Renal Loss Research Articles

#6026 EVOLUTION OF MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Background and Aims Monoclonal gammopathy of uncertain significance (MGUS) is a frequent condition with an estimated prevalence of 3% in people over 50 years of age in the general population. Nowadays, more kidney transplants (KT) are performed in a population susceptible to present MGUS, and the evolution of this entity in KT recipients is currently unknown. Method We carried out a retrospective study of a cohort of KT recipients diagnosed with MGUS between 1996 and 2020, including patients with MGUS identified prior to kidney transplantation or during follow-up. We describe baseline, kidney transplantation, and hematological characteristics, analyzing the evolution of the hematological parameters according to the moment of appearance of MGUS. Results A total of 51 patients were included; in 28 (54.9%) MGUS appeared before transplantation, and in 23 (45.1%) after transplantation. Thirty-two (62.7%) were males, with glomerular pathology in 17 (33.3%) as the leading cause of chronic kidney disease. Hypertension (90.2%) and diabetes (27.5%) were the most common comorbidities. At renal transplantation, the median age is significantly higher in the pre-transplant MGUS group (62 years [IQR 54-66]) vs. 48 years [IQR 40-68]; p = 0.04). This group had a higher induction immunosuppression load than the post-transplant MGUS group (p = 0.01) due to a greater incidence of immunized KT recipients (p = 0.05). There were no differences in rejection, infections, or post-transplant neoplasia between both groups; however, higher renal graft loss was observed in the post-transplant MGUS group (10.7% vs. 43.5%; p = 0.02), probably explained by a longer follow-up time in this group. The most detected paraprotein was IgG (60.8%) and lambda light chain (51%), with a median blood concentration of 0.4 g/dl (IQR 0.2-1.4). In 45.1% of the cases, the paraprotein remained stable; it disappeared in 27.5%, and MGUS progressed to hematological neoplasia in 21.6%, including multiple myeloma, amyloidosis, and post-transplant proliferative syndrome. We did not detect significant differences in the evolution according to the moment of diagnosis of the MGUS (p = 0.7). Twelve renal biopsies were performed during post-transplant follow-up, detecting renal involvement by paraprotein in 5 (9.8%). Only 1 of them (1.96%) was defined as a monoclonal gammopathy of renal significance for not meeting the criteria for malignancy. Conclusion Close monitoring of MGUS in KT recipients is still necessary given the possibility of progression to hematological neoplasia, with a non-negligible percentage in our serie of patients. Our cohort does not allow us to detect significant differences with an impact on the clinical course of MGUS or KT regarding the moment of the development of MGUS before or after transplantation.

#5571 THERAPY WITH BUROSUMAB IN ADULT PATIENTS WITH X-LINKED HYPOPHOSPHATEMIA: A YEAR OF FOLLOW-UP

Abstract Background and Aims X-linked hypophosphatemic rickets (XLH) is a genetic disorder secondary to the mutation of the PHEX gene that results in increased circulating levels of FGF23. Increased FGF23 causes hypophosphatemia secondary to renal phosphate loss. Clinically, the disease is characterized by reduced growth, bone alterations, weakness, chronic pain and reduced mobility. From a biochemical point of view, patients have hypophosphatemia, increased values of alkaline phosphatase, increased fraction excretion of phosphate (FEP). Recently, therapy with Burosumab, a monoclonal antibody against FGF23, has been introduced. Burosumab by reducing the receptor availability of circulating FGF23 reduces its activity. This leads to a normalization of serum phosphate and in paediatric patients an improvement of the clinical phenotype. In adult patients, the effectiveness of therapy in improving the clinical outcome and quality of life is being investigated. The purpose of the study was to evaluate the efficacy in improving the biochemical, bone and clinical picture of adult patients with XLH in therapy with Burosumab for one year. Method We enrolled patients with XLH naive for Burosumab therapy. In all we evaluated the biochemical aspects (phospahatemia, alkaline phosphatase, FEP), bone Radiographic Global Impression of Change score and clinical improvements (six-minute walk test, UP and go timed test, WOMAC Index) pre therapy and after a year of therapy. Burosumab was administered monthly at a dose of 1 mg/Kg. Results We enrolled 5 patients (45 ± 10 year old, weight 60 ± 10 Kg, Burosumab dose 60 ±10 mg) with genetic diagnosis of XLH. The comparison between pre therapy and post-one-year therapy showed in all patients: increase in average phosphatemia (pre 1.9± 0.5 mg/dl vs post 3.4 ±0.6 mg/dl p = 0.003), reduction in FEP (pre 50 ±15% vs 20 ±10% p = 0.004), reduction of UP and go timed test (pre 20± 5 sec vs post 11 ±5 sec p = 0.005) increase of the distance in the six minutes’ walk test (pre 150 ± 30 meters vs post 250 ± 50 meters p = 0.01), improvement of the WOMAC test (pre 15± 3 vs post 5± 2; p = 0.008) and reduction of the Radiographic Global Impression of Change score (pre -2 ±0.5 and post 2± 0.4; p = 0.001). The serum value of alkaline phosphate was high and it did not change with the Burosumab therapy (pre 200±50 UI/L vs post 220±60 UI/L; p: n.s. n.v. 33–98 UI/L). No patients had significant complications during the first year of treatment. Conclusion The therapy with Burosumab was well tolerated by patients. It resulted in a marked improvement in the biochemical picture associated with a better quality of life identified by increased strength (improved walk test and UP and go timed test) reduction of pain (best WOMAC test) and bone damage score. In conclusion, Burosumab may be a good and safe therapy option for adults’ patients with XLH.

#6465 MIR-451B AND CHRONIC KIDNEY DISEASE: A NOVEL TARGET TO MODULATE RENAL VEGF SIGNALING

Abstract Background and Aims Chronic kidney disease (CKD) is a progressive disorder that affects over 15% of adults worldwide. A major component of CKD pathophysiology is renal microvascular rarefaction and loss that pairs the progression of the disease and complications. We developed a translational swine model of CKD and showed that loss of renal function associates with a significant decrease in renal vascular endothelial growth factor (VEGF) signaling and progressive microvascular (MV) rarefaction. VEGF is a key endogenous cytokine for MV proliferation and repair, but underlying mechanisms of renal VEGF downregulation in CKD are unknown. We hypothesized that micro-RNA (miRNA)-mediated processes contribute to the downregulation of renal VEGF signaling in CKD. Method Unbiased renal micro-RNA (miRNA)-seq was performed in a swine model of CKD stage 3 (14 weeks of bilateral renal artery stenosis + atherogenic diet) and normal controls (n = 5/group). Micro-RNAs up- (>1.4 FC, p<0.05) and down-regulated (<0.7 FC, p<0.05) were identified, followed by target prediction analysis (miRwalk 3.0, Target Scan 7.2). Renal gene and protein expression of VEGF was measured by qPCR and western blot, respectively, and renal MV architecture was studied by 3D micro-CT. Results Unbiased miRNA-seq and target prediction analysis identified four miRs upregulated in the kidney of CKD pigs vs. controls, of which miR-451b (validated by qPCR), broadly conserved among species, was capable of targeting VEGFA (FC = 4.46, p = 0.04). Renal gene and protein expression of VEGF was downregulated in CKD vs. controls, associated with significant cortical and medullary microvascular rarefaction (Figure 1). Conclusion Our data suggest that post-transcriptional modulation of renal VEGF signaling may serve as a prominent mechanism of VEGF downregulation, which leads to MV rarefaction and disease progression in CKD. Furthermore, this work in progress identified a novel candidate (miR-451b) and may set the stage for its targeted modulation to preserve VEGF signaling as a potential strategy to protect the renal microvasculature in CKD.

#5525 NEPHROTOXICITY OF CHIMERIC ANTIGEN RECEPTOR T CELL (CAR-T) THERAPY: ACUTE KIDNEY INJURY AND ELECTROLYTE DISORDERS

Abstract Background and Aims Chimeric antigen receptor T cell therapy (CAR-T) has improved the prognosis of patients with refractory hematologic malignancies. The most important toxicities are the cytokine release syndrome (CRS), where interleukin 6 (IL-6) plays a major role, and the immune effector cell-associated neurotoxicity syndrome (ICANS). A low incidence of acute kidney injury (AKI) with a high frequency of electrolyte imbalance has been described with CAR-T therapy. The aim of our study is to describe the nephrotoxicity of CAR-T therapy and to focus on AKI and the physiopathology of hypophosphatemia. Method A prospective single-center case series was performed which included all patients undergoing CAR-T therapy between 2020 and 2022. Clinical data included medical history, previous chemotherapy treatments, concomitant treatments, and clinical evolution. Daily monitoring of renal function, electrolytes and IL-6 was obtained after infusion of CAR-T. A urine sample was obtained on days 0, +7 and +14 with parathyroid hormone (PTH) and 25-OH vitamin D. AKI was classified according to the KDIGO criteria. Results 40 patients received CAR-T therapy during the follow-up period. The median age was 62 years. The same number of men as women were included. The most frequent comorbidities were hypertension (27.5%), followed by diabetes (12.5%) and chronic kidney disease (12.5%). 12 patients presented AKI. Baseline serum creatinine (SCr) in patients with AKI was 0.9 mg/dL (0.68-1.04) with a SCr peak of 1.27 mg/dL (1.1-1.7). The time from CAR-T therapy infusion to SCr peak was 6.5 days (4-10). Of these 12 patients, 8 presented stage 1, 3 stage 2, and 1 stage 3 AKI. There were no differences between the AKI and non-AKI group in baseline characteristics, inflammatory markers, CRS, ICANS or hospital length stay. Hypophosphatemia was the most frequent electrolyte imbalance, occurring in 36 patients (90 %), 22 (61 %) patients experienced moderate hypophosphatemia (phosphorus < 2 mg/dL) while 14 (39 %) patients experienced mild hypophosphatemia. 29 patients (72 %) presented hypokalemia and 25 patients (62.5 %) hyponatremia. Patients with moderate hypophosphatemia had a significantly higher elevation of IL-6 but there were no differences in PTH or vitamin D (Table 1). Although there were no significant differences in fractional excretion of filtered phosphate (FEPO4), patients with moderate hypophosphatemia trend to have higher FEPO4 values. Conclusion Electrolyte disturbances are common in CAR-T therapy, with hypophosphatemia being the most frequent. There is probably a mechanism for renal phosphorus loss related to systemic inflammation. AKI is less frequent and has mild characteristics in these patients.

#3589 OXALATE METABOLISM IN PRIMARY HYPEROXALURIA TYPE 1 TREATED WITH LUMASIRAN IMMEDIATELY AFTER BIRTH: STILL NOT EARLY ENOUGH

Abstract Background and Aims Severe primary hyperoxaluria type 1 (PH1) with rapid onset nephrocalcinosis and renal function loss in early infancy required so far combined liver and kidney transplant. RNA interfering drugs are the new challenge for these children. Here we present the first case of a newborn affected by PH1 treated with RNA-interfering Lumasiran 6 hours after birth. Method Diagnosis of PH1 (homozygous mutation AGXT c.731T>C9 [p.Ile244Thr]) was done at 11 weeks of pregnancy on chorionic villus due to family history. Parents are first cousins, both heterozygous carriers of the mutation. Their first child is homozygous, affected by PH1, in dialysis for massive nephrocalcinosis since two months of life, kidney-liver transplanted at 14 months, with multiple comorbidities, severe retinal oxalate deposition, early ischemic stroke and post-transplant lympho-proliferative disease. Mother blood Oxalate, Glycolate and Urinary Oxalate during pregnancy proved normal (3 umol/L and 4 umol/L; 35 umol/mmol). Fetal morphology at ultrasound was normal, showing a male fetus large for gestational age, due to gestational diabetes, and polyhydramnios. At 37w cesarean section was performed. Birth weight 4120 g; Length 49.9 cm (99° centile for gestational age). Apgar score 9/9. Cord blood and amniotic fluid were obtained for Oxalate dosage and Sanger sequencing for diagnosis confirmation. Umbilical central venous line and bladder catheter were placed for immediate start of infusions and serial sampling. Results PH1 was confirmed due to Homozygous mutation AGXT c.731T>C9 [p.(Ile244Thr)]. Oxalate on cord blood was 15 umol/L (nv <10), on amniotic fluid 55 umol/L (nv 19-71), on first urine 401 umol/mmolCr (nv < 300 umol/mmolCr). Blood Oxalate at 6h of life rose to 32 umol/L, Glycolate to 107 umol/L and urinary Oxalate to 573 umol/mmolCr. Serum Creatinin was normal (0.3 mg/dl). At 6 hours of life the child was treated with Glycolate Oxidase RNAi Lumasiran at the dose 6 mg/kg subcutaneously, in combination with Pyridoxin 10 mg/kg/day. Hyperhydration (240 ml/kg/day) was maintained iv for 16 days in combination with oral water and potassium citrate (500 mg in 500 ml/day) above breast feeding. Blood Oxalate was serially assessed every 48 hrs showing a peak level of 108 umol/l (nv <10) at day 6, higher than the supersaturation level of 60 umol/L, then a gradual decline (65-56-62 umol/L at 10-20-30 days respectively). Lumasiran 6 mg/kd was repeated at 30 and 60 days according to schedule, then at 3 mg/kg every month. After the second dose of Lumasiran a steeper decline of blood Oxalate was observed (31-17 umol/L at 45-60 days respectively) reaching the upper normal limit of 12 umol/L after three doses, at 80 days. Urinary Oxalate in spite of Lumasiran early start rose until a maximum of 4173 umol/mmolCr (nv for age <300 umol/mmolCr) at 13 days and gradually declined to 765 umol/mmolCr at 80 days, after three doses. Blood and urine Glycolate initially paralleled Oxalate then increased after each Lumasiran dose. Renal ultrasound normal at birth, showed only minimal hyperechogenic spots during the first 2 months, then mild bilateral hyperechogenic papillary deposits without signs of nephrocalcinosis/stones. Renal function at 3 months of life is normal (serum Creatinine 0.2 mg/dl); child growth on the higher centiles (7 kg), with no adverse events. Conclusion Blood and urine Oxalate serial analysis in a severe case of PH1 treated immediately after birth show that Glycolate Oxidase inhibition has a latency of at least 15 days, even when no previous deposits are present. In these days extremely high level of urine and blood Oxalate, far higher than supersaturation level, are reached, in spite of normal renal function, hyperhydration, B6 and citrate supplementation. This case confirms that familiar severe forms of PH1 should be treated immediately after birth with Lumasiran in combination with aggressive supportive therapy to avoid irreversible nephrocalcinosis and renal failure. Prenatal treatment of these cases might be considered in future.

#4554 FRAX® ASSOCIATION, BONE DENSITOMETRY, BIOCHEMICAL PARAMETERS OF BONE MINERAL METABOLISM AND ADVANCED CHRONIC KIDNEY DISEASE

Abstract Background and Aims Currently, there are calculation tools that predict the risk of fractures (fx), one of which is the Fracture Risk Assessment Tool (FRAX®). Patients with advanced chronic kidney disease (CKD) have a higher risk of fx than the general population and it is an independent factor for fx. However, this tool does not consider the presence or absence of CKD, where alterations in bone mineral metabolism have important clinical consequences and their prevention should be the objective of CKD control. The aim of our study is to evaluate the FRAX® tool in patients with advanced CKD and to analyze possible relationships with parameters of bone mineral metabolism. Method Observational, descriptive, retrospective study of a series of cases of patients with advanced chronic kidney disease in our center, where demographic data, FRAX® calculation, personal history of Diabetes Mellitus, etiology of CKD, personal history of fx, measurement of bone mineral densitometry by dual energy X-ray absorptiometry (DXA), estimated glomerular filtration rate (CKD-EPI), levels of serum calcium and phosphorus, vitamin D 1. 25 levels, Parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23), use of phosphorus chelating treatment and vitamin D were collected. Descriptive results of continuous variables are expressed as mean and standard deviation or median and interquartile range (IQR) according to their distribution. For categorical data, frequency and percentage are reported. To analyze the impact of the variables on the event to be studied, a univariate and multivariate Cox regression model was used. Results 59 patients with advanced CKD with DXA performed within one year of the FRAX® analysis were analyzed. The median age was 66 years (IQR 22). 59.3% were male. 35.6% had a personal history of diabetes mellitus. The most frequent etiology of CKD was unknown etiology (18.6%), followed by vascular (16.9%). History of some type of fx:13.6% (3.6% vertebral). Estimated glomerular filtration rate CKD-EPI: 20.7 ml/min/1,73 m2 (IQR 7.5). 16.9% had osteoporosis of the femoral neck and 22% of the spine. DXA decreased in femoral neck 78% and in spine 59.3%. Low risk of major osteoporotic fracture according to FRAX® of 76.3% and 64.3% (without and with DXA) and elevated risk of major osteoporotic fracture according to FRAX® 5.1% and 8.5% (without and with DXA). Risk of hip fracture 25.4% and 30.5% (without and with DXA). These data are summarized in Figure 1 and Figure 2. In the multivariate analysis there is no relationship between bone mineral metabolism parameters and DXA. The results showed a negative correlation between glomerular filtration rate CKD-EPI and FRAX® hip (HR -1.7; 95% CI 1.46-9.6 p = 0.027) which would suggest an association between loss of renal function and loss of DXA. Patients with diabetes mellitus have a higher risk of fx (HR 3.7; 95% CI 1.46-9.6 p = 0.009). Conclusion In patients with advanced CKD, FRAX® index identifies patients at high fracture risk for whom active treatment for osteoporosis should be instituted. In patients with advanced chronic kidney disease, FRAX® underestimates those patients with decreased bone mass and elevated risk of osteoporosis. We did not find any association with biochemical parameters of bone mineral metabolism which could guide us in anticipating the treatment of osteoporosis. The loss of renal function accelerates the loss of bone mass, so we believe that the introduction of this variable is necessary in the equation, especially in this profile of patients.

#6093 CLINICAL UTILITY AND LIMITATIONS OF BIOELECTRICAL IMPEDANCE ANALYSIS FOR ESTIMATING BODY COMPOSITION AND WATER DISTRIBUTION IN ADPKD PATIENTS

Abstract Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic cause leading to end stage renal disease (ESRD). The most striking ADPKD feature, which is the growth of renal cysts leading to nephromegaly and renal function loss, is attributed to the loss of PKD1 and PKD2 genes coding respectively for Polycystin 1 and Polycystin 2, which are proteins located on the primary cilium. ADPKD is considered a systemic disease as several extra-renal manifestations including liver cysts and hepatomegaly, valvular heart disease, aneurysms and diverticulosis can be associated to it. Because of the remarkable renal and hepatic involvement, patients affected by organomegaly may suffer from pressure-related conditions like malnutrition. Nutritional and hydration status can be assessed through Biolectrical Impedance Analysis (BIA), used both in the healthy population and in patients affected by chronic kidney disease (CKD). It is nowadays still not clear whether the presence of renal and hepatic cysts may exert an influence on raw BIA measurements and consequently if this represents an accurate tool to assess nutritional and hydration status in patients affected by ADPKD. Hence, this study was carried out in order to evaluate BIA efficacy and limitations in the ADPKD population. Methods We enrolled 132 adult patients (>18 years of age), 71 being affected by ADPKD, 33 being affected by non-ADPKD related CKD and 28 healthy controls. Each patient accepted to undergo BIA analysis and anthropometric measurements (height, weight, BMI), which were performed on the same day. We, then, classified ADPKD patients according to their residual renal function degree and compared them to the corresponding non-ADPKD of the same grade of renal insufficiency. Results We observed that in ADPKD patients showing organomegaly, in particular hepatomegaly, there is a positive correlation between this factor and BIA parameters including TBW%, ECW% and ICW%. On the other hand, no significant correlation with age and GFR was found. As far as PhA concerned, which is an indicator of malnutrition both in healthy and ADPKD patients, we observed that it is independent of ADPKD and mostly correlated with age. It has also been demonstrated that PhA significantly decreases in presence of organomegaly or when renal diameters are increased, even in subjects with a preserved or mildly reduced eGFR. Conclusion The results of our study are concordant with the only one present in the literature. Phase angle (PhA) has shown to be an important index for malnutrition in patients affected by chronic kidney disease (CKD) secondary to ADPKD or not. Together with other values derived from BIA evaluation, this could be used in the future in order to guide the therapeutic choice even in patients with a preserved renal function or a mildly reduced one.

#6833 ARE KT RECIPIENTS TAKING THEIR IMMUNOSUPPRESSANT MEDICATION? PRELIMINARY EVIDENCE FROM A SUPER-SPECIALIZED TRANSPLANT CENTRE IN SUB-SAHARAN AFRICA

Abstract Background and Aims Immunosuppressant non-adherence is a leading cause of preventable renal allograft dysfunction, rejection and graft loss. The barriers to immunosuppressant adherence as well as associated risk factors of non-adherence vary across studies in different locations. This study aimed to investigate the prevalence of immunosuppressant non-adherence among adult kidney transplant recipients and identify barriers to adherence in a renal transplant cohort. Method A cross sectional survey was conducted using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS), the Immunosuppressant Therapy Barrier Scale and the Beliefs about Medicines Questionnaire. Adherence was defined according to the BAASIS, with barriers to adherence and beliefs about medicines compared between the two groups. Participants were recruited from the out-patient clinic at Zenith Medical and Kidney centre. An advert for the study was placed in consultation rooms and patients were approached to join the study when they attend appointments. IBM SPSS Statistics for Windows, Version 23 (Armonk, NY: IBM Corp) was used for data analysis. Results The rate of non-adherence was 50.7% out of 67 kidney transplant recipients attending outpatient clinic. There were statistically significant associations between non-adherence and occupation (P = 0.049). Participants who are on MMF were more adherent than those on sirolimus (97.0% vs 79.4% and 0.0% vs 8.8%) and this difference is statistically significant (P = .038). Also, participants who have had one or more post-transplant hospital admission are more non-adherent when compared with those that have never been admitted (P = .022) The only significant barrier to adherence was when patients travelled out of town (P < 0.005). Adherence was not associated with patients’ belief about their medicines. Conclusion Interventions aimed at ensuring constant access to immunosuppressant drugs and those based on habit forming may significantly improve adherence in this cohort.

#3312 EFFICACY OF TRANSCATHETER AORTIC VALVE IMPLANTATION FOR SEVERE AORTIC VALVE STENOSIS IN HEMODIALYSIS PATIENTS

Abstract Background and Aims In Japan, of the >340,000 chronic dialysis patients, approximately 60% have lifestyle-related diseases including diabetes and nephrosclerosis. Two-thirds of maintenance dialysis patients (age, ≥65 years) often develop aortic stenosis (AS) and other serious and complex systemic cardiovascular disease complications associated with chronic kidney disease mineral and bone disorder (CKD-MBD). Furthermore, renal function loss and a prolonged state of renal failure are observed requiring renal replacement therapy (RRT). AS in dialysis patients progresses quickly, and the frequency of hospitalized treatment for heart failure increases with the worsening condition, leading to ADL deterioration, which may subsequently cause dialysis hypotension/interruption. At our hospital, of the 420 maintenance dialysis patients who died during hospitalization in 5 years before 2020 (420/2,637 = 16%), 32 cases (8%) developed AS complications, which became their direct cause of death in 12 cases (3%), and aortic valve replacement (AVR) was performed in 5 cases (1%). Maintenance hemodialysis patients (HD) are at high risk group and have a poor prognosis for life. Previously, transcatheter aortic valve implantation (TAVI) was not indicated., but recently TAVI has been approved in Japan. Efficacy of TAVI for HD patients remains unclear, here we investigated several outcomes. Method A total of 123 maintenance dialysis patients with severe AS were included in 2019–2021. We examined TAVI group and AVR group for length of hospital stay, hospitalization costs, life expectancy, and rates of complications such as occurrence of arrhythmias. Results Over a 3-year period, we performed TAVI for 58 maintenance dialysis patients (mean age, 81 years); their median duration of hospitalization was 14 days for a median cost of 6,259,350 JPY. The mean age was older than that of 66 patients who underwent open-heart AVR during the same period (mean age, 73 years; 35 days for 7,192,570 JPY); therefore, the cost was less, and the rate of complications, including vital prognosis and arrhythmia, was not inferior in hospitalization period. Conclusion In conclusion, TAVI is effective for elderly maintenance dialysis patients with severe AS and has a positive health care economics, ADL maintenance.

New Preloaded System for Renal and Visceral Arteries in Fenestrated Endografting.

The New Preloaded System (NPS) for renal/visceral arteries (TVVs) is an emerging technology in fenestrated endografting (FEVAR) that allows TVVs cannulation and stenting through the same access of the endograft main body. However, only few preliminary experiences are currently available in the literature. The aim of this study is to report the outcomes of NPS-FEVAR in juxta/para-renal (J/P-AAAs) and thoracoabdominal (TAAAs) aneurysms repair. This is a prospective (NCT05224219), single-center/observational study of patients submitted to NPS-FEVAR for J/PAAAs and TAAAs between 2019 and 2022 (July). Definitions and outcomes were evaluated according to the current SVS-reporting standard. Technical success (TS) and TS preloaded related, spinal cord ischemia (SCI), and 30-day mortality were assessed as early endpoints. Survival, freedom from reinterventions (FFRs), and freedom from TTVs-instability (FFTVVs-instability) were analyzed during follow-up. Among 157 F/B-EVAR cases, 74 (47%) NPS-FEVAR were planned and enrolled in the study [48 (65%) J/P-AAAs; 26 (35%) TAAAs]. The main indication for NPS-FEVAR was the presence of a hostile iliac axis (54%-73%) or the necessity of expeditious pelvic/lower-limb reperfusion for SCI prevention in TAAAs (20%-27%). Overall, 292 TVVs were accommodated by 289 fenestrations and 3 branches; 188 of 289 (65%) fenestrations were preloaded. NPS-FEVAR configuration was from "below" and "from below to above" in 28 (38%) and 46 (62%) cases, respectively. TS and TS preloaded system-related was 96% (71/74) and 99% (73/74), respectively. Target visceral vessels patency at the completion angiography was 99% (290/292). Failures were 2 renal arteries loss and 1 massive bleeding from a percutaneous closure system breakage. The latter patient developed postoperative multiorgans failure and died on the fifth postoperative day, causing only 30-day/in-hospital mortality (1.3%). One (1.3%) patient with a JAAA and preoperative bilateral occlusion of the hypogastric arteries suffered SCI. The median follow-up was 14 (IQR: 8) months. The estimated 3-year survival was 91% with no aneurysm-related mortality during follow-up. The estimated 3-year FFR and FFTVVs-instability were 85 and 92%, respectively. New preloaded system FEVAR is a safe and effective option in the treatment of J/PAAAs and TAAAs in the presence of hostile iliac access or to guarantee an expeditious pelvic/lower limb reperfusion, leading to satisfactory results in terms of TS, early and mid-term clinical outcomes. New preloaded system for fenestrated and branched endografting allows to increase the feasibility of the advanced endovascular aortic repair in challenging iliac access, thoracoabdominal aneurysm repair and reduce difficulties in target visceral vessels cannulation.

Zinc(Ⅱ)-induced Neuroimmunological Renal Chronic Kidney Disease Prevention and Suppressive Progression

Zinc(Ⅱ) supplementation with 30 mg/day should become likely therapeutic chronic kidney disease (CKD) prevention implications with immense importance of CKD-associated immunological and neurological complications. Zinc induced neuroimmunological suppressive CKD progression with Stage 2 ～ 3A, 3B, zinc supplementation (30 mg/day) may be beneficial for nutritional status in CKD children and adolescents, and zinc could reduce urinary protein excretion composed of albumin and/or minimize proteinuria excretion in proteinuric CKD. In CKD 4-5 stage, risk of cardiovascular disease (CVD) become higher that zinc supplementation of 25 mg/day in zinc homeostasis has a beneficial effect for CVD in vascular dysfunction. Thus, zinc intake of 30 mg/day and serum zinc level of 60～76 μg/dL could slow down CKD Stage 4 progression. Zinc induced CKD Stage 5 (eGFR < 15) is involved that zinc is actively bound to several proteins that the decrease of circulating zinc levels in CKD is partly caused by renal losses of zinc, becoming zinc-deficiency with advanced stage CKD and ESRD in CKD. Serum zinc and serum albumin levels are 37.4 ± 5.4 and 2.6 ± 0.6 µg/dL, respectively, for as eGFR 6.6 (5.2–8.3). Zn intake of 45-75 mg/day and serum zinc level of ≤78.3 µg/dL are beneficial for HD and maintenance hemodialysis (MHD) patients, in which Zinc 15 mg/day and Selenium 50–70 μg/day that are recommended may be thought to prevent ESRD stage. Zinc induced NAD(P)H oxidase (Nox) activation occurring ROS generation in CKD cell involves assembly that ROS include the superoxide anion (O2•–), hydrogen peroxide (H2O2), and hydroxyl radicals (OH•), and in the kidney. Zinc(Ⅱ) ions-binding protein molecular mechanism is involved that Zn2+ ions-several protein complexes coordinated binding model of ligands of such as albumin, a-macroglobulin and transferrin in several proteins had been found on the binding specificity by Zn2+ ions-centered tetrahedral geometric coordination, in which causing zinc-activated serine, histidine and aspartate hydrogen residues enhance renal function activity and resulting inhibition of CKD progression proceeds.

Memory T follicular helper cells drive donor-specific antibodies independent of memory B cells and primary germinal center and alloantibody formation

Human leukocyte antigen antibodies are important immunologic mediators of renal allograft loss and are difficult to control. The inability to permanently eliminate donor-specific antibodies (DSA) is partly due to an incomplete understanding of the cellular mechanisms driving alloantibody formation, recurrence, and maintenance. Memory T follicular helper (mTfh) cells rapidly interact with memory B cells upon antigen re-exposure for anamnestic humoral responses, but little is known about Tfh memory in transplantation. We hypothesized that alloreactive mTfh cells form after transplantation and play a critical role in DSA formation following alloantigen re-encounter. To test this hypothesis, we utilized murine skin allograft models to identify and characterize Tfh memory and interrogate its ability to mediate alloantibody responses. We identified alloreactive Tfh memory as a mediator of accelerated humoral alloresponses independent of memory B cells and primary germinal center, or DSA, formation. Furthermore, we demonstrate that mTfh-driven alloantibody formation is susceptible to CD28 costimulation blockade. These findings provide novel insight into a pathologic role for memory Tfh in alloantibody responses and strongly support shifting therapeutic focus from the singular targeting of B cell lineage cells and alloantibodies themselves to multimodal strategies that include inhibition of mTfh cells to treat DSA.

Research Progress on the Potential Mechanisms of Acute Kidney Injury and Chronic Kidney Disease Induced by Proton Pump Inhibitors

ABSTRACT Proton pump inhibitors (PPIs) are acid-suppressing medications widely used in peptic ulcers; however, their widespread use has led to many adverse renal events. Among these events, the most common form of acute kidney injury (AKI) is acute interstitial nephritis (AIN), which is the clinical manifestation. Several clinical trials and cohort studies have shown a significant relationship between PPIs and AKI induction; however, the pathogenesis of PPIs leading to AKI is unclear. In this paper, we reviewed the potential mechanisms by which PPIs cause AKI and proposed new conjectures. We considered that PPIs led to the development of AKI through a combination of mechanisms. By searching and reviewing PubMed and Embase, a total of 29 studies were finally included and reviewed, and the findings suggested that the mechanisms by which PPIs induce AKI are mainly related to oxidative stress, immune response, inflammatory response, mitochondrial damage, calcium overload, and the induction of cellular necrosis. In addition, tubular cell necrosis can cause tubulointerstitial fibrosis and progressive renal unit loss. Long-term follow-up observations also suggested that PPIs can contribute to AKI progression to chronic kidney disease (CKD). Therefore, we will also explore the potential link between PPIs and CKD.

History of Sleep Disorders in Chronic Kidney Disease: First Approach.

In this study, we examined the history of sleep disorders in chronic kidney disease, 60 years after the advent of hemodialysis and renal transplant of genetically nonrelated organs, which have spurred a critical mass of data. We analyzed selected literature on sleep disorders in chronic kidney disease from 1959 onward. Sleep disturbances are present in the general population. They cause loss of renal function and progressive nephron loss. Insomnia, sleep apnea, restless leg syndrome, and periodic limb movements represent sleep disturbances in chronic kidney disease. These symptoms manifest early in chronic kidney disease and are a rule in patients on dialysis and kidney transplant recipients. Sleep disturbances cause fatigue, excessive daily sleepiness, impaired daytime function, impaired health-related quality of life, increased morbidity, and increased mortality. Sleep disorders affect most patients with chronic kidney disease. No ascertained pharmacological therapy exists, and even a successful transplant does not totally restore a refreshing sleep. Longer nocturnal hemodialysis is of benefit. Sleep apnea may be cured with continuous positive airway pressure.

TUMOR INDUCED OSTEOMALACIA: A CASE REPORT

Background:Tumor-induced osteomalacia (TIO), which is also known as oncogenic osteomalacia, is an uncommon paraneoplastic syndrome characterized by a renal phosphate loss causing hypophosphatemia, leading to rickets in children and osteomalacia in adults. It is caused by mesenchymal tumors, which secrete FGF-23 (fibroblast growth factor-23) and rarely other phosphotonins. It can present with a wide range of symptoms and there is often a delay in its diagnosis. Early diagnosis is important and surgical excision can cure the disease in most patients, thus preventing the complications.We report a case of TIO, who was diagnosed at an early stage and underwent curative surgery. Case presentation: A 30 years old female presented with pain in both legs, more severe in the left leg since about 1 year. She also had difficulty in walking, low back ache, muscle pain, mild pain in both the knee joints as well. On examination, she had limping gait, muscle power in the left leg was grade 3-4 otherwise, there was no significant findings on examination. Blood investigations showed elevated alkaline phosphatase (ALP)- 387IU/ml, low serum phosphorus- 1.2mg/dl, normal calcium - 9.8mg/dl, 25-OH Vitamin D- 24.69ng/ml, Parathyroid hormone (PTH)- 61pg/ml.Other blood tests were unremarkable. X- rays of both the legs and pelvis showed a classicalpseudo-fracture in proximal part of both the fibulae and proximal part of the right femur. This suggested hypophosphatemicosteomalacia. TmP/GFR was found to be very low (1.4mg/dl), which confirmed renal phosphate wasting. Later we got Fibroblast growth factor – 23 (FGF-23)- 617RU/ml, which was elevated. This confirmed FGF-23 related hypophosphatemicosteomalacia. In view of the patients age, onset of symptoms, lack of family history, absence of dental and hearing abnormalities, we suspected an acquired rather than a genetic cause. The patient underwent whole body Gallium-68 DOTANOC PET scan, which revealed somatostatin receptor expressing soft tissue density lesion in subcutaneous plane in the mid- anterior right leg, suggestive of FGF-23 secreting mesenchymal tumor.The patient was initially treated with replacement dose of oral phosphorus and calcitriol, along with calcium and vitamin D supplements. Later the patient underwent surgery for excision of the tumor in the right leg. The tumor was around 2cm size and the histopathology was suggestive of gaint cell rich tumor- possibly a phosphaturic mesenchymal tumor. Post surgery, the patient had significant improvement in her symptoms, gait improved and pain reduced. The serum phosphorus level was 3.8mg/dl post-operatively. The serum phosphorus level was maintained without phosphorus replacement. The patient was advised to repeat FGF-23 levels, but the patient failed to get it done. Conclusion: The diagnosis of TIO requires high index of suspicion and should always be looked as a differential diagnosis when we are evaluating a patient with osteomalacia. A detailed history and examination followed by a step wise biochemical evaluation and imaging is important to diagnose TIO in early stages. Surgical resection of the causative tumor will lead to definitve cure of the disease in most patients and avoids the complications like osteoporosis and fractures, thus improving the quality of life of the patients.

Risk factors and outcomes of Pneumocystis pneumonia in solid organ transplant recipients: Impact of posttransplant lymphoproliferative disorder.

Pneumocystis jirovecii pneumonia (PJP) is a potentially fatal infection afflicting the immunocompromised population, including solid organ transplant (SOT) recipients. Several risk factors have been described; however, little is known regarding the risk of PJP in SOT recipients with posttransplant lymphoproliferative disorder (PTLD). We performed a nested case-control study of SOT recipients diagnosed with PJP from 2000 to 2020. PJP was defined as positive microscopy or polymerase chain reaction testing with compatible symptoms and radiographic findings. Control patients were matched 2:1 by year of first transplant, first transplanted organ, transplant center, and sex. Multivariable conditional logistic regression was performed to test associations with PJP and Cox regression analyzed post-PJP outcomes. Sixty-seven PJP cases were matched to 134 controls. The most common transplant was kidney (55.2%). Fourteen patients had a history of PTLD, 12 of whom developed PJP. After adjusting for age, acute rejection, cytomegalovirus infection, PJP prophylaxis, and lymphopenia (lymphocyte count<.5×109 /L), PTLD was independently associated with PJP (OR 14.0, 95% CI 1.7-114.5; p=.014). Lymphopenia was also a significant association (OR 8.2, 95% CI 3.2-20.7; p<.001). PJP was associated with mortality within 90days of diagnosis (p<.001), but not after 90days (p=.317). PJP was also associated with 90-day death-censored renal allograft loss (p=.026). PTLD is independently associated with PJP after adjustment for recognized risk factors. This is likely influenced by PTLD-directed chemotherapy, particularly rituximab-containing regimens. PJP is associated with early mortality, but this effect is not persistent after 90days. PJP prophylaxis should be considered in SOT recipients with PTLD.

Diagnostic and therapeutic strategies for vascular complications after renal transplantation: a single-center experience in 2,304 renal transplantations.

Vascular complications after renal transplantation are one of the serious surgical complications, which can affect the transplantation outcome and even endanger life if not treated properly. We performed a retrospective analysis of the 2,304 renal transplantations procedures completed between the period of Jan., 2015 and Jan., 2022, which consisted of 1,658 male patients and 646 female patients. Among the above cases, there were 54 cases of vascular complications after renal transplantation, the incidence of vascular complications in our study was 2.34% (54/2,304), the most common vascular complication was transplanted renal artery stenosis (TRAS, n = 36), followed by external iliac artery dissection (n = 5), renal artery rupture (n = 4), renal vein thrombosis (n = 3), renal artery thrombosis (n = 2), renal artery dissection (n = 1), renal artery pseudoaneurysm (n = 1), and internal iliac artery pseudoaneurysm (n = 1), and renal artery kinking (n = 1). 40 patients were treated by percutaneous transluminal angioplasty (PTA), including 3 balloon catheter dilatation and 37 endovascular stentings, and 14 underwent open surgery. Eventually, 9 patients had graft nephrectomy, resulting in an overall treatment rate of 81.5%. Most vascular complications can be treated satisfactorily with PTA. However, the overall treatment of renal artery rupture, thrombosis, renal artery kinking, and other complications is poor, and the rate of transplanted renal loss is high.

Application Value of Random Urine Potassium-to-Creatinine Ratio in Diagnosing Renal Potassium Loss

To analyze the value of applying random urine potassium-to-creatinine ratio (rUK/Ucr) in diagnosing renal potassium loss. patients diagnosed with hypokalemia, including 373 cases of renal potassium loss, 83 cases of non-renal potassium loss , and 358 cases of normal serum potassium, between 2017 and 2021 were enrolled. The clinical data of the patients were collected and the correlation between rUK/Ucr and 24-hour urine potassium (24 hUK) in the three groups was analyzed. The receiver operating characteristic (ROC) curve was used to analyze the value of applying rUK/Ucr in diagnosing renal potassium loss. Serum potassium decreased in the normal serum potassium group, the renal potassium loss group, and the non-renal renal potassium loss group ( P<0.01). The 24 hUK and the rUK/Ucr of the renal potassium loss group were higher than those of the non-renal potassium loss group and normal serum potassium group ( P<0.01). rUK/Ucr showed low to moderate correlation with 24 hUK. The AUC of 24 hUK and rUK/Ucr for determining renal potassium loss were 0.73 and 0.71, respectively. When the optimal cutoff point of rUK/Ucr for determining renal potassium loss was 3.4, the sensitivity was 67.6% and the specificity was 67.5%. rUK/Ucr shows a moderate correlation with 24 hUK and its accuracy in determining renal potassium loss is comparable to that of 24 hUK. When 24-hour urine samples cannot be obtained, it is recommended that rUK/Ucr be used instead of 24 hUK to determine whether renal potassium loss exists, with the optimal cutoff point for diagnosis being 3.4.

Effect of Eculizumab on Iron Metabolism in Transfusion-independent Patients With Paroxysmal Nocturnal Hemoglobinuria

Effect of Eculizumab on Iron Metabolism in Transfusion-independent Patients With Paroxysmal Nocturnal Hemoglobinuria

What UV is what you get: skin injury by ultraviolet (UV) light results in renal cell loss and damage in the presence of a CD177high neutrophil population.

Abstract Immune-mediated communication between organs has been implicated in the pathogenesis of many inflammatory and autoimmune diseases. We previously showed that skin injury by UV light triggers neutrophil migration to the kidney, stimulating expression of renal injury genes. This skin-kidney axis is highly relevant to lupus patients, for whom skin exposure to UV sunlight rays can lead to kidney disease flares. Here, we applied 10X single-cell RNA-seq on saline-perfused digested kidneys and Ly6G-enriched neutrophils of B6 mice, prior to and 2 days after a single dose of UV, to define renal cell subsets damaged by skin exposure to UV and how neutrophils mediate the injury. Dimensional reduction analysis revealed 14 kidney cell types and showed that exposure to UV led to the loss of podocytes and distal tubular cells (DTCs) and an expansion in endothelial and stromal cells. Differential gene expression analysis showed that podocytes and DTCs in UV-exposed mice upregulated genes associated with renal injury, including type I interferon genes, and downregulated genes important for cellular integrity and function. Neutrophil scRNA-seq revealed a unique activated CD177 highneutrophil population in the kidneys of UV exposed mice, defined as the endpoint of the psuedotime trajectory by diffusion mapping. Ligand-receptor pair analyses showed skin injury by UV altered neutrophil interactions with renal structural cells, with expanded binding to stromal cells. While the CD177 highneutrophil cluster was dominant in the kidney, it was also found in the lung, but not in the skin and blood. These studies introduce a novel model by which CD177 highneutrophils may mediate podocyte, DTC, and stromal kidney injury secondary to sterile skin inflammation. Supported by grants from NIH (1R21AR079661 – 01, 5P20GM130454-02), The Department of Defense (W81XWH2110889), and Dartmouth Health Start Up Funds.