bluuebunny/crossref_metadata_2025 huggingface dataset:
#4085 POLY(ADP-RIBOSE) POLYMERASE 1 AFFECTS THE VASOPRESSIN-MEDIATED AQP2 EXPRESSION VIA AN INTERACTION WITH BETA-CATENIN
Authors: Jang Hyo-Ju , Park Eui-Jung , Jung Hyun Jun , Kwon Tae-Hwan
Published: June 2023

Background and Aims

Poly(ADP-ribosy)lation (PARylation), which is mediated by poly(ADP-ribose) polymerases (PARPs), catalyzes the transfer of ADP-ribose from NAD+ molecules to acceptor proteins, regulates diverse cellular processes. Since PARP1 gene-deficient mice revealed an increase in urine volume, we aimed to examine the role of PARP1, the most abundant type of protein in the PARPs family, in the vasopressin-mediated AQP2 regulation.

Method

1) Immunoblotting for PARP1 in mpkCCDc14 cells; 2) Pulldown assay of biotin-conjugated NAD+ and immunoprecipitation (IP) assay using poly(ADP-ribose) (PAR) antibody; 3) qRT-PCR and immunoblotting for AQP2; and 4) Bioinformatics for elucidating PARP1-interacting proteins in kidney collecting duct (CD) cells.

Results

Immunoblots showed that dDAVP treatment (10−9 M, 2 h, 6 h, 24 h, and 48 h) induced the cleavage of PARP1 (both 89 kDa and 25 kDa) in mpkCCDc14 cells. dDAVP treatment (10−9 M, 24 h) also increased the abundance of total PARylated proteins in biotin-NAD+ pulldown and IP assay of PAR in mpkCCDc14 cells. On the other hand, siRNA-mediated PARP1 knockdown significantly attenuated the dDAVP-induced mRNA and protein abundance, suggesting a role of PARP1 in AQP2 regulation. PARP1 cleavage induced by dDAVP was not changed under PARP1 knockdown, indicating that PARP1 cleavage is unlikely to be involved in AQP2 regulation. In contrast to PARP1 knockdown, PARP1 inhibitor (PJ34) did not reduce the dDAVP-induced AQP2 abundance, despite the significant decrease in the PARylation. The results suggest that dDAVP-regulated AQP2 expression is associated with PARP1 protein per se, but not with PARP1-mediated PARylation. Bioinformatics study revealed that 408 proteins interact with PARP1 in the kidney CD cells. Among them, 49 proteins were mapped on the vasopressin V2 receptor (V2R) signaling pathway. In particular, β-catenin, which is phosphorylated (S552) by dDAVP, was identified as the PARP1-interacting protein mapped on the V2R signaling. Immunoblotting demonstrated that siRNA-mediated knockdown of PARP1 was associated with decreased dDAVP-induced phosphorylation of β-catenin at S552 in mpkCCDc14 cells.

Conclusion

PARP1 is likely to play a role in vasopressin-mediated AQP2 regulation via the protein interaction with β-catenin rather than PARylation of proteins and/or PARP1 cleavage in the kidney CD cells.
#4097 BASELINE CHARACTERISTICS OF THE KOREAN GENETIC COHORT OF INHERITED CYSTIC KIDNEY DISEASE
Authors: Cho Jeong Min , Park Hayne Cho , Lee Jin Woo , Ryu Hyunjin , Kim Yong Chul , Ahn Curie , Lee Kyu-Beck , Kim Yeong Hoon , Han Seungyeup , Kim Yaerim , Bae Eun Hui , Oh Kook-Hwan , Oh Yun Kyu
Published: June 2023

Background and Aims

We report the baseline and genetic characteristics of the nationwide genetic cohort for Korean hereditary cystic kidney disease prior to detailed molecular analysis.

Method

We performed a 3-year prospective, multicenter cohort study at 9 hospitals from May 2019 to May 2022. Patients with more than 3 renal cysts were enrolled and classified into 3 categories: typical and atypical autosomal dominant polycystic kidney disease (ADPKD), and pediatric PKD. Clinical and genetic characteristics were compared among categories. Genetic analysis was performed by using gene panel comprised of 89 ciliopathy-related genes.

Results

A total of 798 patients were enrolled. Mean age was 42.7 ± 17.3 years, and 47.8% were male. Patients were categorized into typical ADPKD (560, 70.2%), atypical ADPKD (165, 20.7%), and pediatric PKD (73, 9.1%). Typical ADPKD by Mayo imaging classification (MIC) I was as follows: 1A 55 (9.9%), 1B 149 (26.9%), 1C 198 (35.8%), 1D 90 (16.3%), and 1E 61 (11.0%) (n = 553). Atypical ADPKD by MIC II included bilateral cystic with bilateral atrophic (31, 37.3%), lopsided (27, 32.5%), unilateral (9, 10.8%), segmental (8, 9.6%), bilateral cystic with unilateral atrophic (7, 8.4%), and asymmetric (1, 1.2%). The mean age was lower in the typical ADPKD group compared to atypical group (45.3 ± 13.3 vs. 48.9 ± 15.8, p = 0.003). Height-adjusted total kidney volume was greater in the typical group than atypical group (947.4 ± 762.5 mL/m vs. 528.2 ± 587.6 mL/m, p<0.001). Pathogenic variants were found in 57.3% of the patients by ciliopathy-related gene panel. Typical ADPKD group demonstrated higher discovery rate (62.3%) compared to atypical ADPKD group (41.8%) or pediatric PKD group (53.4%).

Conclusion

This is the first nationwide cohort for genetic characterization of Korean hereditary cystic kidney disease patients. We report the baseline characteristics and genetic findings of the cohort prior to detailed molecular analysis.
#4098 PATIENT ACUITY AND CARDIOVASCULAR OUTCOME IN HEMODIALYSIS PATIENTS: A KOREAN NATIONWIDE COHORT STUDY
Authors: Kim Hyo Jeong , Park Jung Tak , Heo Ga Young , Kim Kyung Won , Kwon Youg Uk , Kim Soo Hyun , Kim Gui Ok , Kim Hyung Woo
Published: June 2023

Background and Aims

Patients acuity has been reported to be associated with poor outcome in hospitals. However, the effect of the patient acuity of hemodialysis center on the prognosis of individual patients is not well known. In this study, the association between the severity of illness in hemodialysis facility and major adverse cardiac and cerebrovascular event (MACCE) in patients undergoing hemodialysis was investigated.

Method

15,633 participants receiving hemodialysis in the primary health care center who participated in the Periodic Hemodialysis Quality Assessment by Health Insurance Review & Assessment Service (HIRA) were examined. The main predictor was severity-to-nurse ratio, defined as a sum of Charlson comorbidity index of all patients divided by the number of nurses in each hemodialysis facility. The primary and secondary outcome were MACCE, and all-cause mortality, respectively.

Results

During a median follow-up of 5.5 years, MACCE and all-cause mortality occurred in 7,966 (51.0%) and 6,536 (41.8%) participants. Participants with higher severity-to-nurse ratio tended to have higher incidence rate of MACCE. The hazard ratios (HRs) of MACCE for the second, third, and highest quartiles compared with the lowest quartile of severity-to-nurse ratio were 1.05 (95% confidence intervals [CI], 0.98-1.11; P = 0.151), 1.07 (95% CI, 1.00-1.14; P = 0.053), and 1.08 (95% CI, 1.00-1.16; P = 0.040). When treating severity-to-nurse ratio as a continuous variable, MACCE risk increased by 1% per 1 increase in severity-to-nurse ratio (HR, 1.01; 95% CI, 1.00 - 1.02; P = 0.003). Compared to the lowest quartile group, the HRs of all-cause mortality for second, third and fourth quartile were 1.12 (95% CI, 1.04-1.19; P = 0.002), 1.11 (95% CI, 1.03-1.19; P = 0.005), and 1.16 (95% CI, 1.07-1.25; P<0.001), respectively.

Conclusion

As the part of the Joint Project on Quality Assessment Research by HIRA, the present study showed that the patient acuity was strongly associated with an increased risk of poor outcomes in hemodialysis patients.
#4175 PERFORMANCES OF THE 5-YEAR KIDNEY FAILURE RISK EQUATION IN A TERTIARY SINGLE CENTER CHRONIC KIDNEY DISEASE COHORT (CKD CAREMEAU)
Authors: Prouvot Julien , Gerbal Marion , Ahmadpoor Pedram , Garo Florian , Cariou Sylvain , Renaud Sophie , Pambrun Emilie , Reboul Pascal , Moranne Olivier
Published: June 2023

Background and Aims

Chronic kidney disease (CKD) is a common disease with a heterogeneous course. The Kidney Failure Risk Equation (KFRE) is designed to predict 5-year End stage renal disease (ESRD). This score has shown poor performance in predicting 5-years ESRD in elderly patients, probably because of a competitive risk with death. Indeed, patients with type 2 diabetes are numerous and older than non-diabetic patients, with higher risks of death, and thus à higher competitive risk. In this context, we aimed to evaluate the performance of the KFRE score at 5 years, in a cohort from a tertiary center, according to diabetic status.

Method

The CKD Caremeau (CKDC) cohort is a single-center tertiary cohort of adults seen by a nephrologist for CKD. We studied CKDC patients included between January 2008 and December 2017 and followed them. We excluded patients younger than 45 years. KFRE score covariates were collected at the first visit, and Renal replacement therapy (RRT) (dialysis or kidney transplantation) and death before ESRD were collected during follow-up through December 2022. Multiple imputation (Monte Carlo) was used for missing albuminuria. Score performance was calculated with discrimination (area under curve (AUC)) and calibration (observed versus predicted risks), according to diabetic status, at 5 years.

Results

Of the 3046 patients included, 1288 (42%) had diabetes. 558 (18%) albuminuria were missing and imputed. For diabetic patients, median follow-up time was 5.3 [3.0–7.6] years, median age was 73 [66–80] years, 843 (65%) patients were males, median eGFR was 38 [27–50], median albuminuria was 204 [57–671] mg/g, 177 (14%) developed ESRD, and 398 (30%) died, with a median 5-years KFRE score of 4 [0.65–17.6] %. For non-diabetic patients, median time of follow-up was 5.5 [3.3–8.2] years, median age was 72 [63–81] years old, 1027 (58%) were males, median eGFR was 40 [27–53], median albuminuria was 113 [38–399] mg/g, 205 (12%) experimented ESRD, and 501 (29%) died, with a median 5-year KFRE score of 2 [0.18–14] %. Discrimination was not modified by diabetic status at 5 years (p = 0.67). Calibration was also unaffected by diabetic status, with an overall overestimation at 5 years.

Conclusion

The performance of the KFRE score was not modified by diabetic status, meaning that age is probably more important than diabetic status for the competitive risk of death in CKD patients.
#4183 A PHENOTYPIC DRIVEN RITUXIMAB MAINTENANCE APPROACH IS EFFECTIVE AND SAFE IN PATIENTS WITH ANCA ASSOCIATED VASCULITIS
Authors: Tonoli Mattia , Affatato Stefania , Guerini Alice , Salviani Chiara , Delbarba Elisa , Gregorini Alessandra Gina , Scolari Francesco , Mescia Federica , Alberici Federico
Published: June 2023

Background and Aims

Rituximab (RTX) has emerged as the first-line treatment to maintain remission in ANCA-Associated Vasculitis (AAV). However, the ideal strategy to RTX re-dosing is still unclear [1].

Method

In this monocentric and retrospective study we evaluated the efficacy and safety of two RTX-based maintenance regimens in patients with AAV. Fixed-dose (FD) RTX dosing, consisting of at least 3 pre-emptive RTX administrations every 6 months, was preferred in patients judged to be at high relapse risk. Instead, a biomarker-guided on-demand (OD) RTX dosing strategy was preferred for patients deemed at lower risk of relapse; this consisted in RTX re-treatment only in case of B-cell repopulation or rise in ANCA titer. The single patient relapse risk was assessed according to the disease phenotype (granulomatous vs vasculitic), the ANCA specificity and the disease status (onset vs relapse). Relapses were defined as increase of disease activity requiring escalation of immunosuppression; major relapses were defined in case of life/organ-threatening manifestations.

Results

The study included 100 patients followed for a median of 24 months (IQR 20-30), 51% treated with an OD and 49% with a FD strategy. The main baseline characteristics of our cohort are shown in the Table; patients treated with a FD strategy were more often GPA, PR3-ANCA positive, with relapsing disease and ENT involvement and less frequent renal involvement. The FD group received a median of 4 (IQR 4-4) administrations of RTX for a median cumulative dose of 2 g (IQR 2-2). Only 6 (11.8%) patients in the OD group received RTX as maintenance therapy with a median of 1 (IQR 1-3) administration of RTX for a median cumulative dose of 0.75 g (IQR 0.5-1.75). Thirteen relapses occurred, 6 in the FD group and 7 in the OD one. Remission rates were comparable in the two cohorts, with respectively 87.6% and 85.9% of the patients in remission at 24 months (Figure 1 - panel A). No significant differences in remission rates across the 2 groups were observed after considering only major flares or after stratification according to clinical diagnosis (MPA/GPA) and ANCA specificity (Figure 1 - panel B to F). Ten and 20 severe infections (p = 0.383) and 3 and 1 cancer (p = 0.581) occurred respectively in the FD and OD group.

Conclusion

In our case series, a phenotypic-driven approach to RTX maintenance showed comparable efficacy and safety between fixed and on-demand dosing, despite different baseline characteristics between the two groups. These results suggest that personalizing RTX maintenance may be a feasible and safe strategy.
#4184 MALE CHRONIC KIDNEY DISEASE IS A STATE OF PREMATURE TESTICULAR AGING
Authors: David Karel , Narinx Nick , De Loor Jetty , Antonio Leen , Vanderschueren Dirk , Claessens Frank , Decallonne Brigitte , Evenepoel Pieter
Published: June 2023

Background and Aims

Sex steroid levels have been reported to be decreased in male patients with chronic kidney disease (CKD), parallel to the severity of the kidney dysfunction. These studies, at large, used immuno-assays, a method that is inferior to gold standard chromatography measurements and, in addition, failed to give insights into the underlying pathophysiology as they lacked data on gonadotropin levels. The aim of this study was to comprehensively map the gonadal status in male CKD patients not yet on dialysis and age- and BMI-matched controls, using gold standard techniques.

Method

We performed a case-control study in 120 male CKD patients (age 65.0 y, BMI 26.8 kg/m2), matched (1:1) with non-CKD controls for age and BMI. We divided CKD patients into 3 categories based on KDIGO classification: CKD 1–2 (n = 24), CKD 3 (n = 42) and CKD 4–5 (n = 54). We measured total testosterone (T) and estradiol (E2) using liquid chromatography tandem mass-spectrometry. Sex hormone binding globulin (SHBG), prolactin, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured on the Roche Cobas 8000 platform. Free T levels were calculated via Vermeulen formula. Inhibin B (a readout for testicular Sertoli cell function) was measured by ELISA.

Results

CKD patients showed lower total T (426.0 ng/dL [297.5-516.5] vs. 541.0 ng/dL [452.0-647.8]; p<0.0001) and free T levels (7.4 ng/dL ±3.2 vs. 9.4 ng/dL +/-2.2; p<0.0001) as compared to non-CKD counterparts. SHBG and E2 levels, conversely, were comparable in cases and controls. Inhibin B levels were lower in CKD patients as well (112.7 pg/mL [38.1-189.0] vs. 181.1 [122.2-236.4]; p<0.0001). LH and FSH levels were higher in CKD patients (9.1 IU/L [5.4-16.2] vs. 5.4 IU/L [3.6-8.1]; p<0.0001 and 7.8 IU/L [5.0-20.2] vs. 5.6 IU/L [4.0-9.7]; p<0.0001 respectively). Consequently, the T/LH ratio and inhibin B/FSH ratio, respectively reflecting Leydig and Sertoli cell function, were markedly depressed in CKD (1.8 nmol/IU [0.7-3.0] vs. 4.0 nmol/IU [2.4-5.2]; p<0.0001 and 14.4 ng/IU [1.2-33.6] vs. 32.2 ng/IU [32.2 [16.3-56.7]; p<0.0001). In the CKD cohort, regression analysis identified eGFR and age as independent determinants of T/LH ratio (R2 0.29). According to the T/LH ratio a male CKD patient of 45y old has a testicular age of an 81y old control.

Conclusion

Male patients with CKD not yet on dialysis show low total and free T levels, confirming CKD as a risk factor for male hypogonadism. The low T/LH and inhibin B/FSH ratio point to testicular failure as the underlying pathophysiological mechanism.
#4201 DYNAMICS OF INFLAMMATION EARLY AND LATE AFTER RENAL TRANSPLANTATION: CHARACTERIZATION OF THE IMMUNOLOGICAL PROCESSES IN A RAT RENAL TRANSPLANT MODEL
Authors: Stolz Gudrun , Langer Robert , Zeng Xiaokui , Yang Dai , Hinkeldein Tanja , Dolff Sebastian , Witzke Oliver , Kribben Andreas , Wilde Benjamin
Published: June 2023

Background and Aims

The pathophysiology of rejection after renal transplantation (RTx) has not been unraveled completely. In previous studies, Th17 cells were shown to be involved in several autoimmune diseases affecting the kidney, e.g. lupus nephritis, glomerulonephritis and ANCA vasculitis. The aim of this study was to decipher the dynamics of rejection after RTx with focus on the Th17 cells and IL17 cytokine family.

Method

For this purpose, the established Fischer to Lewis rat RTx model was used. In this model, renal rejection is elicited and develops over time. The donor renal grafts were harvested from Fischer rats and exposed to static cold storage using HTK or UW buffer. The Lewis recipients were treated for 10 days post-transplant with ciclosporin A and then immunosuppressive therapy stopped. Recipients were harvested early (2 hours, 30 days) and late after RTx (12 weeks, 28 weeks). To analyze the dynamics of inflammation, kidney sections were stained for CD3+ (T-cells) and MPO (neutrophils). RT-PCR was used to detect cytokine gene expression of several target genes within the renal grafts. IL17A Elispot was established to analyse circulating Th17 cells in the recipients.

Results

Generally, the cold ischemia time of the renal allograft was associated with the lifetime of the recipients. Furthermore, with increasing cold ischemia time of the graft, intra-renal CD3+ T-cell infiltration was enhanced. An increased CD3+ and a diminished number of MPO+ neutrophils were detected in the renal grafts late after RTx compared to early timepoints. Moreover, the intra-graft IL17C gene expression was enhanced late after renal transplantation while CXCL1 and CXCL2 were upregulated early after renal transplantation. IL17A gene expression reached higher levels than IFNg in later timepoints e.g. 30 days, while in early stages IL17A was below IFNg. The impact of cold storage buffer on the immunogenicity of the renal transplant was investigated, too. The use of UW led to a higher intra-renal CD3+ T-cell infiltration at later timepoints compared with HTK. In early stages after transplantation, higher levels of intra-renal MPO+ neutrophils were found upon cold storage using UW compared to cold storage using HTK.

Conclusion

The inflammatory process during chronic kidney rejection is T-cell driven and may involve the IL17C cascade. The early phase is dominated by neutrophils with enhanced intra-renal expression of CXCL1 and CXCL2. Furthermore, the polarization of the T-cell driven immune response may change depending on the time point after transplantation.
#4202 FLUID OVERLOAD AT THE BEGINNING OF PERITONEAL DIALYSIS: A CROSS-SECTIONAL STUDY TO DETERMINE ITS ASSOCIATION WITH SERUM BIOMARKERS
Authors: Afonso Rita , Pimenta Gonçalo , Matias Patrícia , Vida Ana Carlota , Lobo Sara , Santos Elisabete , Branco Patricia , Calça Rita
Published: June 2023

Background and Aims

Volume management in peritoneal dialysis (PD) patients is of major importance as fluid overload has been associated with cardiovascular and non-cardiovascular morbidity and mortality. Clinical examination itself has a poor diagnostic accuracy for minor deviations from normohydration, highlighting the need of additional tools. The aim of this study was to evaluate the association between serum biomarkers (CA-125 and NT-proBNP) and volume status, evaluated by clinical and bioimpedance analysis, at the initiation of PD technique.

Method

Single-center cross-sectional study including PD patients that started technique between 2017 and 2022. Demographic and clinical data were collected from the electronic records. Parameters evaluated were clinical examination, serum biomarkers, bioimpedance and dialysis adequacy.

Results

A total of 79 patients (51 male) were included with a mean age of 57±15 years. All of them started with CAPD and 52% were under icodextrin. Hypertension, cardiovascular disease and diabetes were present in 94%, 51% and 34%, respectively. The great majority were under renin-angiotensin-aldosterone system inhibitors (91%), beta-blockers (48%) and diuretic therapy (94%). Baseline PET showed that 77% were high or high-average transporters. Mean weekly Kt/V was 2.4±15. The mean residual renal function (RRF) and residual diuresis were 6.7±15 mL/min/1.73 m2 and 1.6±0.8 L (4% anuric), respectively, and 11% had ultrafiltration failure. Median nPCR was 0.9 g/Kg/day (IQR 0.3). Median NT-proBNP and CA-125 were 1337 pg/mL (IQR 3401) and 14.6 U/mL (IQR 17.6), respectively. NT-proBNP was positively associated with overhydration (OH >2 L) (r = 0.31; p = 0.009), CA-125 (r = 0.28; p = 0.01) and icodextrin use (p = 0.002). It was negatively associated with weekly Kt/V (r = -0.35; p = 0.003), RRF (r = -0.36; p = 0.002), ultrafiltration test (UFT) (r = -0.35; p = 0.003) and nPCR (r = -0.28; p = 0.001). CA-125 was positively associated with higher overhydration (OH > 3.6 L), D/P creatinine (r = 0.3; p = 0.004) and icodextrin use (p = 0.001). It was negatively associated with weekly Kt/V (r = -0.3; p = 0.01), UFT (r = -0.25; p = 0.03) and nPCR (r = -0.23; p = 0.04). NT-proBNP was still associated with overhydration in a multivariable analysis, adjusted to diabetes, icodextrin use, RRF and CA-125 (p = 0.024).

Conclusion

Serum NT-proBNP and CA-125 seem to be good markers of overhydration at PD baseline. They were also associated with worse dialytic efficacy and ultrafiltration, lower residual renal function and an early need of icodextrin use. Malnourished patients were associated with higher NT-proBNP and CA-125. Early and effective management of hydration may improve clinical outcomes, allowing personalized dialysis prescription and nutritional support.
#4205 ESTIMATED PROXIMAL TUBULE FLUID PHOSPHATE (EPTFP) CONCENTRATION: AN EARLY MARKER OF CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER (CKD-MBD)?
Authors: Rotondi Silverio , Tartaglione Lida , Pasquali Marzia , Perrotta Adolfo , Romano Chiara , Tinti Francesca , Mazzaferro Sandro
Published: June 2023

Background and Aims

MBD develops early in CKD and is associated with kidney damage progression, but CKD-MBD markers, of initial CKD-MBD like FGF23 and α-Klotho are not available in clinical practice. Recently ePTFp has been proposed as a new early marker of MBD. In fact, the progressive reduction of nephron number, with the proportional FGF23 increments, reduce renal tubular phosphate reabsorption to maintain phosphate balance. As a consequence, PTFp concentration per single nephron progressively increases, leading to progression of kidney tubular damage. For this reason, PTFp could represent an innovative early marker of CKD-MBD. We evaluated the relationship of ePTFp with FGF23, α-Klotho and kidney damage progression.

Method

In CKD stage G2-4, we assayed serum FGF23, α-Klotho and ePTFp [ePTFp = (Phosphaturia / creati-ninuria) x creatininemia x 3,33]. The progression of CKD was evaluated during 5 years and the patients were splitted in two groups according to the basal ePTFp median value. 30 healthy subject pro-vided the normal value of ePTFp.

Results

In 68 CKD patients (age 58,9 ± 15.6 y.o. eGFR 45 ± 21 mL/min), ePTFp averaged 2.4±1.3 mg/mg which was higher than the control group (ePTFp = 1.2±0.5; p<.01). ePTFp increased progressively along with the increasing CKD stages with values higher than the control group since stage 2 (Table 1). ePTFp showed a positive correlation with FGF23 (r: 0.69; p<.001) and a negative correlation with α-Klotho (r:-237; p<.05) and eGFR (r:-647; p<.001). Follow-up was available in 30 patients (Table 2) and showed a greater reduction of eGFR in the 15 patient with higher ePTFp (threshold 2 mg/dl) (Fig. 1).

Conclusion

Our data show early and progressive increments of ePTFp in CKD along with increments of FGF23 and PTH and reduction of α-Klotho, as per reciprocal pathophysiologic dependence. ePTFp values > than 2 mg/dl identified patients at highest risk of CKD progression. Accordingly, ePTFp, a surrogate of renal tubular cells phosphate overload, could represent a novel marker of CKD-MBD development and of increased risk of kidney damage potentially helpful to make therapeutic choice.
#4210 ZETOMIPZOMIB DEMONSTRATES CLINICALLY MEANINGFUL IMPROVEMENT IN UPCR IN NEPHROTIC RANGE PROTEINURIA PATIENTS: RESULTS FROM THE OPEN-LABEL MISSION STUDY
Authors: Parikh Samir , Saxena Amit , Leff Richard , Hua Steven , Park Eunmi , Henig Noreen
Published: June 2023

Background and Aims

Prospective cohorts have shown that patients with LN and nephrotic range proteinuria at baseline have a lower probability of achieving renal response [1]. These patients may require more time due to slower proteinuria recovery. Results previously reported on the Phase 2, open-label MISSION study evaluating the safety and tolerability of zetomipzomib in active proliferative LN including patients with nephrotic range proteinuria, demonstrated clinically meaningful renal responses [2]. A post-hoc analysis of MISSION patients with nephrotic range proteinuria is presented here.

Method

In the MISSON Phase 2 study, patients with active proliferative LN (Class III or IV ± V) with 24-hour urine protein to creatinine ratios (UPCR) ≥1.0 mg/mg despite stable background therapy received 60 mg of zetomipzomib subcutaneously once weekly (first dose: 30 mg) in addition to stable background therapy for 24 weeks. End of treatment (EOT) was at Week (W) 25, and end of study (EOS) occurred at W37. The primary endpoint was the number of patients with ≥50% reduction in UPCR from baseline after 24 weeks of treatment. Nephrotic range proteinuria was defined as UPCR ≥3.0 mg/mg at baseline as per KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases.

Results

Of 17 evaluable patients who reached EOT, 4 patients had nephrotic range proteinuria, with 3 having hypoalbuminemia (serum albumin ≤3.5 g/dL) at baseline. Patients with nephrotic range proteinuria had mean LN duration of 4.14 years with mean 24-hour UPCR of 5.78 mg/mg, mean serum albumin of 3.0 g/dL, mean blood pressure of 124/81 mmHg and mean eGFR of 122.5 mL/min/1.73 m2. All 4 patients were on concomitant corticosteroids (mean dose: 19.81 mg/d), mycophenolate mofetil, hydroxychloroquine and antihypertensives. After 24 weeks of zetomipzomib treatment, 3/4 patients with nephrotic range proteinuria achieved ≥50% reduction in UPCR at W25 (EOT) and W37 (EOS, 12 weeks post-treatment) (Table 1). Serum albumin levels also improved and normalized by EOS in all 3 patients with hypoalbuminemia at baseline (Table 1). eGFR levels generally remained stable throughout the study. Reduction of daily steroid dose to 10 mg/day was observed in all 4 patients as early as W13 and at EOT/EOS while other background therapy doses remained stable throughout the study. Improvement and/or normalization in key serologic biomarkers, including anti-dsDNA and C3/C4, were also observed in patients with abnormal levels at baseline.

Conclusion

In this post-hoc subgroup analysis of MISSION Phase 2 study, zetomipzomib treatment demonstrated clinically meaningful improvement in UPCR and normalization of albumin levels in patients with nephrotic range proteinuria and hypoalbuminemia. These results further support the potential activity of zetomipzomib in hard-to-treat LN patients.
#4234 ADAM17 MODULATES IFN-MEDIATED INFLAMMATION IN RENAL TUBULAR CELLS
Authors: Riera Marta , Riveira-Muñoz Eva , Galdon Eric , Garcia-Vidal Edurne , García Eva Rodríguez , Crespo Marta , Ballana Ester , Barrios-Barrera Clara
Published: June 2023

Background and Aims

In diabetic patients, hyperglycemia has been associated with a hypoxic state that contributes to an increased rate of morbidity due to Acute Kidney Failure (AKI). For this reason, we are interested in studying the molecular mechanisms involved in the development of AKI to contribute to the search for effective therapies that can help prevent these episodes. We focused on ADAM17, a disintegrin and metalloproteinase that sheds the ectodomains of cell surface proteins, among which inflammatory cytokines stand out. In an animal model, we showed that the absence of ADAM17 in the renal tubule reduces protein expression related to fibrosis and inflammation induced by diabetes. In this context, we aimed to study the role of ADAM17 in modifying the expression of inflammatory molecules regulated by interferon (IFN) in renal proximal tubule cells subjected to hyperglycemic stress. In this study, we analyzed the effect of ADAM17 deletion in human renal tubular cells (HKC-8) incubated in high-glucose medium and subjected to hypoxia.

Method

ADAM17 was depleted using CRISPR/Cas9 (ADAM17-KO). Cells were incubated for 6 h or 24 h with high (35 mM HG) or normal (5.5 mM NG) glucose concentrations and were subjected to hypoxia plus 2h re-oxygenation (HIPX). Gene expression of several IFN-regulated inflammatory markers (IL6, IL8, CXCL10, ISG15, IL1a, IL1b, IL12A, CCL5, and CCL2) was determined in wild-type (WT) and ADAM17-KO cells.

Results

The absence of ADAM17 in HKC-8 cells induced changes in the mRNA expression of genes controlled by IFN, which is accentuated by the hyperglycemic stimulus. Under hypoxic and re-oxygenation conditions, these changes were in the same line, with more discrete values compared to control cells. TNFa, CXCL10 and LNC2 were the most relevant genes reduced in injury conditions in the ADAM17-KO cell line.

Conclusion

ADAM17 deletion modulates the expression of most IFN-regulated genes that could undergo post-transcriptional changes and subsequently act as an acute mechanism of protection from injury. The results show that ADAM17 plays a major role in the underlying inflammatory response to acute kidney injury, indicating its potential as a therapeutic target. The analysis of circulating proteins will provide information about this process to better understand the mechanism of action of ADAM17 in the protection of renal tubular damage.
#4240 SUCCESSFUL PROPHYLAXIS WITH STROVAC VACCINE AGAINST URINARY TRACT INFECTION AFTER KIDNEY TRANSPLANTATION
Authors: Haziyev Elgun
Published: June 2023

Background and Aims

Urinary tract infections (UTI) are the most common of infections after renal transplantation with an estimated incidence between 10 and 98%. Recurrent urinary tract infections (rUTIs) increase mortality and reduce graft survival after renal transplantation. The present case describes an immunization strategy against bacterial strains after kidney transplantation.

Method

We administered urinary tract vaccine for prophylaxis for rUTIs after kidney transplantation. A kidney transplant recipient with 3 or more UTI episodes/year underwent immunization with 3 subcutaneous injections (once a week) of inactivated bacteria-StroVac (follow-up 12 months before to 12 months after immunization). StroVac contains 10 strains of inactivated bacteria (6 types of Escherichia coli, Proteus mirabilis, Morganella morganii, Enterococcus feacalis, Klebsiella pneumoniae). A year later the StroVac Booster was administered once. Urine culture analysis was given every 3 months for a year. Clinical and laboratory comparisons were made. The results were evaluated statistically.

Results

Before initiation of prophylaxis, patient had a UTI incidence of 5. The patient had symptoms such as fever, dysuria, or urgency and were positive in urine dipstick examination for pyuria or nitrituria. Vaccination with StroVac significantly reduced the incidence of UTI yielding a mean annual incidence of 1 (p<0.05).

Conclusion

StroVac is an effective and lasting non-antibiotic prophylaxis for rUTI, easy to administer with low rates of adverse events and should be offered to patients with rUTI after kidney transplantation.
#4261 RELATIONSHIP BETWEEN FLUID OVERLOAD AND AVERAGE PLASMA REFILL RATE IN HEMODIALYSIS PATIENTS
Authors: Wang Lin-Chun , Mermelstein Ariella , Raimann Jochen , Moissl Ulrich , Zhang Hanjie , Thijssen Stephan , Kotanko Peter
Published: June 2023

Background and Aims

Attaining the optimal balance between achieving adequate volume removal while preserving organ perfusion remains challenging in patients on maintenance hemodialysis (HD). Quantification of fluid status using bioimpedance spectroscopy (BIS) has become routine in many countries. Inadequate vascular space refill from the interstitial tissue (plasma refill rate, PRR) is the main contributing factor of hemodynamic instability during HD. We aimed to explore the association between fluid overload (FO) and plasma refill rate (PRR) in chronic HD patients.

Method

Pre-HD FO [l] was assessed once per subject by BIS (Body Composition Monitor; Fresenius Medical Care) in four urban HD dialysis clinics in the U.S. For each treatment within 30 days before and after the BIS measurement, we calculated the respective pre-HD FO by assuming that differences in pre-HD body weight were equivalent to differences in FO. We then used intradialytic hematocrit (measured with the Crit-Line® Monitor, Fresenius Medical Care) and ultrafiltration data to quantify the average PRR, normalized by body weight (Wang et al. Kidney360, 2023): To calculate the starting blood volume (BV), we first calculated the ending BV using the Nadler equation, followed by back-calculating the starting BV based on the cumulative change in relative BV. Plasma refill volume was calculated as the sum of the changes in blood volume and ultrafiltration volume; plasma refill volume was then divided by treatment time and estimated clinical dry weight to calculate the PRR [ml/kg/hr].

Results

We analyzed 746 HD sessions from 79 patients (age 61 ± 15 years; 52 (66%) males; 41 (52%) black and 33 (42%) white). Across all HD sessions, PRR was positively associated with FO [slope estimate 0.92 (95% confidence interval 0.83 to 1.02) ml/kg/hr per 1 l of FO, P value < 0.0001] (Figure 1). This was also the case in subgroup analyses of fluid depleted (r = 0.94, P<0.001), normohydrated (r = 1.03, P<0.0001), and fluid overloaded subjects (r = 0.83, P<0.0001).

Conclusion

Across the entire fluid status spectrum, from fluid depletion to fluid overload, higher FO was associated with higher PRR on average (overall, an increase of 0.92 ml/kg/hr in PRR for each additional liter of FO). While patients with greater FO would be expected to better tolerate higher ultrafiltration rates, there is large inter-individual variability in PRR. Further investigation of the utility of PRR throughout HD may offer novel insights into fluid management and intradialytic symptom mitigation.
#4264 PERITONEAL DIALYSIS AFTER FAILED KIDNEY TRANSPLANT: A SUITABLE OPTION
Authors: Francisco Diogo , Carnevale Andreia , Ávila Gonçalo , Calça Ana Rita , Matias Patrícia , Branco Patrícia
Published: June 2023

Background and Aims

Despite great advances in graft survival, kidney transplant (KT) recipients frequently return to dialysis. The aim of this study was to perform an analysis of peritoneal dialysis (PD) outcomes of patients with a failed KT.

Method

Single-center retrospective cohort study with end-stage renal disease (ESRD) patients who started PD from 1st January 2010 to 31st December 2017. Two groups were analyzed - patients who started PD with no previous renal replacement therapy (RRT) - PD first -, and patients who transitioned directly from a failed kidney transplant.

Results

Among 152 patients who started PD, 115 were PD first and 15 transitioned from KT. The population included 63,1% of male gender, with a mean age of 52,4 ± 15,5 years and had PD median vintage of 30 months (IQR 20,6). Patients who transitioned from KT were significantly younger (mean age 42,8 ± 14,3 vs. 53,7 ± 15,3, p = 0,015) and had lower prevalence of diabetes mellitus (13,3% vs. 40,0%, p = 0,044). In KT patients, glucocorticoids were continued until there was residual diuresis and non-glucocorticoid immunosuppression was maintained for a median of 180 days (± 176) after PD start. Nearly a third (30,0%) of patients had no hospitalizations and 35,5% had more than 2 hospital admissions. Annual hospitalization rate was higher in prior KT group (1,40 vs. 0,48, p = 0,002). Prior KT associated with higher annual peritonitis rate (0,70 vs. 0,20, p = 0,017). A higher number of MACE was also observed in prior KT group (33,3% vs. 7,9%, p = 0,004). Residual diuresis was significantly lower in the group with previous KT. Neither ultrafiltration failure (6,7% vs. 9,9%, p = 0,974), nor technique survival (death or hemodialysis transfer 53,3% vs. 54,8%, p = 0,917; logrank 0,354) were different between groups.

Conclusion

Although higher incidence of diabetes mellitus was observed in PD first group, no differences were identified in ultrafiltration failure rates between groups. Despite significantly lower diuresis in prior KT group, both groups had adequate dialysis efficacy (mean Kt/V>1,7) and similar technique survival. Higher peritonitis rate and MACE incidence was observed in prior KT group, possibly associated with maintenance immunosuppression. Nevertheless, PD is a valid choice for RRT after a failed KT and should be offered to these patients.
#4281 TERTIARY HOSPITAL EXPERIENCE IN AN ESSENTIAL SUBSPECIALTY: ONCONEPHROLOGY
Authors: Garcia Sheila Bermejo , Bolufer Mónica , Viggiano Davide , Callejo Ana , Felip Enriqueta , López Marina , Vergara Ander , Pamplona Irene Agraz , Matamoros Oriol Bestard , Romeo Maria Jose Soler
Published: June 2023

Background and Aims

Kidney complications of cancer patients and cancer in renal patients have increased in recent years. The objective of this study is to evaluate the characteristics of the patients referred to the Onconephrology Unit from January 2021 to December 2021, studying the cognitive and mood status of these patients.

Method

This is a prospective observational study of the Onconephrology consultation at a University Hospital Center during 2021. Clinical and analytical characteristics of the patients and clinical indication for referral were analyzed. In addition, sleep quality, mood and cognitive status were assessed using validated rating scales (Epsworth, Geriatric Depression Scale and Montreal).

Results

Seventy-four patients were evaluated, mean age was 69.6(±11) years, 41(55.4%) men, 47(63.5%) had hypertension, 18(24.3%) diabetics, and 11(14.9%) were affected by heart disease. In addition, creatinine 1.93(±1.1)mg/dl, eGFR 39.97(±20.3)mL/min, proteinuria 187[29-515.9]mg/g, and 4(5.4%) had microhematuria. The most frequent cancers were intestinal, gynecological and mammary with 12.16% (n = 9) each. 58.3% (n = 42) of patients had metastatic disease. 48.7%(n = 36) received chemotherapy and 58.1%(n = 43) targeted therapies. Platinum was the most frequently used chemotherapy and anti-VEGF in terms of targeted therapies, followed by tyrosine kinase inhibitors, anti-PD1 and anti-PDL1. The most frequent clinical indication for referral was acute renal failure (n = 36;48.7%) followed by chronic kidney disease (n = 27;36.49%) and proteinuria (n = 5;6.76%). Rating scales were obtained in 51 patients: 49% (n = 25) were snorers, followed by 17.6% (n = 9) with insomnia and 11.8% (n = 6) with OSAS. 27 patients (36.5%) had cognitive impairment. Mild depression was detected in 13 cases (25.5%) and moderate depression in 11.6% (n = 6). 21 renal biopsies were performed, the most frequent diagnosis was acute interstitial nephritis (71.4%, n = 15) followed by thrombotic microangiopathy (19% n = 4). A total of 15 patients (20.3%) died during the year.

Conclusion

Most patients referred to Onconephrology are affected by advanced oncological disease and consequently had a high mortality. The most frequent indication for referral was acute kidney injury (48.7%). Comprehensive patient care is important, given the prevalence of depressive syndrome. Onconephrology is an example of a comprehensive and multidisciplinary approach to improve the survival and quality of life of patients with advanced cancer and renal disease.
#4285 CAUSES OF PEDIATRIC END STAGE KIDNEY DISEASE IN SUDAN
Authors: Hussein Rasha , Ye Xiaoling (Janice) , Ellidir Rashid , Ali Elitigani , Bakhiet Yassir , Karar Mohamed , Yousif Mohamed , Mustafa Ghassan , Allam Nahla , Yahia Samira , Ahmed Amna , Abdelraheem Mohamed , Kotanko Peter
Published: June 2023

Background and Aims

Sudan is a large Sub-Saharan country with a population of about 48 million people, 41% of them under the age of 15 years and a median age of 18.9 years. To data, no data have been reported on the etiology of end stage kidney disease (ESKD) in children and young adults of less than 18 years of age.

Method

We conducted a chart review of all ESKD patients below the age of 18 years treated in a tertiary referral center, the Soba University Hospital (SUH) in Khartoum, the capital of Sudan. The research was approved by the SUH ethical committee. We report descriptive statics, including age, sex, ESKD causes, and kidney biopsy frequency.

Results

We included 885 patients in this analysis, their mean age (SD) was 12 (3.0) years and 57.7% were males. Glomerulonephritis, mostly post-streptococcal glomerulonephritis, was the leading cause of ESKD (36.8%), followed by unknown etiologies (25.3%) and congenital anomalies of kidney and urinary tract (CAKUT; 14.9%). In most patients with glomerulonephritis the diagnosis was based on kidney histology (96.6%). ESKD was attributed to HUS in about 7% of patients. As expected, SLE was more prevalent in females (3:1 ratio) and hereditary nephritis in males (3:1).

Conclusion

Glomerulonephritis and CAKUT account for over 50% of pediatric ESKD patients in this study from a tertiary referral center in Sudan.
#4306 DIALYSIS ADEQUACY AND INCIDENT ATRIAL FIBRILLATION IN HEMODIALYSIS PATIENTS
Authors: Heo Ga Young , Park Jung Tak , Kim Hyo Jeong , Kim Kyung Won , Kwon Youg Uk , Kim Soo Hyun , Kim Gui Ok , Han Seung Hyeok , Yoo Tae-Hyun , Kang Shin-Wook , Kim Hyung Woo
Published: June 2023

Background and Aims

Atrial fibrillation (AF) can lead to stroke, heart failure, and mortality, and has a greater prevalence in dialysis patients than in the general population. Several studies have proposed that uremic toxins might promote AF development. However, the association between dialysis adequacy and incident AF has not been well established.

Method

In this retrospective study, we analyzed 27,475 patients receiving maintenance hemodialysis, included in the Periodic Hemodialysis Quality Assessment by Health Insurance Review & Assessment Service (HIRA). The main exposure was single pooled Kt/V and the primary outcome was the development of AF.

Results

During a median follow-up of 4.8 years, incident AF occurred in a total of 4,229 (15.4%) patients. Participants with higher single pooled Kt/V tended to have lower AF incidence. In survival analysis, there was a graded association between the risk of incident AF and single-pool Kt/V quartiles: subdistribution hazard ratios and 95% confidence intervals (CI) for the second, third, and the highest quartile compared with the lowest quartile were 0.90 (95% CI, 0.83-0.98), 0.85 (95% CI, 0.78-0.93), and 0.80 (95% CI, 0.73-0.89), respectively. When treating single-pool Kt/V as a continuous variable, a similar association was found. In addition, the risk of incident AF in the highest quartile of urea reduction ratio was 0.83-fold (95% CI, 0.76-0.91) lower than in the lowest quartile. Sensitivity analyses showed consistent results. This association was more pronounced in men.

Conclusion

As the part of the Joint Project on Quality Assessment Research by HIRA, this nationwide cohort study showed that lowering uremic toxin burden through increased dialysis clearance could be associated with a lower AF development risk in patients receiving maintenance hemodialysis.
#4372 TYK2-INDUCED STAT ACTIVATION IS ESSENTIAL FOR VASCULAR PRO-CALCIFIC EFFECTS OF LEUKEMIA INHIBITORY FACTOR
Authors: Razazian Mehdi , Voelkl Ioana Alesutan , Pitigala Lakmi , Luong Trang T D , Estepa Misael , Zickler Daniel , Pasch Andreas , Holfeld Johannes , Mueller Mathias , Vlahou Antonia , Eckardt Kai-Uwe , Voelkl Jakob
Published: June 2023

Background and Aims

Hyperphosphatemia in chronic kidney disease (CKD) is closely linked to medial vascular calcification. Phosphate is able to induce pro-inflammatory effects in vascular smooth muscle cells (VSMC), which could actively augment calcification processes. This study investigated the role of the IL-6 family member leukemia inhibitory factor (LIF) during vascular calcification.

Method

Experiments were performed in primary human aortic VSMCs, ex vivo mouse aortic rings and cholecalciferol treated mice, as well as serum samples from CKD patients and healthy controls.

Results

Phosphate exposure induced LIF release in VSMCs, while supplementation of LIF aggravated calcification and expression of pro-calcific markers in VSMCs. Silencing of LIF or addition of soluble LIF receptor (LIFR) as putative LIF antagonist ameliorated the pro-calcific effects of phosphate. Similarly, effects of phosphate or LIF were blunted by silencing of LIFR or its coreceptor GP130 in VSMCs. Mechanistically, LIF induced phosphorylation of TYK2, which was required for STAT1/3 activation. TYK2 overexpression augmented VSMC calcification, while silencing of either TYK2 or STAT1/3 ameliorated phosphate- and LIF-induced expression of pro-calcific markers. Pharmacological inhibition of TYK2 ameliorated calcification in VSMCs, mouse aortic rings and mice after cholecalciferol treatment. Furthermore, calcification was ameliorated in TYK2-deficient mouse aortic rings and mice after cholecalciferol overload. In a pilot study, LIFR was reduced in serum from patients with CKD and LIFR levels were associated with serum calcification propensity.

Conclusion

Vascular calcification is augmented by LIF, which identifies a crucial role of TYK2 in the pro-calcific reprogramming of VSMCs. Inhibition of this signalling axis might be able to reduce the burden of vascular calcification in CKD.
#4378 GLOMERULAR HYPERFILTRATION AS RISK FACTOR FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS AFTER ACUTE MYOCARDIAL INFARCTION
Authors: Lee Hyo Jin , Jeong Kyunghwan , Hwang Hyeon Seok , Kim Jin Sug , Yoon Soo-Young , Kim Jong Ho , Kim Dae Kyu , Lim So Jin
Published: June 2023

Background and Aims

A reduced glomerular filtration rate (GFR) is a definite risk factor for major adverse cardiovascular event (MACE) in acute myocardial infarction (AMI) patients. While glomerular hyperfiltration (GHF) is associated with early phases of kidney disease, it is unclear whether GHF is associated with higher risk of MACE.

Method

9,561 AMI patients with estimated GFR ≥ 60 mL/min/1.73 m2 were enrolled from prospective population-based national cohort. GHF was defined as GFR > 90th percentile after adjustment for age, sex, lean body mass and history of diabetes and hypertension, systolic blood pressure, left ventricular ejection fraction and use of angiotensin converting enzyme inhibitor or receptor blocker. Patients were divided into two groups (normal filtration group vs. GHF group) and occurrence of 3-year MACEs after AMI were investigated. Sensitivity analyses with different adjusted variables for hyperfiltration or with different patient exclusion criteria, and propensity score matching were conducted to determine consistency of our results.

Results

The GFR in 956 patients with GHF was 113.1±13.1 and it was significantly higher than those in normal filtration patients (87.7±13.1; P<0.001). The incidence rate of MACEs was higher in patients with GHF, and patient with GHF showed significantly higher risk of MACEs even after adjustment for several confounders (hazard ratio [HR] 1.37; 95% confidence interval [CI] 1.11-1.63) compared to normal filtration patients. GHF group had significantly higher risk of all-cause mortality (HR 1.65; 95% CI 1.26-2.17) and cardiac death (HR 1.80; 95% CI 1.28-2.54). There was no significant difference in the risk of non-cardiac death between two groups. Sensitivity analyses and propensity score matched analysis also showed similar findings.

Conclusion

GHF was independently associated with increased risk of MACE after AMI and the hazardous effects of GHF was pronounced in all-cause mortality and cardiac death. Our findings suggest that GHF might be a useful marker for predicting MACE after AMI.