bluuebunny/crossref_metadata_2025 huggingface dataset:
#1992 Triglyceride-glucose index and risk of cardiovascular events, graft loss and new onset diabetes after transplantation in renal transplant recipients
Authors: Lee Hyo Jin , Lee Yu Ho , Kim Jin Sug , Jeong Kyunghwan , Lee Jeong-Yeun , Kim Hyun Kyu , Yoon Hye Eun , Na Ki Ryang , Lee Dong Ryeol , Yang Jaeseok , Kim Myoung Soo , Hwang Hyeon Seok
Published: May 2024

Background and Aims

Insulin resistance is prevalent disorder, but its clinical significance remains undetermined in renal transplant recipients. We explored the clinical implication of triglyceride-glucose (TyG) index in renal transplant recipients, recognizing it as a valuable marker for insulin resistance.

Method

A total of 6354 renal transplant recipients were enrolled from a nationwide, prospective cohort between May 2014 and December 2022. The TyG index was assessed between 6- and 12-months post-transplantation. We evaluated the association between TyG index and the risk of composite of cardiovascular events and death, renal allograft loss, and new onset diabetes after transplantation (NODAT).

Results

During the mean follow-up period of 39.2 ± 26.1 months, a total of 106 composite events of cardiovascular events and death, 174 events of renal allograft loss, and 438 events of NODAT were observed. The cumulative rate for composite events, graft loss, and NODAT was greater in patients with higher TyG quartile (all P < 0.001). In multivariate analysis, higher quartile of TyG was associated with an increased risk of composite events (HR 1.81, 95% CI 1.14–2.86), renal allograft loss (HR 2.13, 95% CI 1.28–3.55), and NODAT (HR 2.52, 95% CI 1.90–3.34). Higher quartile of TyG was associated with future graft dysfunction (adjusted mean eGFR differences of −4.72, 95% CI −7.39 – −2.04). There was a linear escalation in the risk of composite events and graft loss with the incremental rise in the TyG index, concomitant with an exponential augmentation in the risk of NODAT.

Conclusion

Renal transplant recipients with higher TyG index are associated with higher risk of composite of cardiovascular event and death, renal allograft loss, and NODAT.
#2990 Prevalence and risk factors of altered control of BP during the night in a large hemodialysis population investigated by 48 hours ABPM
Authors: Torino Claudia , Mallamaci Francesca , Sarafidis Pantelis , Ekart Robert , Balafa Olga , Del Giudice Antonio , Aucella Filippo , Morosetti Massimo , Tripepi Rocco , Marino Carmela , Tripepi Giovanni Luigi , Zoccali Carmine
Published: May 2024

Background and Aims

Altered BP control during the night (non-dipping, reverse dipping and nocturnal hypertension) is recognized as a powerful risk factor for death and CV events in the hemodialysis (HD) population. However, these alterations have been described in relatively small studies and the epidemiology and risk factors for subtypes non-dipping and nocturnal hypertension are still poorly characterized in the current literature. We investigated the problem in a large Registry (The EURECAm Registry) that is the sole that adopted state of the art 48 h ABPM recording in the HD population.

Method

We included in this analysis 534 HD patients, enrolled in 7 centers, led by members of the EURECA-m working group, in 3 European countries. 48 h ABPM was measured by using well validated instruments (AAMI/ESH/ISO). As recommended by the European Society of Hypertension guidelines, recordings were made at 15-minute intervals during the day and 30 minutes during the night. Hypertension was defined as 48 h blood pressure (BP) >130/80, nocturnal hypertension as a nighttime BP >120/70 mmHg, non-dipping as a night/day systolic BP fall <10% and reverse dipping as a night/day ratio >1.

Results

Among 534 HD patients, 317 were hypertensive and. 217 normotensive. As many as 274 patients were non-dippers (51%), 32% were reverse dippers, and 381 (71%) had nocturnal hypertension. Of note, forty-one per cent of non-dippers, 37% of reverse dippers and 19% of patients with nocturnal hypertension were normotensives. As expected, the majority of reverse dippers (87%) had frank nocturnal hypertension. In a combined analysis of non-dippers and reverse dippers, as compared to dippers, these patients more frequently exhibited atrial fibrillation and had lower Heart Rate both pre-dialysis (72± 11 vs 77±13 bpm, P = 0.004) and post-dialysis (74± 13 vs 78±14 bpm, P = 0.03) and lower serum albumin (3.9±0.4 vs 4.0±0.3 g/dL, P = 0.02) but did not differ for age and gender.

Conclusion

In a large cohort of HD patients investigated by the state-of-the-art technique, 48 h ABPM alterations in the nocturnal BP profile were almost universal, and nocturnal hypertension was the more prevalent alteration, followed by non-dipping and reverse dipping. These alterations were independent of age and gender. Long-term, granular follow-up analyses are warranted to identify the prognostic value of these alterations.
#1844 Pregnancy outcome among kidney transplant recipients
Authors: Gad Donia
Published: May 2024

Background and Aims

Background 

The possibility of a term pregnancy is one of the benefits of solid organ transplantation for women. The gonadal dysfunction, caused by the failure of the kidney or another organ, is reverted within a few months after normal graft function. Unplanned pregnancies in transplant recipients, however, may compromise graft function and survival, and may also risk unnecessary fetal exposure to immunosuppressive medications.

Aims

To study the prevalence of pregnancy and pregnancy related complication after kidney transplantation (KT).

Method

Retrospective cohort study conducted on 236 patients out of 3000 kidney transplant recipient who underwent renal transplantation (RT) at Mansoura Urology and Nephrology Centre between March 1976 and December 2019. divided into group I; 118 kidney transplant female's recipient experienced pregnancy at any time after kidney transplant and group II; 118 kidney transplant female's recipients who didn`t experience pregnancy after renal transplantation, they were matched according to age and duration of renal transplantation and comparable in primary immunosuppressant drugs. all kidney recipients were reviewed for preoperative & operative and post-operative details also we record maternal and fetal complication.

Results

Prevalence of pregnancy in our center is 191 pregnancies in 118 women who had underwent kidney transplantation between 1976 and 2019. We have found that the mean age of pregnancy between (26.27 ± 4.37-29.89 ± 4.6), the mean gestational age between (33.69 ± 6.4 – 33 ± 7.5) weeks, the live birth rate is 126 (66%). Preterm delivery rate in our study is 85 (44.5%), neonatal death 8 (4.1%), miscarriage 59 (30.9%), intrauterine fetal death 6 (3.1%) and birth defect 4 (2%). The prevalence rates of gestational hypertension is 87 (45.5%), pre-eclampsia 48 (25.1%), gestational diabetes 19 (9.9%), urinary tract infection 36 (18.8%), and graft rejection 8 (4.1%) during pregnancy. caesarean section is the most common method of delivery in our study 133 (69.6%). Kidney transplant recipients who aged more than or equal to 30 years at time of pregnancy are at higher risk for having non live-birth outcome (OR: 3.2, p value: 0.05). Proteinuria more than or equal to 0.5 g/day before pregnancy is a significant risk factor for having non live-birth outcome (OR: 4.7, p value: 0.009). Also, proteinuria ≥0.5 g/day during pregnancy is associated with increases risk for non-live-birth (OR: 10.2, p value: 0.013). Gesatational hypertension is associated with increases risk for non-live-birth (OR: 8.3, p value: 0.010).Preeclampsia is associated with increases risk for non-live-birth (OR: 4.6, p value: 0.005).

Conclusion

Although the outcome of live births is favourable, the risks of maternal and fetal complications are high in kidney transplant recipients including pregnancy-induced hypertension, increased rates of preeclampsia, gestational diabetes, and caesarean section rates. The risk of miscarriage, prematurity, and low birth rate is also high.
#2251 Long-term systolic blood pressure variability as an independent risk factor for cardiovascular events in kidney transplant recipients
Authors: Viazzi Francesca , Bussalino Elisabetta , Picciotto Daniela , Macciò Lucia , Gandolfo Maria Teresa , Parodi Angelica
Published: May 2024

Background and Aims

Cardiovascular (CV) events represent the main cause of death in patients undergoing renal transplantation. Several studies have described the role of blood pressure variability (BPV) in predicting all-cause mortality and fatal and non-fatal CV events in the general population and in diabetic patients. Systolic blood pressure variability (SBPV) has recently been proposed as a predictor of clinical outcomes in patients with chronic kidney disease.

However, evidence is still scarce about the prognostic role of BPV in the setting of renal transplantation.

The aim of the study was to evaluate the role of long-term SBPV in the development of fatal and non-fatal CV events (myocardial infarction, unstable angina or revascularization, stroke and hospitalization for heart failure) in subjects undergoing kidney transplantation.

Method

We performed a single-center retrospective observational analysis in a cohort of 272 kidney transplant patients (mean age 64 ± 13 years, 66% men), with a transplant duration ≥12 months and with at least 6 blood pressure measurements at defined intervals (3 months ±15 days) over an assessment period of 18 months.

BPV was expressed as standard deviation of ambulatory systolic blood pressure (SBP) and patients were accordingly classified in tertiles (low <9.3 mmHg, medium 9.3-13 mmHg, high >13 mmHg).

The role of SBPV was analyzed by Kaplan-Meier (logrank) and its independent effect by Cox Regression.

Results

Over a mean follow-up of 58.7 ± 17.2 months, 27 subjects (9.9%) developed CV events. For each increase of 2.7 mmHg in SBP standard deviation, the risk for fatal or non-fatal CV events increased almost 3-folds (P = 0.02) and patients in the highest tertile of SBP standard deviation showed a 4-fold increased risk (P = 0.01) (Fig. 1). This relationship was maintained even after incremental adjustment for time-averaged pulse pressure, age, diabetes, prior CV event, and dialysis vintage (HR 3.2, 95% CI 1.1–10.0, p 0.04) (Table 1).

Conclusion

Long-term BPV represents an independent risk factor for CV events in kidney transplant patients. It is therefore essential to seek for stable long-term blood pressure levels in this population in order to minimize the residual CV risk.
#2581 Cryptococcosis in kidney transplant recipients: a nationwide multicenter retrospective cohort study—CRITERE study
Authors: Tardieu Laurene , Divard Gillian , Scemla Anne , Kaminski Hannah , Kamar Nassim , Levi Charlène , Moal Valérie , Tourret-Arnaud Jérôme , Quintrec Moglie Le , Rafat Cédric
Published: May 2024

Background and Aims

Cryptococcosis stands as the third most common invasive fungal infection in solid organ transplant recipients. Clinical management and prognosis of the disease remains largely unexplored in the context of kidney transplant recipients. Our main objective was to describe the natural history of cryptococcosis after kidney transplantation from the graft patterns of kidney injury to the long term outcomes.

Method

We established a nationwide cohort of adult kidney transplant recipients diagnosed with cryptococcosis between 2002 and 2019 in France. All data were gathered starting from the transplantation date and encompassed up to the latest follow-up consultation. All putative causes of AKI as claimed by the attending clinicians were recorded. Cases were matched (ratio 1:6) with kidney transplant recipients from the French prospective multicenter cohort DIVAT with parameters at time of transplant including immunosuppression and known risk factors of cryptococcosis such as age, history of smoke, history of cancer and HIV status. Transplant outcomes (graft failure and patient death) were then compared between matched patients.

Results

88 patients were included. Patients were predominantly male (n = 61, 69.3%), with a mean age of 57.0 years [SD ±13.3]. The majority of patients were primary kidney transplants (n = 71, 80.7%) with a median time from ESRD to transplantation of 2.8 years [IQ 1.25-5]. The majority of patients received ATG as induction therapy for their transplant (n = 50, 69.4%)Acute kidney injury (AKI) at diagnosis involved 37.3% of the patients with 13.3% requiring renal replacement therapy. AKI staging was distributed as follows, AKI grade 1 in 12.5% of patients, grade 2 in 13.3% of patients, and grade 3 in 11.5% of patients. During the induction stage, 39% of patients developed amphotericin B-related AKI. AKI resulting from tacrolimus overdose subsequent to tacrolimus/fluconazole interaction occurred in 25.7% of patients during the consolidation stage. Among the patients alive at 3 months following the diagnosis of cryptococcosis, 33.7% of patients exhibited graft dysfunction. Following cryptococcosis, 5 patients displayed T cell rejection and 4 patients developed antibody-mediated rejection. A total of 41 patients with cryptococcosis were matched to 246 controls (ratio 1:6), after a median follow-up of 52.3 [28.1-90.2] months, patients with cryptococcosis exhibited a higher risk of mortality with 35.9% compared with 9.8% (p < 0.001) and graft failure with 33.3% compared with 15.0% (p = 0.0005).

Conclusion

This study has shown that kidney injury manifests itself through a sequential, multi-step process that initially includes pre-renal impairment, ATN and iatrogenic mechanisms. Amphotericin B-related AKI, followed by tacrolimus overdose represent common causes of AKI.
#2323 Sodium-glucose cotransporter 2 inhibitors in kidney transplant recipients—effectiveness and safety
Authors: Freitas Joana , Silvano José , Ribeiro Catarina , Pedroso Sofia , Malheiro Jorge , Almeida Manuela , Fonseca Isabel , Martins La Salete
Published: May 2024

Background and Aims

Given the increasing incidence of posttransplant diabetes and the heightened cardiovascular burden among transplant recipients, the use of SGLT2 inhibitors (SGLT2i) in this population is attractive due to their cardiovascular and renoprotective advantages. However, evidence for diabetic kidney transplant recipients (DKTRs) is limited, primarily due to concerns regarding potential worsening of renal graft dysfunction and adverse effects.

Method

This retrospective study was conducted to evaluate the effectiveness and safety of SGLT2 inhibitors in kidney transplant recipients (KTRs). Individuals with type 1 diabetes (n = 2) and individuals submitted to a double kidney and pancreas transplant (n = 5) were excluded from the study to avoid diabetes type bias . The primary focus was on assessing SGLT2 inhibitors effect on parameters such as hemoglobin A1c levels, body mass index (BMI), lipid panel, hemoglobin levels, renal allograft function (estimated glomerular filtration rate), and urinary protein-to-creatinine ratio. Demographic, clinical, and laboratory data were collected and subjected to analysis using descriptive statistics with SPSS Statistics software. The data were presented as means ± standard error, and comparisons were conducted using the paired sample t-test. A significance level below 0.05 (P < 0.05) was considered statistically relevant.

Results

A total of 104 renal transplant patients were included. The study spanned a median observation period of 14 (2.0–71.0) months. Mean HbA1c decreased from 7.3 to 6.9% (P = 0.001). A significant improvement in BMI (27.6 to 27.0 kg/m2; P = 0.008), total and LDL-Cholesterol(P < 0.001 and P = 0.004, respectively) were also observed. Mean haemoglobin rate at baseline was 13.3 g/dL and also improved at end of follow-up to 13.5 g/dL (P = 0.065). Mean estimated glomerular filtration rate at baseline was 60.1 (26–120) mL/min/1.73 m2 and decreased to 54.8 throughout the follow-up (P = 0.007), while mean serum cystatin increased from 1.7 to 2.0 mg/L (P < 0.001). Regarding urinary protein:creatinine ratio, levels slightly but not significantly rose [+0.33 g/g]. Urinary tract infections occurred in 10% of the recipients. No other side effects were observed during the treatment course or neither the patients needed to discontinue the medication.

Conclusion

This study establishes that the use of SGLT2 inhibitors is both feasible and well-tolerated in kidney transplant recipients (KTRs), with no significant observed side effects. Further studies are required to clarify the impact of SGLT2 inhibitors on long-term patient and allograft survival.
#1455 Pregnancy and related complications after kidney transplantation—a retrospective study
Authors: Elkat Ahmed
Published: May 2024

Background and Aims

Background 

Within 2 to 3 weeks of a successful renal transplantation, the fertility of women in childbearing age improves; however, pregnancy after kidney transplantation is challenging and may be associated with serious maternal and fetal complications.

Aims

To study the prevalence of pregnancy and pregnancy related complication after kidney transplantation (KT).

Method

Retrospective cohort study conducted on 236 patients out of 3000 kidney transplant recipient who underwent renal transplantation (RT) at Mansoura Urology and Nephrology Centre between March 1976 and December 2019, divided into two groups, group I; 118 kidney transplant recipient who experienced pregnancy at any time after kidney transplantation and Group II; 118 kidney transplant recipients who didn`t experience pregnancy after renal transplantation, they were matched according to age, duration of renal transplantation and they are comparable in primary immunosuppressant drugs. All kidney recipients were reviewed for preoperative, operative, and post-operative details also we record maternal and fetal complication.

Results

Prevalence of pregnancy in our center is 191 pregnancies in 118 women who had underwent kidney transplantation between 1976 and 2019. We have found that the mean age of pregnancy between (26.27 ± 4.37-29.89 ± 4.6), the mean gestational age between (33.69 ± 6.4 – 33 ± 7.5) weeks, the live birth rate is 126 (66%). Preterm delivery rate in our study is 85 (44.5%), neonatal death 8 (4.1%), miscarriage 59 (30.9%), intrauterine fetal death 6 (3.1%) and birth defect 4 (2%). The prevalence rates of gestational hypertension is 87 (45.5%), pre-eclampsia 48 (25.1%), gestational diabetes 19 (9.9%), urinary tract infection 36 (18.8%), and graft rejection 8 (4.1%) during pregnancy. caesarean section is the most common method of delivery in our study 133 (69.6%).

Conclusion

The risk of maternal and fetal complications is still high in RT patients and requires multidisciplinary care. All should be considered in patient counseling and clinical decision making. So we recommend educating the transplanted patients to allow for outcome optimization and minimization of complications.
#1862 Post-kidney transplantation de novo monoclonal gammopathy of undetermined significance—impact on patients and graft long-term outcomes
Authors: Domingos Diogo , Querido Sara , Matias Patrícia , Mendes Alexandra , Azevedo Ana Paula , Weigert André
Published: May 2024

Background and Aims

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell condition with a reported prevalence of 3 to 4% in population older than 50 years and progression to multiple myeloma in approximately 1% of the cases. The clinical significance of MGUS in patients diagnosed prior to kidney transplantation (KT) has previously been studied, however, the impact on survival and morbidity of newly diagnosed MGUS on the period after KT, remains unclear.

The aim of this study was to compare the outcomes between patients with MGUS emerging after KT versus non-MGUS patients.

Method

This is a retrospective single-center cohort analysis of a population of 793 kidney transplant recipients between 1985 and 2022. Diagnosis of MGUS after KT was based on positive serum protein electrophoresis and confirmed by serum immunofixation.

We performed a randomized selection of a matched control group, adjusted for age, gender, and KT duration. Both groups were compared for number of infections (bacterial and viral), acute rejections, neoplastic complications, and for overall patient and graft survival.

Results

This study included a total of 112 patients, with a mean age of 60 years (±11), of which 86 (77%) were older than 50 years. Median follow-up duration was 149 [IQR 89-207] months.

We identified 56 patients (7%) with MGUS after KT. Only 1 (1.7%) patient progressed to multiple myeloma. Induction immunosuppression type was not associated with higher development of MGUS.

We found no difference between the MGUS group and the control group in the incidence of infections, acute graft rejections, or solid and hematologic neoplasia (Table 1). There was also no difference between overall patient and graft survival.

Conclusion

MGUS is a premalignant disease frequently present in KT recipients, with a higher prevalence compared to the general population, although its development after KT does not appear to contribute to a worse prognosis or to a higher progression to multiple myeloma.
#1396 Anxiety level in kidney transplant recipients with adverse cardiovascular events
Authors: Smaliakova Maria
Published: May 2024

Background and Aims

Kidney transplantation is the most cardioprotective method of renal replacement therapy and it has a positive effect on the psycho-emotional state of patients. However, kidney transplant recipients have a higher cardiovascular risk and a higher prevalence of anxiety and depression than people in the general population.

The aim of the study was assessment of anxiety levels and the quality of life of kidney transplant recipients preceding adverse cardiovascular events.

Method

The study included 154 kidney transplant recipients. 54 (35.1%) of them had adverse cardiovascular events (acute coronary syndrome, complicated hypertensive crisis or rhythm disturbance) for three years of observation. The comparison group was 100 (64.9%) recipients without cardiovascular complications during the observation period. The study groups were comparable by age, gender, graft function and traditional cardiovascular risk factors.

Results

The average level of situational anxiety of kidney transplant recipients was 39 ± 7, the level of personal anxiety—43 ± 8. The structure was dominated by recipients with moderate personal anxiety—55.2% (n = 85) and moderate situational anxiety—66.9% (n = 103). However, the proportion of persons with high personal anxiety was quite high—40.9% (n = 63). The structure of anxiety levels had no significant differences depending on subsequent cardiovascular complications. Nevertheless, kidney transplantation recipients with adverse cardiovascular events had higher previous level of situational anxiety than recipients without cardiovascular events—41 ± 7 versus 38 ± 7, p < 0.05.

During the study kidney transplant recipients were asked to rate their quality of life on a scale of 1 to 10. Recipients with subsequent adverse cardiovascular events had a lower subjective quality of life than recipients without cardiovascular complications—7 (6-8) versus 8 (7-8), p < 0.01.

Conclusion

Based on the study it was found that recipients with adverse cardiovascular events in the late postoperative period are characterized by a higher level of situational anxiety and a lower quality of life before these complications.
#1431 Risk factors of adverse cardiovascular events in the early postoperative period in kidney transplant recipients
Authors: Smaliakova Maria , Kalachyk Aleh
Published: May 2024

Background and Aims

Kidney transplantation improves quality of life and increases life expectancy in patients with Stage 5 Chronic Kidney Disease. However, the frequency of adverse cardiovascular events in the postoperative period remains high and reduces the effectiveness of transplantation.

The aim was to study the incidence of cardiovascular risk factors in the preoperative period in kidney transplant recipients with adverse cardiovascular events in the early postoperative period.

Method

The study included 51 kidney transplant recipients whose age was 46.1 ± 4.6 years. 12 (23.5%) recipients had adverse cardiovascular events (acute myocardial infarction, unstable angina, rhythm disturbance, complicated hypertensive crisis) in the early postoperative period. 39 (76.5%) recipients with uncomplicated postoperative period formed the comparison group. The study groups were comparable by gender and age.

Results

Traditional cardiovascular risk factors were assessed. The study groups had comparable rates of arterial hypertension, obesity, hyperglycemia, dyslipidemia and smoking in the preoperative period and graft function in the postoperative period.

The study groups didn't have significant differences in the incidence of anemia and hemoglobin blood concentration. But the erythropoietin blood level in the preoperative period in recipients with adverse cardiovascular events was higher—38.5 (23.5-155.0) mU/mL versus 16.0 (10.0-32.0) mU/mL, p < 0.01, and hypererythropoietinemia was diagnosed more often—58.3% (n = 7) versus 25.6% (n = 10), p < 0.05, than in patients without cardiovascular events.

The incidence of elevated interleukin-6 blood level in the preoperative period was higher in recipients with adverse cardiovascular events—25.0% (n = 3) versus 5.1% (n = 2), p < 0.05. At the same time C-reactive protein levels and white blood cell counts were not significantly different.

Recipients with adverse cardiovascular events had a lower left ventricular ejection fraction—59.5 ± 10.6% versus 65.6 ± 7.1%, p < 0.05, and a higher incidence of left ventricular diastolic dysfunction in the preoperative period—75.0% (n = 9) versus 35.9% (n = 14), p < 0.05, than in recipients without cardiovascular complications.

Conclusion

Kidney transplant recipients with adverse cardiovascular events in the early postoperative period had a higher incidence of left ventricular diastolic dysfunction, increased blood levels of erythropoietin and interleukin-6 and a lower left ventricular ejection fraction before transplantation than recipients with an uncomplicated postoperative period.
#1315 Management and long-term outcome of recurrent idiopathic FSGS in pediatric renal transplant recipients
Authors: Toder Moran Plonsky , Magen Daniella , Pollack Shirley , Eisenstein Israel , Tibi Rami , Yakubov Renata , Zebegret Irina Libinson
Published: May 2024

Background and Aims

Focal segmental glomerulosclerosis (FSGS) is a leading cause of pediatric end-stage renal disease (ESRD). While approximately 30% of pediatric FSGS is attributed to monogenic disorders, most cases are idiopathic, carrying a high risk of post-transplantation recurrence and graft loss. Commonly used protocols for recurrent FSGS (rFSGS) include plasmapheresis or immunoadsorption, and/or immunomodulatory therapy. We retrospectively evaluated the efficacy and safety of early plasmapheresis followed by rituximab therapy for induction of remission in rFSGS.

Method

Between 2014-2023, 8/65 pediatric renal transplant recipients at our center were diagnosed with idiopathic FSGS. Five patients underwent preventive plasmapheresis initiated between day 7 pre-transplantation to day 1 post-transplantation, depending on donor source (living/deceased). rFSGS, was diagnosed based on nephrotic range proteinuria of no other cause, and managed with daily plasmapheresis, followed by frequency tapering. Failure to achieve complete remission while on prolonged plasmapheresis was managed with Rituximab therapy.

Results

6/8 patients (75%) experienced rFSGS. All achieved partial or complete remission with plasmapheresis therapy. Nevertheless, 5/6 patients exhibited plasmapheresis-dependence, thereby necessitating rituximab therapy. Of these, 3/5 patients achieved sustained remission enabling plasmapheresis cessation, while in 2/5 showed markedly improved proteinuria, enabling reduction of plasmapheresis frequency to once weekly. Adverse effects included rituximab-induced serum sickness in one patient, requiring therapy discontinuation. While one patient suffered from graft loss due to humoral rejection, no graft was lost to rFSGS, and all other grafts remained functional over an average follow-up period of 50 months.

Conclusion

We suggest that early introduction of plasmapheresis and rituximab therapy effectively induces remission in most post-transplantation rFSGS, is well tolerated, and prevents graft loss. Additional, large scale studies are needed to establish our observation.
#1076 DNA hypomethylation of Syk induces oxidative stress and apoptosis via the PKCβ/ P66shc signaling pathway in diabetic kidney disease
Authors: Liu Fang , Qin Chunmei
Published: May 2024

Background and Aims

Epigenetic alterations, especially DNA methylation, have been shown to play a role in the pathogenesis of diabetes mellitus (DM) and its complications, including diabetic kidney disease (DKD). Spleen tyrosine kinase (Syk) is known to be involved in immune and inflammatory disorders. We, therefore, investigated the possible involvement of Syk promoter methylation in DKD, and the mechanisms underlying this process.

Method

Kidney tissues were obtained from renal biopsies of patients with early and advanced DKD. A diabetic mouse model (ApoE−/−DM) was generated from ApoE knockout (ApoE−/−) mice using a high fat and high glucose diet combined with low-dose streptozocin (STZ) intraperitoneal injection. We also established an in vitro model using HK2 cells.

Results

A marked elevation in the expression levels of Syk, PKCβ, and P66shc in renal tubules was observed in patients with DKD. In ApoE−/− DM mice, Syk expression and the binding of Sp1 to the Syk gene promoter were both increased in the kidney. In addition, the promoter region of the Syk gene exhibited hypomethylation. Syk inhibitor (R788) intervention improved renal function and alleviated pathologic changes in ApoE−/− DM mice. Moreover, R788 intervention alleviated oxidative stress and apoptosis and down-regulated the expression of PKCβ/ P66shc signaling pathway proteins. In HK2 cells, oxLDL combined with high glucose stimulation upregulated Sp1 expression in the nucleus (compared with control and oxLDL groups), and this was accompanied by an increase in the binding of Sp1 to the Syk gene promoter. SP1 silencing down-regulated the expression of Syk and inhibited the production of reactive oxygen species and cell apoptosis. Finally, PKC agonist intervention reversed the oxidative stress and apoptosis induced by Syk inhibitor (R406).

Conclusion

In DKD, hypomethylation at the Syk gene promoter was accompanied by an increase in Sp1 binding at the promoter. As a consequence of this enhanced Sp1 binding, Syk gene expression was upregulated. Syk inhibitors could attenuate DKD-associated oxidative stress and apoptosis via down-regulation of PKCβ/ P66shc signaling pathway proteins. Together, our results identify Syk as a promising target for intervention in DKD.
#2683 Targeted antibiotic modulation of the gut microbiome ameliorates hypertensive kidney damage
Authors: Bartolomaeus Hendrik , Wimmer Moritz , Anandakumar Harithaa , Vecera Valentin , Löber Ulrike , Forslund Sofia K , Müller Dominik N , Wilck Nicola
Published: May 2024

Background and Aims

High blood pressure is associated with measurable inflammation, which precedes and promotes damage to the heart and kidneys. Microbiome-derived metabolites, particularly indole metabolites, modulate inflammation and host physiology, partially through aryl hydrocarbon receptor (AhR) signaling. To better understand the potential of a microbiome-targeting therapeutic approach to achieve organ protection in hypertension, we used narrow-spectrum antibiotics without enteral absorption to specifically deplete gram-negative or -positive bacteria in double transgenic rats (dTGR).

Method

Four-week-old dTGR (transgenic for human renin and angiotensinogen) were treated with oral Vancomycin (Vanco), Polymyxin B (Poly) or Vehicle (Veh) for 3 weeks. Seven-week-old SD rats were included as healthy controls. Microbiome, clinical and immune phenotype were analyzed by shotgun metagenomic sequencing, echocardiography, telemetric blood pressure (BP) measurement, clinical chemistry, bulk RNAseq and flow cytometry.

Results

Hypertensive kidney damage was ameliorated in Vanco treated dTGR, as assessed by renal Lcn2 expression, blood urea nitrogen and albuminuria. Vanco treated dTGR had significantly decreased cardiac hypertrophy. Poly treatment showed no effect. BP levels for both antibiotic treatments were not significantly different from Veh, despite a significantly improved endothelium-dependent and -independent vasorelaxation in isolated mesenteric arteries in both treated groups. Surprisingly, Vanco treatment led to a massive increase of gram-positive Lactobacilli and associated gene abundance for the production of indole lactic acid (ILA, via araT). We could previously show that ILA inhibits differentiation of pathological Th17 cells through AhR modulation. In line, Vanco treatment reduced the increased number of pathological Th17 in the kidney and intestine of dTGR. Poly treatment did not alter the inflammatory signature.

Conclusion

Modulation of the intestinal microbiome by narrow-spectrum antibiotics affects hypertensive organ damage. Our data underscores the importance of the gut microbiome in modulating hypertensive organ damage and helps to identify potential therapeutic strategies in the microbiome. Ongoing experiments investigate pro- and postbiotic therapeutic approaches and their AhR dependency.
#1838 SGLT2 computational structural studies investigating polypharmacy
Authors: Lloyd Aled , Austin-Muttitt Karl , Mullins Jonathan
Published: May 2024

Background and Aims

Sodium Glucose Cotransporter 2 (SGLT2) is the main active transport protein involved in sodium and glucose reabsorption in the kidney. SGLT2 inhibitors (SGLT2i) are widely recommended for patients with diabetes, heart failure and chronic kidney disease (CKD). Many multimorbid patients will be prescribed these compounds resulting in polypharmacy. We have performed a computational drug repurposing screen to identify other licensed drugs capable of binding at or near the SGLT2i active site aiming to identify compounds that could either compete with SGLT2i or inhibit sodium and glucose transport.

Method

The library of BNF listed compounds was obtained from NCBI PubChem. D-I-TASSER was used to generate monomeric structural models and MODELLER was used to incorporate MAP-17 and empaglifozin from a reference structure (PDB 7VSI). CHARM-GUI was used to insert the protein into a membrane. The centroid of a 5 nanosecond GROMACS molecular dynamics (MD) equilibration was used for docking studies using PLANTS. A bespoke tool was used to identify compounds interacting with key protein residues. CHARM-GUI and bespoke software were used to prepare membrane-bound systems to run in GROMACS using GPU's in Google Colab. 10 nanosecond simulations were undertaken (300 Kelvin and 1 bar) to discriminate between binding and non-binding events.

Results

The SGLT2-MAP17 structure in the inward-open conformation obtained showed good agreement with published structures. Existing SGLT2i (empaglifozin, dapaglifozin, canaglifozin, ertuglifozin) all feature in the top 1% of docked compounds in the repurposing screen. 17 compounds were investigated by MD, with all remaining bound to the protein in simulation. Ceftriaxone, tobramycin, clindamycin, fluvastatin, atorvastatin and ticagrelor were among the compounds with potentially significant interactions.

It is not clear whether the stable ligand interactions identified here would result in inhibition of sodium and glucose transport, or if the interactions might provide competitive inhibition for SGLT2i compounds currently used. The compounds identified have no hitherto recognised interactions with SGLT2i; nor do they result in adverse effects suggesting inhibition of the protein. This study is limited by considering only the protein-ligand interaction and not wider pharmacokinetic or pharmacodynamic factors.

Conclusion

The indication of interactions with several compounds likely to be prescribed alongside SGLT2 inhibitors, such as antibiotics, statins and antiplatelet agents, warrants further investigation of the potential for polypharmacological complications.
#1861 Association of the polymorphisms of the angiotensin converting enzyme and FRMD3 genes in the development of diabetic kidney disease
Authors: Garcia Juan Daniel Diaz
Published: May 2024

Background and Aims

Individual genetic biomarkers, called single nucleotide polymorphisms (SNPs), have been proposed that could represent potential non-invasive markers for the early diagnosis of diabetic kidney disease (DKD), in addition to their association with a characteristic phenotype.

Aim

To determine the association of polymorphisms of the Angiotensin Converting Enzyme and FRMD3 genes with the risk of developing ERD in patients with type 2 diabetes.

Method

Case-control study, comparative, observational, ambispective and cross-sectional, in which men and women, over 18 years of age with T2D with and without ERD and healthy patients, who underwent DNA extraction, participated. genomic and subsequent genotyping, and detection of SNPs by mass spectrometry.

Results

A total of 400 patients participated, 199 men and 201 women, within which they were divided into three groups: 100 patients with type 2 diabetes and ERD confirmed by renal biopsy, 100 patients with type 2 diabetes without ERD and 200 healthy controls.

A total of 3 polymorphisms of the ACE and FRMD3 genes were studied. Among the polymorphisms analyzed in the logistic regression, rs179975 CA (OR, 6.2; 95% CI: 1.15-7.48, p = 0.03), rs1888747 GA (OR, 6.6; 95% CI: 4.60-8.45, p = 0.002) and rs10868025 resulted. CG (OR, 4.1; 95% CI: 2.40-5.60, p = 0.002) Table 1.

Conclusion

Our study demonstrated the association of well-established genetic variants of the ACE and FRMD3 gene polymorphisms with the presence of ERD, showing that these SNPs, specifically rs179975 CA, rs1888747 GA and rs10868025 GC, may represent important genetic markers in the development of ERD and could be a predisposing factor due to the high frequency and strength of association that were observed in our studied population, this being the first study in Latin America.
#1591 Analysis of microvesicles and their relationship with oxidative stress as biomarkers of cardiovascular damage in chronic kidney disease
Authors: Arévalo Gemma Valera , Espada Paula Jara Caro , Alique Matilde , Lozano Claudia Yuste , del Mar Rodriguez San Pedro Maria , Garcia Victor Cabanillas , Rubio Andrea Figuer , Ruiz Enrique Morales , Chamond Manuel Ramírez , Carracedo Julia
Published: May 2024

Background and Aims

Chronic kidney disease (CKD) is associated with a higher incidence of cardiovascular diseases. These diseases are preceded by endothelial dysfunction and alterations in coagulation systems. One of the challenges of research in this field is the search for diagnostic and predictive biomarkers of cardiovascular pathology. Our hypothesis is that endothelial dysfunction and cardiovascular risk could be evidenced by the increased release of endothelial microvesicles (EMVs) and platelet microvesicles (PMVs), as well as a greater expression of tissue factor (TF). We also propose a relationship between the release of microvesicles and the oxidative stress observed in these patients. The aim of the study was to analyze the levels of MVEs and MVPs, the expression of FT and its relationship with pro-oxidant and antioxidant parameters as possible early biomarkers of cardiovascular and thrombotic risk in different stages and treatments of CKD.

Method

It is a cross-sectional study consisted of 116 patients (40 with advanced chronic disease (CKD), 40 undergoing hemodialysis (HD) and 36 undergoing peritoneal dialysis (PD)), as well as 17 healthy subjects (CT). Microvesicle phenotyping was performed by direct immunofluorescence and flow cytometry in plasma isolated by centrifugation from peripheral blood. The analysis of oxidative stress parameters was carried out by spectrophotometry, after isolation of plasma and mononuclear and polymorphonuclear leukocytes by means of a ficoll gradient.

Results

Patients on PD have higher plasma PMVs levels (p = 0.0005 vs ACKD and p = 0,0002 vs HD), while those on HD and PD have higher levels of EMVs compared to ACKD (p = 0,0001 and p = 0,0125, respectively). FT expression in PMVs is lower in HD (p < 0.0001 vs ACKD) and FT expression in EMVs is lower in HD and PD compared to ACKD (p = 0,0004 and p= 0.0033, respectively) (Fig. 1). Patients with CKD have a higher activity of pro-oxidant enzymes (XO, GPx), as well as high levels of lipid peroxidation by-products (TBARS-MDA) and lower activity of antioxidant enzymes (GSH, CAT, SOD) at the plasma and cellular level. A positive relationship has been observed between pro-oxidant parameters and the release of MVP and MVE, as well as the expression of FT (Table 1). Patients with cardiovascular events during the years of follow-up have higher levels of FT expressed in microvesicles, and long-term survival decreases in patients with elevated FT levels.

Conclusion

Patients with CKD have higher plasma levels of PMVs and EMVs and higher FT expression, related to a state of oxidative stress. These parameters could be considered as biomarkers for predicting, diagnosing, and prognostic cardiovascular events in CKD.
#2704 Effects of high dietary salt on immunome and microbiome composition – results from a randomized clinical trial
Authors: Bartolomaeus Hendrik , Anandakumar Harithaa , Chen Chia-Yu , Mähler Anja , Müller Dominik N , Forslund Sofia K , Wilck Nicola
Published: May 2024

Background and Aims

Increased dietary salt intake ranks among the most prominent nutritional risk factors worldwide and has been tied to arterial hypertension and all-cause mortality. The mechanisms responsible are incompletely understood and have recently been extended to include inflammatory and microbiome-associated mechanisms. Building on our preliminary data, the present study investigates whether a moderate increase in salt intake in healthy subjects primes host physiology to a more transiently unstable state, potentially leading to changes in the microbiome-immune axis.

Method

We conducted a prospective, randomized, double-blinded trial to evaluate the effect of high dietary salt in healthy participants (NCT03024567), where the intervention group (n  =  19) was given 6 g of salt (NaCl capsules) in addition to the habitual salt intake, resulting in an average doubling of the salt intake recommended by expert societies. A placebo group (n = 19) received gelatin capsules for 14 days. Clinical parameters, fecal samples and PBMC were collected at baseline and day 14. Shotgun metagenomic sequencing, metabolomics (stool and serum), and single-cell sequencing (Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq)) of whole PBMCs and CD4+ sorted T cells (∼150 k single cells) was performed.

Results

Microbiome analysis confirms previous findings showing an increased dissimilarity of microbiome composition (Jensen-Shannon Divergence) under a high-salt. Differential abundance of the microbiome's functional space, as quantified by functional gut-specific modules, picked up a salt-specific module (M00494, NatK-NatR (sodium extrusion) two-component regulatory system) in the salt intervention group. CITEseq revealed a significant reduction of circulating NK cells and an increase in classical monocytes as well as changes to several T cell subsets. Furthermore, within several immune cell subsets, we detected differently expressed genes (DEGs) solely in the salt group. We found 602 DEG in naïve conventional T cells (Tconv) and 202 DEGs in non-naïve Tconv, e.g. belonging to NF-kB and T cell receptor signaling pathways.

Conclusion

Our placebo-controlled study is the first to utilize different omics techniques to investigate and identify high-salt-induced changes in the microbiome and immunome in healthy individuals that may be relevant for health-to-disease transition.
#1846 Oxalate nephropathy in diabetic kidney disease: another factor to take into account?
Authors: Roldán Deborah , Melero Eva López , Guerrero Maria Carmen , Arcos Hansely , Ocaña Javier , Gruss Enrique , Shabaka Amir
Published: May 2024

Background and Aims

Patients with diabetes mellitus (DM) have an increased urinary excretion of oxalate. Around 40% of patients with oxalate nephropathy have DM. The aim of this study was to describe the prevalence of tubular deposits of calcium oxalate (CaOx) crystals in patients with diabetic kidney disease (DKD) and investigate its association with renal survival.

Method

We performed an observational retrospective study that included patients with DKD in renal biopsies performed at our centre between January 1999 and December 2021. We revised the biopsy specimens for the presence of intratubular CaOx crystals. We excluded patients with a histological findings of non-diabetic kidney disease and those lost to follow-up. Renal survival was defined as a state free from developing end-stage kidney disease (ESKD) requiring renal replacement therapy.

Results

The study included 87 patients with a mean age of 63.1 ± 13 years, 73.5% were male, and 88.5% had type 2 DM (11.5% type 1 DM). Baseline GFR at the moment of kidney biopsy was 38.5 ± 23 ml/min, and baseline median proteinuria was 3.46 (1.35-5.70) g/day. We found intratubular CaOx deposits in 11 biopsies (12.6%). These findings were only found in patients with type 2 DM (14.3% vs 0%), and was more frequently present in patients with a history of renal stones (33.3% vs 11.1%). There were no differences in baseline GFR, proteinuria or vintage of DM between patients with intratubular CaOx deposits and those with no signs of oxalte nephropathy. CaOx deposition was not associated with other histological lesions such as percentage of glomerular sclerosis, grade of interstitial fibrosis and/or tubular atrophy, interstitial inflammation, arterial hyalinosis or arteriosclerosis.

After a median follow-up of 41 months, 49.4% of patients developed ESKD while 26.4% died without progressing to ESKD. The patients who progressed to ESKD had a higher baseline serum creatinine (2.56 ± 1.45 vs 1.98 ± 1.07 ml/min, p = 0.037) and lower serum albumin (3.08 ± 0.70 vs 3.57 ± 0.74 g/dl, p = 0.003). In the regression analysis there was no association between intratubular CaOx deposits and progression to ESKD (OR = 2.96, 95% CI 0.73-12.03). In the adjusted model, no histological lesions were associated with renal survival. In the survival analysis, the presence of intratubular CaOx deposits was not associated with neither renal nor patient survival.

Conclusion

Oxalate nephropathy, defined as the presence of intratubular CaOx deposits in kidney biopsies, may be found in patients with DKD. In our cohort, 14.3% of type 2 DM patients with DKD had concomitant oxalate nephropathy. Its presence was not associated with a worse renal or patient survival.