bluuebunny/crossref_metadata_2025_split huggingface dataset:
#3769 MECHANOSENSITIVE ION CHANNEL PIEZO1 MEDIATES BLOOD PRESSURE HOMEOSTASIS BY REGULATING RENIN EXPRESSION IN MICE
Authors: Yang Xiaoqiang , Wang Le , Zeng Honghui , Luo Siweier , Zhou Yiming 
Published: June 2023

Abstract

Background and Aims
The renin-angiotensin system (RAS) plays a crucial role in the maintenance of fluid-electrolyte and blood pressure homeostasis. Renin, the step-limiting protease of the RAS, is produced, stored, and secreted by the renal juxtaglomerular (JG) cells, which are closely regulated by the blood pressure. Studies have shown that local blood flow-associated shear stress play an important role in renin expression and secretion. To date, however, the molecular identity through which JG cells respond to the blood pressure remains unclear.

Method
In this study, we determined the expression and subcellular localization of Piezo1 in JG cells by qPCR, Western blot, Immunofluorescence (IF), and multiplex immunohistochemistry. Then, a Fluo-4 AM-based calcium-imaging system was used to detect the dynamic changes of intracellular calcium in response to Piezo1 specific agonist Yoda1 and mechanical stress (MS)-induced by perfusion. Next, CRISPR/Cas9 technology was used to generate Piezo1 knockout JG cells to further confirm its contribution. Then, we used RNA-seq experiment to investigate the downstream signaling of Piezo1 in JG cells. Finally, we generated adeno-associated virus (AAV)-mediated kidney-specific Piezo1 knockdown mice to investigate the in vivo effect of Piezo1.

Results
We found that the mechanosensitive ion channel Piezo1 was co-expressed with renin in JG cells in mouse kidney slides as well as As4.1 cells, a commonly used JG cell line. Activation of Piezo1 by its agonist Yoda1 induced an intracellular calcium increase and reduced the expression of renin in these cells, while knockout of Piezo1 in JG cells abolished the effect of Yoda1. Meanwhile, fluid induced mechanical stress also led to an intracellular calcium increase and renin downregulation in wildtype but not Piezo1 knockout JG cells. Mechanistically, we demonstrated that activation of Piezo1 upregulated the Ptgs2 expression via the calcineurin-NFAT pathway and increased the production of Ptgs2 downstream molecule COX-2 and PGE2 in JG cells, which inhibited cAMP production and reduced renin expression in JG cells. In mice, we demonstrated that activation of Piezo1 significantly downregulated the blood pressure in wildtype but not kidney-specific Piezo1 knockdown mice.

Conclusion
In summary, these results revealed that activation of Piezo1 could lead to downregulation of the renin expression in vitro and in vivo, subsequently reduction of blood pressure, highlighting its therapeutic potential as a drug target of the renin-angiotensin system.
#4126 LONG-TERM VISIT TO VISIT VARIABILITY IN HBA1C AND KIDNEY RELATED OUTCOMES IN PERSONS WITH DIABETES
Authors: Xu Yang , Dong Shujie , Fu Edouard L , SjÖlander Arvid , Grams Morgan E , Selvin Elizabeth , Carrero Juan Jesus 
Published: June 2023

Abstract

Background and Aims
Glycated hemoglobin (HbA1c) is central to the routine monitoring of glycemic control in persons with diabetes, and poor glycemic control is an established contributor to the occurrence and progression of CKD, but whether long-term visit-to-visit variability in glycemic control predicts kidney outcomes is not well studied.

Method
We included all adults with type 1 or type 2 diabetes in Stockholm, Sweden, during 2006–2019, who had at least one annual outpatient HbA1c test in three consecutive years. We evaluated associations between baseline and time-varying HbA1c variability score (HVS, the percentage of total HbA1c measures that vary by &gt;0.5% [5.5 mmol/mol] during a 3-year window), with the risk of CKD progression (composite of &gt;30% eGFR decline and kidney failure), acute kidney injury (AKI, by clinical diagnosis or increase in creatinine ≥0.3 mg/dL over 48 h or 1.5 times creatinine over 7 days), and worsening of albuminuria.

Results
We included 93,598 adults with diabetes undergoing 891,536 routine HbA1c tests (median 8 tests per person) during a median follow-up of 5.2 years. Compared with persons showing low HbA1c variability (HVS 0–20%), any increase in variability was associated with a higher risk of adverse kidney outcomes. For example, for patients with a baseline HbA1c variability of 81–100%, the adjusted HR was 1.47 (95% CI, 1.38-1.56) for CKD progression, 1.27 [1.19-1.36] for AKI, and 1.28 [1.21-1.36] for worsening of albuminuria. Results were robust across subgroups (diabetes subtypes, baseline eGFR or albuminuria categories) and in sensitivity analyses including time-weighted average HbA1c or alternative metrics of variability.

Conclusion
A higher long-term visit-to-visit HbA1c variability is robustly associated with the risks of CKD progression, AKI and worsening of albuminuria.
#4917 AN EXOME-WIDE STUDY OF RENAL OPERATIONAL TOLERANCE
Authors: Massart Annick , Danger Richard , Olsen Catharina , Emond Mary , Viklicky Ondrej , Jacquemin Valérie , Soblet Julie , Duerinckx Sarah , Croes Didier , Perazzolo Camille , Hruba Petra , Daneels Dorien , Caljon Ben , Sever Mehmet Sukru , Pascual Julio , Pirson Isabelle , Ghisdal Lidia , Smits Guillaume , Giral Magali , Abramowicz Daniel , Abramowicz Marc , Brouard Sophie 
Published: June 2023

Abstract

Background and Aims
Renal operational tolerance is a rare and beneficial state of prolonged renal allograft function in the absence of immunosuppression. The underlying mechanisms are unknown. We hypothesized that tolerance might be driven by inherited protein coding genetic variants with large effect, at least in some patients.

Method
We set up a European survey of over 218,000 renal transplant recipients and collected DNAs from 40 recipients of an allogeneic kidney transplant who maintained good graft function (serum creatinine &lt;1.7 mg/dL and proteinuria ≤1g/day or /g creatinine) in the absence of immunosuppression for at least one year. We performed an exome-wide association study comparing the distribution of moderate to high impact variants in 36 tolerant patients, selected for genetic homogeneity using principal component analysis, and 192 controls, using an optimal sequence-kernel association test adjusted for small samples.

Results
We identified rare variants (allele frequency &lt; 1%) of HOMER2 (3/36, FDR 0.0387), IQCH (5/36, FDR 0.0362), and LCN2 (3/36, FDR 0.102) in 10 tolerant patients vs 0 controls. One patient carried a variant in both HOMER2 and LCN2. Furthermore, the three genes showed an identical variant in two patients each. The three genes are expressed at the primary cilium (p0= 0.01), a key structure in immune responses. Both LCN2 variants were located 9 base pairs apart, in the 20 amino-acid long signal peptide of the encoded NGAL protein, suggesting the possibility of a shared functional effect

Conclusion
Rare protein coding variants in a small set of primary cilium genes are associated with operational tolerance in a sizable portion of patients. Our findings have important implications for a better understanding of immune tolerance in transplantation and other fields of medicine.
ClinicalTrials.gov Identifier NCT05124444.
#4958 IMPROVEMENT OF NUTRITIONAL STATUS AFTER PARATHYROIDECTOMY IN PATIENTS RECEIVING MAINTENANCE HEMODIALYSIS
Authors: Disthabanchong Sinee , Saeseow Sarunya , Khunapornphairote Sirote , Suvikapakornkul Ronnarat 
Published: June 2023

Abstract

Background and Aims
Improvement in quality of life and survival have been reported after parathyroidectomy in patients with end-stage kidney disease. In addition to bone loss, protein-energy wasting has also been linked to excess parathyroid hormone (PTH) level. The present study examined the changes of nutritional parameters after parathyroidectomy in patients receiving maintenance hemodialysis compared non-parathyroidectomized patients.

Method
One hundred eighty-seven hemodialysis patients who underwent parathyroidectomy during 2012–2018 were identified (PTX group) and matched 1:1 to 479 patients with parathyroid hormone (PTH) levels ≤1000 pg/mL (non-PTX control group) and 187 patients with PTH levels &gt;1000 pg/mL (pre-PTX control group) by propensity score. The matchings yielded 120 matched pairs from PTX and non-PTX groups (cohort 1) and 76 matched pairs from PTX and pre-PTX groups (cohort 2). Baseline and follow-up nutritional data were compared over the 12-month study period.

Results
In cohort 1, substantially lower serum albumin and creatinine/body surface area (Cr/BSA) and higher proportions of patients with serum albumin ≤38 g/L (low serum albumin) and Cr/BSA ≤380 μmol/L/m2 (low serum Cr/BSA) were observed in the PTX group. These parameters and the percentage of patients with total lymphocyte count &lt;800 cells/mm3 (low TLC) improved substantially after parathyroidectomy. At follow-up, serum albumin, Cr/BSA and proportions of patients with low serum albumin and Cr/BSA became comparable to the non-PTX control group. The percentage of patients with low TLC was also lower at follow-up in the PTX group. Mixed-models analysis confirmed significant differences in the changes of serum albumin, Cr/BSA, proportions of patients with low serum albumin and TLC between the two groups. In cohort 2, there was no significant difference in baseline nutritional parameters. At follow-up, serum Cr/BSA was higher and proportions of patients with body mass index (BMI) ≤18.5 kg/m2, low TLC and low Cr/BSA were lower in the PTX group. Weight gain was more frequent and of greater magnitude in the PTX group in both cohorts. Higher baseline PTH level, parathyroidectomy and lower baseline serum albumin and creatinine were significantly associated with ≥10% increase in the BMI.

Conclusion
Parathyroidectomy was associated with nutritional improvement in maintenance hemodialysis patients with severe hyperparathyroidism.
#5499 COULD MESANGIAL C3 DEPOSITION BE AN INDEPENDENT PROGNOSTIC MARKER IN IMMUNOGLOBULIN A NEPHROPATHY?
Authors: Cetinkaya Hakki , Gursu Meltem , Yazici Halil , Cebeci Egemen , Eren Necmi , Altiparmak Mehmet Riza , Akcay Omer Faruk , Sahin Gulizar Manga , Basturk Taner , Atilgan Kadir Gokhan , Aydemir Nihal , Turgutalp Kenan , Dheir Hamad , Yılmaz MÜrvet , Sirali Semahat Karahisar , Tatar Erhan , Boz Saide Elif Gullulu , Mirioglu Safak , Kazan Sinan , Aydin Emre , Aydin Zeki , Turkmen Kultigin , Kutlay Sim , Karagoz Ferdi , Ogutmen Melike Betul , Ozturk Savas , Ozkan Oktay , Yıldız Nuriye , Dincer Mevlut Tamer , Yasar Emre , Gok Mahmut , Turkmen Aydin , Dede Fatih , Derici Ulver 
Published: June 2023

Abstract

Background and Aims
Immunoglobulin A nephropathy (IgAN) is a common primary glomerulonephropathy and the role of complement activation in the pathogenesis has not been fully clarified. There is evidence that mesangial C3 deposition plays a role in the development of the disease. The aim of this study was to examine the effect of C3 deposition on the prognosis of IgAN patients.

Method
The study included 1135 patients with IgAN confirmed by biopsy using the datatbase of the Turkish Nephrology Association Glomerular Diseases Working Group (TSN-GOLD). Patients were excluded from the study if they were aged &lt;18 or &gt;75 years, or if C3 staining had not been performed in the immunofluorescent analysis. C3 deposition was defined as immunofluorescent staining within the mesangium as 1+ negative and no staining, and 2+ and 3+ positive intensity staining (&lt;2+ and ≥2+). Evaluation was also made according to the Oxford MEST-C classification. The primary endpoint was the development of end-stage renal failure (ESRF), and kidney transplantation, and an increase of 30% in glomerular filtration rate (GFR) compared to the basal value, or an elevation in proteinuria to a nephrotic level (3.5 gr/day) were accepted as poor prognosis.

Results
Mesangial C3 deposition was determined in 603 (53.1%) patients. In the evaluation of basal values between the groups with and without deposition, no statistically significant difference was determined in respect of age, gender, BMI, proteinuria level, or the presence of hypertension. In the follow-up period of mean 78 months survival, no significant difference was determined between the two groups in respect of the primary endpoint (C3+:53.1% vs. C3-:46.9%, p = 0.43). A significant correlation was determined between C3 deposition and segmental glomerulosclerosis (S1) according to the Oxford MEST-C classification (p = 0.001).

Conclusion
Although a correlation was seen between mesangial C3 deposition and the S1 MEST-C classification, the use of these alone or together as a prognostic factor in IgAN is not appropriate.
#5596 MODERATE AND SEVERE KIDNEY DYSFUNCTION ASSOCIATED WITH LEFT VENTRICLE DIASTOLIC DYSFUNCTION: A COHORT WITH DATA FROM ELECTRONIC HEALTHCARE RECORDS
Authors: Porras Cindy P , Bots Michiel , Verhaar Marianne , Vernooij Robin 
Published: June 2023

Abstract

Background and Aims
Left ventricular diastolic dysfunction is observed in patients with chronic kidney disease (CKD) and may lead to heart failure with preserved ejection fraction (HFpEF). In this study, we investigate the association between kidney dysfunction and left ventricular diastolic dysfunction (LVDD) in a cohort using data from electronic healthcare records.

Method
We utilized electronic healthcare data from the Utrecht Patient Oriented Database (UPOD), including all patients treated at University Medical Center Utrecht (UMCU), a university teaching hospital. We extracted demographic patient data, admission data, medication orders, and laboratory results. All performed echocardiography from baseline (i.e., first visit to the hospital) to end of follow-up (i.e., death or censoring) were included. The estimated glomerular filtration rate (eGFR) was calculated using the creatinine formula without ethnicity. Participants were divided into four groups depending on their eGFR (mL/min/1.73 m2) as follows: normal kidney function (eGFR ≥ 90), mild kidney dysfunction (eGFR ≥ 60–89), moderate kidney dysfunction (eGFR ≥ 30–59), and severe kidney dysfunction (eGFR &lt; 30). The association of eGFR with E/A and E/e’ ratio was tested by multivariable adjusted cox proportional hazards survival analysis, reporting hazard ratios (HR) and 95% confidence intervals (CI).

Results
We identified 6,216 participants who received echocardiography as part of their routine care between 2012 and 2022. The mean age was 66.9 (SD: 12.04 years), and 41.7% of individuals were females. In total, 90.4% and 24.5% of the patients had, respectively, hypertension and diabetes. Twenty-six per cent of participants had normal kidney function, 48.2% had mild kidney dysfunction, and 21.3% and 4% had moderate and severe kidney dysfunction, respectively.  In total, 16,935 echocardiography were performed. The median time from the first to the final echocardiography was 0.78 (IQR: 2.89 years). Adjusted multivariable analysis showed that patients with moderate (HR: 1.19; 95% CI: 1.09, 1.31) and severe kidney dysfunction (HR: 1.36; 95% CI: 1.14, 1.62) had higher probabilities of having E/A ratio &lt;0.75 or &gt;1.8 compared with those with normal kidney function. Similarly, for an E/e’ ratio &gt;14, participants with moderate and severe kidney dysfunction had higher probabilities, HR: 1.62 (95% CI: 1.49, 1.77) and 2.10 (95% CI: 1.83, 2.42), respectively, compared with participants with normal kidney function.

Conclusion
Moderate and severe kidney dysfunction are independently associated with LVDD. This association is independent of sex, age, hypertension, and diabetes status and is stronger for severe kidney dysfunction. Early recognition of LVDD in kidney dysfunction might help identify those at highest risk of developing HFpEF.
#5854 RENAL TRANSPLANTATION: THE BEST THERAPEUTIC OPTION FOR HEART TRANSPLANT RECIPIENTS WITH ADVANCED CKD
Authors: Redondo Gerson Berná , Cordoba Cristian , De Arizon Leonor Fayos , Mónica Pérez , Molas Carme Facundo , Guirado Lluis , Cabanas Nuria Serra 
Published: June 2023

Abstract

Background and Aims
Chronic kidney disease is a frequent complication of heart transplant recipients (HT) and is associated with worse survival. Current literature shows that probably the best renal replacement therapy option for these patients is kidney transplantation (KT). The aim of our work is to assess the results of renal transplantation in HT recipients.

Method
Retrospective descriptive single-center study including all heart transplant recipients patients who received a kidney transplantation in our center between 1992 and 2022. Data on renal and overall vital survival as a well as the factors that could have influenced them and associated complications were analyzed.

Results
We included 14 patients, 64% men, with a mean age of 56 years at the time of the KT. A total of 30.8% received an anticipated KT. A total of 85.7% received a KT from a cadaveric donor. In 90% the induction immunosuppression consisted of thymoglobulin, prednisone, mycophenolate, and differed tacrolimus. The mean time between heart and kidney transplantation was 15 years. Six months after KT the mean GFR was 40 mil/min/1,73 m2, at 12 months 35 ml/min/1,73 m2 and at 5 years 30 ml/min/1,73 m2. Renal graft survival was 84% and patient survival was 93% at 10 years. Regarding complications, the most frequent were urological (38.5%) followed by infectious (30.8%). The incidence of acute rejection was 18%.

Conclusion
Our data confirms that kidney transplantation in heart transplant recipients has very positive results. It is necessary to promote collaboration between CT and RT units with the aim of identifying promptly those patients who are candidates for KT, being able to perform it in the best conditions (preemptive transplantation, possibility of living donor transplanation).
#5990 COMPLEMENT GENES PROFILE OF PATIENTS WITH SEVERE HYPERTENSION AND RENAL THROMBOTIC MICROANGIOPATHY
Authors: Akaeva Mariam , Bobrova Larisa , Kozlovskaya Natalia , Vorobyeva Olga , Stolyarevich Ekaterina , Shatalov Peter 
Published: June 2023

Abstract

Background and Aims
Hereditary or acquired complement system dysregulation found to be driving cause of endothelial damage in atypical haemolytic uremic syndrome (aHUS) – ultrarare life-threatening disease, that always manifests with renal thrombotic microangiopathy (TMA), resulting in poor outcome in absence of appropriate treatment. Nevertheless, several studies show high incidence of rare genetic variants of complement system in other TMA’s, including hypertension-induced TMA. Here we report results of complement genes screening in patients (pts) with histologically identified renal TMA and severe hypertension in Russia, at first diagnosed as hypertension-induced TMA.

Method
A total of 28 Caucasian pts diagnosed with renal TMA (confirmed by kidney biopsy in all cases) and severe hypertension enrolled in the study. The main characteristic of the clinical picture was the absence of microangiopathic hemolysis and thrombocytopenia in prevailing of the pts, thus most of the primary and secondary causes of TMA clinically excluded. Examination of DNA samples was performed in all pts using next generation sequencing (NGS) technology. For statistical analysis continuous variables were presented as Mean (±Standart deviation) or Median (interquartile range) as appropriate.

Results
Baseline demographic and clinical characteristics of group are listed in Table 1. 13 pts (46%) had malignant form of hypertension (MHT) confirmed by eye examination. Mean systolic arterial pressure (SAP) observed at the time of presentation was 210±29 mmHg, mean diastolic arterial pressure (DAP) was 122±19 mmHg. Kidney morphology revealed chronic TMA lesions in 12 pts (43%), acute and chronic alterations simultaneously detected in 13 pts (46%). Predominantly acute lesions with glomerular and extraglomerular thrombi found in 3 (11%) pts only. Complement genes abnormalities revealed in 7 (25%) out of 28 pts. Complement factor I (CFI) rare variants were found in 2 pts (CFI c. 772&lt;A, CFI c.1217G&gt;A), one of this pts also had additional variant in complement factor H related protein 4 (CFHR4 c.766G&gt;A). Complement factor C3 rare variant was observed in 1 pt (C3 c.2203C&gt;T), membrane cofactor protein (MCP or CD46) rare variant in 1 pt (CD46 c. 198A&gt;T), complement factor H related protein 5 (CFHR5) variant detected in 1 pt (CFHR5 c.136C&gt;T), homozygous deletion of CFHR1 and CFHR3 detected in 1 pt and heterozygous deletion of the same complement factor H related protein genes found in another pt.

Conclusion
A quarter of pts with TMA and severe hypertension may have genetic defects in the complement system. These results confirmed that complement-mediated HUS may be misdiagnosed as hypertension-induced TMA. Lack of convincing hematological signs of TMA is common in this group, making aHUS diagnosis more sophisticated.
#6395 TUBULORETICULAR INCLUSIONS: A NEW PROGNOSTIC BIOMARKER IN KIDNEY TRANSPLANTATION
Authors: Gleeson Sarah , Beadle Jack , Moran Linda , Fitzgerald Ted , Roufosse Candice , Willicombe Michelle 
Published: June 2023

Abstract

Background and Aims
Tubuloreticular inclusions (TRIs) seen on electron microscopy (EM) are classically associated with lupus nephritis (LN) and systemic viral infections in native biopsies. Traditionally a marker for enhanced type I interferon expression, little is known about their significance post-transplant. We aimed to look at a large cohort of transplant biopsies showing TRIs to investigate associations and outcomes.

Method
A retrospective analysis was performed on two prospective databases; an in-centre transplant registry and a histopathology database holding data on all kidney biopsies performed at our centre. All patients biopsied since 2015, who had EM examination were included. Where patients had more than one biopsy showing a TRI the earliest one was included. Demographic, clinical and transplant data was collected from the laboratory records.

Results
2283 kidney transplant biopsies were performed between January 2015 and November 2022; 1898 (83.1%) had EM performed. Of 1898 with EM, 176 (10.8%) had evidence of TRIs. Of 176 patients, 34% were female, the median age was 52.2 (38.9-59.4) years, 32% had underlying glomerulonephritis as their cause of ESKD, 65% were deceased donors and 75% were of non-white ethnicity. TRIs were associated with serological evidence of autoimmunity (16%), viral infections (26%) and donor specific antibodies (28%), with no association found in 41%. Rejection occurred in 49%, including 31% of patients with no recognised association with TRIs. Allograft outcomes were poor, with all-cause allograft survival and death-censored allograft survival of 66% and 60%, after a follow up of 1.9 +/− 1.8 years post index biopsy. A comparison with a matched control group is planned

Conclusion
In extension to previous work, we show that TRIs appear to be associated with alloimmunity. In this regard they may be a useful biomarker especially in cases where the diagnosis is unclear or biopsy findings are ‘subthreshold’. Irrespective of aetiology, TRIs are associated with poor outcomes and warrant further consideration.