Tubulointerstitial Nephropathy Research Articles

#2316 Towards the new era of nephrology. What implications do genetic studies have on individuals with kidney disease?

Abstract Background and Aims The study of kidney disease (KD), including genetics, may involve a significant change in the management, treatment, and prognosis of the patient. Method Retrospective study assessing the impact of genetic studies (GS) requested by the nephrology department at Virgen Macarena Hospital over 43 months (June/2019 to December/2022). We analyze diagnoses before and after GS, as well as their impact. The sequencing platforms used include Illumina HiSeq-MiSeq-NovaSeq and Ion Torrent. Common databases consulted include ClinVar, RefSeq, Ensembl, NCBI, ExAC, aHUS, and BIER. Results A total of 118 patients with genetic studies (GS) were analyzed. The mean age was 45.2 ± 16, with 51% being male and 49% female. 78% had first and/or second-degree relatives with kidney disease, and in 43 cases (36%), no family history was known. The mean creatinine (Cr) was 1.9±2 mg/dl, glomerular filtration rate (GFR) was 67 ± 40 ml/min, and urine albumin/creatinine ratio (UAC) was 770 ± 1700 mg/g, with hematuria present in 57.6% of patients. A renal biopsy (RB) was performed in 32 patients (27%). The indications for genetic testing were as follows: extension of studies in biopsied nephropathy (20%), cystic kidney disease (29%), non-biopsiable or chronic kidney disease (21%), family history (33%), and for research or trial purposes (1%). In 22%, a study of a known familial mutation was conducted, while the remaining cases involved gene panel analysis. The pre-genetic diagnoses were as follows: 39% glomerular disease, 22% other conditions (suspected Alport and Fabry), 16% autosomal dominant polycystic kidney disease (ADPKD), 8% complement-associated pathology (CAP), 5% other cystic diseases, 4% tubulointerstitial nephropathies (TIN), 3% nephropathy of unknown origin, 2% diabetic nephropathy, and 2% nephroangiosclerosis. GS was positive in 76 patients (N = 76; 64%). Variants were detected in 76 patients, with 14 patients exhibiting two concurrent variants in the same or different genes, and 4 patients having up to 3 variants. The most frequent variants were identified in the genes: COL4A, PKD1, C3, MCP, and CFH. Of these, 37% were pathogenic mutations, 26.6% were likely pathogenic, 33% were variants of uncertain significance (VUS) possibly related to the pathology, and 3.2% were unrelated VUS. In cases with negative GS results (42; 35%), we considered that the pre-genetic diagnosis was excluded in 17% of the overall patient cohort. Post-GS diagnoses included Alport (30; 25%), ADPKD (16, 14%), CAP (13; 11%), focal segmental glomerulosclerosis (6; 5%), TIN (4; 3%), autosomal recessive polycystic kidney disease (ARPKD) (1; 1%), congenital anomalies of the kidney and urinary tract (CAKUT) (1; 1%), and other conditions (5; 4%). The concordance between the pre-genetic diagnosis and GS result was 52% (N = 61). It led to a change in diagnosis in 48% of patients (N = 56); both positive and exclusionary results had an impact on clinical management in 83% (N = 98), and it resulted in a change in treatment in 20% (N = 24). Conclusion Genetic studies allow us to trace the origin of the kidney disease, providing a fundamental diagnostic tool. According to the literature, the most frequently diagnosed variants were those related to Alport syndrome, renal polycystic disease (with PKD1 being the most common), and mutations associated with complement pathway pathology. The implications and diagnostic changes brought about by genetic studies justify their implementation. In some cases, they also reclassify the kidney disease in our patients, enabling access to specific treatments.

A Therapeutic Dose of Lithium Triggers Anti-inflammatory Mechanisms in The Kidneys of Treated Mice

Lithium (Li+) is an effective mood stabilizer in people with schizoaffective disorders with more than 2 million prescriptions per year. Accumulation of Li+ in blood can cause neprotoxicity, manifesting in nephrogenic diabetes insipidus, renal tubular acidosis and tubulointerstitial nephropathy. Damage to renal cells often leads to a local immune response, playing a pivotal role in the ensuing renal injury and subsequent recovery. While both pro- and anti-inflammatory actions of Li+ were reported in various tissues, our understanding of the immunomodulatory effects of Li+ in the kidney is fragmentary. Here, we studied how immune mechanisms contribute to the development of Li+-induced adverse effects in the kidneys of C57BL/6 mice receiving a 0.3% lithium carbonate diet for 28 days. Given the insidious development of Li+-induced renal injury, we hypothesize that nephrotoxic effects of Li+ are alleviated by its anti-inflammatory action. We used fluorescence-activated cell sorting, qPCR, immunoblotting and proteome profiler arrays to assess the pyroptotic inflammatory cascade, characterize the infiltrating immune cells and cytokine markers in the renal tissue isolated from Li+-treated and control mice. We found that both biomarkers of tubular damage, kidney injury marker, KIM-1, and neutrophil gelatinase-associated lipocalin, NGAL, are elevated in the renal tissue of Li+-treated mice. This correlated with a moderate but significant increase in renal fibrosis in mice on Li+ diet. Expression of most genes associated with pyroptotic inflammatory cascade, including NLRP3, Casp-1, IL-1b, was not different in the renal tissue isolated from control and Li+-treated mice. Higher mRNA levels of apoptosis-associated speck-like protein (ASC), in the renal tissue of Li+-treated mice could be attributed to its a pro-apoptotic, rather than inflammasome forming, function. This is in line with elevated levels of CD93 marker in the kidneys of mice on Li+ diet, reflecting increased clearance of apoptotic cells. In general, Li+-treated mice had markedly higher levels of anti-inflammatory cytokine markers in the renal tissue, most notably, IL-10 and adiponectin, and lower abundance of pro-inflammatory markers, such as CD26, CLCX16, PCSK9 and osteopontin. Higher abundance of proinflammatory IL-6 in the kidneys of Li+-treated mice made a notable exception. However, this cytokine can also be released by tubular epithelial cells under insult and induce polarization of anti-inflammatory M2 macrophages. Mice on Li+-diet had higher levels of macrophages (F4.80+ cells) in the renal tissue. Future studies will determine their polarization phenotype. Overall, our results suggest that Li+-induced toxic insult to the tubular epithelial cells is paralleled by the anti-inflammatory immune response localized to the renal tissue. NIDDK 1R01DK125464. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Profile of Hemodialyzed Patients with Renal Insufficiency at Bab el Oued University Hospital

Hemodialysis emergencies are common and pose a threat to the prognosis of patients. We receive patients with acute renal failure requiring dialysis sessions daily at the Bab el Oued University Hospital Center. Through this study, we aimed to delineate the clinical, biological, etiological, and evolutionary profile of these patients in order to adapt and improve their management in collaboration with various stakeholders. This was a longitudinal, descriptive study conducted at the hemodialysis center of the Bab el Oued University Hospital, between December 2018 and November 2019, including patients with acute renal failure requiring one or more hemodialysis sessions. In addition to demographic data, the collected information included: source institution, medical history, acute or chronic renal involvement and its etiology, indication for dialysis, vascular access, and evolution.During this period, we provided 1621 hemodialysis sessions involving 250 patients, 162 with acute renal failure (ARF) and 88 with chronic renal failure (CRF). We included the 88 patients with ARF and excluded those with CRF. The mean age was 59 years with a range of 10 to 94 years. There were 66% males and 34% females, with a male-to-female ratio of 1.93. Approximately 39% of patients were hypertensive, 32% were diabetic, and 26% had mainly urological neoplasms. Our patients came from various departments of the Bab el Oued University Hospital in 66% of cases and from other institutions in 34% of cases. As for etiologies, we identified 68% tubulointerstitial nephropathies, 17% obstructive nephropathies, 10% glomerular nephropathies, and 5% vascular nephropathies. Regarding dialysis indications, uremic syndrome accounted for 39% of cases, hyperkalemia for 33%, acute pulmonary edema for 14%, acidosis for 11%, and urgent transfusion for 3% of cases. Vascular access consisted of femoral catheters in 77% and jugular catheters in 23% of cases. The outcomes were complete recovery in 14%, partial recovery in 20%, transfer to chronic dialysis in 8%, death in 35%, and loss to follow-up in 23%. The morbidity and mortality among patients undergoing emergency dialysis remain high despite the availability of dialysis and improvements in renal failure management in Algeria. We should work more collaboratively with various stakeholders and strive to computerize patient records to be more responsive and better track and manage these patients with high morbidity and mortality.

Any reduction in maternal kidney mass makes a difference during pregnancy in gestational and fetal outcome

Little is known about the effect tubulointerstitial nephropathies have in modulating maternal-fetal outcomes in pregnancy. Therefore, we analyzed the main outcomes of pregnancy in these women to gain a better understanding of the role of a reduction in maternal kidney mass. From the Torino Cagliari Observational Study (TOCOS) cohort, we selected 529 patients with a diagnosis of tubulointerstitial disease and focused on 421 patients with chronic kidney disease (CKD) stage 1, without hypertension but with proteinuria less than 0.5 g/day at referral. From a cohort of 2969 singleton deliveries from low-risk pregnancies followed in the same settings we selected a propensity score matched control cohort of 842 pregnancies match 2:1 for age, parity, body mass index, ethnicity, and origin. Time to delivery was significantly shorter in the study cohort 38.0 (Quartile 1-Quartile 3: 37.0-39.0) versus 39.0 (Q1-Q3 38.0-40.0) weeks, with respect to controls. Incidence of delivery of less than 37 gestational weeks significantly increased from controls (7.4%) to women with previous acute pyelonephritis (10.8%), other tubulointerstitial diseases (9.7%) and was the highest in patients with a single kidney (31.1%). Similarly, neonatal birthweight significantly and progressively decreased from controls (3260 g [Q1-Q3: 2980- 3530]), previous acute pyelonephritis (3090 g [Q1-Q3: 2868- 3405], other tubulointerstitial diseases (3110 g [Q1-Q3: 2840-3417]), and to solitary kidney (2910 g [Q1-Q3: 2480-3240]). Risk of developing preeclampsia was significantly higher in the CKD cohort (3.6% vs 1.7% in low-risk controls). Thus, even a small reduction in functional kidney mass, such as a pyelonephritic scar, is associated with a shorter duration of pregnancy and an increased risk of preterm delivery. The risk is proportional to the extent of parenchymal reduction and is highest in cases with a solitary kidney.

IgG4-Related Disease with IgG1-Dominant Membranous Nephropathy: A Rare Case Report

ABSTRACT Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disorder affecting various organs and tissues. Kidney involvement in IgG4-RD commonly manifests as IgG4-related tubulointerstitial nephritis or IgG4-related membranous nephropathy, with the latter occurring less frequently. The identification of the phospholipase A2 receptor (PLA2R) antigen has improved our understanding of primary membranous nephropathy. Here, we present the case of a 60-year-old Chinese man initially diagnosed with IgG4-related pancreatitis, who achieved clinical remission with glucocorticoid therapy followed by low-dose glucocorticoid maintenance therapy. Two years later, the patient developed nephrotic syndrome. A kidney biopsy revealed membranous nephropathy characterized by glomerular subepithelial deposition of IgG1 and positive PLA2R staining. Rituximab (RTX) treatment resulted in complete clinical remission of nephrotic syndrome, and no recurrence was observed during the 24-month follow-up period. IgG4-RD complicated by membranous nephropathy is a rare pathological feature characterized by glomerular subepithelial IgG1 deposition and positive PLA2R antigen staining. In the present case, RTX treatment was effective in achieving clinical remission. These findings contribute to the evolving understanding of the relationship between IgG4-RD and membranous nephropathy.

Lithium-Associated Tubulointerstitial Nephropathy, Role of Collecting Duct Cell Proliferation

Lithium-Associated Tubulointerstitial Nephropathy, Role of Collecting Duct Cell Proliferation

Manifestation of oculorenal syndrome in a dog chronically receiving zonisamide

AbstractTubulointerstitial nephropathy and uveitis, otherwise more broadly known as oculorenal syndrome in human medicine, is a condition that has, to the authors’ knowledge, not been described in veterinary medicine. This report describes an 8‐year‐old, male, neutered, mixed breed dog with a 6‐year history of idiopathic epilepsy, chronically receiving zonisamide, who was presented for sub‐acute and recurrent episodes of severe generalised weakness, altered mentation and inappropriate urination. Throughout the dog's hospital visits, recurrent anterior uveitis, progressive severe metabolic acidosis, proteinuria, persistent granular casts and severe renal tubular acidosis, which progressed to renal insufficiency, were evident. Due to a poor prognosis and perceived poor quality of life, the dog was humanely euthanased. Postmortem examination and histopathology revealed tubulointerstitial nephropathy. In conjunction with clinical uveitis, this presentation reflects similarities with the human oculorenal syndrome, here referred to as canine oculorenal syndrome suspected secondary to chronic zonisamide administration.

Fluid shear stress triggers cholesterol biosynthesis and uptake in inner medullary collecting duct cells, independently of nephrocystin-1 and nephrocystin-4.

Renal epithelial cells are subjected to fluid shear stress of urine flow. Several cellular structures act as mechanosensors-the primary cilium, microvilli and cell adhesion complexes-that directly relay signals to the cytoskeleton to regulate various processes including cell differentiation and renal cell functions. Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy leading to end-stage kidney failure before adulthood. NPHP1 and NPHP4 are the major genes which code for proteins that form a complex at the transition zone of the primary cilium, a crucial region required for the maintenance of the ciliary composition integrity. These two proteins also interact with signaling components and proteins associated with the actin cytoskeleton at cell junctions. Due to their specific subcellular localization, we wondered whether NPHP1 and NPHP4 could ensure mechanosensory functions. Using a microfluidic set up, we showed that murine inner medullary collecting ductal cells invalidated for Nphp1 or Nphp4 are more responsive to immediate shear exposure with a fast calcium influx, and upon a prolonged shear condition, an inability to properly regulate cilium length and actin cytoskeleton remodeling. Following a transcriptomic study highlighting shear stress-induced gene expression changes, we showed that prolonged shear triggers both cholesterol biosynthesis pathway and uptake, processes that do not seem to involve neither NPHP1 nor NPHP4. To conclude, our study allowed us to determine a moderate role of NPHP1 and NPHP4 in flow sensation, and to highlight a new signaling pathway induced by shear stress, the cholesterol biosynthesis and uptake pathways, which would allow cells to cope with mechanical stress by strengthening their plasma membrane through the supply of cholesterol.

Computational investigation of a novel uromodulin gene mutation (p.Y286C) in a family with autosomal dominant tubulointerstitial renal disease: A case study

Autosomal dominant tubulointerstitial kidney disease caused by a pathogenic variant in the UMOD gene (ADTKD) is a rare tubulointerstitial nephropathy characterized by hyperuricemia, gout, and slowly-progressing chronic renal insufficiency. The disease invariably progresses to end-stage renal disease (ESRD), and is believed to be one of the most common monogenic forms of kidney disease. It presents complete penetrance and inter- and intrafamilial clinical heterogeneity. The index case is a 17-year-old female who, at the age of seven began her renal function evaluation due to a family history of chronic renal insufficiency without etiological diagnosis. At this time she was already presenting with joint pain and increased serum creatinine and uric acid. Genetic testing detected a heterozygous variation in UMOD gene, c.857 A>G; p.Y286C, in two tested affected individuals but not in an unaffected family member. Here, an in silico analysis of the impact of this variant was performed, which provided support as to the deleterious nature of the variant. We also described clinical and laboratory data of 6 affected members, whose age of ESRD showed high variability, in agreement with the literature. This case provides evidence of the pathogenicity of a novel variant detected in the UMOD gene, in addition to providing clinical and laboratory data of individuals carrying this variant, highlighting the intrafamilial clinical variability.

Dry eyes, dry mouth & dormant limbs - A case series

Hypokalemic paralysis is a rare complication of distal renal tubular acidosis from any cause. Those cases diagnosed to have primary Sjogren’s syndrome is rare. Renal tubular acidosis caused by tubulointerstitial nephropathy is an extra glandular manifestation of primary Sjogren’s syndrome. We report three cases of flaccid quadriparesis diagnosed to have hypokalemia due to distal renal tubular acidosis and on furthur evaluation turned out to be Sjogren’s syndrome.

Determinants on urinary excretion of oxalate and other key factors related to urolithiasis among patients with chronic kidney disease: a single center study

PurposeUrolithiasis is a known risk factor for chronic kidney disease (CKD). However, how CKD might affect the risk of incidence of urolithiasis is not widely studied.MethodsUrinary excretion of oxalate as well as other key factors related to urolithiasis was analyzed in a single center study of 572 patients with biopsy-proven kidney disease.ResultsThe mean age of the cohort was 44.9 years and 60% were males. The mean eGFR was 65.9 ml/min/1.73 m2. Median urinary excretion of oxalate was 14.7 (10.4–19.1) mg/24-h and associated with current urolithiasis (OR 12.744, 95% CI: 1.564–103.873 per one logarithm transformed unit of urinary oxalate excretion). Oxalate excretion was not associated with eGFR and urinary protein excretion. Oxalate excretion was higher in patients with ischemia nephropathy as compared with patients with glomerular nephropathy and tubulointerstitial nephropathy (16.4 vs 14.8 vs 12.0 mg, p = 0.018). And ischemia nephropathy (p = 0.027) was associated with urinary oxalate excretion on adjusted linear regression analysis. Urinary excretion of calcium and uric acid was correlated with eGFR and urinary protein excretion (all p < 0.001), with ischemia nephropathy and tubulointerstitial nephropathy associated with uric acid excretion (both p < 0.01) as well. Citrate excretion was correlated with eGFR (p < 0.001) on adjusted linear regression.ConclusionExcretion of oxalate and other key factors related to urolithiasis was differentially associated with eGFR, urinary protein, and pathological changes in CKD patients. The influence of these intrinsic traits of the underlining kidney disease should be considered when evaluating urolithiasis risk in patients with CKD.

#3381 PROFILES OF HEMOGLOBIN TRAJECTORY IN CKD PATIENTS AND ASSOCIATED RISKS OF MAJOR ADVERSE CARDIOVASCULAR EVENTS: THE CKD-REIN COHORT STUDY

Abstract Background and Aims Anemia in chronic kidney disease (CKD) has been repeatedly associated with increased cardiovascular and all-cause morbidity and mortality. Most observational studies have focused on one single measurement of hemoglobin, but very few have investigated the trajectory of hemoglobin over time. Our aim was to identify, in moderate to severe CKD, typical profiles of hemoglobin trajectories, and to estimate their associated risk of major adverse cardiovascular event (MACE). Method We used data from the CKD-REIN cohort, which included 3033 patients with moderate to severe CKD from 40 nationally representative nephrology clinics in France between 2013 and 2016. A minimum of one hemoglobin measurement was necessary to be included. The primary endpoint was MACE defined as the first event among cardio-vascular death, myocardial infarction, stroke or hospitalization for acute heart failure. Secondary events included initiation of kidney replacement therapy (KRT) and death. A joint latent class mixed model was used to identify classes of hemoglobin trajectory and estimate the risk of each event. Once the model had identified classes and assigned participants in their class, we described the characteristics of patients in each class a posteriori. We also performed a posterior analysis to describe the course of estimated glomerular filtration rate (eGFR) in each class. Results A total of 3011 subjects were included in the analysis: 66% were men, median age at inclusion was 69 years. A total of 33874 hemoglobin measurements have been analyzed (median of 10 per patient). A total of 460 MACE, 522 KRT before MACE and 216 deaths before MACE or KRT, were recorded over a median follow-up of 4.3 years (Interquartile Range IQR 2.3-5.0). Five distinct classes were identified with a predominant one, Class-1 (‘constant’) including 63% (n = 1885) of the studied population with an overall stable trajectory surrounding a hemoglobin concentration of 13 g/dL (See figure below). For this class, risks of events were very low throughout the follow-up. Patients in this class had fewer cardiovascular risk factors, lower eGFR, and less often increased proteinuria at baseline than in other classes. Class-2 trajectory (‘late strong decline’, n = 75, 2.5%) had an abrupt decline at 2 years of follow-up; concomitantly risks of KRT and death before MACE emerged but the risk of MACE remained low over the follow-up. Patients classified in this class had more often tubulo-interstitial or unknown nephropathy than in other classes. Classes 3 ‘(late moderate decline, n = 438, 14.6%) and 4 (‘early moderate decline, n = 356, 11.8%) exhibited more moderate decline of hemoglobin level occurring on average at 3 and 1 year of follow-up, respectively. For these two classes, the risk of KRT before MACE increased from the start of these declines but their risks of MACE increased from the cohort entry. Class-5 (‘early strong decline’, n = 257, 8.5%) had a collapsing trajectory right from the entry into the cohort, and had a risk of MACE increasing rapidly in the very first year. Patients from Class-3 and Class-5, who had the highest risk of MACE, also had a worse cardiovascular profile at baseline. The average eGFR trajectories estimated in each of the 5 identified classes of hemoglobin showed similar patterns as those for hemoglobin. Conclusion In patients with CKD under nephrology care, most of patients have normal and stable hemoglobin values over time. In about one third of patients, 4 profiles of hemoglobin decline were observed, likely matching those of eGFR decline. These 4 classes with declining profiles had different levels of MACE risk and a strong increased risk of KRT after hemoglobin decline. This study suggests that more attention should be paid to dynamic changes of hemoglobin in the management of CKD.

#2850 EFFICIENCY OF THE GENETIC STUDY IN THE DIAGNOSIS OF AUTOSOMAL DOMINANT TUBULOINTERSTITIAL NEPHROPATHY

Abstract Background and Aims Autosomal dominant tubulointerstitial nephropathy (ADTKD) is a rare underdiagnosed cause of chronic kidney disease (CKD). ADTKD is a renal disease with a non-specific phenotypic expression that cause a slow progression over time. Given the great variability in its inter-familial presentation and among the same family members carrying the same mutation, its diagnosis is a challenge. Five genes have been identified to date such as Uromodulin (UMOD), Renin (REN), Hepatocyte Nuclear Factor 1b (HNF1β), Mucin-1 (MUC1) and, more recently, new genes, SEC61A1(encoding protein transport protein Sec61 subunit α and atypical (DNAJB11). Our main objective is to analyze the diagnostic yield of the genetic study in cases of clinical suspicion of ADTKD in patients with CKD of unknown etiology. We present a case series of patients from our center with CKD of unknown etiology and clinical suspicion of ADTKD. Genetic analysis of the gene SEC61A1 and DNAJB11 was not available at that time. Method This is a descriptive observational retrospective study from 2016 to 2021 at the Virgen del Rocio University Hospital in Seville, Spain. A total of 26 cases had phenotypic presentation of ADTKD. We collected clinical, laboratory, radiologic, and pathologic data. We performed in all the cases genetic testing for UMOD, MUC1, REN and HNF1β mutations. We collected data in a database, including age of presentation of kidney disease, sex, family history of kidney disease, the presence of hypertension at early age (defined as under 40 years of age), hyperuricemia (defined as uric acid &amp;gt;7.5 mg/dl) at early age (&amp;lt;40 years), hemoglobin at the time of diagnosis, age at last follow up with renal function and estimated glomerular filtration rate (eGFR) using the CKD-EPI (CKD Epidemiology Collaboration), urine elemental, renal ultrasound and renal biopsy if it had been performed. Descriptive results of quantitative variables are expressed as median. For categorical data, frequency and percentage are reported. Results Of the 26 cases with suspected ADTKD, 4 cases presented a genetic study that confirmed the diagnosis, that is, 15% of the cases. The median age at the time of the diagnosis was 41 years (IQR 32.7–48). 84% of the cases were male; 34% of cases had a family history of CKD of unknown etiology. 65% percent of the cases had a history of hyperuricemia at early age (&amp;lt;40 years), with a personal history of hypertension &amp;lt;40 years in 30% of the cases; 44% of the cases had renal lithiasis. The median glomerular filtration rate (CKD-EPI) at the time of diagnosis was 70 ml/min/1.73 m2 (46.4–70.7). In most of the patients, the urine elemental was normal. Renal cysts were found on ultrasound in 46% of patients. In 5 of the twenty-six patients a renal biopsy was performed, in which 60% presented data compatible with ADTKD with interstitial fibrosis and tubular atrophy. 4 of the patients with clinical suspicion of ADTKD obtained a genetic study that confirmed the diagnosis. The most frequently identified gene was HNF1β, being present in two of the four patients. The other genes identified were UMOD and MUC. The results are summarized in Table 1. Conclusion Adequate selection of patients based on clinical suspicion is essential to give greater profitability to the genetic study of this entity. The negativity of the study cannot exclude the diagnosis, since at the moment not all the causative genes of this pathology have been identified and it is necessary to use massive sequencing techniques or even the analysis of the complete exome to see the possibility of other variants of the disease.

A Rare Complication of Ascariasis: A Case of Acute Interstitial Nephritis.

Acute interstitial nephritis (AIN) due to helminths is a rare cause of acute kidney injury (AKI). Helminthiases often progresses insidiously, making diagnosis difficult. This was the case of a 72-year-old man, who presented with renal failure, itching and diarrhoea. Urinalysis revealed leukocyturia, microhaematuria and mild proteinuria. A full blood count revealed leucocytosis with eosinophilia. A stool parasitological examination revealed fertilised eggs of Ascaris lumbricoides. Tubulointerstitial nephropathy secondary to A. lumbricoides infection was suspected. A percutaneous renal biopsy was not performed since the patient refused the anti-platelet therapy discontinuation. Mebendazole, albendazole and prednisone therapy was administered. After worm eradiation and discharge, recovery from the parasitosis, absence of pruritus and eosinophilia, and progressive improvement of renal function were observed, strongly suggesting a causal relationship between Ascaris infection and AIN. Parasite infection should be considered in the differential diagnosis of unexplained renal failure because early diagnosis and treatment are necessary to avoid irreversible complications.

#5245 SUCCESSFUL THROMBOLYSIS OF AN ATRIAL TUNNELED DIALYSIS CATHETER AS A LAST RESORT VASCULAR ACCESS

Abstract Background and Aims The prolonged survival of patients on dialysis has resulted in a higher frequency of complications and failure related to vascular access. As a result, the situation of depleted vasculature in hemodialysis is becoming increasingly prevalent. The use of an atrial tunneled dialysis catheter (ATDC) has been reported as an effective solution for vascular access in these patients, but limited data is available on the associated complications, particularly thrombosis. Method This study reports the experience of a single nephrology center in Tunis with thrombosis of an ATDC as a last resort vascular access for dialysis. Results A 32-year-old patient with undetermined tubulo-interstitial nephropathy receiving dialysis presented in November 2022 with depleted vasculature. An ATDC was inserted as a final solution for vascular access, with an initial complication of a catheter-related bloodstream infection, which was resolved with broad-spectrum antibiotics with favorable results. One month later, dialysis could not be initiated through the ATDC. Catheter thrombosis was diagnosed as a guidewire was unable to pass through the catheter's lumen. The patient was successfully treated with thrombolysis using 50 mg of Alteplase, allowing dialysis to be resumed with a blood flow of 300 mL/min. Conclusion ATDC is a lifesaving and safe option for patients with depleted vasculature, with only 51 cases reported since 1999 [1]. The treatment of catheter thrombosis is not well defined, and to the best of our knowledge, no thrombolysis protocol has been established. This successful case may contribute to filling the knowledge gap in this field.

#5808 EFFECTIVENESS OF ORAL FOSFOMYCIN PROPHYLAXIS IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Background and Aims Urinary tract infections (UTIs) are one of the most common infectious complications in kidney transplant recipients (KTR), which are of great importance due to their high morbidity and recurrent nature. Our main objective was to evaluate the effectiveness of oral fosfomycin prophylaxis in a group of high-risk patients with recurrent/relapsing urinary tract infections. Method Retrospective study of a cohort of 60 KTR with frequent UTIs who had been prescribed daily fosfomycin calcium or fosfomycin trometamol every 7-10 days for prophylactic purposes. Demographic, clinical, analytical and microbiological data were collected during a year before and after prophylaxis. Results The median age was 61.8 (55.6-71.2) years, 68.3% were men, with 7.4 (2.8-13.6) years since the transplant. The main etiologies of the underlying renal disease were: autosomal dominant polycystic kidney disease 20%, chronic glomerulonephritis 18.3%, chronic tubulointerstitial nephropathy 10%, and diabetic kidney disease 10%, In 51.7% there was chronic pathology of the urinary tract (mainly vesico-prostatic disease, 24.8% and vesico-ureteral reflux, 15%), with a history of urological surgery in 23.3%. Up to 20% of the KTR had some type of endourological device (permanent/intermittent bladder catheter, percutaneous nephrostomy, Bricker, etc). The most frequently isolated germs were: E. coli and K. pneumoniae, 35.2 and 13.6% pre-prophylaxis and 28.3 and 22.6%, post-prophylaxis, respectively. The median number of UTI pre vs post-prophylaxis was 2 (1-4.75) vs. 1 (0.5-1.6) episode/patient/year (p&amp;lt;0.001), with a reduction in UTI episodes in 69% of patients. Admissions were also reduced, going from 35% in the pre-prophylaxis year to 10% post (p = 0.001). After prophylaxis, the percentage of resistance to fosfomycin increased from 26 to 54%. and a greater number of multi-resistant germs were isolated, 17.7 pre- vs 35% post-. The renal function remained stable during follow-up [CKD-EPI pre- 47.2(20.8) vs 47.2(21.2) ml/min post-]. Conclusion Oral fosfomycin prophylaxis may be useful in KTR despite the underlying urological pathology, managing to reduce UTI episodes and the need for admission for this reason.

#4440 PREVALENCE OF GENES INVOLVED IN HEREDITARY KIDNEY DISEASE AS A TOOL FOR THE DEVELOPMENT OF A GENE PANEL

Abstract Background and Aims Genetic study is the fundamental tool for the diagnosis of Hereditary Kidney Diseases (HKD). The proliferation of its use has led to an increase in diagnostic complexity due to phenotypic overlap and genotypic heterogeneity. The aim of this study is to evaluate the prevalence of genes in our series of adult patients with suspected monogenic kidney disease in order to develop the basis for the elaboration of a gene panel that will make its usefulness in our routine clinical practice profitable. Method A retrospective descriptive observational study was performed with the collection of all genetic studies that were positive in the period between October 2014 and December 2020 in our center. With a description of the causative genes involved, as well as the clinical data of the proband patients who turned out to be carriers of these variants. Descriptive results of continuous variables are expressed as mean and standard deviation (SD) or median and interquartile range (IQR) according to their distribution. For categorical data, frequency and percentage are reported. Results The results of a total of 77 genetic studies on probands were collected, of whom 51% were women with a mean age at diagnosis of 46 years (SD ± 13.4) and 64.9% had a family history of kidney disease. Renal function measured by mean estimated glomerular filtration rate (eGFR) using the CKD-EPI (CKD Epidemiology Collaboration) was 90.1 ml/min/1,73 m2 (SD ± 29.64) with a mean proteinuria quantified in 24-hour urine of 627.9 mg (SD ±43.7) and 7.7% were on renal replacement therapy. (Table 1) 40.25% of probands were carriers of a mutation for Alport syndrome, in this group the most frequent gene was COL4A3 in 50% of cases. The second most frequent entity was autosomal dominant polycystic kidney disease (ADPKD) with 37% of the studies and among these the great majority were carriers of a variant in the PKD1 gene with 96.5%. The remaining diagnostic entities in order of frequency were Fabry disease, autosomal dominant tubulointerstitial nephropathy (ADTKD), congenital anomalies of the kidney and urinary tract (CAKUT), nephrotic syndrome, hereditary angiopathy with nephropathy, aneurysm and cramps syndrome (HANAC) and tuberous sclerosis (Figure 1). Conclusion Alport syndrome was the most frequently identified entity in patients with suspected monogenic renal disease in whom the genetic study was performed. Based on the results of our series, a proposal has been made for the genes to be included in a panel for hereditary renal diseases in our center. The development of these panels increases the efficiency and increases the cost-effectiveness of genetic studies in the diagnosis of these patients.

Chronic Tubulointerstitial Nephropathy of Agricultural Communities

Chronic interstitial nephritis in agricultural communities is an emerging public health concern affecting numerous agricultural communities in tropical countries, including regions in India, with a significant impact on the health and well-being of affected individuals. The affected individuals suffer from various psychosocial, nutritional, and metabolic challenges due to organ failure, which affects their quality of life. The etiology remains poorly understood, and various risk factors, which include various environmental and occupational hazards, have been implicated in its development. The recent discovery of lysosomal proximal tubulopathy has reignited interest in its pathogenesis. Along with the representative feature of chronic interstitial nephritis, changes suggestive of tubular injury have also been reported. It is suggested to use the term “chronic tubulointerstitial nephropathy of agricultural community” instead of chronic interstitial nephritis of the agricultural communities. Chronic tubulointerstitial nephropathy in agricultural communities is a slowly progressive disease that initially does not cause any symptoms in patients and most patients have a delayed onset of symptoms. Several diagnostic criteria have been introduced over the past years and one introduced by the Ministry of Health of Sri Lanka is widely used. The management of this chronic illness is no different from other causes of chronic interstitial nephritis and our focus should be on implementing various preventive strategies to reduce its incidence in agricultural communities and protect the health and well-being of agricultural workers. By disseminating knowledge about chronic tubulointerstitial nephropathy in agricultural communities, we can contribute to the development of evidence-based interventions to reduce the burden of the disease on affected communities. Moreover, we would like to sensitize physicians to this entity to increase awareness and identify potential endemic areas in various agricultural communities.

Beyond the kidney biopsy: genomic approach to undetermined kidney diseases.

According to data from large national registries, almost 20%-25% of patients with end-stage kidney disease have an undetermined kidney disease (UKD). Recent data have shown that monogenic disease-causing variants are under-diagnosed. We performed exome sequencing (ES) on UKD patients in our center to improve the diagnosis rate. ES was proposed in routine practice for patients with UKD including kidney biopsy from January 2019 to December 2021. Mutations were detected using a targeted bioinformatic customized kidney gene panel (675 genes). The pathogenicity was assessed using American College of Medical Genetics guidelines. We included 230 adult patients, median age 47.5 years. Consanguinity was reported by 25 patients. A family history of kidney disease was documented in 115 patients (50%). Kidney biopsies were either inconclusive in 69 patients (30.1%) or impossible in 71 (30.9%). We detected 28 monogenic renal disorders in 75 (32.6%) patients. Collagenopathies was the most common genetic kidney diagnosis (46.7%), with COL4A3 and COL4A4 accounting for 80% of these diagnoses. Tubulopathies (16%) and ciliopathies (14.7%) yielded, respectively, the second and third genetic kidney diagnosis category and UMOD-associated nephropathy as the main genetic findings for tubulopathies (7/11). Ten of the 22 patients having ES "first" eventually received a positive diagnosis, thereby avoiding 11 biopsies. Among the 44 patients with glomerular, tubulo-interstitial or vascular nephropathy, 13 (29.5%) were phenocopies. The diagnostic yield of ES was higher in female patients (P=.02) and in patients with a family history of kidney disease (P<.0001), reaching 56.8% when the patient had both first- and second-degree family history of renal disease. Genetic diagnosis has provided new clinical insights by clarifying or reclassifying kidney disease etiology in over a third of UKD patients. Exome "first" may have a significant positive diagnostic yield, thus avoiding invasive kidney biopsy; moreover, the diagnostic yield remains elevated even when biopsy is impossible or inconclusive. ES provides a clinical benefit for routine nephrological healthcare in patients with UKD.

What do we know about lithium associated hypercalcemia?

IntroductionLithium associated with hypercalcemia may mimic a psychiatric condition and be confused for a relapse of bipolar disorder. The etiology seems to be due to a reduced sensitivity of the parathyroid cells to calcium, altering the parathyroid hormone (PTH) response. Lithium as an essential monovalent cation has some structural similarity to calcium (Ca) and can interact with protein receptors. This leads to changes in the inhibitory configuration of PTH and increased serum calcium concentrations, rising the threshold necessary to suppress hormone secretion.Lithium-induced hyperparathyroidism (HIL) is the main cause of hypercalcemia in these patients.ObjectivesBased on a clinical case of lithium-associated hypercalcemia in a patient with bipolar disorder, review the existing literature and state the needs for periodic monitoring protocols.MethodsCase report and bibliographical review.ResultsA 38-year-old woman, diagnosed with bipolar affective disorder at the age of 18, has been treated with lithium during which she developed secondary tubulointerstitial nephropathy as an adverse effect. Recently, she requested medical evaluation for constitutional syndrome associated with deterioration of general condition with loss of strength and difficulty in walking. Analytically, mild hypercalcemia was detected, and the study was extended to include Ca and PTH.Chronic lithium therapy often develops mild hypercalcemia (approximately 10 to 20 percent of patients taking lithium), most likely due to increased secretion of PTH. Lithium can also unmask previously unrecognized mild hyperparathyroidism in patients with adenomas within a few years of starting therapy or induce parathyroid hyperplasia with a chronic use.The hypercalcemia usually, but not always, subsides when the lithium is stopped. Normalization of serum calcium is more likely to occur one to four weeks post-lithium withdrawal in patients with a relatively short duration of lithium use. It is less likely in patients receiving lithium for more than 10 years.Regarding the case to be presented, a review of the literature is carried out and the need to propose periodic calcium monitoring protocols is exposed.ConclusionsRecommendations include determination of serum calcium every 6 months, urinary calcium and creatinine every 12 months, and bone mineral density monitoring every 1 to 3 years. Regular analytical monitoring including total calcium, PTH and vitamin D, would identify patients with a tendency to hypercalcemia so that appropriate measures could be taken. So as chronic treatment with lithium can develop mild hypercalcemia, I consider it necessary to develop periodic monitoring protocols for this adverse effect.Disclosure of InterestNone Declared