bluuebunny/crossref_metadata_2025 huggingface dataset:
#2173 Safety and efficacy of sodium–glucose transporter-2 inhibitors in kidney transplant recipients: preliminary results
Authors: Skalioti Chrysanthi , Tsiakas Stathis , Smyrli Maria , Tsoutsoura Paraskevi , Boletis Ioannis , Marinaki Smaragdi
Published: May 2024

Background and Aims

Sodium-glucose transporter-2 (SGLT-2) inhibitors have recently emerged as standard of care for delaying the progression of chronic kidney disease. Data regarding the safety and efficacy of SGLT-2 inhibitors in kidney transplant recipients remain limited.

Method

We retrospectively analysed the data of all adult kidney transplant recipients who received SGLT-2 inhibitors at our center. We examined the safety and efficacy at 3-, 6- and 12- months post-treatment.

Results

Thirty-seven kidney transplant recipients (males 70.3%) were treated with SGLT-2 inhibitors at a median time of 8.3 years (IQR 5.2-7.4) post-transplant. Nineteen patients (51.4%) received empagliflozin and 18 (48.6%) dapagliflozin. The median follow-up time post-SGLT-2 inhibitors initiation was 9 months (IQR 5.5-20.8). Type 2 diabetes mellitus was present in 32 kidney transplant recipients (86.5%). The mean estimated glomerular filtration rate (eGFR) pre-SGLT-2 inhibitors therapy was 54.6 ± 17.2 ml/min. During the first 3 months of SGLT-2 inhibitors initiation, the mean eGFR declined by 3.51 ml/min (p:0.024), while at 6 and 12 months no significant changes from the starting value were observed. Urine protein levels decreased from 173 mg (IQR 140-500) to 140 mg (IQR 86-251, p:0.006) in the first 3 months and remained stable at 6 and 12 months. The mean HbA1c declined from 7.06 to 6.80% (p:0.042) at 3 months and the beneficial effect was maintained through the study period. Mean serum magnesium levels exhibited an increasing trend by 0.05 (p:0.080), 0.08 (p:0.074) and 0.09 mg/dl (p: 0.138) at 3, 6 and 12 months, respectively. Urinary tract infections were observed in 7 kidney transplant recipients (18.9%). Stage 1 acute kidney injury occurred in 2 patients, which led to the drug discontinuation in one of them.

Conclusion

Based on our preliminary data, SGLT-2 inhibitors seem to be a safe therapeutic option for reducing urine protein levels, as well as improving glycemic control and electrolyte disturbances in kidney transplant recipients. Long-term monitoring is required to establish the beneficial effect on renal graft function.
#2918 Genetic background of kidney graft cancer
Authors: Bloudickova Silvie Rajnochova , Novotna Anna , Horackova Klara , Zemankova Petra , Nehasil Petr , Viklicky Ondrej , Kleiblova Petra
Published: May 2024

Background and Aims

Renal cell carcinoma (RCC) is one of the most prevalent cancer in kidney transplant recipient (KTR). Majority of RCC occurs in native kidney as opposed to kidney graft. The genetic background of RCC in native kidneys has been determined implicating the clinical importance.

Method

This single-center cohort study aimed to identify genetic background of kidney graft RCC and outcome in KTR who underwent single kidney transplantation between January 2000 and December 2020 and manifested kidney graft RCC. Genetic analysis (NGS) from peripheral blood-derived genomic DNA (gDNA) was performed in both the recipient and donor using cancer-predisposition panel CZECANCA (CZEch CAncer paNel for Clinical Application).

Results

The calculated incidence of kidney graft RCC was 0.43%. Of the eighteen KTR with manifested kidney graft RCC, fifteen KTR and donors underwent NGS. The average patient age at transplantation was 50.3 years (median 54; 5-67 years) and 66 years (median 66; 24-79 years) at the diagnosis of kidney graft RCC. The mean donor age at transplantation was 39.7 years (median 42; 7-68 years) and graft age at kidney graft RCC diagnosis 50.2 years (median 46; 20-83 years). The mean follow-up after RCC diagnosis was 47 months (median 39.1; 0-112 months). The most prevalent was papillary RCC (n=8) followed by clear cell RCC (n=6) and renal pelvis urothelial RCC (n=1). Thirteen RCC were low stage (pT1a/b) disease, one was pT3 and one was unknown stage. Majority of RCC were higher graded. No cancer-predisposition gene was found in KTR or his donor.

Conclusion

Kidney graft RCC is very rare. NGS cancer-predisposition panel CZECANCA has not detected any genetic predisposition for kidney graft RCC. Further research is needed to assess clinical relevance of genetic testing for cancer risk in KTR.
#1023 Patient outcomes and graft survival among kidney transplant recipients with chronic hepatitis C infection: a single center study
Authors: Vallarit Michael John , Jamias Jade
Published: May 2024

Background and Aims

Previous studies have shown that kidney transplant_(KT) recipients with chronic hepatitis C (HCV) infection have lower survival rates after transplantation. With the emergence of direct-acting antiviral therapy for HCV infection, the long-term outcomes for these patients are still unknown.

This aims to evaluate the 5-year graft and patient outcomes of kidney transplant recipients with HCV infection at the National Kidney and Transplant Institute.

Method

A retrospective cohort study of HCV-positive KT recipients which were compared to HCV-negative patients in the same post-transplantation period. Data gathered from the patient's in-hospital and outpatient records and MEDSYS database.

Results

Twelve(12) out of 117 KT recipients with HCV infection were included. Half of these patients had detectable HCV RNA before KT. There was no difference in recipients' age, gender, and donor type between the groups. HCV infection is significantly associated with and an independent predictor of graft loss, rejection, and mortality. Patient survival between groups did not show any significant difference. Rates of graft rejection, graft loss, and patient mortality among HCV-positive recipients did not show statistically significant difference between groups. Graft survival rates at 6 months, 1-, 3-, and 5 years post KT were significantly lower among HCV-positive KT recipients compared to HCV-negative recipients. There were no significant differences in renal function, presence of proteinuria, liver enzyme levels, and incidence of cirrhosis between the groups.

Conclusion

Graft survival was shorter in HCV-positive KT recipients. Patient survival, measures of kidney function, and liver-related complications were similar between HCV-positive and HCV-negative KT recipients after transplantation.
#1617 Effect of pre-renal transplant anticoagulation and antiplatelet therapy on post-transplant outcomes: a retrospective single-center study
Authors: Fuentes Cristina , Maldonado Maria , Oliva Maria Ovidia Lopez , Gonzalez Elena , Navas Miguel Angel , Jimenez Carlos
Published: May 2024

Background and Aims

The management of anticoagulation and antiplatelet therapy in stage V chronic kidney disease (CKD) patients undergoing renal transplantation is controversial. While some centers utilize reversal agents or procoagulants before surgery, other experiences suggest that renal transplantation can be safely performed without discontinuation of such treatments. The aim of this study is to assess the incidence of hemorrhagic and thrombotic complications within the first 72 hours post-transplant in anticoagulated or antiplatelet-treated patients compared to those without these treatments (control group).

Method

Retrospective cohort study of patients undergoing renal transplantation at our center between June 2018 and February 2022, with a 6-month post-transplant follow-up. Epidemiological, clinical, and analytical data were collected.

Results

147 patients, predominantly male (60.3%). 8.1% were anticoagulated, and 16.3% were on antiplatelet therapy. Antiplatelet-treated patients were older (63 years) with a higher prevalence of cardiovascular disease history (54.2%). Anticoagulated patients showed a higher frequency of diabetes (50%) and atrial fibrillation (16.7%). The time on dialysis was also longer in anticoagulated or antiplatelet-treated patients (39.5 and 39 vs 33 months). 80.9% were first-time kidney transplant recipients from brain-dead donors, although the donor's age was lower in the control group. Ischemia time was similar in all three groups with no statistically significant differences. However, the length of hospital stay was longer for those receiving anticoagulation or antiplatelet therapy compared to the control group.

58.3% of anticoagulated patients received warfarin (pre-surgery INR of 1.5). In 50% of cases, reversal was performed using coagulation factors, vitamin K, fresh frozen plasma, or combinations of these therapies. 83.3% of antiplatelet-treated patients received aspirin, mainly for secondary prevention (54.2%), and only 8.3% received reversal therapy through plasma administration.

The incidence of hemorrhagic and thrombotic complications was low (<5%) and did not significantly differ between anticoagulated or antiplatelet-treated patients and those without these treatments, although transfusion rates were higher in the anticoagulation group (75%) compared to 51.4% in the control group and 62.5% in antiplatelet-treated patients.

Conclusion

There are no significant differences regarding hemorrhagic and thrombotic complications between anticoagulated or antiplatelet-treated patients and those without these treatments, while the percentage of blood transfusions and hospital stay was higher in anticoagulated or antiplatelet-treated patients.
#2961 Association of polygenic risk scores for blood pressure with incidence of hypertension and chronic kidney disease
Authors: Kwon Soon Hyo , Lee Haekyung , Kim Na Yeon , Lee Seunggeun , Kim Hyoungnae , Jeon Jin Seok , Noh Hyunjin
Published: May 2024

Background and Aims

Genetic risk for elevated blood pressure (BP) has been associated with a higher risk of hypertension and cardiovascular disease. However, the generalizability of previous findings has been limited due to a lack of studies among Asian populations. This study aimed to investigate whether genetic risk for BP predicts the incidence of hypertension and chronic kidney disease (CKD) in Asian populations.

Method

We performed genome-wide association studies for systolic and diastolic BP (SBP and DBP, respectively) using data from the Korean Genome and Epidemiology Study (KoGES). We then meta-analyzed these results with summary statistics from Biobank Japan to construct polygenic risk scores (PRSs) and examined the association between BP PRSs and incident hypertension or CKD. This study included participants without hypertension, cardiovascular disease, or CKD at baseline (n=4349, median age 48.5 years, 48.8% men). Participants were categorized into four groups based on their PRS percentile (<5, 5–50, 50–95, >95).

Results

As the PRS percentile increases, the median SBP and DBP at baseline also increase. Compared to the lowest SBP PRS percentile, higher PRS percentile was associated with increased risk of hypertension (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.22–1.83 for PRS percentile 5–50, HR 1.94, 95% CI 1.58–2.38 for PRS percentile 50–95, and HR 2.35, 95% CI 1.80–3.07 for PRS percentile >95). Elevated DBP PRS was also associated with higher risk of hypertension (HR 1.27, 95% CI 1.04–1.54 for PRS percentile 5–50, HR 1.72, 95% CI 1.41–2.09 for PRS percentile 50-95, and HR 2.09, 95% CI 1.60–2.72 for PRS percentile >95). The highest PRS percentile for SBP and DBP was associated with earlier onsets of hypertension by median 11 and 9 years, respectively, compared to the lowest PRS percentile for SBP and DBP. However, both SBP and DBP RPSs were not associated with incident CKD.

Conclusion

Genetic risk for elevated BP was associated with a higher risk of incident hypertension and earlier onset of hypertension in the Asian population. However, there was no association between PRS for elevated BP and the incidence of CKD.
#1219 Extracellular vesicles from patients with AMR-induced reprogramming of human podocytes into senescent cells: role of SGLT2i
Authors: Castellano Giuseppe , Armelloni Silvia , Mattinzoli Deborah , LI Min , Ikehata Masami , Alfieri Carlo , Abinti Matteo
Published: May 2024

Background and Aims

Extracellular vesicles (EVs) are organelles released by different cells that deliver biological information into the extracellular space and contribute to several diseases. However, their role in patients with antibody-mediated allograft rejection (AMR) remains uncertain. Our aim was to test the influence of plasma-derived EVs on human conditional immortalized podocytes (PODO) by investigating the possible role of dapagliflozin (Dapa) as a pharmacological agent.

Methods

Twenty-eight Rtx patients were included in the study, 14 with AMR, and 14 control TX patients (RTX). (CTRL). Plasma-derived Evs were used to stimulate PODO for 24 h, followed by exposure to 100 nM Dapa for 24 h. Differential ultracentrifugation at 110,000 g was applied, followed by counting with Nanosight and characterization by high-resolution flow cytometry according to the MISEV2018 criteria. PKH26 dye was used for the EVs-PODO incorporation study using Z-stack microscopy image acquisition. Total RNA and protein were extracted for gene expression and protein analysis, and the cells were fixed for immunostaining evaluation.

Results

We first found that upon activation with EV, PODO incorporated Es and shared them between cells; moreover, AMR-EVs led to an increased expression of tetraspanin marker of cell activation CD9 (p = 0.028) compared with CTRL. Importantly, the incubation of PODO with RTX-EVs induced a senescence-associated secretory phenotype (TNF alpha p = 0.0006, MCP1 p = 0.014); with cytoskeletal dysregulation and increase in gene expression and proteins involved in the epithelial to mesenchymal transition such as VIM (p = 0.026), senescence P21 (p = 0.04), inflammation CD44 (p = 0.034) with downregulation of Klotho (p = 0.002). Interestingly, incubation with Dapagliflozin significantly counteract PODO activation with reduction in P21 expression (p = 0.039) and an increase in Klotho (p = 0.047) abrogating inflammaging.

Conclusions

Our findings demonstrate that plasma EVs of AMR induced cellular senescence in PODO, reprogramming cellular processes such as cytoskeleton shape and composition, secretion of inflammatory cytokines, and decrease of the nephroprotective protein Klotho. This pathogenic process can be efficiently counteracted by SGLT2i.
#1071 The effect and mechanism of SGLT2 inhibitor on improving inflammatory injury of glomerular endothelial cells in diabetes
Authors: Liu Fang , Qin Chunmei
Published: May 2024

Background and Aims

ATP-binding cassette transporter A1 (ABCA1), which reduces intracellular cholesterol accumulation, is highly expressed in the kidney. Studies have shown that sodium-glucose co-transporter 2 inhibitors (SGLT2) inhibitors promote ABCA1 expression in multiple tissues and organs. However, the effect of SGLT2 inhibitors on ABCA1 expression in diabetic kidney disease (DKD) is unclear. In this study, the effect of empagliflozin, an SGLT2 inhibitor, on ABCA1 in glomerular endothelial cells(GECs) of DKD and the possible mechanisms linking ABCA1 to GECs inflammatory injury were investigated.

Method

Kidney tissues were obtained from renal biopsies of patients with early and advanced DKD. db/db mice were used as animal models of type 2 diabetes and the effects of SGLT2 inhibitors on ABCA1 were analyzed by treatment with empagliflozin. The effects of ABCA1 overexpression on glomerular lipid deposition and kidney injury were examined in a type 2 diabetic mouse model with ABCA1 overexpression (db/db + ABCA1 mice), and human renal glomerular endothelial cells (HRGECs) cultured in high glucose and high cholesterol conditions, which simulated type 2 diabetes in vitro.

Results

The expression of ABCA1 in the glomeruli of DKD patients and db/db mice was significantly decreased. Enhancing ABCA1 expression in the kidney tissue of diabetic mice by adenovirus transduction improved renal cholesterol deposition, inhibited the overactivation of C3a/C5a, and improved renal inflammatory injury. In addition, in cultured HRGECs under high glucose and high cholesterol conditions, ABCA1 deficiency increased the deposit of cellular cholesterol, contributed to overactivation of C3a/C5a, and induced inflammatory injury. Overexpression of ABCA1 enhancing cholesterol efflux or inhibition of C3a/C5a activation in vitro significantly protected against glomerular endothelial injury stimulated by high glucose and high cholesterol. Moreover, SGLT2 inhibitor empagliflozin up-regulated the expression of ABCA1 and down-regulated the levels of cholesterol, C3a/C5a and inflammatory cytokines in diabetic mice and HRGECs.

Conclusion

SGLT2 inhibitor (empagliflozin) might play a renal protective role by up-regulating ABCA1-mediated cholesterol outflow, inhibiting the activation of C3a/C5a, and then ameliorating the inflammatory injury of GECs.
#2474 TPPP3 maintains the stability of foot cytoskeleton architecture
Authors: Peng Liping , Chen Qilin
Published: May 2024

Background and Aims

Podocytes have a unique cytoskeleton architecture, and the disturbance of the skeleton architecture can lead to foot processes fusion and then proteinuria. Actin microfilaments dominate the cytoskeleton of the foot process, and microtubules and intermediate filaments dominate the synapses of the foot cells. The structural destruction of foot process actin is closely related to the injury of podocytes. The microtubule and actin often work together in cellular processes through stable connections. As the core structure of the skeleton network, microtubules play a key role in supporting and maintaining the skeleton network. However, the mechanism of microtubule structure destruction and podocyte injury remains unclear.

Method

Immunofluorescence and western blot were used to confirm the correlation between actin injury and decreased acetylation of tubulin in podocytes in vitro and in vivo. Single-cell RNA sequencing comprehensively characterized the expression of TPPP3 in human glomeruli. Immunofluorescence, immunohistochemical, western blot were used to determine the expression of TPPP3, α-tubulin, acetylated tubulin, actin microfilaments.

Results

In the case of podocyte injury, the acetylation level of tubulin decreased (P < 0.05). Reducing tubulin acetylation can lead to microfilaments injury (P < 0.05) and weakened podocyte motility (P < 0.05). TPPP3 was specifically expressed in human glomerular podocytes, and its expression level was significantly decreased after podocyte injury (P < 0.05). Knockdown of TPPP3 leaded to the level of microtubule acetylation decreased (P < 0.05) and microfilaments were damaged (P < 0.05) in podocytes. High acetylation levels of tubulin can partially restore actin microfilament damage caused by TPPP3 reduction in vivo and in vitro (P < 0.05).

Conclusion

TPPP3 is involved in maintaining the normal morphology and function of podocytes by stabilizing the actin microfilament skeleton structure by regulating the acetylation level of microtubules.
#2814 Characterization of cardiological manifestations in patients with sodium-wasting tubulopathies
Authors: Cirillo Luigi , Cocchini Carlotta , Raglianti Valentina , Innocenti Samantha , Landini Samuela , Errichiello Carmela , Buti Elisa , Mazzinghi Benedetta , Francesca Becherucci
Published: May 2024

Background and Aims

Bartter (BS) and Gitelman (GS) syndromes are rare tubulopathies caused by mutations affecting renal NaCl transporters, resulting in similar symptoms like muscle weakness, cramps, and electrolyte imbalances, with GS also presenting with hypomagnesemia. Treatment focuses on electrolyte and fluid balance, using supplements and drugs to inhibit prostaglandin production and RAAS activation. Electrolyte deficits in these conditions can extend the QT interval and increase the risk of potentially fatal cardiac arrhythmias.

This study aims to profile BS and GS patients followed at our hospital, focusing on cardiological phenotyping. We assessed diagnostic, clinical, and lab data, particularly examining the link between electrolyte imbalances (like hypokalemia or hypomagnesemia) and electrocardiographic changes or cardiac symptoms during follow-up.

Method

We screened all BS and GS patients for study inclusion, requiring a genetic diagnosis with disease-causing mutations and comprehensive clinical and electrocardiographic data. We excluded cases lacking sufficient data. We gathered demographic and health information retrospectively, categorizing patients based on electrocardiographic results into groups: 1) persistent long QT interval, 2) transient long QT interval, and 3) no long QT interval. Data were summarized with medians, interquartile ranges, and frequencies.

Results

A total of 27 patients were enrolled in the study, 16 with Bartter Syndrome (BS) and 11 with Gitelman Syndrome (GS); median length of follow-up was 6 years (range 3-19). Only one patient was classified in group 1, with a constant QTc prolongation (446.3 ms); 8 patients (34.8%) fell into group 2 with median QTc values of 420 ms, all exhibiting hypokalemia and hypomagnesemia. The majority (14/23, 61%) were in group 3, with a median QTc of 399.2 ms and 79% displaying hypokalemia and hypomagnesemia. All 9 patients who experienced cardiac-related symptoms were adults, with 8 presenting these symptoms during intercurrent episodes. The study also compared clinical differences between BS and GS patients, noting a higher frequency of hypokalemia and hypomagnesemia in GS, whereas BS patients had more electrocardiographic alterations, although not statistically significant. No echocardiographic abnormalities were detected from the available data, and there were no recorded incidents of malignant arrhythmias or sudden death.

Conclusion

Electrocardiographic abnormalities in BS and GS patients fluctuate, often related to episodic events, with QT prolongation in one-third of cases but no severe cardiac complications, indicating a generally positive prognosis.
#662 Characterization of novel gene mutation sites associated with autosomal dominant polycystic kidney disease on 19 chromosomes
Authors: Zhang Xiao Liang , Yang Junlan
Published: May 2024

Background and Aims

Autosomal dominant polycystic kidney disease (ADPKD) is the most common single-gene inherited kidney disorder, affecting approximately 1 in 500-1000 newborns and often leading to end-stage renal disease. It involves cyst formation in various organs, with renal manifestations including cysts, hematuria, kidney stones, proteinuria, and hypertension. Liver, pancreas, seminal vesicles, spleen, and intracranial aneurysms may also be affected.

Genetic diagnosis, particularly for patients without a family history or with atypical imaging, is considered the gold standard. ADPKD is associated with several pathogenic genes, such as PKD1 and PKD2, as well as others like HNF-1B, GANAB, DNAJB11, SEC63, ALG8, ALG9, PRKCSH, LRP5, SEC61B, and SEC63. Understanding the genetic basis is crucial for early diagnosis and identifying high-risk individuals.

This study, based on genetic data from patients with renal polycystic kidney disease at Zhong Da Hospital Southeast University, identified novel ADPKD gene mutations. It explored structural changes in proteins, predicting effects on phenotype, to contribute to the enrichment of the ADPKD gene database.

Method

In a single-center cross-sectional retrospective study, patients with renal multiple cysts diagnosed from January 2019 to February 2023 at the Zhong Da Hospital Southeast University were included. Genetic and clinical data of patients and their families were collected. Unreported novel gene mutation sites associated with ADPKD were identified, and AlphaFold v2.3.1 was employed to predict protein structures. Changes in protein structure before and after mutations were compared to explore genotype-phenotype correlations and enrich the ADPKD gene database.

Results

The study included 96 patients with renal multiple cysts and their relatives from 62 families. Twelve mutated genes associated with renal cysts were detected in 52 families. Nineteen novel gene mutation sites associated with ADPKD were identified (Table 1, Fig. 1) , including 17 mutations in the PKD1 gene (1 splicing mutation, 7 frameshift mutations, 4 nonsense mutations, 1 whole-codon insertion, and 4 missense mutations), 1 ALG9 missense mutation, and 1 chromosomal structural variation. Truncating mutations in the PKD1 gene were correlated with a more severe clinical phenotype, while non-truncating mutations were associated with greater clinical heterogeneity.

Conclusion

Numerous novel gene mutation sites associated with ADPKD remain unreported. It is essential to analyze the pathogenicity of these novel mutation sites, establish genotype-phenotype correlations, and enrich the ADPKD gene database.
#1232 Integrating genotype and phenotype data is required for renal survival prediction in autosomal dominant polycystic kidney disease
Authors: Evangelou Eirini , Konsta Maria , Vasileiou Kyriaki , Poula Angeliki , Markou Niki , Poulli Tsielestina , Lazaros Leandros , Gkalitsiou Dimitra , Liaveri Paraskevi , Tsirpanlis George
Published: May 2024

Background and Aims

Autosomal dominant polycystic kidney disease (ADPKD) is the cause for 5-10% of end stage kidney disease (ESKD) worldwide. Accurate renal prognosis is essential for effective disease management. Investigation of the prognostic value of combining genetic and phenotypic characteristics in a cohort of ADPKD patients is attempted.

Method

In 66 ADPKD patients (mean age 33 ± 12 years, 32 males) the genetic diagnosis (using targeted Next Generation, tNGS, or Sanger Sequencing or Multiplex ligation-dependent probe amplification, MLPA) and the Mayo Clinic Imaging Category (MCIC) (through Renal Magnetic Resonance Imaging, MRI, for Total Kidney Volume measurement) were assessed. The prediction of ESKD was performed using the Mayo Clinic formula (Irazabal MV et al JASN, 2015). The calculation incorporated variables such as sex, age, e-GFR, and the MCIC. The PROPKD score was derived by considering both phenotypic factors (sex, hypertension and urologic events before the age of 35 years) and genetic data (PKD1-truncating, PKD1-nontruncating and PKD2).

Results

Adjusted for age, the e-GFR was on average, 26 and 27 ml/min higher in PKD2 patients compared to ADPKD-PKD1-truncating and ADPKD-PKD1-non-truncating patients, respectively (p = 0.001). The median prediction of ESKD for ADPKD-PKD1-truncating, ADPKD-PKD1-non-truncating and PKD2 patients was 22 (11-31) years, 22 (11-34) years and 31 (21-59) years, respectively (NS). In patients categorized as high risk according to PROPKD (score 7-9) the predicted time to ESKD was 16 (9-30) years, for those at intermediate risk (score 4-6), 25 (13-34) years and for those at low risk (score 0-3), 28 (16-55) years (NS). Finally, the PROPKD score showed an inverse correlation to the years of ESKD prediction, as determined by the Mayo Clinic formula; a higher PROPKD score was associated with a shorter prediction period for ESKD (Spearman r = −0.3, p = 0.04).

Conclusion

Prognosis of renal survival in ADPKD patients requires not only a specific genetic diagnosis but also consideration of the phenotypic data, as incorporated in the PROPKD score, enhancing the accuracy of renal survival prediction.
#817 Genetic analysis in a group of patients with persistent isolated microscopic hematuria
Authors: Sevillano Angel , Bada Teresa , Trujillo Hernando , Alonso Marina , Corona Clara Cases , Shabaka Amir , Gutiérrez Eduardo , Juarez Gema Maria Fernandez , Caravaca-Fontán Fernando , Praga Manuel
Published: May 2024

Background and Aims

Autosomal dominant Alport syndrome (ADAS) is a genetic disease caused by pathogenic variants in COL4A3 and COL4A4 genes. ADAS is the main cause of isolated persistent microscopic hematuria (PMH). However, other diseases like IgA nephropathy (IgAN) can present with PMH. Establishing a precise genetic diagnosis in this type of patients would avoid invasive studies like kidney biopsies. In this study we performed a comprehensive genetic test in a cohort of patients with isolated PMH to evaluate the frequency of ADAS or other genetic abnormalities and compare the clinical characteristics of patients with or without ADAS

Method

Fifty-two patients with PMH were included in the study. PMH was defined by the presence of 3 or more dysmorphic red blood cells per field in at least 5 consecutive urine sediments and a time-averaged proteinuria <1 gr/day. Average proteinuria was determined for every 6 months of follow-up and time-averaged (TA) proteinuria represented an average of the mean proteinuria measurements in each 6-month period. A comprehensive genetic study using whole exome next-generation sequencing was performed. One hundred and one genes related to familial hematuria, focal segmental glomerulosclerosis and cystic kidney diseases were analyzed. Patients with known secondary causes of hematuria were excluded. The baseline clinical characteristics of patients with and without ADAS were compared. Patients with pathogenic variants in COL4A5 gene were excluded of this analysis.

Results

Thirty-one (60%) patients were diagnosed with ADAS (16 patients with pathogenic variants in COL4A3, 15 in COL4A4), 3 (6%) patients (2 women, 1 man) presented pathogenic variant in COL4A5 gene, and the genetic study was negative in the remaining 18 patients (variants of unknown significance in COL4A3 or COL4A4 were found in 3 of the latter). No other genetic abnormalities were detected in the panel of 101 genes. Table 1 shows the baseline clinical characteristics of patients with and without ADAS. Patients with ADAS presented a higher TA proteinuria [0.23 (0.11-0.6) vs 0.08 (0.05-0.16), p = 0.01], and a more frequent familial history of isolated microscopic hematuria (76% vs 40%, p = 0.01) chronic kidney disease (CKD) (44% vs 0%, p = 0.01) or end stage kidney disease (32% vs 0%, p = 0.02). In the multivariate analysis, only a family history of microscopic hematuria was associated with ADAS: OR 5.62 (1.25-25.49, p = 0.02).

Conclusion

ADAS is the most common cause of PMH. A genetic study should be the first diagnostic step in order to obtain a precise cause of the disease and avoid invasive procedures. A family history of microscopic hematuria and of CKD increases the likelihood of ADAS prior to the performance of genetic test.
#1460 Targeting cyst progression: evaluation of anthelmintic and proton pump inhibitor in a rodent PKD model
Authors: Clanget Tilmann , Heigwer Jana , Bierhoff Kim , Tabatabaeifar Mansoureh , Schaefer Franz
Published: May 2024

Background and Aims

In polycystic kidney disease (PKD) cyst formation and growth leads to progressive kidney damage. Recognizing the need for effective cyst-inhibitory drugs, we previously performed high-content screening of approved, repurposable drugs in a zebrafish model and identified several compounds with cyst-inhibitory activity and low toxicity. Here, we further tested two of the identified compounds, an anthelmintic agent and proton pump inhibitor, in a rodent model of PKD (PCK rat) for their cyst inhibitory and GFR-preserving capacity in mammals.

Method

The identified compounds were administered to 3-week-old male and female PCK rats for a total of 10 weeks to evaluate early drug effects on kidney function. Untreated PCK rats fed a normal ROD16 diet served as controls. After 5 weeks of treatment, total kidney and cystic volume and number of cysts were assessed in vivo by ultrasound. Following 10 weeks of treatment, kidney function was assessed by transcutaneous measurement of FITC-Sinistrin. After perfusion fixation in the same week, the kidneys, liver, heart, and pancreas were harvested for subsequent histological and molecular biological analyses.

Results

In male rats, 5-week proton pump inhibitor treatment was associated with a 50% reduction in the number of cysts (p < 0.05) and a nominal 22% reduction of fractional cystic kidney volume (CKV). Females showed a 16% reduction in cyst count and a modest reduction in fractional CKV. Treatment with the anthelmintic tended to reduce fractional CKV and cyst count in female animals whereas fractional cyst volume in males increased. After 10 weeks of treatment, a trend towards better preservation of GFR was observed for both therapies.

Conclusion

In conclusion, our study demonstrates a potential therapeutic benefit of a proton pump inhibitor and an anthelmintic agent in attenuating the progression of polycystic kidney disease (PKD) in a PCK rat model. The observed reductions in fractional cystic kidney volume and cyst count, coupled with marginal improvements in renal function, document a potential therapeutic effect of these compounds. Our preliminary findings justify further exploration of novel treatment modalities targeting cyst progression and renal dysfunction in this challenging clinical condition.
#1504 Performance evaluation of MicroVue sC5b-9 for analysis of urine samples
Authors: Hulsebus Holly , Gorzkowski Eric , Galvan Manuel
Published: May 2024

Background and Aims

Complement mediated kidney diseases including C3 glomerulopathy (C3G), atypical uremic syndrome (aHUS), lupus nephritis (LN), and immunoglobulin A nephropathy (IgAN) are chronic inflammatory conditions characterized by dysregulated complement activation. Traditionally, complement activation is measured in plasma. However, patients with kidney disease often have an abundance of complement activation fragments in their urine—including soluble C5b-9 (sC5b-9), a marker of terminal pathway activation—highlighting the potential value of sC5b-9 measurement in urine for diagnosis and risk management in patients with C3G, aHUS, LN, IgAN, and other kidney diseases. Herein we evaluated the analytical performance of the Quidel MicroVue sC5b-9 Plus EIA for measurement of sC5b-9 in urine.

Method

The Quidel MicroVue sC5b-9 Plus EIA was evaluated using randomly collected healthy urine samples or healthy urine samples spiked with a known concentration of sC5b-9, as well as chronic kidney disease (CKD) urine samples.

Results

The analytical performance of the Quidel MicroVue sC5b-9 Plus EIA for measurement of sC5b-9 in urine met acceptability criteria for accuracy and precision. Assay accuracy was (100 ± 20%) and intra-assay precision as well as inter-assay precision was ≤ 11% coefficient of variability (CV). sC5b-9 was not detected in healthy urine samples (N = 40), but sC5b-9 was detected in a subset of urine samples from patients with CKD (N = 10). Positive linearity was observed over a wide range of concentrations. sC5b-9 measured in urine was not affected by hemoglobin or triglyceride, and was stable following three freeze-thaw cycles. Lastly, sC5b-9 measured in urine was stable when stored at −20°C and –80°C for 4 weeks. Long term stability testing at –80°C is underway.

Conclusion

Quidel MicroVue sC5b-9 Plus EIA is an accurate, reliable assay for detection of sC5b-9 in urine samples.
#1355 Albuminuria after Induction Treatment and Kidney Prognosis in ANCA-associated Glomerulonephritis
Authors: Chalkia Aglaia , Jones Rachel B , Smith Rona M , Willcocks Lisa , Jayne David R W
Published: May 2024

Background and Aims

Persisting proteinuria has been associated with worse kidney outcomes in ANCA-associated glomerulonephritis (AAGN). However, it remains unclear whether this reflects damage from the initial injury or ongoing inflammation.

Method

A retrospective, single centre study of biopsy-proven AAGN. The group “albuminuria” was defined as urine albumin-to-creatinine ratio (ACR) more than 300 mg/g and the group “no albuminuria”, defined as ACR less than or equal to 300 mg/g at 6 months. We sought the clinical and histopathological characteristics from both the initial and any subsequent biopsies, and long-term kidney outcomes stratified by albuminuria levels.

Results

218 patients were included. Within the first six months, 28 (13%) had either died or progressed to end-stage kidney disease (ESKD). Among the remaining 190 patients, 37% had an ACR>300 mg/g at 6 months. The albuminuria group more frequently presented with a Berden mixed or crescentic class and had higher glomerular activity on the initial biopsy. They were also more often male [odds ratio (OR) 2.69; 95% CI 1.13-6.41], of younger age (OR 0.96; 95% CI, 0.93 to 0.99) and had fewer normal glomeruli in the biopsy (OR 0.96; 95% CI, 0.93 to 0.99) compared to the group without albuminuria. Over the initial 5-year period, the recovery in glomerular filtration rate (GFR) was lower in the albuminuria group (adjusted mean difference in delta GFR −12.5 ml/min per 1.73 m2; 95% CI, −15.8 to −9.1). In multivariable analysis, ACR greater than 300 mg/g was associated with a higher risk of ESKD, even after adjusting for age, Berden classification and GFR at diagnosis (Hazard ratio 7.25; 95% CI, 1.62 to 32.47).

Conclusion

In a well-defined cohort of AAGN, one third of the patients, primarily younger males with a lower percentage of normal glomeruli, had persisting albuminuria after induction treatment which was associated with worse kidney outcomes independent of Berden class and GFR at diagnosis.
#1774 ANCA vasculitis with renal involvement: age as a prognostic factor
Authors: Talavera Andrea Cifuentes , Subiela José Enrique Ruiz-Cabello , Wang Yali Chen , Galindo-Izquierdo María , González Javier García , Ruiz Enrique Morales
Published: May 2024

Background and Aims

Older patients with antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) commonly experience renal impairment and poor prognosis. The European Vasculitis Study Group trials showed that approximately 16.7% and 22.5% of older patients with AAV suffered from end-stage renal disease (ESRD) in 5- and 10-year durations. The aim of this study was to analyze differences in course and outcome of patients with AAV with respect to age.

Method

This retrospective observational study included patients with diagnosis of AAV and biopsy proven renal involvement between 2000-2021. Patients were divided into two groups according to age: ≥65 or <65 years old. We recorded baseline characteristics and clinical data during follow-up. Response was defined as a BVAS reduction of at least 50% or BVAS of 0, while receiving prednisone dose higher than 4 mg; and remission as BVAS of 0 while receiving prednisone dose of 4 mg or less.

Results

We included 42 patients with AAV diagnosis, 47.6% of which were 65 years-old or older. Mean age of the older age group was 77 ± 8 years. No differences were found between older and younger patients at baseline (BVAS, FFS extra-renal symptoms, serum creatinine at diagnosis, hematuria), Patients > 65 years were significantly more likely to present p-ANCA positive MPA, as shown in Table 1.

There was no difference in initial or maintenance immunosuppressive therapy between the two groups. No differences were found between older and younger patients with regard to treatment response. Although we found no statistical differences, older patients had worse renal outcomes. The older adult group had a higher mortality rate, p 0.01. The average time to death was 27 months for patients over 65 years and 34.5 in those who were younger (p 0.71).

Conclusion

No differences were found between older and younger patients with regard to treatment response. However, mortality was higher during follow-up in the group of older patients. Our results suggest that more attention should be paid to older patients with severe renal impairment.
#326 Features of intrarenal hemodynamics in patients with chronic glomerulonephritis on the background of taking anticoagulants
Authors: Abduvakhitova Asalya
Published: May 2024

Background and Aims

Chronic glomerulonephritis (CGN)-glomerular, autoimmune kidney disease, where baseline therapy is clinically proven to be successful. The study evaluates hemodynamic disorders of renal blood flow in patients with CGN on the background of baseline treatment with the inclusion of rivaroxaban.

Method

We researched108 patients CGN against the background of 3-month basic therapy with the inclusion of rivaroxaban (group AC+, 55 patients) and without anticoagulant (group AC-, 53 patients). Initial and after 3 months evaluation in the mode of color Doppler mapping and pulse-wave doppler.

Results

In the course of 3-month therapy, the performance of dopplerography of renal arteries in patients with CGN did not change reliably. But there was a credible and clinically significant increase in the systolic blood flow rate at the level of the Interregional Artery (IA), both compared to the baseline data and towards the end of hospitalization (by 9.27 2.58% p < 0.001 the validity of the difference with the raw data, by 8.60 2.53%, p < 0.01 with the 10th day of therapy), remaining reliably lower than in control group (p < 0.001). The speed at the arc artery (АА) also increased slightly (by 2.46 1.03%, p < 0.05 reliability of the difference with the original data and the end of hospitalization), but although statistical reliability was achieved, the dynamics was clinically insignificant and was less than 2.5%. The resistivity index (RI) at both IA and AA levels did not change reliably.

Conclusion

In CGN patients, intrarenal hemodynamics change with decreased blood flow rates in IA and AA. In the future, against the background of 3-month basic HGH therapy, there was some improvement in blood flow at the IA level but not AA, but no qualitative changes in intrarenal hemodynamics were achieved. The supplementation of long-term anticoagulation therapy with rivaroxaban has increased the effect of therapy on hemodynamic rates, resulting in some improvement in blood flow at both IA and AA levels, but no qualitative improvement has been achieved, possible due to pronounced structural remodeling of kidney vessels in patients with CGN.
#1864 Phosphorilation of SHP-1 switch does not indicate lupus nephritis activity
Authors: Vajgel Gisele , Nascimento Denise Queiroga Do , Junior Braziliano Silva , Oliveira Camila , Castoldi Ângela , Lima Camilla , Souto Fabricio Oliveira , Valente Lucila , Salama Alan , Sandrin-Garcia Paula
Published: May 2024

Background and Aims

Protein tyrosine kinases (PTKs) are enzymes responsible for the phosphorylation of tyrosine residues in lymphocytes. In 2017, Mkaddem et al. suggested that unique PTK signatures in peripheral leukocytes (PBMC) are associated with lupus nephritis (LN) activity [1]. Lymphocytes express two important PTKs, Lyn and Fyn, that modulate inhibitory or activatory signals depending on ligand avidity or phosphorylation status. SHP-1 tyrosine 536 phosphorylation (pSHP1-Y536) by Lyn activates inhibitory signaling and Fyn-dependent phosphorylation of SHP-1 serine 591 (pSHP1-S591) inactivates the phosphatase, enabling activatory immunoreceptor signaling. We hypothesized that active and refractory patients with proliferative LN have a different PTK profile in PBMC, with lower expression of pSHP1-Y536 and greater expression of pSHP1-S591, in comparison with those who have responded to treatment.

Method

In a cohort from the Royal Free Hospital, UCL (London, UK) we performed western blotting of PBMC lysates for SHP1-phospho-S591 and-Y536 from healthy individuals (HC; n = 19), LN patients in remission (n = 11) and with ongoing disease activity (n = 4). Densitometry of bands was carried out and a ratio of S591:Y536 expression was calculated (both normalized to actin). For the flow cytometry analysis, we followed up a Brazilian cohort of LN (n = 24) from Hospital das Clinicas, UFPE (Recife, Brazil). All patients had ongoing active LN with initial renal biopsy (class III, IV or/and V). PBMC samples were collected at 0, 3, 6, 9, 12, 18, and 24 months after biopsy. Isolated PBMC samples were stored at −80°C. PBMC samples were stained with antibodies against pSHP1 S591 and p-SHP1 Y536 and cell viability was checked using zombie red dye. Samples were acquired on the Accuri C6 cytometer (BD) and analyzed using the FLOJO software (BD).

Results

The western blotting relative expression of pSHP-1 S591:Y536 in PBMC was not significantly different when we compared HC with active LN (p = 0.098) and active with remission LN (p = 0.10), Fig. 1. The results obtained by flow cytometry expression ratio of pSHP1-S591:Y536 did not show a significant correlation with the median of proteinuria (Fig. 2), C3, C4, or SLEDAI from time of active kidney biopsy during LN flare throughout induction treatment.

Conclusion

There was no expression pattern of pSHP-1 Y536 and S591 in PBMC of LN patients, regardless of their renal activity or inflammatory status. Therefore, we cannot state those markers as a potential “liquid biopsy” for LN.
#1644 Prognostic significance of hematuria on kidney survival in podocytopathies
Authors: Stefan Gabriel , Simona-Mihaela Cinca , Zugravu Adrian Dorin , Petre Nicoleta , Stancu Simona
Published: May 2024

Background and Aims

Hematuria is common in podocytopathies, but its prognostic impact on kidney survival in these proteinuric diseases is not well-established. Our study examines the prevalence of hematuria at podocytopathy diagnosis and its association with renal survival.

Method

In our retrospective study, we analyzed 236 patients (median age 50 years, 60% male, median eGFR 65.5 mL/min/1.73 m2, median proteinuria 3.9g/g) with biopsy proven podocytopathies—48% membranous nephropathy (MN), 32% minimal change disease (MCD), 20% focal and segmental glomerulosclerosis (FSGS)—diagnosed at a tertiary center from 2010 to 2015.

Hematuria was defined as the presence of 5 or more red blood cells (RBCs) per high-power field in 3 of 3 consecutive centrifuged urine specimens obtained at least 1 week apart.

The follow-up period extended until the onset of end-stage kidney disease (ESKD: start of kidney replacement therapy or renal transplantation), death, or January 2022, with a median duration of 8.5 (95% CI: 8.1, 8.8) years.

Results

In our patient cohort, 31% (n = 73) presented with hematuria, having a median of 120 (IQR: 40-220) red blood cells (RBCs). Those with hematuria more frequently exhibited arterial hypertension (55% vs 36%, p 0.007) and had higher levels of proteinuria (5.3 vs 3.2g/g, p 0.01). However, no significant differences were noted in terms of age (53 vs 48 years, p 0.08), Charlson comorbidity score (2 vs 2, p 0.9), type of podocytopathy (MN 52 vs 47%, MCD 27 vs 34%, FSGS 21 vs 19%, p 0.5), eGFR (62.1 vs 68.8 mL/min, p 0.08), serum albumin levels (3.3 vs 3.4g/dL, p 0.6), total renal chronicity score on histology (0 vs 0, p 0.6), and treatment with ACE inhibitors/angiotensin receptor blockers (43% vs 50%, p 0.4) or immunosuppression (81% vs 74%, p 0.4).

Thirty-two percent of the patients with hematuria reached ESKD versus 9% in the group without hematuria (p 0.001); there were no differences regarding mortality between the two groups.

Mean kidney survival time for the entire cohort was 10.3 (95% CI: 9.9, 10.8) years; renal survival at 1, 3, 5 and 10 years were 97%, 92%, 88% and 82%, respectively. Patients with hematuria at diagnosis had a significant shorter kidney survival time (9.0 (95% CI: 8.0, 10.0) vs 11.0 (95% CI: 10.6, 11.4) years, p 0.001).

In a multivariate Cox proportional hazard model (backward Wald), presence of hematuria at diagnosis (HR 3.64, 95% CI: 1.87, 7.07), lower eGFR (HR 0.96, 95% CI: 0.94, 0.97) and higher total renal chronicity score on histology (HR 1.10, 95% CI: 1.00, 1.22) were independent predictors of reduced kidney survival.

Conclusion

Hematuria is prevalent in the three podocytopathies and independently correlates with poorer kidney survival outcomes. This underscores the possible need for personalized treatment strategies in patients with podocytopathies presenting with hematuria.