bluuebunny/crossref_metadata_2025 huggingface dataset:
SO028LONG-TERM OUTCOMES IN LIVE KIDNEY DONORS: PREVALENCE OF ISCHEMIC HEART DISEASE, DIABETES, CANCER AND CEREBROVASCULAR DISEASE AFTER DONATION COMPARED TO HEALTHY CONTROLS
Authors: Haugen Anders , Dahle Dag Olav , Hallan Stein I , Midtvedt Karsten , Reisater Anna Varberg , Holdaas Hallvard , Mjøen Geir
Published: June 2020

Background and Aims

During long-term follow-up kidney donors are at increased risk of hypertension and end-stage renal disease after donation. Hypertension is a known risk factor for development of cardiovascular disease, but it is unknown whether kidney donors are at increased risk of cardiovascular disease.

We evaluated a large Norwegian kidney donor cohort and assessed prevalence of ischemic heart disease after donation compared to healthy controls. Prevalence of cancer, diabetes and cerebrovascular disease was also calculated.

Method

Follow-up data were retrospectively retrieved from past kidney donors. Healthy non-donor controls from a general population screening study were selected. Controls were selected according to standard donation criteria, assessed in similar time periods as the living donors. Stratified logistic regression was used to estimate associations with various disease outcomes. The diagnoses at follow-up were self-reported for the controls and registered by a physician for the donors.

A total of 1029 donors and 16084 controls were included.

Results

Mean observation time was eleven years after donation. Forty-four per cent of donors were male and mean age at follow-up was 56 years. Among the controls, 39 % were male and mean age at follow-up was 53 years.

At the time of follow up, 3.5 % of donors vs 1.7 % of controls had been diagnosed with ischemic heart disease, 3.7 % vs 4.4 % cancer, 1.8 % vs 1.4 % cerebrovascular disease and 4.1 % vs 1.9 % diabetes.

After adjusting for gender, age at follow up, smoking at baseline, BMI at baseline, systolic blood pressure at baseline and time since donation (time since participation in general population survey for controls), odds ratio for ischemic heart disease was 1.64 (CI 1.10-2.43; P=0.01) in previous kidney donors compared with healthy controls. Other outcomes did not differ significantly between donors and controls.

Conclusion

During long-term follow-up of kidney donors we find an increased risk of ischemic heart disease compared to healthy controls. This information may be important in the follow-up and selection process of living kidney donors.
SO031ANGIOTENSIN II TYPE 1 RECEPTOR (AT1R) EXPRESSION IN RENAL TRANSPLANT BIOPSIES AND ANTI-AT1R ANTIBODIES IN SERUM AS AN INDICATOR OF THE RISK OF TRANSPLANT LOSS
Authors: Sas-Strózik Agnieszka , Donizy Piotr , Kościelska-Kasprzak Katarzyna , Kamińska Dorota , Gawlik Kamila , Mazanowska Oktawia , Madziarska Katarzyna , Zmonarski Sławomir , Hałoń Agnieszka , Magdalena Krajewska , Banasik Mirosław
Published: June 2020

Background and Aims

The manifestation of anti-angiotensin II type 1 receptor (AT1R) antibodies is considered a risk factor for transplant injury, however, the occurrence of AT1-Receptor expression in renal transplant biopsy may be an additional feature which can help to predict transplant loss.

The aim of our study was to evaluate the expression of AT1R together with their antibodies and assess the risk of transplant loss in patients who had a renal transplant indication biopsy.

Method

AT1-Receptor immunoreactivity was analyzed in renal transplant biopsies. Additionally, we analyzed the presence of anti-AT1R antibodies in these patients using ELISA method. The result of more than 10 was assessed as positive.

Immunohistochemical evaluation of AT1-Receptor expression was performed on 4 μm-thick paraffin sections mounted on silanized slides. AT1-Receptor expression was analyzed in five compartments: 1.tubular epithelium, 2.glomeruli, 3.peritubular capillaries, 4.interstitium and 5.renal blood vessels (small and intermediate arteries) based on a 3-step scale.

Results

We checked 156 samples of biopsies for the immunoreactivity of the AT1-Receptor. In all these patients we were able to access the presence of anti-AT1R antibodies.

A group of 67 patients had positive AT1-Receptor expression (R+) and 16 patients had positive anti-AT1R antibodies (R+Ab+) results. A group of 89 patients had no expression of AT1-Receptor (R-), among which 51 had also no anti-AT1R (R-Ab-). One-year post-biopsy graft loss in the R+Ab+ patients was 37% (6/16) compared to 10% (7/69) in the R-Ab- patients (p = 0.006). Two-year and three-year graft loss was 43% vs. 17% (p=0.02) and 50% vs. 21% (p=0.02) respectively.

Moreover, six patients had positive staining of AT1-Receptors in microcirculation (glomeruli and peritubular capillaries), which was associated with antibody mediated rejection.

Conclusion

The presence of anti-AT1R antibodies in serum together with the expression of AT1-Receptor in transplant biopsy was associated with a significantly higher graft loss. The relevance of AT1-Receptor expression analyzed together with anti-AT1R antibodies should be considered for better transplant immunological risk assessment.
SO032THE DISCARD AND DECLINE OF HEPATITIS C VIRUS POSITIVE DONOR KIDNEYS IN THE UNITED STATES
Authors: Alhamad Tarek , Lentine Krista , Axelrod David , Abdulnabi Sami , Schnitzler Mark , Chang Su-Hsin
Published: June 2020

Background and Aims

With more transplant centers in the United States are accepting hepatitis C virus infected (HCV+) deceased donor kidneys (dHCV+), the trend of non-utilization and decline of these organs have not been re-examined.

Method

We used data from the national Organ Procurement and Transplantation Network on deceased donor kidneys between Jan 2000 and Dec 2018 in the United States. Kidney non-utilization for HCV+ was defined as a positive donor HCV status and positive hepatitis as the reason for non-utilization. dHCV+ kidney decline was defined as a donor HCV+ status among kidneys recovered for transplantation but not transplanted. We assessed associations of a dHCV+ status with kidney non-utilization or decline, adjusted for donor characteristics (age, race, sex, body mass index, diabetes, hypertension, kidney donor profile index), using multivariable logistic regression.

Results

A total of 274,570 deceased donor kidneys procured for transplantation between 2000 and 2018 were identified. Among these kidneys, 4.1% were from dHCV+. Proportion of dHCV+ non-utilization among all non-utilized kidneys increased from 2000-2005 (3.9%) and then subsequently declined. This proportion increased slightly to 1.1% in 2014 and decreased to 0.5, 0.8, 0.4, 0.6% in 2015-2018, respectively. Multivariable-adjusted odds ratios for dHCV+ non-utilization and decline by year demonstrate consistently an increasing trend from 2000-2006 followed by a decreasing trend from 2006-2011 (Fig A-B). Multivariable-adjusted odds ratios for dHCV+ (compared to dHCV-) non-utilization and decline increased to 6.56 (95% CI 5.30-8.12) and 6.66 (95% CI 5.39-8.24), respectively, in 2012, and decreased to 2.32 (95% CI 2.01-2.69) and 2.28 (95% CI 1.98-2.64), respectively, in 2018.

Conclusion

dHCV+ non-utilization and decline have decreased in the last few years, particularly after 2014. 2018 had a historic lowest odds ratio for non-utilization and decline of dHCV+ organs, which reflects the increased acceptability of transplant centers to these kidneys. Overall, since 2014, the odds ratios for dHCV+ non-utilization and decline decreased by half. Yet, there is more room for decreasing the non-utilization and decline for these potentially life-saving organs.
SO062TRENDS OF BASELINE-RISK OF MORTALITY AND OBSERVED 3-YEAR MORTALITY IN INCIDENT DIALYSIS PATIENTS IN GERMANY
Authors: Wagner Martin , Rascher Katherine , Cramer Heyke , Schaller Mathias , Bach Rolf Dieter , Von Gersdorff Gero
Published: June 2020

Background and Aims

The risk of mortality varies considerably among end stage kidney disease patients. As the population ages, patients on renal replacement therapy are presenting with an increasing number of non-renal complications such as heart failure and, subsequently, an increased mortality risk. Thus, in recent years, patient care in dialysis units has become more complex. In this study we describe trends in baseline risk of mortality and 3-year mortality risk in a sample of incident dialysis patients in Germany.

Method

The QiN (Quality in Nephrology) dataset is a registry-based observational study in which >90% of all patients treated in dialysis centers of the non-profit kidney care provider KfH are enrolled. In our analyses we included all adult patients beginning hemodialysis (HD) or peritoneal dialysis (PD) treatment between 2008 and 2014 who were enrolled in QiN within 6 months after inception of dialysis. Primary outcome was all-cause death within 3 years. Cox models were censored for transplantation and loss to follow-up. Baseline risk of mortality was assessed by the AROii score (Floege et al. 2015), a predictive model including patient characteristics, laboratory variables and dialysis parameters. In this score higher values indicate greater mortality risk.

Results

A total of n=20369 patients were analyzed, HD n=18255 (89.6%), PD n=2114 (10.4%). Baseline mortality risk increased over time: AROii score for the 2008/09 incidence cohort was median 8.1 (interquartile range 4.4; 11.9), for the 2010/11 cohort 8.8 (5.0; 12.0) and for the 2012-14 cohort 9.0 (5.0; 12.0), p<0.001. The AROii score was highly predictive for observed 3-year mortality (Hazard Ratio [HR] 1.196 [1.190; 1.203], p<0.001; C-statistic 0.736). In spite of higher baseline mortality risk in patients starting dialysis in more recent years, mortality was lower as compared to the earlier cohorts (HR 0.976 [0.964; 0.988), p<0.001). The results were mainly driven by HD patients. In PD patients baseline mortality risk increased, but no trend on mortality was observed.

Conclusion

Our results show that patients starting dialysis in Germany have become sicker over the last decade, as indicated by the AROii risk score. Simultaneously the observed risk of mortality decreased in recent years, indicating success of optimized medical treatment including dialysis therapy as well as non-nephrology medical care.
MO003ADHERENCE TO DIETARY GUIDELINES IN ADULTS UNDERGOING MAINTAINANCE HAEMODIALYSIS: THE DIET-HD STUDY
Authors: Saglimbene Valeria , Su Guobin , Ruospo Marinella , Carrero Juan Jesus , Strippoli Giovanni
Published: June 2020

Background and Aims

While clinical guidelines emphasize dietary modifications as a cornerstone component in the management of patients undergoing dialysis, the adherence to these recommendations has been poorly quantified. The aim of this study is to evaluate the extent of adherence to diet guidelines for adults treated with long-term haemodialysis within the European patients included in the multinational cohort of the “DIETary intake, death and hospitalization in adult with ESKD treated with Haemodialysis” (DIET-HD) study.

Method

Cross-sectional analysis of the DIET-HD study in 6906 adults undergoing haemodialysis in 10 European countries. Patients responded to the Global Allergy and Asthma European Network (GA2LEN) Food Frequency Questionnaire, and dietary intakes were estimated to evaluate the adherence to the European Best Practice Guidelines nutritional recommendations.

Results

Patients showed low adherence to the daily recommended intake of phosphorous (<1000mg, met by 25% of participants) and potassium (<2730mg, met by 28% of participants). Almost half the participants achieved targets for energy (>30 kcal/kg, 45% of participants) and calcium (<800mg/day, 53% of participants) intake, while the recommended sodium (<2300mg/day) and proteins intake (≥1.1g/kg) was achieved in 85% and 67% of participants, respectively. Adherence to renal guidelines varied across participating countries, but followed the same pattern. Only 1% of patients adhered to all six recommendations at the same time.

Conclusion

Adherence to dietary guideline recommendations is poor, particularly regarding phosphorus, potassium, calcium and energy intake.
MO056MODIFICATION OF P16, P21 AND NRF2 EXPRESSION IN A MODEL OF UREMIC VASCULAR CALCIFICATION
Authors: LAGET JONAS , HOBSON SAM , JOVER BERNARD , MUYOR KAREN , Duranton Flore , Kublickiene Karolina , LAJOIX ANNE DOMINIQUE , Stenvinkel Peter , Argiles Ciscart Angel , Gayrard Nathalie
Published: June 2020

Background and Aims

Vascular calcification (VC) is a consequence of ageing that confers development of future cardiovascular events. Accumulation of senescent cells can lead to structural and functional abnormalities in vessel wall towards increased stiffness, reduced compliance and impaired contractile and dilatory capacity. Thus, accumulation of senescent cells in the arterial wall could also contribute to the pathophysiology of VC. To test this hypothesis, the presence of cellular markers of senescence, p16, p21 and NRF2, was assessed in aorta from rat model of VC associated with chronic kidney disease (CKD).

Method

Six-week-old Sprague-Dawley rats underwent 5/6th subtotal nephrectomy (SNx, n=6) or no surgery (Control, n=1). After 8 weeks of renal failure, the regular chow was supplemented with high phosphate (1.2%) and vitamin D (1 µg/day, 5 days per week) for 1 or 4 weeks to initiate vascular calcification (SNx-VC group). At the end of the protocol (Figure 1), blood pressure was measured, and thoracic aorta was taken for determination of calcification by Von Kossa staining, and protein and gene expressions of p16, p21, and NRF2 by immunostaining and qPCR, respectively.

Results

After 4 weeks of dietary intervention, SNx rats showed an increase in pulse pressure (88±15mmHg vs 35 mmHg for the control). Marked VC was also observed in these animals, 17% of calcified area vs <1 % in the control rat. Calcification was focal giving strong and no calcified areas on the same aorta. Expressions of p16, p21and NRF2 proteins were enhanced at the site of calcification in the SNx-VC 4-week (4W) group whereas it was unchanged in aortic media without calcification compared to the control rat (Figure 2). In SNx-VC 1-week (1W) rats, no change in pulse pressure or vascular calcification was observed without obvious changes for staining patterns of selected markers. Using qPCR we found p16 gene expression to be higher in the most calcified aortas (4W) (fold-change = 4.32 vs 1W) and p21 gene expression to be slightly increased (fold-change = 0.53 vs 1W). NRF2 gene expression was enhanced in 1W group compared to control, but decreased in the most calcified samples (4W).

Conclusion

This pilot study suggests that uraemia-induced cellular senescence accompanies VCs, as suggested by the modified expression of p16 or NRF2 genes. Our observations deserve exploration in larger studies using additional senescence markers for validation. If so, cellular senescence kinetics will be evaluated in order to test whether senolytics compounds could be a therapeutic option to arrest VC in CKD.
MO057HYPOXIA AS INDUCER OF FIBROBLAST GROWTH FACTOR 23 IN OSTEOCYTES
Authors: Bonnemaijer Josephine , Koolwijk Pieter , Bravenboer Nathalie , Van Essen Huib , Vervloet Marc
Published: June 2020

Background and Aims

Cardiovascular disease accounts for a major proportion of deaths among chronic kidney disease (CKD) patients. Fibroblast Growth Factor 23 (FGF23), a key regulator in phosphate homeostasis and mainly produced by osteocytes, is associated with CKD progression and cardiovascular mortality. FGF23 is involved in the development of left ventricular hypertrophy that can lead to congestive heart failure. Dysfunction of the heart causes tissue malperfusion, for instance in bones, inducing the hypoxia-inducible signaling pathway. Recently, the hypoxia-inducible factor-1α (HIF-1α) has been suggested as inducer of FGF23. Therefore, we investigated whether hypoxia in osteocytes induces FGF23 production mediated by the stabilization of HIFs.

Method

Human sarcoma osteogenic cells (SaOS2 cell line) and primary human osteocytes were cultured and exposed to hypoxic conditions (1% and 5% O2) and normoxic condition (20% O2) for 24 hours. qPCR was performed to investigate the expression of HIFs and FGF23 mRNA in these cells. HIFs protein expression was also evaluated by Western Blot analysis.

Results

Our data show that HIF-1α, and not HIF-2α, protein increases in SaOS2 cells and primary osteocytes under hypoxic conditions as compared to normoxic condition. In addition, we found that FGF23 mRNA expression is elevated in SaOS2 cells in these hypoxic conditions compared to normoxic condition (Fig.1). This increase was significant in SaOS2 cells exposed to 1% O2 (p <0.05). Preliminary data of primary osteocytes show that FGF23 mRNA is not expressed in hypoxic conditions compared with normoxic conditions (Fig.1).

Conclusion

HIF-1α protein was increased in both SaOS2 cells and primary osteocytes exposed to 1% O2. Hypoxic conditions upregulated FGF23 mRNA in SaOS2 cells. Taken together, these findings suggest that bone malperfusion upregulates FGF23 by stabilizing HIF-1α. This could then close a vicious circle where FGF23 induces cardiovascular disease, and circulatory failure upregulates FGF23.
MO069HIF-1Α C-TERMINAL TRANSCRIPTIONAL ACTIVATION DOMAIN MEDIATED KLF5 SIGNALING DRIVES AKI TO CKD PROGRESSION
Authors: Li Zuolin , Ji Jia-ling , Lv Linli , Yang Yan , Tang Tao-tao , Wang Bin , Liu Bicheng
Published: June 2020

Background and Aims

Acute kidney injury (AKI) is increasingly recognized as a major risk factor for progression to CKD. However, the mechanisms governing AKI to CKD progression are poorly understood. Hypoxia is a key player in the pathophysiology of the AKI to CKD transition. Thus, we aimed to investigate the exact mechanisms of AKI to CKD progression mediated by hypoxia.

Method

Mild ischemic injury and severe ischemic injury (AKI-to-CKD transition) were established by clamping renal pedicle for 30 and 40 minutes, respectively. Meanwhile, the mice model of AKI-to-CKD transition was treated with HIF-1α inhibitor, PX-478. In vitro, PHD inhibition and combined PHD with FIH inhibition mimic the HIF-1α activation caused by mild or severe hypoxia, respectively. Besides the human proximal tubular epithelial cell line HK-2, tubular cells were isolated from mice for primary culture. KLF5 knockdown, FIH and HIF-1α C-terminal transcriptional activation domain (C-TAD) overexpression in tubular cells were achieved by Lentiviral transfection. Immunocoprecipitation was used to explore the relationship between the HIF-1α and FIH-1. Luciferase reporter assay was used to investigate whether KLF5 was regulated transcriptionally by HIF-1α C-TAD. To explore the roles of FIH-1 and HIF-1α C-TAD in vivo, FIH-1 and HIF-1α C-TAD overexpression (Lentivirus-mediated) was given after severe ischemic injury or mild ischemic injury via tail vein injection, respectively.

Results

AKI to CKD progression was highly associated with the time-course expression of tubular HIF-1α in severe ischemia/reperfusion injury. Interestingly, ameliorated AKI-to-CKD transition was observed by treating PX-478, which destabilized HIF-1α. In vitro, fibrogenesis could be induced by combined PHD with FIH inhibitor treatment in TEC. More interestingly, alleviated fibrogenesis could be achieved by knockdown of KLF5 and overexpression of FIH, respectively, while HIF-1α C-TAD overexpression promoted fibrogenesis in tubular cells. Immunocoprecipitation results indicated that HIF-1α and FIH-1 are interactive. Furthermore, we demonstrated that KLF5 could be regulated transcriptionally by HIF-1α C-TAD by luciferase reporter assay. In vivo, AKI to CKD progression was ameliorated significantly when mice model of AKI-to-CKD transition intervened with FIH-1 overexpression (Lentivirus-mediated). However, treatment of HIF-1α C-TAD (Lentivirus-mediated) in mild ischemic injury model could promote progression of CKD significantly.

Conclusion

FIH-1 mediated HIF-1α C-TAD activation was the key mechanism of AKI to CKD transition by transcriptionally regulating the KLF5 pathway in tubules. Blockade of FIH-1 mediated HIF-1α C-TAD in tubules may serve as a novel therapeutic approach to ameliorate AKI to CKD progression.
MO072LONGITUDINAL SERUM BICARBONATE MEASUREMENTS AND RISK OF CHRONIC KIDNEY DISEASE PROGRESSION AND MORTALITY: INSIGHTS FROM THE CKD-REIN COHORT
Authors: Prezelin-Reydit Mathilde , Combe Christian , Harambat Jerome , Massy Ziad , Metzger Marie , Lange Céline , Lambert Oriane , Stengel Benedicte , Leffondré Karen
Published: June 2020

Background and Aims

Metabolic acidosis is a common complication of CKD and may contribute to CKD progression. However, the association between serum bicarbonate and CKD progression has not yet been investigated using longitudinal measurements.

Method

We used data from CKD-REIN, a prospective cohort study conducted in 40 representative French nephrology clinics which included 3033 patients with CKD stages 3 to 5 between 2013 and 2016. Patients who had no serum bicarbonate or no creatinine measure at within 6 months of their inclusion date in the CKD-REIN study were excluded. All serum bicarbonate measurements were taken into account, from inclusion to the occurrence of renal replacement therapy (RRT), death, or end of follow-up, whichever came first. We used a shared random-effect model for the joint analysis of individual trajectories of serum bicarbonate and the hazard of the composite outcome (RRT or death before RRT) and each specific event separately. Hazard ratio were adjusted (aHR) for age, sex, primary kidney disease, metabolic syndrome, cardiovascular disease, proteinuria (< 30, 30-300, > 300 mg/day), and the CKD-EPI estimated glomerular filtration rate (eGFR) at baseline.

Results

A total of 2977 patients (65.4% men, median age 69 years) were included. At baseline, the median eGFR was 31.8 mL/min/1.73m2 and the median bicarbonate concentration was 25 mmol/L. During a median follow-up of 4.5 years, 615 patients received RRT and 378 died before RRT. At any time of follow-up, a decrease of 1 mmol/l of the current level of serum bicarbonate was associated with a significantly increased hazard of RRT or death before RRT (aHR 1.05, 95%CI 1.02-1.08). The estimated effect was stronger on death before RRT (aHR 1.05, 95% CI 1.00-1.09) than on RRT (aHR 1.02, 95% CI 0.99-1.06).

Conclusion

A lower current level of serum bicarbonate is associated with an increased mortality in patients with CKD stage 3 to 5.
MO077TEN YEAR TRENDS IN PAEDIATRIC RENAL REPLACEMENT THERAPY IN EUROPE: DATA FROM THE ESPN/ERA-EDTA REGISTRY
Authors: Bonthuis Marjolein , Harambat Jerome , Vidal Enrico , Jager Kitty J
Published: June 2020

Background and Aims

The ESPN/ERA-EDTA Registry includes data on children with end-stage kidney disease receiving renal replacement therapy (RRT) in Europe for 10 consecutive years. We examined time trends in incidence, prevalence and patient survival for paediatric RRT in Europe.

Method

We included all children aged < 15 years starting RRT in 22 European countries from 2007 to 2016. General population statistics were derived from Eurostat. Incidence and prevalence were expressed per million age related population (pmarp) and time trends were studied with Joinpoint regression. We analyzed patient survival using Cox regression.

Results

The incidence of children commencing RRT < 15 years remained stable over the past ten years, varying between 5.5 pmarp to 6.5 pmarp. The incidence by treatment modality did not change over time: 2.0 to 3.0 pmarp for haemodialysis (HD) and peritoneal dialysis (PD) and 1.0 pmarp for transplantation. Overall prevalence rose by 2% annually (95% CI: 1.5-2.3%) from 29.5 pmarp in 2007 to 35.6 pmarp in 2016.

The increase in prevalence was observed in all age categories, but was strongest among children older than 5 years at RRT initiation. The prevalence of patients on all treatment modalities increased during the study period: from 4.5 to 5.4 pmarp for HD, from 4.9 pmarp to 6.0 pmarp for PD and from 19.6 to 23.9 pmarp for transplantation (Figure).

Four-year adjusted patient survival on RRT was around 96% and similar for those initiating from 2007-2009 and from 2010-2012 (adjusted HR: 0.97, 95% CI: 0.69-1.36).

Conclusion

Over the past decade we found a stable incidence and an increasing prevalence of European children on RRT. Four-year patient survival was good, and did not change over time. These data are important to inform patients and healthcare providers and to aid health policy makers on future resource planning of pediatric RRT in Europe.
TO014COMPARISON BETWEEN HIGH FLUX-HD AND OL-HDF ON SURVIVAL AND ADEQUACY: TEN YEARS EXPERIENCE
Authors: Terlizzi Vincenzo , Lucca Bernardo , Manenti Chiara , Gaggia Paola , Zubani Roberto , Sandrini Massimo , Movilli Ezio , Scolari Francesco
Published: June 2020

Background and Aims

Four RCTs have been published that compared on-line HDF (Ol-HDF) with HD. However, to date, an indisputable answer in determining whether patients treated with Ol-HDF had a better survival than those treated with high-flux HD (Hf-HD) has not been reached. The aim of our study was to retrospectively evaluate the impact of the dialysis modality (Hf-HD, Ol-HDF or acetate-free biofiltration AFB) on patient survival and dialysis adequacy.

Methods

We retrospectively evaluated all the incident patients that started dialysis due to uremia from 01-01-2008 to 31-12-2018 at the U.O. Nephrology ASST Spedali Civili of Brescia. Exclusion criteria were: duration of dialysis treatment less than 3 months, and previous dialytic treatment or kidney transplantation. The dialysis modality performed (Hf-HD vs Ol-HDF), the modality of infusion (pre-dilution or post-dilution) and mean total convective volume (replacement fluid volume + ultrafiltration) during last year’s dialysis session in Ol-HDF were analyzed for each patient.

Results

During observation 677 patients started HD treatment. 70 patients were excluded due to less than 3 months HD treatment. 607 patients (male 390, 64%) were analyzed. 467 pts (77%) were treated with Hf-HD, 103 pts (17%) with Ol-HDF, 36 pts (6%) with AFB. Median duration of HD treatment was 2.6 years (IQR 1.3; 4.7). Ol-HDF was performed in post-dilution mode in 60% of cases (total convective volume 25±4 L); pre-dilution mode was used in 40% of the cases (total convective volume 51±18 L). Patients in the Ol-HDF group were significantly younger than those in Hf-HD and AFB groups (respectively 59±15 years vs 71±15 vs 78±9, p <0.05), and had less diabetes, hypertension and ischemic heart disease (p<0.05) while presenting similar prevalence of cirrhosis (p=0.93) and peripheral vascular disease (p=0.09). Adequacy indices were similar between groups (eKt/V 1.39±0.02 vs 1.41±0.01 vs 1.44±0.04, p=0.47) as well as the protein intake (PCRn 0.92±0.01 vs 0.93±0.01 vs 0.90±0.03 g/Kg/d, p=0.69) and residual renal function (1.5±0.3 vs 1.6±0.1 vs 0.8±0.4 ml/min, p=0.20). Patients on Ol-HDF more frequently had an AV fistula (71% vs 58% vs 59%, p<0.05). At the end of follow-up, 12% of patients had undergone kidney transplantation, 42% continued dialytic treatment while 43% died. Univariate analysis showed a better survival for Ol-HDF patients (Figure 1) (p <0.05). This benefit was confirmed in multivariate analysis (Figure 2) showing that older age, cirrhosis and ischemic heart disease negatively affect survival, while a high protein intake, use of an AV fistula and Ol-HDF (HR 0.43[0.30-0.61]) are protective.

Conclusions

The use of Ol-HDF is associated with better survival compared to Hf-HD. This is confirmed after adjustment for demographic and comorbidities of the patients, characterizing Ol-HDF as an independent predictor of better survival.
P0007EFFECT OF SODIUM BICARBONATE LOAD ON URIC ACID LEVELS IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND METABOLIC ACIDOSIS: PRELIMINARY RESULTS OF THE SOBIC-STUDY
Authors: Repitz Alexandra , Aigner Christof , Sunder-Plassmann Gere , Gaggl Martina
Published: June 2020

Introduction and Aims

Sodium bicarbonate is a commonly used drug that balances metabolic acidosis in patients with chronic kidney disease (CKD) and is said to delay disease progression. Elevated serum uric acid levels are frequently seen in CKD and the prevalence of gout disease in CKD patients is higher than in the normal population. Animal studies suggest that excessive sodium bicarbonate intake may increase uric acid levels, and in Korean Native Broilers led to visceral and articular gout. In turn, individuals with Gitelman/Bartter tubulopathy present alkemic and also show increased gout prevalence. The aim of the study was to evaluate the effect of oral sodium bicarbonate supplementation on uric acid levels after 20 weeks of treatment in patients with CKD and metabolic acidosis.

Methods

Patients with CKD stage 3 and 4 and HCO3- < 21mmol/l enrolled in the ongoing randomized controlled SoBic-study (since 2013) were randomized into the intervention group (target HCO3- 24±1mmol/l) or the rescue group (target HCO3- 20±1mmol/l). Baseline serum uric acid levels were determined prior to sodium bicarbonate supplementation and after 20 weeks. We used Spearman’s correlation and regression analysis to detect a possible association between the amount of sodium bicarbonate intake (milligrams per day) and the alteration of uric acid in patients using a significance level of p=0.05.

Results

Forty-five patients were included in the study until January 2019 (23 intervention group, 22 rescue group) and demographic data is given in table 1. Of the total patient population 24.4% were already affected by hyperuricemia (serum uric acid ≥6.5mg/dl) before participating in the study (47.8% of the intervention group, 13.6% of the rescue-group). During the study period, none of the patients showed symptoms of gout. The mean uric acid level at baseline was 7.3(±1.3) and 7.4(±1.6) after 20 weeks. The median uric acid increased by 0.1 in the intervention group (p=0.651) and decreased by 0.1 in the rescue group (p=0.889) from baseline until 20 weeks. Serum bicarbonate levels and uric acid were not correlated (rs=0.201, p=0.185). The regression analysis showed no association between the uric acid level and the total daily intake of sodium bicarbonate over 20 weeks.

Conclusions

In patients with CKD and metabolic acidosis the treatment with oral sodium bicarbonate for 20 weeks hat no adverse effect on the uric acid level.
P0016EFFECT OF GEMFIBROZIL ON KYNURENINE AMINOTRANSFERASE ACTIVITY AND KYNURENIC ACID PRODUCTION IN RAT KIDNEY
Authors: Zakrocka Izabela , Targowska-Duda Katarzyna , Wnorowski Artur , Kocki Tomasz , Jóźwiak Krzysztof , Turski Waldemar , Załuska Wojciech
Published: June 2020

Background and Aims

Hypertriglyceridemia is the most common lipid disorder in chronic kidney disease. Lifestyle changes and fibrates administration are main methods of lowering triglycerides’ level. PPARα (peroxisome proliferator-activated receptor-α) activation is the primary mechanism of action of fibrates.

A tryptophan metabolite, kynurenic acid (KYNA), is produced from L-kynurenine (L-KYN) by kynurenine aminotransferases (KATs). KAT I and KAT II isoenzymes are the best analyzed KATs. KYNA acts predominantly as a nonselective antagonist of ionotropic glutamatergic receptors, particularly N-methyl-D-aspartate (NMDA) type, which are highly expressed in the kidney. Natriuretic and hypotensive effects of KYNA are well described. Diet rich in fatty acids was reported to elevate central and peripheral KYNA level.

The goal of presented study was to analyze the influence of gemfibrozil, one of the fibrates given to treat hypertriglyceridemia, on KYNA production and the activity of KAT isoenzymes: KAT I and KAT II, in rat kidney in vitro. Additionally, the molecular docking of gemfibrozil to KAT I and KAT II structures was performed to study drug-enzyme interaction. On the final step the microarray datamining was carried out to investigate whether gemfibrozil affects the expression of KAT-coding genes.

Method

The effect of gemfibrozil on KYNA synthesis together with KAT I and KAT II activity was tested in rat kidney homogenates in vitro after 2 hours incubation in the presence of L-KYN and gemfibrozil. The drug was examined at the concentration of 1 µM, 10 µM, 50 µM, 100 µM, 500 µM and 1 mM. Production of KYNA was analyzed using the high performance liquid chromatography (HPLC) with fluorometric detector.

Results

Gemfibrozil at 100 µM, 500 µM and 1 mM decreased KYNA production in kidney homogenates in vitro to 66% (P < 0.05), 58% (P < 0.01) and 41% (P < 0.01) of control value, respectively. At 100 µM, 500 µM and 1 mM concentration gemfibrozil lowered renal KAT I activity in vitro to 68% (P < 0.05), 56% (P < 0.01) and 52% (P < 0.01) of control value, respectively. Moreover, gemfibrozil at 500 µM and 1 mM concentration decreased kidney KAT II activity in vitro to 47% (P < 0.001) and 26% (P < 0.001) of control value, respectively. Results of the molecular docking suggested that gemfibrozil may affect the active site of both KAT I and KAT II. Publicly available microarray datasets suggested that the expression of KAT-coding genes does not change after gemfibrozil administration.

Conclusion

Gemfibrozil decreases KYNA production in rat kidney in vitro through inhibition of KAT I and KAT II isoenzymes. Presented results indicate a novel mechanism of gemfibrozil’s action in the kidney. Its potential role in nephrotoxicity needs verification in upcoming studies.
P0019MICROVESICLES FROM MESENCHYMAL STEM CELLS OVEREXPRESSING MIR-34A INHIBIT TGF-BETA-1-INDUCED EPITHELIAL-MESENVHYMAL TRANSITION IN RENAL TUBULAR EPITHELIAL CELLS IN VITRO
Authors: He Juan , Jiang Yali , Wang Yan , Tian Xiujuan , Sun Shiren
Published: June 2020

Background and Aims

The application of microRNAs (miRNAs) in the therapy of kidney diseases is hampered by difficulties in delivering miRNAs effectively. Nano-sized microvesicles (MVs) are known as natural carriers of small RNAs. Our prior work has demonstrated that MVs isolated from mesenchymal stem cells (MSCs) attenuated kidney injuries induced by unilateral ureteral obstruction and 5/6 subtotal nephrectomy in mice. The present work aimed at evaluating the effects of miR-34a-5p (miR-34a)-modified MSC-MVs on transforming growth factor (TGF)-β1 induced fibrosis and apoptosis in vitro.

Method

Bone marrow MSCs were further modified by lentiviruses overexpressing miR-34a, and MVs were collected from these MSCs to treat HK-2 renal tubular cells exposed to TGF-β1. Alterations in epithelial-mesenchymal transition (EMT) and cell survival were further determined.

Results

We first demonstrated that MVs generated by miR-34a-modified MSCs contained more miR-34a. By analyzing the expression levels of epithelial markers (E-cadherin and Tight Junction Protein 1 (TJP1)) and mesenchymal markers (α-SMA and fibronectin), we found that the pro-fibrotic TGF-β1 induced EMT was remarkably suppressed by miR-34a-enriched MSC-MVs. Notch-1 receptor and Jagged-1 ligand, two major molecules of Notch signaling pathway, are predicted targets of miR-34a. We further found that the elevation in Notch-1 and Jagged-1 induced by TGF-β1 was inhibited by miR-34a-enriched MSC-MVs. The inhibitory effects of miR-34a-enriched MSC-MVs on EMT and Notch signaling pathway were stronger than the control MSC-MVs. In addition, TGF-β1 exposure also induced apoptosis in HK-2 cells. Although miR-34amofidied MSC-MVs could inhibit TGF-β1-triggered apoptosis in HK-2 cells, the effects were less significant than the control MSC-MVs. This phenomenon may be resulted from the pro-apoptotic effects of miR-34a.

Conclusion

Our study demonstrates that miR-34a-overexpressing MSC-MVs inhibit EMT induced by pro-fibrotic TGF-β1 in renal tubular epithelial cells, possibly through inhibiting Jagged-1/Notch-1 pathway. Genetic modification of MSC-MVs with anti-fibrotic molecule may present a novel strategy for treatment of renal injuries.
P0035URINARY CITRATE AS A MARKER OF RENAL FUNCTION IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
Authors: Borrego-Utiel Francisco-Jose , Herrera Isidoro , Merino Garcia Enoc , Moriana Dominguez Clara , Camacho Reina Victoria , Ocaña Perez Esther
Published: June 2020

Background and Aims

In autosomal dominant polycystic kidney disease (ADPKD) is frequent to find low urinary citrate levels. Recently it has been suggested that urinary citrate could be a marker of covert metabolic acidosis. Our aim was to analyze relationship between urinary citrate levels and renal functionality in ADPKD patients.

Method

We determined citrate, calcium and uric acid in 24-hour collected urine from 91 ADPKD patients

Results

Urinary citrate/creatinine ratio was 214±158 (range 5.3-678) mg/g Cr with levels significantly higher in females. When considering chronic kidney disease (CKD) stages we observed a progressive decrease in urinary osmolality and in urinary citrate, calcium and uric acid elimination. Low levels of citrate (<300 mg/g Cr) were present in 40% in CKD-1 stage, in 69.7% in CKD-2 stage, 92% in CKD-3 stage and 100% in CKD-4 + 5 stages. Urinary citrate was correlated with serum creatinine (r= -0.66, p<0.001) and eGFR (r= 0.56, p<0.001). Urinary citrate significantly correlated with urinary calcium but correlation with urinary uric acid was weaker. We did not find any correlation with serum bicarbonate. Using multiple lineal regression analysis we found as predictors of urinary citrate to glomerular filtration rate, female gender and urinary calcium levels. In a subgroup of patients we measured total kidney volume and we found an inverse correlation with urinary citrate levels that dissappeared when it was corrected with glomerular filtration rate. We did not also find a relationship between urinary elimination of calcium or uric acid and TKV after adjusting with eGFR.

Conclusion

Urinary citrate is very frequently reduced in ADPKD patients being present from very early CKD stages. Their levels are inversely correlated with glomerular filtration rate and directly with urinary calcium excretion. We did not found a relathionship with serum bicarbonate. We think that it would be interesting to study urinary citrate in other nephropathies and verify if it could be a marker of covert metabolic acidosis.
P0043SYMPTOMS IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE: FINDINGS FROM QUALITATIVE PATIENT INTERVIEWS
Authors: DasMahapatra Pronabesh , Cline Jennifer , Pulikottil-Jacob Ruth , Maski Manish , Cantor Sarah , Hariri Ali , Krupnick Robert , Modur Vijay
Published: June 2020

Background and Aims

Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) experience various symptoms due to increasing kidney volume and its associated complications. To understand symptom burden, qualitative interviews were conducted to characterize the ADPKD patient experience pertaining to the most common and disturbing symptoms.

Method

Combined concept elicitation and cognitive debriefing interviews were performed by trained interviewers following a preliminary conceptual model based on a targeted literature review. We currently report on the concept elicitation component, which explored relevant and bothersome symptoms in ADPKD patients, due to either the disease or associated treatments. Nineteen telephone interviews were conducted in four waves of 5, 4, 6, and 4 patients, respectively.

Results

The mean age of patients was 47 years (SD: 9 years); 68% (n=13) were female, and the mean estimated glomerular filtration rate (eGFR) was 41 ml/min/1.73m2 (SD: 25 ml/min/1.73m2), with the majority 47% (n=9) in stage 3 chronic kidney disease (CKD). The classes of treatments included antihypertensives (74%, n=14), vasopressin receptor antagonists (21%, n=4); diuretics (16%, n=3), analgesics (16%, n=3) and erythropoietin (5%, n=1). The most frequently mentioned symptoms were fatigue (89%, n=17), pain (84%, n=16), and nocturia (74%, n=14); all were considered at least moderately disturbing to patients’ lives. Most patients experienced constant fatigue (74%, n=14) that worsened over time. Patients’ descriptions of pain were variable, including back and side pain, severe cystic pain, and muscle pain; a few patients also mentioned shoulder pain, or pain due to kidney stones. Among patients reporting nocturia (n=14), about half (57%, n=8) rated nocturia on the upper end of the disturbance scale, regardless of number of voids per night, often accompanied by sleep disruption. While less frequently occurring, itchy skin, muscle cramping, abdominal swelling, and inability to eat were spontaneously mentioned among the most disturbing symptoms.

Conclusion

The novel component of this study is the significant disruption of nocturia in patients with ADPKD even in the absence of vasopressin receptor antagonist administration. In addition, it confirms the findings of the literature review and highlights the patient experience in ADPKD, most notably fatigue, nocturia, and pain as the most frequent and bothersome symptoms experienced by patients. Subjective evaluation of the ADPKD patient experience is critical to understand symptom severity and the burden of disease, to potentially quantify disease progression, and to assess the impact of emerging therapies.
P0086FOCAL SEGMENTAL GLOMERULOSCLEROSIS AND TROMBOCYTOPENIA WITHOUT BLEEDING DIATHESIS: WHEN GENETICS MATTER
Authors: Olivo Elisa , Leonardi Sabina , Di Maso Vittorio , Artero Mary Louise , Bianco Francesco
Published: June 2020

Background and Aims

A 45-year old patient presented to our renal unit because of increased serum creatinine (2 mg/dL), proteinuria (2g/24h collection) and haematuria; platelets were 12000/mcL. His family history was negative. He had already undergone cataract surgery and was wearing a hearing device. Alport syndrome was suspected and kidney biopsy performed. Light microscopy showed focal segmental glomerulosclerosis (FSGS), while immunofluorescence was negative. Electron microscopy was not available. No specific treatment was undertaken and he progressed to end-stage renal disease (ESRD) in 10 years. The patient chose peritoneal dialysis. He was considered at high risk of bleeding but the Tenchkoff catheter was inserted without problems. After 3 months he received kidney transplant and again no pathological bleeding occurred.

Method

A genetic test was requested using next generation sequencing (NGS).

Results

A mutation of myosin heavy chain 9 (MYH9) gene which encodes the non-muscle myosin heavy chain-IIA (NMMH-IIA) was found. This mutation is associated with thrombocytopenia and proteinuria; platelets are giant and display normal aggregation, even in those patients who have a very low count. Proteinuria can be mild or in the nephrotic range, with or without microhaematuria. Kidney involvement is highly heterogeneous and leads to ESRD in half of the cases. Light microscopy shows FSGS as the prevalent pattern whereas electron microscopy is characterized by podocyte foot process effacement. In fact, NMMH-IIA is expressed in podocytes and controls cytoskeleton and cell migration. The differential diagnosis with Alport disease is challenging because additional features of MYH9 mutation are sensorineural deafness and pre-senile cataract. For all these reasons, accurate kidney biopsy study, family history and genetics are decisive.

Conclusion

Genetic testing has a pivotal role in understanding kidney diseases and should be more and more used.
P0089KEAP1/NRF2 PATHWAY REGULATES GFR BY INCREASING THE GLOMERULAR EFFECTIVE AREA WITHOUT AFFECTING THE AFFERENT/EFFERENT ARTERIOLE RATIO
Authors: KIDOKORO KENGO , Wada Yoshihisa , Kondo Megumi , Tokuyama Atsuyuki , Itano Seiji , Sasaki Tamaki , Wigley Chris , Proksch Joel , Meyer Colin , Kashihara Naoki
Published: June 2020

Background and Aims

The Keap1/Nrf2 pathway regulates the expression of a series of cytoprotective, anti-inflammatory and antioxidant genes. The Nrf2 activator, bardoxolone methyl (BARD), has consistently increased estimated GFR (eGFR) in clinical studies in patients with chronic kidney disease. BARD demonstrated improvement of renal function assessed by inulin clearance, the clinical gold standard for measuring GFR, in diabetic kidney disease patients. These findings suggest the Keap1/Nrf2 system is deeply involved in the regulatory mechanisms of GFR. However, the precise mechanisms are not fully elucidated. We pharmacologically and genetically investigated the mechanisms of GFR regulation by Keap1/Nrf2 system using in vivo multiphoton microscope (MPM) imaging techniques.

Method

C57BL/6 (Cont), Nrf2 knockout (Nrf2-KO), and Nrf2-activated Keap1-knockdown mice (Keap1-KD) were used. The mice were treated the synthetic triterpenoid RTA dh404 (10 mg/kg/day by gavage) which is a Nrf2 activator for rodents, for a week. We successfully developed the technique to evaluate single-nephron GFR (SNGFR) using MPM (Circulation 2019). The glomerular hemodynamics, diameter of the afferent/efferent arterioles and glomerular permeability were also evaluated. The calcium influx into cells in response to ATP and angiotensin II stimulation and the effect on [Ca2+]i by RTAdh404 were evaluated using Fluo 4 and Fura red in cultured mesangial cells and podocytes. Production of reactive oxygen species and nitric oxide (NO) availability were assessed by fluorescent method using CellROX® Deep Red and diaminofluorescein-FM diacetate (DAF-FM DA) upon the exposure to these stimuli.

Results

SNGFR in Keap1-KD mice was significantly higher than in the control (9.13±0.55 vs 4.40±0.39 nl/min, Figure 1). RTA dh404 increased SNGFR in the control but not in the Nrf2-KO mice (6.00±0.40 vs 4.66±0.35 nl/min, Figure 1). There was no significant change in the ratio of the glomerular afferent/efferent arteriole diameter in all groups. RTA dh404 treatment increased glomerular volume but did not affect the glomerular permeability of albumin and 40kd-dextran. RTA dh404-treatment inhibited calcium influx into cultured podocytes and mesangial cells induced by angiotensin II or ATP, thereby affecting contractile responses. Oxidative stress and NO-bioavailablity were also ameliorated with RTA dh404.

Conclusion

The Keap1/Nrf2 pathway plays a pivotal role in controlling GFR and presumably underlies the effect of BARD on GFR in patients.