bluuebunny/crossref_metadata_2025 huggingface dataset:
#1091 Quantifying the potential contribution of drugs to the occurrence of acute kidney injury in patients with chronic kidney disease
Authors: Liabeuf Sophie , Massy Ziad , Gras-Champel Valérie , Frimat Luc , Laville Maurice , Jacquelinet Christian , Pecoits-Filho Roberto , de Pinho Natalia Alencar , Hamroun Aghilès , Laville Solene M
Published: May 2024

Background and Aims

Patients with CKD have high risk of AKI. Quantifying the contribution of drugs to the occurrence of AKI in this population and assessing its risk factors is important to design preventive interventions. We sought to comprehensively describe drug-related components associated with AKI in patients with CKD. We documented the incidence of drug-related AKI, the proportion of preventable AKI, identified the various drugs potentially associated with it, explored the risk factors, and assessed the one-year incidences of the recurrence of drug-related AKI, kidney failure, and death.

Method

The CKD-REIN study is a national prospective cohort of 3,033 nephrology outpatients with a confirmed diagnosis of CKD (eGFR <60 mL/min/1.73 m²) in France. AKIs and adverse drug reactions (ADRs) were prospectively identified from hospital charts, medical records, and patient interviews. Nephrologists used the Kidney Disease: Improving Global Outcomes criteria to adjudicate all stages of AKI, and expert pharmacologists used validated tools to adjudicate ADRs (including drug-related AKIs). A drug-related AKI was considered serious when the outcome is death, a life-threatening situation, hospital admission, disability, permanent damage, or another important medical event. We used cause-specific Cox proportional hazard models to investigate the patients’ baseline clinical characteristics associated with the risk of drug-related AKI.

Results

Over a median [interquartile range] period of 4.9 [3.4-5.1] years, 832 cases of AKI were reported in 639 (21%) of the 3,033 study participants. Over a quarter of the AKI events were drug-related (n = 236, 28%); from those, 47% were hospital- and 53% community-acquired AKI. From the 168 serious drug-related AKI events, 28% were considered preventable or potentially preventable. The three most frequently implicated drug classes were diuretics, renin-angiotensin system inhibitors, and contrast agents. At least two concomitant medications were implicated in more than half of the AKIs with a drug-related component, RASis and diuretics, two diuretics, and diuretics and antibiotics were the 3 most frequent associations (Figure). A history of cardiovascular events, and the presence of diabetes, lower levels of hemoglobin and eGFR, poor medication adherence, and ≥5 drugs being taken daily were associated with a greater risk of drug-related AKI. The one-year cumulative incidences of recurrent drug-related AKI, kidney replacement therapy, and death were 7%, 15%, and 11%, respectively, after the first drug-related AKI.

Conclusion

Drug-related AKI is prevalent among patients with CKD. Further training in drug management for both CKD patients and healthcare professionals involved in their care might mitigate the incidence of drug-related AKI.
#2593 Comparison of four predictive scoring models as assessment tools for cardiac surgery-associated acute kidney injury in post cardiac surgery patients
Authors: Iway Cathleen
Published: May 2024

Background and Aims

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a predominant contributor to hospital-acquired AKI in ICU following sepsis. Despite a rising frequency of CSA-AKI, currently examined predictive models have not consistently delivered accurate stratification. Utilizing risk stratification systems offers clinicians the opportunity to identify patients at high risk, extend monitoring intervals, facilitate timely referral to nephrology services, and promptly initiate effective preventive and therapeutic interventions known to enhance renal function. This study seeks to identify the most effective model by comparing four established predictive scoring systems.

The objective of this single-center retrospective, cross sectional study is to compare the clinical values of the Cleveland Clinical Score, Mehta Score, Simplified Renal Index and Acute Kidney Injury following Cardiac Surgery (AKICS) Score in predicting CS-AKI among patients who underwent cardiac surgery.

Method

A comprehensive examination of medical records was conducted for all individuals who underwent open-heart surgery between January 2010 and January 2019. Those patients who had CSA-AKI were subsequently identified. These identified individuals underwent assessment using the four predictive scoring models, leading to their categorization into high or low-risk groups for AKI development. Binary logistics regression was then used to describe the association between CSA-AKI development and the four scoring methods as predictors.

Results

Among the 114 cases of open-heart surgeries, 86 were eligible for inclusion in the study. Half of the patients, specifically 43 individuals (50%), developed CS-AKI, with 5 requiring renal replacement therapy. Among the four scoring methods evaluated, only the Mehta score (95% CI, p 0.019) and AKICS score (95% CI, p 0.011) demonstrated statistical significance in predicting CS-AKI. The odds ratios for both the Mehta Score (1.10) and AKICS Score (1.19) exceeded 1, suggesting that an increase in either score is associated with a higher likelihood of AKI occurrence. Conversely, the Cleveland Clinical Score (p 0.106) and Simplified Renal Index (p 0.399) were not found to be predictive.

Conclusion

In this single-center study, both the Mehta score and the AKICS scoring system demonstrated predictability for AKI after open-heart surgery. However, the Cleveland Clinical Scoring and Simplified Renal Index did not exhibit predictive capability in this context.
#2564 Terlipressin given by continuous infusion versus boluses in the treatment of hepatorenal syndrome: a systematic review and meta-analysis
Authors: Villavicencio Jayson , Panganiban Bea Regine , Villanueva Cary Amiel , Lao Janice Jill
Published: May 2024

Background and Aims

Hepatorenal syndrome (HRS) is one of the complications among patients with cirrhosis. Available guidelines recommended terlipressin with albumin as part of HRS management. To date there is no consensus on whether terlipressin should be given via bolus or continuous intravenous infusion. This study aims to compare the effectiveness and safety of continuous intravenous infusion versus intravenous boluses of terlipressin in the treatment of patients with HRS and cirrhosis.

Method

A comprehensive search for databases of randomized controlled trials (RCTs) comparing continuous intravenous infusion versus intravenous boluses of terlipressin among adult patients with hepatorenal syndrome was done. PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov were searched using relevant terms including hepatorenal syndrome, acute kidney injury, cirrhosis, terlipressin, bolus, and continuous infusion until December 2023. Response to therapy defined as decrease in serum creatinine or regression of acute kidney injury was the primary outcome of interest, while safety in terms of drug-related events, mortality, and transplant-free survival were the secondary outcomes. Data extraction was performed using a standardized data form. The reviewers independently screened the studies and assessed the methodological quality using the Cochrane Risk of Bias tool and any discrepancies were resolved by consensus among the authors. Random-effects meta-analysis was done using Review Manager 5.4.

Results

A total of three studies, one high quality and two moderate quality RCTs, were included in the review, involving a total of 240 patients. Pooled analysis showed that continuous infusion was as effective or better than bolus infusion in achieving the primary outcome (RR 1.12, 95% CI 0.95-1.32, I2 = 0%). In one study, 28- and 90-day mortality were not significantly different, while 90-day transplant-free survival was not significantly different between continuous and bolus groups from another trial (53% vs 69% p = 0.26). Higher incidence of adverse events were also reported in the bolus group, RR 0.37, 95% CI 0.13-1.04 (p = 0.06).

Conclusion

There is limited evidence to suggest that continuous infusion of terlipressin may demonstrate resolution of acute kidney injury more frequently than bolus infusion, and that continuous infusion is associated with decreased adverse events. Larger randomized controlled trials with higher quality are needed to ascertain the effects on mortality, need for renal replacement therapy, and transplant-free survival.
#59 Fibroblast Growth factor 23 for prediction of outcome in community-acquired acute kidney injury: a prospective observational study
Authors: Elkot Mahmoud , Sayed-Ahmed Nagy , Ahmed  , Nassar Mohammed Kamal
Published: May 2024

Background and Aims

Serum FGF23 level has been found to be elevated in AKI through multiple previous studies. Moreover, higher FGF23 level was associated with mortality and adverse outcomes in critically ill patients and patients undergoing cardiac surgery who developed AKI suggesting that FGF23 can have a prognostic value in AKI. The current study aims to investigate the association of serum FGF23 levels with morbidity and mortality in patients with community-acquired AKI.

Method

A longitudinal prospective study was carried out that included 64 patients who presented with community-acquired AKI to Mansoura Nephrology and Dialysis Unit (MNDU) at Mansoura University Hospital. Serum intact FGF23 level was measured after admission. patients were followed up during hospital stay and then at 90-day after admission. The primary outcomes were hospital and 90-day mortality and renal recovery.

Results

In this study, nine of the studied 64 AKI patients (14.1%) died during hospital admission and 18 out of 62 AKI patients (29%) died during the 90-day follow up period including those who died during hospital admission. Hospital mortality was significantly higher in patients with shock, sepsis, hypoalbuminemia, or high FGF23 in univariate analysis (p < 0.05). However, when binary logistic regression was carried out, shock was the only significant independent predictor for mortality [p value = 0.015; adjusted odds ratio = 12.465], while serum FGF23 did not independently predict in-hospital [p value = 0.589; adjusted odds ratio = 1.001] or 90-day mortality [p value = 0.055; adjusted odds ratio = 1.003] when entered in the regression equation together with the other confounders. Serum FGF23 in this study was not also associated with renal recovery, need for renal replacement, or the duration from peak serum creatinine to renal recovery (p > 0.05).

Conclusion

This research showed that serum iFGF23 could not predict mortality, renal recovery, or need for renal replacement therapy in patients with community-acquired AKI.
#2136 Hyponatremia as a presenting symptom of secondary adrenal insufficiency induced by immune checkpoint inhibitors
Authors: Glezerman Ilya
Published: May 2024

Background and Aims

Endocrinopathies are common complication of treatment with immune checkpoint inhibitors (ICI). Adrenal axis may be affected through either direct adrenal toxicity leading to primary hypoadrenalism or due to pituitary dysfunction resulting in secondary adrenal insufficiency. Patients with secondary insufficiency may have variable presentation and, in some cases, initially present with hyponatremia only. This abstract reports a cohort of patients who developed hyponatremia as initial symptom of secondary adrenal insufficiency.

Method

After obtaining approval from the institutional review board, medical records of the nephrology service at a large cancer center were reviewed. Patient is well included in the study if they developed moderate (plasma Na <130 mEq/L) and severe (plasma Na <120 mEq/L) hyponatremia during treatment with ICI and met a biochemical criterion for adrenal insufficiency (morning serum cortisol level <3.0 mcg/dL).

Results

Nine patients who met the criteria were identified (Table 1). There were 5 males and four females. Mean age was 67.6 year. Median number of ICI therapy cycles was 10 but treatment number ranged from 2-84. For patient's would treat with combination of CTLA-4 and PD 1 inhibitors and 5 patients were treated with PD 1 inhibitor alone. Four patients had severe hyponatremia and five presented with moderate hyponatremia. All patients were normotensive on presentation. All patients had low morning cortisol level but only two patients had low ACTH level. All patients had low normal ACTH levels. One patient underwent ACTH stimulation test which was negative. Additionally for patient has had normal thyroid function. Eight patients underwent an MRI and 4 of them had evidence of possible pituitary inflammation. All patients were started on physiologic corticosteroid replacement with prompt resolution of hyponatremia. All patients required ongoing corticosteroid replacement therapy.

Conclusion

Secondary adrenal insufficiency in the setting of ICI toxicity can present with initial diagnosis of hyponatremia. Patients in this cohort were normotensive on presentation despite adrenal insufficiency and therefore required high index of suspicion for the diagnosis. Most patients in the study also had low normal ACTH levels however responded clinically to treatment with corticosteroid replacement indicating that adrenal sufficiency was the cause of hyponatremia. ACTH test may be falsely negative in these patients if adrenal insufficiency developed less than six weeks prior and adrenal atrophy did not occur yet.
#1651 Urinary oxygen partial pressure: closely associated with hourly urine output induced by furosemide in patients with acute renal injury
Authors: MA Yixin , Yuan Siyi , Hu Rongrong , Chen Ronping , Chen Limeng
Published: May 2024

Background and Aims

Urine oxygen level, an indicator of kidney medullar oxygenation, is promising for predicting the onset of acute kidney injury (AKI). Furosemide, a commonly used diuretic in ICU, significantly increases urine output and is believed to change kidney medullar oxygenation. We monitored the longitudinal change of urinary oxygen partial pressure during bolus or pump administration of furosemide, aiming to describe the reaction pattern in an AKI-susceptible patient population.

Method

The prospective observational pilot study included seven adult patients in the ICU because of cardiac surgery or sepsis. We monitored the continuous urinary oxygen partial pressure for 8-24 hours through a device placed between the urinary catheter and collecting bag during furosemide administration, recorded hourly urine output simultaneously from a urine bag, and followed the patients in the hospital for the onset and development of AKI.

Results

We recruited three female patients and four male patients with an average age of 54 years and a medium of 5 days in ICU with an AKIN stage I of AKI during their hospital stay. None of them developed more severe stage AKI or required any kidney replacement therapy. We found a reverse correlation pattern between hourly urine output and urinary oxygen partial pressure. Specifically, the urine oxygen level dropped during urine volume increase caused by furosemide bolus administration and abolished by furosemide administration through a pump with more stable urine output. The paired t-test showed a significant increase in average urine oxygen level (mean difference = 21.2 mmHg, p = 0.044) recorded during the “high hourly urine output” period compared to the “low hourly urine period”.

Conclusion

We first found a drop in urinary oxygen partial pressure during the high urine output period elicited by bolus furosemide administration. It shed light on the confounding factors in AKI predicating during possible furosemide administration.
#2232 Personalized kidney replacement therapy in critically ill patients: unity makes strength!
Authors: Castro Ana , Dias Bruno Fraga , Sala Inês , Braga Beatriz Gil , Fernandes João , Queirós José , Freitas Cristina
Published: May 2024

Background and Aims

The complexity of the critically ill patient with kidney disease has increased in recent years. A holistic and multidisciplinary approach is, therefore, necessary in order to provide the best therapeutic guidance. Multiple modalities of kidney replacement therapies (KRT) are available in this setting, namely continuous kidney replacement therapies (CKRTs) and hybrid therapies, also such as sustained low-efficiency dialysis (SLED) and slow continuous ultrafiltration (SCUF). These techniques can be used in conjunction with other extracorporeal clearance therapies such as plasmapheresis (PF), and immunoadsorption (IA). Their prescription must be individualized according to the characteristics of each patient. In our hospital all KRT and extracorporeal techniques used are reviewed daily by a nephrologist. This study aims to describe the 20-year experience of our centre in individualized KRT prescription in intensive care.

Methods

A retrospective cohort, single centre study was conducted. We reviewed adult patients (age ≥18 years) admitted in all the ICUs of our hospital centre between January 2002 and December 2022, who required a KRT.

We aimed to describe demographic data, different stages of kidney disease [AKI, AKI in CKD, chronic hemodialysis (HD), peritoneal dialysis (PD), kidney transplant (KT), rapidly progressive kidney failure (RPKF), other causes], the KRT used and the main outcomes.

Results

During the study period, 1578 patients who required a KRT were admitted to the ICU. Median age was 65 (IQR: 45-81) years old and 59.9% were male. Among these patients 715 (45.3%) had AKI, 380 (24.1%) were in HD, 315 (20%) had AKI in CKD, 130 (8.2%) had a KT and 31 (2%) were in PD. Four patients had RPKF and 3 patients had other causes for KRT, such as hyperammonemia and sodium valproate poisoning. The main KRT performed were: SLED—1365 (86.5%) patients; continuous venovenous hemodiafiltration (cvvHDF)—120 (7.6%) patients; SLED + cvvHDF—66 (4.2%). Other KRT executed were SLED + PF (11 patients), continuous venovenous hemofiltration (cvvHF) (8 patients) and SCUF (2 patients). Among all patients mortality rate was 42.3%, 33% had renal recovery and 7.4% started chronic HD. In AKI group the median age was 64 (IQR: 48-80) years and 56.3% were male. 576 (80.7%) performed SLED, 91 (12.7%) did cvvHDF and 36 (5.0%). Mortality rate was of 52.1%, renal recovery 45% and 2.9% started chronic HD.

Conclusion

Our ICU multidisciplinary approach model with a critical care nephrology specialists team translates into a large amount of accumulated experience with SLED. Our results are comparable to centres that predominantly use CKRTs. The range of different techniques used reflects the fact that KRT has become a complex treatment for critically ill patients, which allows for the prescription to be precisely tailored to the different daily clinical needs.
#2062 Protein interactome and trafficking of uromodulin in HEK and MDCK cell model
Authors: Parveen Humaira , Boder Philipp , Mary Sheon , Van Agtmael Tom , Delles Christian
Published: May 2024

Background and Aims

Uromodulin (UMOD) is a kidney-specific glycoprotein and the most abundant urinary protein in healthy individuals. Genome-wide association studies have shown an association between UMOD variants, kidney diseases, and hypertension. UMOD exhibits bidirectional secretion as it releases into the renal interstitium and circulation. However, the molecular trafficking of UMOD and its interaction remains poorly defined. We aimed to establish a stable Human Embryonic Kidney (HEK293) cell line expressing human UMOD to identify the potential regulators of UMOD expression or secretion. This study will provide significant implications for conditions such as hypertension, chronic kidney diseases, acute kidney injury, or UMOD-autosomal dominant tubulointerstitial kidney disease (UMOD-ADTKD).

Method

A HEK-UMOD-expressing cell line was generated by introducing human UMOD transcript 1 expression and using a tetracycline-inducible expression vector (pcDNA™FRT⁄TO vector) with yellow fluorescent protein tag at the C-terminal and previously established MDCK-UMOD cell line was also used. An untargeted proteomic approach was used to identify proteins, using GFP trap co-immunoprecipitation assay followed by mass spectrometry analysis.

Results

We identified 1367 and 1140 UMOD interacting proteins in HEK and MDCK cell models respectively. There were 620 proteins common to both these models. Through gene ontology, we unravel the molecular mechanisms involved in the biosynthesis, folding, and transport of UMOD. We observed several proteins associated with clathrin-mediated transporting. To study the role of clathrin in UMOD transport, we treated the polarised MDCK-UMOD cells with pitstop 2. There was significantly more secretion of UMOD with pitstop 2 treatment in the apical compartment compared to untreated cells however there was no significant difference in UMOD secretion in the basolateral compartment.

Conclusion

These results suggested that clathrin-coated vesicles are involved in transporting and sorting UMOD. Further studies need to investigate the functional importance of these proteins in UMOD trafficking and their implications in different physiological processes.
#821 Kibra mediates the activation of hippo by classic signal pathway related to NPHP1 defect
Authors: Yang Yichen , Sun Liangzhong
Published: May 2024

Background and Aims

Nephronophthisis (NPH) is an autosomal recessive cystic kidney disease, which is the most common genetic cause of end-stage renal disease (ESRD) in children. The pathogenesis of NPH has not been clear yet. There are more than 20 different pathogenic genes identified at present, among which NPHP1 is the most prevalent one. Hippo signal pathway has been suggested to be involved in the pathogenesis of NPH cause by NPHP4 and NPHP9 defects, respectively. In the present study, we attempted to explore the state of hippo signal pathway in NPHP1 defect in both MDCK cells and C57/6j mice.

Method

NPHP1 knockout (NPHP1KO) MDCK cells and NPHP1KO C57BL/6J mice were constructed by CRISPR/Cas9 technology. Recombined kibra knockdown siRNA, kibra knockdown AAV9 (AAV9-Kibra-KD) and NPHP1 overexpress AAV9 construct (AAV9-NPHP1-OE) were constructed, respectively. The expression and phosphorylation of core molecules of hippo pathway in different group of MDCK cells and the kidney C57BL/6J mice were investigated through Real-time Quantitative PCR, western blotting, immunofluorescence. The renal pathology of the mice kidney was also observed.

Results

In NPHP1KO MDCK cells and the kidney of NPHP1KO mice, the expression of KIBRA, p-MST, p-LATS and p-Yap were increased, which indicates the activation of hippo signal pathway. The activation of hippo pathway could be suppressed partially by NPHP1 re-expression both in NPHP1KO MDCK cells and the kidney of NPHP1KO mice, which means the activation of hippo pathway was related to NPHP1 defect both in vitro and in vivo. Moreover, the kidney pathological changes were improved by NPHP1 re-expression.

Kibra is the upper regulator of hippo signal pathway, we observed that kibra knockdown inhibited the activation of hippo pathway both in NPHP1KO MDCK cells and the kidney of NPHP1KO mice, which indicates that kibra mediates the activation of hippo pathway related to NPHP1 defect both in vitro and in vivo. As well, kibra knockdown ameliorated renal fibrosis CTGF expression, interstitial inflammation and renal cyst formation in NPHP1KO mice.

Conclusion

We conclude that NPHP1 defect activates hippo pathway which involves in the pathogenesis of NPH. Kibra mediates the activation of hippo related to NPHP1 defect by classic signal pathway. Hippo signal maybe a target for the treatment of NPHP1 defect NPH.
#788 Mitigation of tubular apoptosis and cystogenesis in ADPKD: the impact of TRPM8 through restriction of mitochondrial function
Authors: Jao Tzu-Ming , Huang Jenq-Wen , Tsai Chia-Hui , Hu Liang-Shuan , Hsieh Chi-An
Published: May 2024

Background and Aims

Autosomal dominant polycystic kidney disease (ADPKD), characterized by numerous fluid-filled cysts and a progressive decline in renal function, is a prevalent hereditary kidney disorder. Approximately 70% of individuals affected by ADPKD may develop end-stage renal disease, typically manifesting around the median age of 58 years. Despite its prevalence, effective clinical treatments for ADPKD remain elusive.

Transient receptor potential melastatin member 8 (TRPM8), serving as a sensor for cold temperatures and activated by the cooling agent menthol, orchestrates cellular Ca2+ signaling by facilitating Ca2+ entry into the cytosol. However, the role of TRPM8 in ADPKD remains undefined.

Method

The WT 9-12, an epithelial cell line isolated from the proximal tubule of a patient with ADPKD, was utilized for in vitro experiments. Eight-week-old wild-type (WT), Pkd1 knockdown (pkd1kd), and Trpm8, Pkd1 double mutant (T-/-P) mice were used for experiments. Renal Trpm8 was activated by administration of a 0.5% menthol diet for 7 months in mice. The cyst index was measured by H&E stain and calculated using Image J. Apoptosis was evaluated by TUNEL assay (In Situ Cell Death Detection Kit, TMR red). Protein and mRNA expression of mice kidneys was detected by Western blotting and qRT-PCR, respectively. Blood urea nitrogen (BUN) was measured by HITACHI 7600 analyzer.

Results

The activation of TRPM8 by menthol treatment resulted in an elevation of intracellular Ca2+ levels, subsequently impeding proliferation in WT9-12 cells. Consistently, Trpm8 activation suppressed kidney weight, kidney weight-to-body weight ratio, BUN, fibrosis, and cystogenesis in Pkd1kd mice, while no such effects were observed in WT and T-/-P mice. This suggests a protective role of Trpm8 in ADPKD. Mechanistically, Trpm8 activation mitigated tubular apoptosis in the kidneys of Pkd1kd mice, as evidenced by reduced TUNEL-positive cells and downregulated Bax and cleaved caspase-3, with no such effects observed in WT and T-/-P mice. Intriguingly, the proliferation-associated signaling pathway, ERK, was also suppressed by Trpm8. Proteomic analysis of mice kidneys revealed that Trpm8 regulates mitochondrial dysfunction, EIF2 and Sirtuin signaling pathways. The result was verified in WT9-12 cells showing reduced mitochondrial respiration, particularly impacting oxidative phosphorylation by TRPM8.

Conclusion

Trpm8 inhibits tubular apoptosis and cyst formation through the restriction of mitochondrial function, subsequently retarding ADPKD development in mice. These findings illuminate a novel and promising strategy for intervening in ADPKD.
#2498 PKD2 recurrent haplotype in ADPKD patients
Authors: Corradi Valentina , Caprara Carlotta , Rigato Matteo , Mancini Barbara , Marzano Nenzi , Giuliani Anna , Perbellini Omar , Gastaldon Fiorella , Ronco Claudio , Zanella Monica
Published: May 2024

Background and Aims

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic renal ciliopathy characterized by progressive renal cyst expansion and extrarenal manifestations following loss-of-function mutations. ADPKD is primarily caused by PKD1 (72-75%) and PKD2 (15-18%), with a high level of allelic heterogeneity: it is rare to identify the same germ-line mutation in different families since mutations are “private”. In recent years the identification of several new genes has underlined the genetic heterogeneity of ADPKD.

The Aim of this study is to describe a cohort of PKD2 gene-linked families with the same germ-line mutation.

Method

Patients (pts) with ADPKD referral to the Genetic Kidney Diseases clinic of the UOC of Nephrology of ULSS8 Berica (San Bortolo Hospital in Vicenza) were enrolled and followed prospectively. Diagnosis of ADPKD was made upon the revised Ravine's criteria. Complete clinical details were recorded, including family history and pedigree. We performed NGS with Sophia Genetic “Nephropathies Solution” Panel or Sanger sequencing to identify disease-causing mutations in the cohort. Furthermore, microsatellite analysis was performed in PKD2 gene pts with same germ-line nonsense mutation c.2533C>T (p.Arg845Ter), to identify disease haplotype.

Results

We identified a cohort of 30 ADPKD pts belonging to 13 families with same PKD2 germ-line nonsense mutation c.2533C>T (p.Arg845Ter). Regarding pedigree analysis, 8 families had their origin from the same geographical area and the remaining 5 were from an area 100 km away. In 4 families, we found a common individual. Concerning the microsatellite analysis, all 30 pts shared the same haplotype Chromosome 4 CEN – VG2 (TG)20, VG3 (TA + GA)32, VG4 (CA)13, D4S2929 (AC)26, D4S1563 (TG)20 – TEL indicating that those families may originate from a common ancestor.

Conclusion

We found the same PKD2 germline mutation in 30 ADPKD pts belonging to 13 families that share the same haplotype. Since, ADPKD mutations are “private” and Vicenza province counts almost 860000 inhabitants, our findings provide an evidence that a founder effect exists, maybe due to a founder effect in our region.
#2556 Therapeutic monitoring in patients with APRT deficiency using UPLC-MS/MS-based plasma assay
Authors: Thorsteinsdottir Unnur Arna , Runolfsdottir Hrafnhildur , Eiriksson Finnur , Edvardsson Vidar Örn , Pálsson Runólfur , Thorsteinsdottir Margret
Published: May 2024

Background and Aims

Adenine phosphoribosyltransferase (APRT) deficiency is a rare disorder of purine metabolism, characterized by urinary excretion of the poorly soluble 2,8-dihydroxyadenine (DHA), leading to nephrolithiasis and chronic kidney disease (CKD). Treatment with xanthine oxidoreductase (XOR) inhibitor, allopurinol or febuxostat, reduces DHA excretion and slows or halts CKD progression. The aim of the study was to optimize and validate an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS)-based assay for simultaneous quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma, for monitoring of pharmacotherapy in patients with APRT deficiency.

Method

The UPLC-MS/MS-based assay was optimized employing the chemometric approach design of experiments, using the software Modde Pro 13 (Sartorius, Umeå, Sweden). The assay was validated and used for absolute quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in plasma samples from both untreated and treated APRTd patients and healthy controls.

Results

Accuracy and precision were within ±15% for all analytes, and the analytes were stable in plasma for 12 months at −80°C. The median (range) concentration of DHA in plasma samples from six APRT deficiency patients was 204.0 (187.2–315.8) ng/mL when they were untreated and 69.2 (below the limit of quantification [BLQ]–131.6) ng/mL when treated with allopurinol (400 mg/day), and BLQ when febuxostat (80 mg/day) was the therapeutic agent. The median (range) plasma adenine concentration was 238.1 (218–502) ng/mL in the untreated patients, and 561.1 (418–2104) and 856.0 (726–1711) ng/mL in those on treatment with allopurinol and febuxostat, respectively. DHA was not detected in plasma samples from healthy controls. The median (range) plasma concentration of allopurinol, oxypurinol and febuxostat in patients receiving XOR inhibitor therapy was 1657 (BLQ-3266) ng/mL, 8102 (4778–34906) ng/mL and 109 (BLQ-1657) ng/mL, respectively.

Conclusion

The UPLC-MS/MS-based assay provides accurate and precise quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma. Measurement of plasma DHA is being implemented as a diagnostic test for APRT deficiency and the full assay for monitoring of XOR inhibitor treatment in patients with the disorder.
#2406 Echocardiographic characteristics of autosomal dominant polycystic kidney disease
Authors: Koska-Ścigała Agata , Jankowska Magdalena , Jankowska Hanna , Dudziak Maria , Hellmann Marcin , Dębska-Ślizień Alicja
Published: May 2024

Background and Aims

Cardiovascular complications in patients with autosomal dominant polycystic kidney disease (ADPKD) are one of the most frequently investigated extrarenal manifestations. The results are many times contradictory. This is caused by a limited size of studied populations and high inter- and intrafamilial heterogeneity of ADPKD. Expanding knowledge of populations of patients from different regions and cohorts is crucial for improving the understanding and treatment of cardiovascular morbidity and mortality. This study aims to explore the prevalence of cardiovascular abnormalities in echocardiography and to analyze their relationships with clinical characteristics across different stages of CKD progression in patients with ADPKD.

Method

Sixty-eight patients were included in the study. All patients underwent transthoracic echocardiography with the use of GE Vingmed Ultrasound (GE Norway Health Tech, Oslo, Norway). Information about demography, prior medical history and taking antihypertension drugs was recorded. The results of creatinine, lipids and haemoglobin were collected. To diagnose the rapid progression of CKD, creatinine was sampled twice, in a one-year interval.

Results

Using different indicators of left ventricular hypertrophy (LVH), we found it in above 40% of ADPKD patients. A single associate of left ventricular mass was eGFR decline after one year of observation. Other highly prevalent findings were asymptomatic left ventricular diastolic dysfunction (ALVDD) (39%), left atrium (LA) enlargement (39%) and mild valvular regurgitations (80%). Ejection fraction, aortic root dimension, tricuspid annular plane systolic excursion (TAPSE) and prevalence of mitral valve prolapse were not importantly increased. Apart from age, the strong determinant of ALVDD diagnosis was the treatment with beta-blockers. Cardiac indices were not different across the eGFR stages.

Conclusion

LVH, LA enlargement, ALVDD and valvular regurgitations are characteristics of cardiac phenotype in ADPKD. Cardiac indices were not different across different stages of CKD pointing towards the diagnosis of ADPKD being main drive of their occurrence.
#1607 Prevalence and risk factors of aortic root dilatation in children with X-linked Alport syndrome
Authors: Aksenova Marina , Tutelman Konstantin , Anykalchuk Lilia
Published: May 2024

Background and Aims

Aortic dilatation in X-linked Alport syndrome (XLAS) is considered a specific manifestation. On the other hand, all patients with CKD have been shown to have an increased risk of aortopathies. The aim was to define prevalence and risk factors for aortic dilatation in children with XLAS.

Method

Retrospective cross-section single center study included XLAS’ children (n = 98,64 M) and patients with CACUT (comparison group, n = 26,12 M). The aorta was measured at level of the sinus of Valsalva (SoV), aortic dilatation was determined by z-score >2 for BSA. Body mass index (BMI, kg/m2), z-scores of mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP), mean blood pressure (MBP), proteinuria (Pr, mg/m2/day), eGFR (ml/min/1.73 m2), z-scores of left ventricular mass index (LVMI), left ventricular end diastolic diameter (LVEDD), relative wall thickness of the left ventricle (RWT, N < 0,42) data were obtained.

Results

There were no difference in age (11,12 ± 3,75 vs 10,87 ± 2,34 yrs; p = 0,78), gender (males 0,55 vs 0,46; p = 0,45), BMI (18,7 ± 3,7 vs 19,1 ± 4,7; p = 0,78), eGFR (103,1 ± 16,9 vs 90,5 ± 11,4; p = 0,50), prevalence of hypertension (0,11 vs 0,19; p = 0,21) between the groups. The prevalence of SoV dilatation did not differ between XLAS and CACUT (0,06 vs 0,08; p>0,18). SoV dilatation was associated with male gender (β1 = 0,31, p = 0,02; β2 = 0,34, p = 0,02), LVMI (β1 = 0,26, p = 0,02; β2 = 0,24, p = 0,02) in both groups, with BMI (β1 = -0,27, p = 0,03), LVEDD (β1 = 0,21, p = 0,04) in children with XLAS. No statistically significant effect of SBP, DBP, MBP, Pr, eGFR on SoV dilatation has been demonstrated.

Conclusion

The prevalence of SoV dilatation in children with XLAS was higher than in general population, but comparable to children with CACUT. The male gender, low BMI, LVMI and LVEDD were associated with SoV dilatation in XLAS. We did not show the relationship between blood pressure load, proteinuria, eGFR and SoV dilatation in XLAS.
#1236 Translation reprogramming in autosomal dominant polycystic kidney disease
Authors: Leemans Charlotte , El Hachem Najla , Mekahli Djalila , Decuypere Jean-Paul , Rapino Francesca , Jouret François , Close Pierre
Published: May 2024

Background and Aims

Global regulation of mRNA translation has emerged as a central mechanism driving cellular adaptation to innate or acquired metabolic challenges. tRNA modifications are emerging as key drivers in the reprogramming of mRNA translation. Metabolic dysregulation is a central feature in the pathophysiology of PKD1-associated autosomal dominant polycystic kidney disease (ADPKD). Here, we aim at investigating the putative role of mRNA translation regulation in the development of cysts in ADPKD.

Method

The classical murine Inner Medullary Collecting Duct (IMCD) cells knocked out for Pkd1 by CRISPR-Cas9 were used. We combined proteomics and transcriptomics analyses of wild-type versus Pkd1-KO IMCD cells. A series of bioinformatic tools was used to identify pathways and processes dysregulated at the level of mRNA translation. Moreover, global mRNA translation rates were assessed in Pkd1-KO cells by measuring translating ribosomes and nascent protein synthesis by flow cytometry labelling methods. Finally, systematic analyses of tRNA regulation (sequencing and modification) were performed in Pkd1-KO cells.

Results

The proposed combination of analyses highlighted pathways differentially regulated in Pkd1-KO cells. We focused on pathways and proteins significantly upregulated in Pkd1-KO as compared to controls cells. On top of expected up-regulated pathways, we also uncovered a series of specific cellular and molecular pathways that are specifically and significantly upregulated in Pkd1-KO cells, including intracellular vesicular metabolism and ciliary transport. Interestingly, the pathway “tRNA modification” was significantly enriched in Pkd1-KO cells. Given the role of tRNA modifications in translation reprogramming during cell adaptation, we further validated that several enzymes known to regulate tRNA modification were differentially expressed in Pkd1-KO cells. In order to investigate the changes in tRNA modifications taking place in Pkd1-KO cells, we performed an unbiased analysis of tRNA modifications (LC-MS). This uncovered reproducible differences in the abundance of specific tRNA modifications between control and Pkd1-KO IMCD cells.

Conclusion

Our data uncovered different patterns of tRNA modifications between Pkd1-KO versus wild-type IMCD cells. This suggests that a specific tRNA-modification-dependent reprogramming of mRNA translation may occur in ADPKD. These data will be further validated using patient derived ADPKD cyst models.
#2633 Navigating complexity: a case report of chronic kidney disease with renal stone unravelling a rare metabolic disorder
Authors: Green Darren , Eltahan Alshymaa , Lewis David , Rana Seema
Published: May 2024

Clinical Presentation

A 48-year-old female of Asian heritage was referred for renal assessment after experiencing recurrent acute kidney injury (AKI) with incomplete recovery between episodes. This was initially attributed to dehydration and interstitial nephritis stemming from long-standing vomiting, a manifestation of gastroscopy-proven erosive gastritis, compounded by the use of high-dose proton pump inhibitors (PPI). Her relevant medical history is of right nephrectomy in 1996 due to recurrent urinary tract infections (UTIs), and previous left renal calculus in 2019 with no visible stones on further CT imaging. Despite living with a single kidney, her baseline eGFR had been normal prior to referral. While unaware of her mother's medical history, her father was recently diagnosed with kidney disease (no clear history) and her sister Wilson's disease.

A kidney biopsy was undertaken given the incomplete eGFR recovery between episodes. The biopsy revealed adequate tissue including 24 glomeruli, no significant glomerular pathology was seen. There is 65% tubulointerstitial atrophy and fibrosis, and yellow to red-brown-tinged crystals within tubular lumina and epithelial cells, prompting a histiocytic reaction. These crystals were birefringent under polarized light and did not stain with Perl's and Von Kossa stain (Fig. 1a-d). Immunofluorescence was negative for all immunoglobulins and complement fractions. No immune complex/substructure deposits were seen in the glomeruli on electron microscopy.

Blood tests assessing APRT activity indicated values within the carrier range (Table 1). The patient and her family have been referred for a comprehensive genetic testing for APRT genetic mutations.

Treatment with Allopurinol 300 mg daily resulted in a sustained eGFR improvement from 19 to 33 ml/min/1.73m2 at 6 months after initiation (Fig. 1).

Discussion

Adenine phosphoribosyl transferase (APRT) deficiency, also known as Dihydroxyadenineuria, is a rare autosomal recessive inherited condition leading to kidney stones. If left untreated, up to 25% progress to end-stage kidney disease (ESKD). Although inherited, half of patient present in adulthood and may do so with laboratory findings of CKD rather than specifically with stones [1].

This case highlights the significance of precise diagnosis in calculi-related kidney diseases. Early intervention can alter the trajectory of specific conditions, averting progression to ESKD. This case is unusual in being a carrier of an autosomal recessive condition presenting with full manifestations of the disease.

Patient Consent

The patient has given verbal, documented consent for case publication.

Acknowledgment

We thank all renal and pathology staff members at Salford Care Organisation who contributed to the diagnosis and management of our case.
#2258 Hypochloremia and inflammation in a cohort of patients undergoing cardiac catheterization: a disturbing association
Authors: Monzon Tania , Amado Ernesto Francisco Valga , Santana Ana Yurena Sánchez , Aladro Sara , Galvan Mario , Perez Patricia
Published: May 2024

Background and Aims

Serum chloride is an emerging marker of mortality in patients with hypertension, heart failure, sepsis, and chronic kidney disease. The causes of this finding are still unknown, although it is suggested that both haemodynamic and inflammatory factors may play a role. On the other hand, Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been found to be associated with increased inflammation in various cohorts.

Method

Retrospective cohort study. We analysed data from 558 patients who underwent cardiac catheterization at our hospital between June and October 2022. Baseline, pre- and post-procedural analytical data, as well as concomitant treatment were obtained (Table 1).

Results

The mean age was 65.89 years. Women accounted for 31.2%. 40.9% had diabetes, 71.9% had hypertension, and 21.9% had ischaemic heart disease. Pre-procedural serum creatinine (Crs) was 1.08 mg/dl (±0.44). Patients with pre-procedural hypochloremia (defined as serum chloride levels less than 98 mEq/L) had higher NLR (5.89 vs 3.6) (p = 0.002) and PLR (139.44 vs 132.08) (p = 0.009). This relationship was maintained in the post procedure analysis. (Table 1 and Fig. 1).

Conclusion

In our sample, the presence of hypochloremia (serum chloride levels below 98 mEq/L) was associated with higher NLR and PLR levels both pre and post cardiac catheterization.
#2809 Peroxiredoxins, the potential predictor of eGFR decline in patients with IgA nephropathy
Authors: Krata Natalia , Tanska Julia , Moszczuk Barbara , Knioła Emilia , Monticolo Marta , Foroncewicz Bartosz , Mucha Krzysztof
Published: May 2024

Background and Aims

Multiple factors may contribute to development and progression of glomerulopathies (GN), one of them is oxidative stress (OS). 2-cysteine-peroxiredoxins (PRDXs) possess the ability to reduce excessive levels of OS mediators and are crucial for cellular OS regulation. In our pilot study, we found that PRDXs 1-5 are differentially changed in patients with IgA nephropathy (IgAN), lupus nephritis (LN) and membranous nephropathy (MN). Thus, the aim of the current study was to evaluate if PRDXs 1-5 may be a prognostic marker for these 3 types of GN.

Method

We followed-up (5-year observation) 80 previously recruited patients with: IgAN (n = 36); MN (n = 23) and LN (n = 21). Patients were classified, based on the eGFR change (decline vs. stable and/or increase) and baseline PRDXs 1-5 levels (Table 1). The Mann Whitney-U, Kruskal-Wallis Test and Pearsons’ correlation were used for statistical analysis, the p-values <0.05 were considered significant.

Results

Baseline measurements indicated that the mean serum PRDXs 1-5 concentrations differ between the GN types. During the follow-up, we observed the significant association of eGFR decline with low baseline PRDX-2 level (p = 0.049) in patients with IgAN (Fig. 1).

Conclusion

We suggest the possible link between peroxiredoxins and deterioration of kidney function, particularly in IgAN patients.
#752 Ponatinib exacerbates renal damage in MRL/lpr lupus model mice through the lipid metabolism pathway
Authors: Li Xuemei , Wang Gangan
Published: May 2024

Background and Aims

The role of tyrosine kinase inhibitors (TKIs) in lupus nephritis is controversial. Ponatinib is a third-generation tyrosine kinase inhibitor that targets multiple receptors. This study aims to explore the effect of ponatinib in lupus nephritis, with the hope of providing insights for the clinical application of ponatinib.

Method

At 8 weeks of age, mice were randomly divided into four groups. One group received no treatment, while the other three groups were respectively administered Ponatinib, prednisolone acetate, and a combination of Ponatinib and prednisolone acetate. The treatment was concluded when the mice reached 16 weeks of age. ELISA was employed to measure the levels of anti-dsDNA IgG, ANA, and C3 in mouse serum. DEGs and DELs were identified using the DESeq2 package in R. Pathway and gene ontology enrichment analyses were performed using the MetaCore database.

Results

Compared to the negative control, those mice receiving ponatinib showed a significant increase in the urinary protein/creatinine ratio (P < 0.01), along with notable elevations in blood creatinine and blood urea nitrogen. Pathological examination of kidney tissue suggested predominant acute lesions, including transparent thrombi, cellulose-like necrosis, cellular/fibrous crescents, and interstitial inflammation. Interestingly, serum testing in MRL/lpr mice revealed no significant differences in lupus activity-related indicators, including autoantibodies ANA, double-stranded DNA, and complement C3, between the negative control group and the ponatinib group. Furthermore, it was discovered that the kidney damage caused by ponatinib in MRL/lpr mice could be reversed by prednisone. RNA-Seq of kidney tissue from MRL/lpr mice showed a total of 44 differentially expressed genes when comparing the negative control with mice receiving ponatinib, including 23 upregulated and 21 downregulated genes. Pathway analysis revealed that the top four pathways were all related to lipid metabolism.

Conclusion

Ponatinib significantly exacerbated kidney damage in MRL/lpr mice and did not induce changes in lupus activity.