently predicted a steeper eGFR decline during follow-up (beta=-0.44 ml/min/1.73m2/year, P=0.0007); 24.6% of participants with CAN at baseline experienced subsequent eGFR loss ≥5 ml/min/1.73m2 per year as compared to 18.6% of participants without CAN (OR=1.39 [1.18 - 1.64], P&amp;lt;0.0001, after adjustment for age, sex, duration of diabetes, BMI, HbA1c, eGFR, urinary albumin-creatinine ratio, and positive CVD history at baseline). Consistent with these findings, in a time-to-event analysis, baseline CAN was associated with a 40% increase in the risk of experiencing a ≥40% eGFR loss during follow-up (adjusted HR=1.40 [1.20-1.63], P&amp;lt;0.0001). In summary, CAN was an independent predictor of kidney function loss in T2D participants. Further studies are needed to understand whether this association reflects a shared etiology of CAN and diabetic kidney disease or a direct deleterious effect of autonomic nervous system alterations on kidney function. Disclosure Y. Tang: None. C. Bueno junior: None. H. Shah: None. L. Ang: None. R. Pop-busui: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Averitas Pharma, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Nevro Corp., Regenacy. A. Doria: None. Funding National Heart, Lung, and Blood Institute N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010)

Circulating Osteoprotegerin in Chronic Kidney Disease and All-Cause Mortality.

BackgroundChronic kidney disease (CKD) is associated with cardiovascular disease (CKD), mineral and bone disorder (CKD-MBD) and high mortality. Bone-related factors such as osteopontin (OPN), osteocalcin (OC), osteoprotegerin (OPG) and fibroblast growth factor 23 (FGF23) were linked to cardiovascular complications of CKD and are expected to have predictive value in CKD patients.PurposeThe aim of this study was to assess the relationship of OPN, OC, OPG and FGF23 to clinical characteristics and to evaluate their ability to predict mortality in patients with different CKD stages.MethodsThe following study groups were enrolled: subjects with end-stage renal disease (38 ESRD), CKD stages 3 and 4 (19 CKD3-4) and non-CKD controls (19), respectively. Blood was withdrawn once to perform the measurements and cardiac computed tomography was used to evaluate coronary calcium score (CS). Patients were followed for 5 years for the ascertainment of their all-cause mortality.ResultsSerum OPN, OC and OPG concentrations increased significantly along with the progression of renal disease. We found a significant positive correlation among these proteins. Additionally, OPN and OPG were significantly and positively correlated to CS. Serum OPG revealed the strongest correlation to the calcium turnover markers of GFR decline and was significantly associated with an increased risk of death in subjects with CKD3-4 or ESRD (HR 5.8, CI 95%).ConclusionSingle measurement of osteoprotegerin is associated with 5-year all-cause mortality in patients with CKD3-4 or ESRD. We suggest assessing its concentration, preferably in combination with calcium score, to stratify mortality risks in CKD patients.

MO537INTERACTION OF PLASMA HOMOCYSTIENE, RENAL FUNCTION AND CARDIO-METABOLIC RISK FACTORS- AN OBSERVATION IN A RURAL POPULATION OF BANGLADESH

Abstract Background and Aims Elevated plasma total homocystiene (tHcy) levels are associated with atherosclerotic diseases in coronary, cerebral and peripheral blood vessels. It is possible that hyperhomocysteinemia may lead to intrarenal arteriosclerotic lesions and decline in GFR or impaired renal function. Aim of this study was to elucidate the association of plasma homocystiene level with renal function and cardiovascular risk factors in rural population. Method A well defined rural area was selected. Study subjects were identified by computer generated random numbers after entering household listings and then Kish table was used to choose a participant. Adult subjects (≥18 years) were only included. The approached participant was explained the purpose, if consented, then given an appointment to be present at a research hospital on a separate date for clinical and biochemical evaluation. A face to face interview was conducted. Clinical history, physical examination anthropometrics were recorded on data sheet. Fasting blood sample and morning spot urine was collected. Then serum tHcy was measured by chemiluminescent microparticle immunoassay (CMIA) technology. Study population were investigated with Spot urine ACR, Fasting glucose, serum lipid profile, creatinine, homocysteinine , Folic acid and Vit B12. Results Early results of 234 random subjects are presented here. The mean age was 41 ± 13(18-92) years with male 33% and female 67%. Mean eGFR was 99± 26 ml/min, tHcy 11.6 ± 5.9 μmol/l, Vit B12 329 ± 187 pg/ml and Folic Acid 5.57 ± 2.63 ng/ml. A tHcy cut-off value in study subjects ≥15 μmol/l was seen in 17 % and &amp;lt;15 μmol/l in 83%. Serum creatinine, Uric Acid, Cholesterol, LDL was significantly higher and Vit B12, Folic acid lower in tHcy ≥15 μmol/l group. Further grouping showed tHcy level was significantly higher in Vit B12&amp;lt;200 pg/ml and Folic acid &amp;lt;3ng/l group. Correlation studies showed homocystiene positively correlated with age, systolic blood pressure, creatinine, LDL and negatively with Folic acid and Vit B12. Conclusion Our findings suggest that elevated plasma homocystiene level might influence and are associated with altered markers of renal, cardiac and metabolic risk factors in rural population. Preventive approaches are required towards this issue as larger population segment belongs to rural areas.

MO112SYSTEMIC OXALOSIS IN PRIMARY HYPEROXALURIA TYPE 3 – ARE THE PATIENTS AT RISK?

Abstract Background and Aims Primary Hyperoxaluria type 3 (PH3) is said to be the less problematic form of PH and with low risk of chronic kidney disease (CKD) and end stage renal disease. However, a recent OxalEurope registry evaluation reported both urine and plasma oxalate levels in a comparable range as in PH1 and PH2 patients. In addition, PH3 patients remain symptomatic with recurrent kidney stones, even in adulthood, and 24% of the 95 patients evaluated were on CKD ≥ 2 at last follow up. Hence, it was speculated, that PH3 patients may also be on risk to develop systemic oxalate deposition. Method We retrospectively analyzed the imaging procedures performed so far in patients regularly seen at the German Hyperoxaluria Center, which included: eye exams; x-rays of the hand; bone MRI (3 Thesla of the left knee and proximal tibia); and Speckle tracking echocardiography using 2D Cardiac Performance Analysis VC (TomTec Imaging Systems GmbH, Germany), which measures changes in global longitudinal strain (GLS), an index of left ventricular contractibility. The normal range for GLS is ≤18%. All patients or parents signed an informed consent. Results From the 49 PH3 patients registered at the German Hyperoxaluria center, 12 pediatric and 4 adult patients are seen on a regular basis, at least twice a year, and the rest are followed in other centers. All the 16 patients were in stable kidney function and in no less than CKD 2. Eye examination was performed in six patients and was normal in all. Four patients received an x-ray of the left hand, which was normal in 3, but in one patient with a problematic clinical course (multiple stone removal procedures, decline in GFR), tiny sclerosing areas, although no true metaphyseal bands, were seen at caput MCP IV and the thumb. Therefore, MRI of the left knee and proximal tibia was performed in this and another patient, which showed no signs of systemic oxalate deposition. Speckle tracking echocardiography was done in 6 patients and was abnormal in one (GLS – 17.3 and left ventricular hypertrophy) and borderline in the twin sibling (GLS – 18.6). The patient with the abnormal GLS also had salivary stones in the parotid gland, as were also found in his other, older sibling in a routine x-ray of the jaw before orthodontic treatment. Conclusion Although this is currently only data of a small cohort of patients, the parameters available so far show, that systemic oxalate deposition may also occur in PH3. Based on our experience on PH1, we regard Speckle tracking echocardiography as the best parameter to detect early systemic calcium-oxalate depositions. Hence the reduction in global longitudinal strain, thus ventricular contractability, is a clear proof of such deposits. Of course, data in more patients are needed to elucidate the true risk of systemic oxalate deposition and we are therefore currently screening all our PH3 patients.

MO040REAL-WORLD USE OF TOLVAPTAN AND ITS IMPACT ON EGFR IN A NORTH EAST UK COHORT

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is a cause of progressive chronic kidney failure (CKD) and end stage kidney disease (ESKD). Tolvaptan has been shown within clinical trials to slow down decline of kidney function in patients with ADPKD at risk of rapid progression. We performed a retrospective review of a cohort of ADPKD patients who had been established on tolvaptan therapy to determine its efficacy in a real- world clinic setting. Method Subjects who had a clinical diagnosis of ADPKD and who had been established on tolvaptan for a period of &amp;gt;18 months were reviewed retrospectively in terms of their eGFR. Subjects were between the ages of 18-65 years old and both males and females were included in this study. Other inclusion criteria involved a pre-treatment slope of &amp;lt;-2.5 ml/min/1.73m2 based on readings for a 3 year period, a pre-treatment eGFR of 30-90 ml/min/1.73m2 and ability to tolerate tolvaptan treatment and be maintained on treatment for at least12 months. We calculated based on eGFR slopes, predicted time to reach CKD stage 5 with and without tolvaptan therapy. Given this was a retrospective review, eGFR were estimated during clinic visits whilst on tolvaptan treatment, rather than after a drug washout period. Results The cohort of patients included 20 from Newcastle upon Tyne Hospitals and 2 from Sunderland Royal Infirmary. The mean rate of eGFR decline prior to treatment was -5.92 ml/min/1.73m2 per year for the cohort. Following tolvaptan treatment, the average decline in eGFR was reduced to -2.57 ml/min/1.73m2 per year. Therefore, tolvaptan lessened average eGFR decline within this cohort by 3.35 ml/min/1.73m2 per year, gaining 7 years and 9 months delay until CKD stage 5. The majority of patients (n=19) received full dose tolvaptan (90mg/30mg). At an individual level, 3 patients failed to respond at all to tolvaptan, with no improvement in decline of GFR and 2 others had a very mild improvement only (change in eGFR slope of &amp;lt;0.5 ml/min/1.73m2 per year). 6 patients had a dramatic improvement in eGFR slope (&amp;gt;5 ml/min/1.73m2 per year). Conclusion The real life use of tolvaptan seemed to give a dramatic improvement in eGFR slopes, much more than the previously reported clinical studies have shown. This may be in part due to patient selection and only including patients who tolerated therapy, a “tolvaptan clinic” effect where great personal care is given to these patients and to excellent compliance with medication. Reasons for both non-response and exaggerated response need to be evaluated carefully to determine how individualisation of tolvaptan therapy can be best used.

FC 003HYPERURICEMIA HAS VASOACTIVE EFFECTS IN CHOLESTEROL CRYSTAL-INDUCED ACUTE KIDNEY INJURY

Abstract Background and Aims Numerous observational studies have reported an association between hyperuricemia (HU) and cardiovascular disease where atherosclerosis is a leading cause. In advanced atherosclerosis, cholesterol crystal (CC) embolism is a life-threatening complication with an average mortality of 62.8%. Clinical manifestations include skin necrosis, intestinal injury and acute kidney injury (AKI). Autopsies and tissue biopsies reveal CC inside the arterial lumen. In a new model of CC-induced AKI, we recently found that fibrin clots formed around CC obstruct peripheral arteries and cause tissue infarction and organ failure. However, the role of asymptomatic HU in CC-induced AKI is currently unknown. Thus, we hypothesized that asymptomatic HU improves the outcomes after CC-induced AKI. Method In vivo, 6 weeks old Alb-creERT2;Glut9lox/lox and Glut9lox/lox control mice were intraperitoneally injected with tamoxifen to deplete hepatic Glut9 expression. Both groups of mice were placed on a standard chow diet enriched with inosine for two weeks. Afterward, a solution of CCs was injected into the left kidney arteries of mice to induce AKI. Serum and kidneys were collected 24 hours later, and kidney function, infarct size and kidney injury evaluated using GFR measurement, colorimetric assays, ELISA and immunohistochemistry of kidney sections. For in vitro studies, we isolated platelets from healthy mice and cultured them in the presence or absence of soluble uric acid (sUA) prior to CC activation. After stimulation, platelet aggregation assays and flow cytometry were performed. Results Our in vivo data showed that Alb-creERT2;Glut9lox/lox mice developed asymptomatic HU without kidney impairment (serum UA levels 9-15 mg/dL), while Glut9lox/lox control mice remained healthy. HU mice displayed a rapid decline in GFR of approx. 80% as compared to only 30% in healthy mice after CC-induced AKI, which was in line with increased serum BUN and IL-6 levels. The rapid GFR decline was due to vasoconstriction in arteries of the contralateral kidney as determined by αSMA/fibrin staining and a reduced ratio of lumen versus artery area in mice with HU after AKI. HU mice also had significantly less kidney infarct size as well as reduced kidney injury (necrosis and edema) and arterial occlusion. The in vitro data showed that sUA had no impact on platelet aggregation, activation and degranulation as compared to medium control in response to CCs. Conclusion We now show that HU has vasoconstrictive effects in the contralateral kidney by reducing GFR, while at the same time protects mice from CC-induced AKI suggesting a compensatory physiological mechanism of autoregulation to protect nephrons. On the other hand, in patients with chronic kidney disease, HU-related vasoconstriction might lead to increased arterial blood pressure; thus, increasing the risk for cardiovascular complications due to platelet activation and aggregation.

FC 031LARGE SCALE VALIDATION OF THE NEW INTERNATIONAL PROGNOSTIC SCORE OF IGA NEPHROPATHY ON A FRENCH COHORT WITH PROLONGED FOLLOW-UP

Abstract Background and Aims IgA Nephropathy is the most frequent primary glomerulonephritis worldwide, with a progression to End Stage Renal Disease in up to 30% of cases within 20 years after diagnosis. The severity of this disease is nevertheless extremely heterogenous with a majority of slow progression to late stages of Chronic Kidney Disease. The early stratification of risk to progress to ESRD is crucial. In this aim, International IgA Nephropathy Network recently developped a risk prediction tool (IINN tool) to allow an estimation of the probability to progress. The objective of our study was to validate this prediction tool (i) in our French Caucasien retrospective cohort (ii) on long term prognosis. Method All biopsy-proven IgA Nephropathy patients from Saint Etienne retrospective cohort for whom proteinuria, mean arterial pressure, CKD-EPI based GFR estimate and adequate Oxford classification at diagnosis were available have been included for analysis. For each patient the estimate of risk to progress to ESRD and/or 50% GFR decline was computed at 5, 10 and 15 years according to the IINN tool. For each time of follow-up, risks were grouped and ranked by deciles, and the median observed rate of event was compared to the median of predicted risk by decile, at 5, 10 and 15 years of follow-up. Correlation between observed and predicted risk was expressed as a Pearson correlation coefficient. A R²&amp;gt;0.8 was considered adequate to validate the prognosis tool. Results A total of 468 patients have been included for analysis, with a median age of 38.9 years old, a median proteinuria of 0.5g/day, a mean CKD-EPI of 81,6 mL/min/1,73m² and mean arterial pressure of 96.9mmHg at diagnosis. The cumulative number of events at 5,10, 15 years were respectively of 34, 54, 68. The median follow-up was 12 years. The correlations between observed/predicted risks were R² =0,990 [0,959 ; 0,998] at 5 years, R² = 0,984 [0,930 ;0,996] at 10 years and 0,964 [0,851 ;0,992] at 15 years after diagnosis. Conclusion In our study we validated the IINN tool to predict the risk to progress to ESRD and/or 50% eGFR decline (i) in a French Caucasian cohort and (ii) even after 5, 10 and 15 years after diagnosis, allowed by a particularly long follow-up.

MO073HISTOLOGICAL PREDICTORS OF PROTEINURIA AND RENAL OUTCOMES IN PRIMARY MEMBRANOUS NEPHROPATHY: IS INTERSTITIAL FIBROSIS THE MAIN CHARACTER?

Abstract Background and Aims Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in older white adults, with an incidence of 12 cases per millions of people per year. Primary MN (PMN, 75%-80% of MNs) is an organ-specific autoimmune disease caused by antibodies anti-PLA2R and anti-THSD7A. Regardless of treatment one third of patients progresses to end-stage renal disease and two third develop non-progressive chronic kidney disease. Renal biopsy is the gold standard for MN diagnosis. Several clinical and biochemical markers have been associated with the risk of progressive loss of kidney function while contrasting results have been obtained by the few studies which have examined the prognostic value of histologic findings. In this study the clinical outcome of patients with PMN has been considered based on the prognostic value of histological findings. Method Forty-nine patients with PMN of our Nephrology Unit at Padova University Hospital from 2003 to 2018 were considered. 16 patients were excluded from the study due to missing data. Age, comorbidities, proteinuria (g/day) and renal function (eGFR, CKD-EPI) were collected. eGFR decline and decrease of proteinuria were used as clinical outcomes. The follow-up was considered from renal biopsy to the last visit (in absence of GFR decline or decrease in proteinuria). Histological grading (0-3) was assigned to parameters (glomerulosclerosis (GS), tubular atrophy (TA), interstitial fibrosis (IF), vascular hyalinosis (VH)) and were evaluated separately or in combination (as GSTIV score). Morphometric analysis was used to quantify IF and expressed in percentage as the mean of area covered by pixel. Statistical analysis was performed using Fisher’s exact test and Mann-Whitney U-test where appropriate. Cox regression analyses (univariate and multivariate) were performed to identify variables associated with both renal outcomes and p&amp;lt;0.05 was considered as significant. ROC curves were used to determine interstitial fibrosis cut-off values predictive for both outcomes. Area under the curve (AUC) between 0.8 and 1.0 was considered as significant. Diagnostic accuracy was assessed by Specificity (Sp), Sensibility (Se), positive (PPV) and negative (NPV) predictive values and positive (LR+) and negative (LR-) likelihood ratios. Results Patients with no decrease of proteinuria had a greater degree of IF vs those with a full response (p=0.006). Univariate Cox analyses identified age ≥65 years (HR 4.92), pre-existing CKD (HR 12.98) and IF (HR3.05) as significant predictors of renal function decline in all patients. Multivariate Cox analysis confirmed these variables (age ≥65 years HR 3.05, CKD HR 6.35, IF HR 3.03). In patients without CKD only IF was significantly associated with eGFR decline in both Cox univariate and multivariate analysis (HR 4.34 and 5.05 respectively). ROC analysis showed that IF threshold of 17.80% identified patients with eGFR reduction (AUC 0.65, Se 0.50, Sp 0.79, PPV 0.75, NPV 0.45, LR+ 2.38, LR-0.63) and IF threshold of 18.04% the lack of proteinuria reduction (AUC 0.78, Se 0.70, Sp 0.83, PPV 0.67, NPV 0.80, LR+ 4.12, LR- 0.36). Conclusion Our study shows that IF could be used as a histologic predictor of renal and proteinuria outcomes. Biopsy report should therefore also include quantitative IF data that could be helpful for the choice of a more appropriate therapeutic approach.

POS-435 CHANGE IN eGFR BY CKD STAGE IN PRIMARY HYPEROXALURIA TYPE 1

The genetic disorder primary hyperoxaluria type 1 (PH1) is marked by an increased hepatic production of oxalate. The resulting hyperoxaluria leads to recurrent nephrolithiasis and nephrocalcinosis which are commonly observed in childhood. About 50% of PH1 patients develop end stage kidney disease (ESKD) by 33 years of age. Clinical trials of potential therapeutic agents are challenging due to disease rarity and time needed to reach hard clinical endpoints (such as ESKD). Thus, slope of eGFR over time is an attractive surrogate endpoint. However, clinical experience suggests that eGFR decline is not uniform across disease course. Thus we looked at the slope of change in eGFR during sequential stages of CKD in a PH1 cohort. PH1 patients enrolled in the Rare Kidney Stone Consortium (RKSC) registry who were >2 years of age, did not have ESKD at diagnosis, and had ≥2 serum creatinine values between dx their last follow up prior to ESKD were studied. eGFR was estimated using the full age spectrum equation. ESKD was defined as the first occurrence of transplant, initiation of dialysis, or eGFR less than 15 ml/min/1.73m2. Absolute change in eGFR over time was estimated by linear regression within each CKD stage, and estimates across CKD stages were compared using GEE models. A total of 129 PH1 patients met inclusion criteria. Seventy (54.3%) were male and 99 (76.7%) were Caucasian. Median [IQR] age at PH1 dx was 8.6 [3.3, 21.6] years. There were 121 patients with follow-up in CKD stage 2; 72 in stage 3a; 41 in stage 3b; and 14 in CKD stage 4. (Table 1) Absolute annual change in eGFR increased with CKD stage (P=0.007 for trend). (Table 1). As hypothesized, eGFR decline was not uniform across CKD stages in this PH1 population, with a higher rate of eGFR decline at CKD stages 3b and 4. Thus, absolute eGFR and CKD stage need to be accounted for when analyzing eGFR slope in this patient group. These data also suggest that measures to prevent GFR decline to < 45 ml/min/1.73m2 are particularly important, as the disease course accelerates thereafter.