Progressive Decline In Renal Function Research Articles

Pathogenesis and methods of diagnosis of chronic kidney disease in cats: retrospective analysis (1981–2007)

The aim: to conduct a retrospective analysis of literature sources on the pathogenesis and methods of diagnosis of chronic kidney disease in cats.
 Materials and methods. The research was conducted by the method of scientific literature open-source analysis: PubMed, Elsevier, electronic resources of the National Library named after V.I. Vernadsky (1981–2007).
 Results. Chronic kidney disease is a common reason for cat owners to go to veterinary clinics. The term “chronic kidney disease” has a broader meaning than the more limited and not very specific name – chronic renal failure; it is also used to indicate the preazotemic stage of the disease. Chronic kidney disease is characterized by a gradual deterioration of the clinical condition of animals due to progressive decline in renal function. An idea of the pathogenesis and methods of diagnosis of chronic kidney disease in the period from 1981 to 2007 is presented.
 Conclusions. According to the results of retrospective analysis of literature sources for the period from 1981 to 2007, the basis was identified aspects of the pathogenesis of chronic kidney disease in domestic cats, which have not lost relevance today. The main link during chronic kidney disease in cats is the development of hyperazotemia and, as a consequence, endogenous intoxication of the body, which develops gradually and leads to the death of the animal. The morphological basis of chronic kidney disease in cats is the development of diffuse nephrosclerosis, which is reflected in the results of clinical, biochemical and instrumental studies. According to biochemical analysis of blood, in cats recorded an increase in urea and creatinine, the results of clinical studies of urine showed a decrease in its relative density, as well as the development of proteinuria, the appearance of erythrocytes and cylinders. According to the results of hematological research, anemic syndrome develops due to decreased erythropoietin synthesis. With age in cats, ultrasound examination of the kidneys reveals a decrease in their volume due to uniform sclerosis of the parenchyma: it is determined by its thinning and increased echogenicity due to the accumulation of connective tissue components, which is a sign of nephrosclerosis. Although kidney biopsy is the most informative method of diagnosing chronic kidney disease, it has many contraindications, which does not allow its use in the routine diagnosis of nephropathy in domestic cats. its thinning and increase in echogenicity due to the accumulation of connective tissue components, which is a sign of nephrosclerosis, is determined. Although kidney biopsy is the most informative method of diagnosing chronic kidney disease, it has many contraindications, which does not allow its use in the routine diagnosis of nephropathy in domestic cats. Its thinning and increase in echogenicity due to the accumulation of connective tissue components, which is a sign of nephrosclerosis, is determined

Unravelling the Role of PAX2 Mutation in Human Focal Segmental Glomerulosclerosis.

No effective treatments are available for familial steroid-resistant Focal Segmental Glomerulosclerosis (FSGS), characterized by proteinuria due to ultrastructural abnormalities in glomerular podocytes. Here, we studied a private PAX2 mutation identified in a patient who developed FSGS in adulthood. By generating adult podocytes using patient-specific induced pluripotent stem cells (iPSC), we developed an in vitro model to dissect the role of this mutation in the onset of FSGS. Despite the PAX2 mutation, patient iPSC properly differentiated into podocytes that exhibited a normal structure and function when compared to control podocytes. However, when exposed to an environmental trigger, patient podocytes were less viable and more susceptible to cell injury. Fixing the mutation improved their phenotype and functionality. Using a branching morphogenesis assay, we documented developmental defects in patient-derived ureteric bud-like tubules that were totally rescued by fixing the mutation. These data strongly support the hypothesis that the PAX2 mutation has a dual effect, first in renal organogenesis, which could account for a suboptimal nephron number at birth, and second in adult podocytes, which are more susceptible to cell death caused by environmental triggers. These abnormalities might translate into the development of proteinuria in vivo, with a progressive decline in renal function, leading to FSGS.

A prediction model for the decline in renal function in people with type 2 diabetes mellitus: study protocol

BackgroundChronic kidney disease (CKD) is a well-established complication in people with diabetes mellitus. Roughly one quarter of prevalent patients with diabetes exhibit a CKD stage of 3 or higher and the individual course of progression is highly variable. Therefore, there is a clear need to identify patients at high risk for fast progression and the implementation of preventative strategies. Existing prediction models of renal function decline, however, aim to assess the risk by artificially grouped patients prior to model building into risk strata defined by the categorization of the least-squares slope through the longitudinally fluctuating eGFR values, resulting in a loss of predictive precision and accuracy.MethodsThis study protocol describes the development and validation of a prediction model for the longitudinal progression of renal function decline in Caucasian patients with type 2 diabetes mellitus (DM2). For development and internal-external validation, two prospective multicenter observational studies will be used (PROVALID and GCKD). The estimated glomerular filtration rate (eGFR) obtained at baseline and at all planned follow-up visits will be the longitudinal outcome. Demographics, clinical information and laboratory measurements available at a baseline visit will be used as predictors in addition to random country-specific intercepts to account for the clustered data. A multivariable mixed-effects model including the main effects of the clinical variables and their interactions with time will be fitted. In application, this model can be used to obtain personalized predictions of an eGFR trajectory conditional on baseline eGFR values. The final model will then undergo external validation using a third prospective cohort (DIACORE). The final prediction model will be made publicly available through the implementation of an R shiny web application.DiscussionOur proposed state-of-the-art methodology will be developed using multiple multicentre study cohorts of people with DM2 in various CKD stages at baseline, who have received modern therapeutic treatment strategies of diabetic kidney disease in contrast to previous models. Hence, we anticipate that the multivariable prediction model will aid as an additional informative tool to determine the patient-specific progression of renal function and provide a useful guide to early on identify individuals with DM2 at high risk for rapid progression.

Aristolochic Acid Induces Renal Fibrosis and Senescence in Mice.

The kidney is one of the most susceptible organs to age-related impairments. Generally, renal aging is accompanied by renal fibrosis, which is the final common pathway of chronic kidney diseases. Aristolochic acid (AA), a nephrotoxic agent, causes AA nephropathy (AAN), which is characterized by progressive renal fibrosis and functional decline. Although renal fibrosis is associated with renal aging, whether AA induces renal aging remains unclear. The aim of the present study is to investigate the potential use of AAN as a model of renal aging. Here, we examined senescence-related factors in AAN models by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group demonstrated aging kidney phenotypes, such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidneys, and increased renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, as well as reactive oxygen species accumulation. Klotho, an antiaging gene, was also significantly decreased in the kidneys of AA-treated mice. Collectively, the results of the present study indicate that AA alters senescence-related factors, and that renal fibrosis is closely related to renal aging.

Progressive decline of function in renal allografts with normal 1-year biopsies: Gene expression studies fail to identify a classifier.

Histologic findings on 1-year biopsies such as inflammation with fibrosis and transplant glomerulopathy predict renal allograft loss by 5 years. However, almost half of the patients with graft loss have a 1-year biopsy that is either normal or has only interstitial fibrosis. The goal of this study was to determine if there was a gene expression profile in these relatively normal 1-year biopsies that predicted subsequent decline in renal function. Using transcriptome microarrays we measured intragraft mRNA levels in a retrospective Discovery cohort (170 patients with a normal/minimal fibrosis 1-year biopsy, 54 with progressive decline in function/graft loss and 116 with stable function) and developed a nested 10-fold cross-validated gene classifier that predicted progressive decline in renal function (positive predictive value=38 ± 34%%; negative predictive value=73 ± 30%, c-statistic=.59). In a prospective, multicenter Validation cohort (270 patients with Normal/Interstitial Fibrosis [IF]), the classifier had a 20% positive predictive value, 85% negative predictive value and .58 c-statistic. Importantly, the majority of patients with graft loss in the prospective study had 1-year biopsies scored as Normal or IF. We conclude predicting graft loss in many renal allograft recipients (i.e., those with a relatively normal 1-year biopsy and eGFR>40) remains difficult.

Glucose control, diabetic retinopathy, and hemodialysis induction in subjects with normo-microalbuminuric type 2 diabetic patients with normal renal function followed for 15 years

AimsA high urinary albumin excretion (UAE) and low glomerular filtration rate (GFR) are risk factors for progressive renal function loss in type 2 diabetic patients. In addition, diabetic retinopathy (DR) is also a risk factor for progressive renal function decline in microalbuminuric type 2 diabetic patients. We aimed to elucidate the factors, including DR, associated with a more severe situation of diabetic nephropathy, i.e., hemodialysis (HD) induction in normo- and microalbuminuric type 2 diabetic patients without renal dysfunction. MethodsNormo- and microalbuminuric type 2 diabetic patients with normal renal function whose GFRs had been measured by iohexol injection in 1995–1997 and had been followed for over 5 years were analyzed (n = 199). HbA1c levels was divided into HbA1c ≥ 7.0 (n = 146) and <7.0 (n = 53) groups. The UAE levels were classified as normoalbuminuria (NA, n = 114) and microalbuminuria (MA, n = 85). Seventy-two patients had DR, and 96 had hypertension. Patients were followed up for 15.7 ± 6.0 years and frequency of and duration to the HD induction were evaluated. ResultsDuring the study period, 8 patients received HD induction. There were no remarkable differences in the rates of HD induction between patients with and without HbA1c ≥7.0, microalbuminuria, DR or hypertension. A Kaplan-Meier analysis revealed that HbA1c ≥7.0 (p = 0.037) and DR (p = 0.037) were associated with a significantly higher risk of HD induction than HbA1c <7.0 and no DR, respectively while albuminuria grade and hypertension were not associated with the risk of HD induction. There was significant negative correlation between HbA1c and annual decline rate of eGFR and annual decline rate of eGFR in the patients with prepro-proliferative DR (PDR) was significantly higher than that in the patients without DR. In the multivariate analysis, HbA1c and PDR showed significant relationships with the annual decline rate of eGFR. ConclusionsIt was reasonable that poorer glycemic control affected HD induction for 16 years follow-up. However, DR, especially PDR, should also be considered a substantial risk factor for HD induction although microalbuminuria and hypertension did not predict it at the early stage of diabetic nephropathy in type 2 diabetic patients with normal renal function.

Diffusion tensor imaging for the study of early renal dysfunction in patients affected by bardet-biedl syndrome

Kidney structural abnormalities are common features of Bardet-Biedl syndrome (BBS) patients that lead to a progressive decline in renal function. Magnetic resonance diffusion tensor imaging (DTI) provides useful information on renal microstructures but it has not been applied to these patients. This study investigated using DTI to detect renal abnormalities in BBS patients with no overt renal dysfunction. Ten BBS subjects with estimated glomerular filtration rates over 60 ml/min/1.73m2 and 14 individuals matched for age, gender, body mass index and renal function were subjected to high-field DTI. Fractional anisotropy (FA), and mean, radial and axial diffusivity were evaluated from renal cortex and medulla. Moreover, the corticomedullary differentiation of each DTI parameter was compared between groups. Only cortical FA statistically differed between BBS patients and controls (p = 0.033), but all the medullary DTI parameters discriminated between the two groups with lower FA (p < 0.001) and axial diffusivity (p = 0.021) and higher mean diffusivity (p = 0.043) and radial diffusivity (p < 0.001) in BBS patients compared with controls. Corticomedullary differentiation values were significantly reduced in BBS patients. Thus, DTI is a valuable tool for investigating microstructural alterations in renal disorders when kidney functionality is preserved.

Особенности поражения почек при системных заболеваниях соединительной ткани

Системные заболевания соединительной ткани (СЗСТ) — достаточно большая гетерогенная группа заболеваний, имеющих определенные характерные клинические проявления и нарушения иммунорегуляции, приводящие к образованию аутоантител. Субклинические или явные признаки вовлечения почек имеют значительное усугубляющее влияние на клиническое течение СЗСТ. Нарушение функции почек характерно для таких СЗСТ, как системная красная волчанка (СКВ), ревматоидный артрит (РА), системная склеродермия, синдром Шегрена, аутоиммунные миопатии (дерматомиозит и полимиозит). На современном этапе, учитывая доступность многих диагностических манипуляций и возможности этиопатогенетического лечения, терапевтам, ревматологам и нефрологам необходимо своевременно заподозрить наличие заболевания почек у пациентов с СЗСТ и принять необходимые меры по диагностике и лечению. Современные стратегии классификации и лечения СКВ скорректированы с учетом результатов биопсии почек, что значительно улучшило прогноз поражения почек при этом заболевании. Одно из наиболее тяжелых поражений почек у пациентов с СЗСТ — это почечный склеродермический криз (ПСК), характеризующийся тяжелой гипертонией, прогрессирующим снижением функции почек и тромботической микроангиопатией, своевременное назначение ингибиторов ангиотензинпревращающего фермента таким пациентам показывает значительный эффект в борьбе с ПСК. Контроль активности основного заболевания улучшает функцию почек у большинства пациентов с синдромом Шегрена, аутоиммунными миопатиями и РA. С другой стороны, хроническое использование иммунодепрессантов и нестероидных противовоспалительных препаратов, а также сопутствующие заболевания, такие как диабет, гипертония и сердечно-сосудистые осложнения, могут являться основными причинами поражения почек у пациентов с ревматическими заболеваниями. Кроме того, первичные заболевания почек с длительным анамнезом могут привести к проявлениям, имитирующим первичные ревматологические расстройства. В этом обзоре мы фокусируемся на диагностике нарушений функции почек вследствие основного заболевания, побочных эффектах препаратов и принятии решений о своевременном соответствующем лечении.

The chloride channel CFTR is not required for cyst growth in an ADPKD mouse model.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of bilateral renal cysts which enlarge continuously, leading to compression of adjacent intact nephrons. The growing cysts lead to a progressive decline in renal function. Cyst growth is driven by enhanced cell proliferation and chloride secretion into the cyst lumen. Chloride secretion is believed to occur mainly by the cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR), with some contribution by the calcium-activated chloride channel TMEM16A. However, our previous work suggested TMEM16A as a major factor for renal cyst formation. The contribution of CFTR to cyst formation has never been demonstrated in an adult ADPKD mouse model. We used mice with an inducible tubule-specific Pkd1 knockout, which consistently develop polycystic kidneys upon deletion of Pkd1. Cellular properties, ion currents, and cyst development in these mice were compared with that of mice carrying a co-deletion of Pkd1 and Cftr. Knockout of Cftr did not reveal any significant impact on cyst formation in the ADPKD mouse model. Furthermore, knockout of Cftr did not attenuate the largely augmented cell proliferation observed in Pkd1 knockout kidneys. Patch clamp analysis on primary renal epithelial cells lacking expression of Pkd1 indicated an only marginal contribution of CFTR to whole cell Cl- currents, which were clearly dominated by calcium-activated TMEM16A currents. In conclusion, CFTR does not essentially contribute to renal cyst formation in mice caused by deletion of Pkd1. Enhanced cell proliferation and chloride secretion is caused primarily by upregulation of the calcium-activated chloride channel TMEM16A.

In The Absence Of Cardiometabolic Diseases Is Age An Independent Factor In Assessing Renal Health And Function? A Pilot Study

Estimated glomerular filtration rate (eGFR) is a measure of renal filtration and clearance of serum creatinine and is conventionally used to characterize the progressive decline in renal function (RF). Assessment of RF and renal health (RH) is traditionally believed to be age-dependent. However, in the absence of cardiometabolic diseases (hypertension, diabetes, hyperlipemia, etc.), this may not be the case. Recently, novel markers of RH and RF support the notion that age is a secondary factor influencing renal decline. PURPOSE: To determine the magnitude of age as an influencing factor involved in the decline of RF with novel markers of RH and function in the absence of cardiometabolic risk factors. METHODS: Fifty-four participants (n = 27 men; n = 27 women; age 33.4 + 12.5 yr; height 171.7 + 10.9 cm; weight 77.9 + 15.9 kg; BMI 26.5 + 5.5; SBP 120 + 10.4; DBP 77.7 + 6.7; CHOL 174 + 30; and GLU 95 + 7) completed a single health assessment to quantify renal health and function. Blood and urine samples were collected by the same technician under standardized conditions and stored at -80 °C until project completion. Serum creatinine (sCR), urine creatinine (uCr), cystatin C (CyC), and urine epidermal growth factor (uEGF) were used to calculate estimates of renal health and function via uEGF/uCr ratio (uEGFR), eGFR - modification of diet in renal disease (MDRD), CKD-EPI, and SCr/CyC eGFR. Renal health and function markers were analyzed and compared in age groups (20s, 30s, 40s, 50s) using 4 (group) by 1 (sample) ANOVAs. RESULTS: There were no significant differences between age groups in the biomarkers and estimates of RH and RF. sCR (F = 0.17, p = 0.91), uEGF (F = 0.87, p = 0.46), CyC (F = 1.98, p = 0.13), CyC eGFR (F = 2.81, p = 0.10), MDRD (F = 2.08, p = 0.12), CKD-EPI (F = 0.34, p = 0.80), and SCr/CyC eGFR (F = 2.05, p = 0.12). uEGFR was significantly different between (F = 1.93, p = 0.14) different between age groups. uCr was significantly different ((F = 5.33, p = 0.003) between 40s and 50s. CONCLUSION: Changes in RH and RF appear to be independent of age in the absence of cardiometabolic diseases, indicates RH and RF could potentially be maintained in adulthood, middle age, and possibly attenuated in the senior years with the continued absence of cardiometabolic diseases.

Long Non-coding RNA: An Emerging Contributor and Potential Therapeutic Target in Renal Fibrosis.

Renal fibrosis (RF) is a pathological process that culminates in terminal renal failure in chronic kidney disease (CKD). Fibrosis contributes to progressive and irreversible decline in renal function. However, the molecular mechanisms involved in RF are complex and remain poorly understood. Long non-coding RNAs (lncRNAs) are a major type of non-coding RNAs, which significantly affect various disease processes, cellular homeostasis, and development through multiple mechanisms. Recent investigations have implicated aberrantly expressed lncRNA in RF development and progression, suggesting that lncRNAs play a crucial role in determining the clinical manifestation of RF. In this review, we comprehensively evaluated the recently published articles on lncRNAs in RF, discussed the potential application of lncRNAs as diagnostic and/or prognostic biomarkers, proposed therapeutic targets for treating RF-associated diseases and subsequent CKD transition, and highlight future research directions in the context of the role of lncRNAs in the development and treatment of RF.

Renoprotective effects of sodium glucose cotransporter 2 inhibitors in type 2 diabetes patients with decompensated heart failure

BackgroundSodium-glucose cotransporter 2 inhibitor (SGLT2i) reduces the risk of the composite renal endpoint and weakens the progressive decline in renal function in patients with chronic heart failure (HF). However, a detailed mechanism of SGLT2i on renal function and outcome remains uninvestigated.MethodsWe prospectively included 40 type 2 diabetic mellitus (T2DM) patients (median 68 years old, 29 male) who were hospitalized for decompensated HF and received SGLT2i during the index hospitalization. Of them, 24 patients had increases in estimated glomerular filtration rate (eGFR) at 12-month follow-up and 16 had decreases in eGFR. We investigated the baseline factors associating with the improvement in renal function.ResultsLower plasma B-type natriuretic peptide (BNP) level and the use of renin-angiotensin system inhibitor (RASI) were independently associated with increases in eGFR during the follow-up period (p < 0.05 for both). Patients with both low plasma BNP levels and uses of RASI achieved significant increases in eGFR irrespective of the baseline HbA1c levels.ConclusionsLower plasma BNP level and the use of RASI at baseline were the key factors contributing to the renoprotective effects of SGLT2i among patients with decompensated HF and T2DM.

A phosphate and calcium-enriched diet promotes progression of 5/6-nephrectomy-induced chronic kidney disease in C57BL/6 mice

C57BL/6 mice are known to be rather resistant to the induction of experimental chronic kidney disease (CKD) by 5/6-nephrectomy (5/6-Nx). Here, we sought to characterize the development of CKD and its cardiac and skeletal sequelae during the first three months after 5/6-Nx in C57BL/6 mice fed a calcium- and phosphate enriched diet (CPD) with a balanced calcium/phosphate ratio. 5/6-NX mice on CPD showed increased renal fibrosis and a more pronounced decrease in glomerular filtration rate when compared to 5/6-Nx mice on normal diet (ND). Interestingly, despite comparable levels of serum calcium, phosphate, and parathyroid hormone (PTH), circulating intact fibroblast growth factor-23 (FGF23) was 5 times higher in 5/6-Nx mice on CPD, relative to 5/6-Nx mice on ND. A time course experiment revealed that 5/6-Nx mice on CPD developed progressive renal functional decline, renal fibrosis, cortical bone loss, impaired bone mineralization as well as hypertension, but not left ventricular hypertrophy. Collectively, our data show that the resistance of C57BL/6 mice to 5/6-Nx can be partially overcome by feeding the CPD, and that the CPD induces a profound, PTH-independent increase in FGF23 in 5/6-Nx mice, making it an interesting tool to assess the pathophysiological significance of FGF23 in CKD.

Metabolic syndrome severity score and the progression of CKD.

Metabolic syndrome severity, expressed by the continuous metabolic syndrome risk score (MetS score), has been demonstrated to be able to predict future health conditions. However, little is known about the association between MetS score and renal function. A total of 22,719 participants with normal renal function abstracted from the Kailuan Study were followed from 2006 to 2016. The new onset of chronic kidney disease (CKD) was defined as eGFR <60ml/min per 1.73m2 and/or proteinuria >300mg/dl. Progressive decline in renal function was defined as an annual change rate of eGFR below the 10th percentile of the whole population. In the multivariate-adjusted model, we found that the risk of progressive decline in renal function increased consistently with the MetS score, with an odds ratio of 1.49 (95% CI, 1.28, 1.73) for those subjects>75th percentile compared with those <25th percentile. Additionally, a high MetS score was found to be associated with an increased risk of CKD, with a hazard ratio of 1.53 (95% CI, 1.33, 1.78) for subjects >75th percentile compared with those <25th percentile. Our findings suggested that the MetS score was associated with an increased risk of a progressive decline in renal function and was also a strong and independent risk factor for the development of CKD. These findings provide evidence of the potential clinical utility of the MetS score for assessing metabolic syndrome severity to detect the risk of decreased renal function and CKD.

Circulating proteins protect against renal decline and progression to end-stage renal disease in patients with diabetes.

Diabetic kidney disease (DKD) and its major clinical manifestation, progressive renal decline that leads to end-stage renal disease (ESRD), are a major health burden for individuals with diabetes. The disease process that underlies progressive renal decline comprises factors that increase risk as well as factors that protect against this outcome. Using untargeted proteomic profiling of circulating proteins from individuals in two independent cohorts with type 1 and type 2 diabetes and varying stages of DKD followed for 7 to 15 years, we identified three elevated plasma proteins-fibroblast growth factor 20 (OR, 0.69; 95% CI, 0.54 to 0.88), angiopoietin-1 (OR, 0.72; 95% CI, 0.57 to 0.91), and tumor necrosis factor ligand superfamily member 12 (OR, 0.75; 95% CI, 0.59 to 0.95)-that were associated with protection against progressive renal decline and progression to ESRD. The combined effect of these three protective proteins was demonstrated by very low cumulative risk of ESRD in those who had baseline concentrations above median for all three proteins, whereas the cumulative risk of ESRD was high in those with concentrations below median for these proteins at the beginning of follow-up. This protective effect was shown to be independent from circulating inflammatory proteins and clinical covariates and was confirmed in a third cohort of diabetic individuals with normal renal function. These three protective proteins may serve as biomarkers to stratify diabetic individuals according to risk of progression to ESRD and might also be investigated as potential therapeutics to delay or prevent the onset of ESRD.

New familial cases of karyomegalic interstitial nephritis with mutations in the FAN1 gene

BackgroundKaryomegalic interstitial nephritis (KIN) is a rare disease entity first described by Burry in 1974. The term KIN was introduced by Mihatsch et al. in 1979. KIN is characterized by chronic tubulointerstitial nephritis associated with enlarged tubular epithelial cell nuclei, which leads to a progressive decline of renal function. The prevalence of this disease is less than 1% of all biopsies, and its pathogenesis is unclear. KIN results from mutations in FAN1 (FANCD2/FANCI-Associated Nuclease 1), a gene involved in the DNA damage response pathway, particularly in the kidney. In this study, we report two Tunisian consanguineous families with KIN caused by mutations in the FAN1 gene.MethodsDirect sequencing of the coding regions and flanking intronic sequences of the FAN1 gene was performed in three affected members. Three prediction programs (Polyphen-2 software, SIFT, and MutationTaster) were used to predict the functional effect of the detected variations.ResultsTwo causative frameshift variants in the FAN1 gene were identified in each family: The previously described frameshift mutation c.2616delA (p.Asp873ThrfsTer17) and a novel mutation c.2603delT (p.Leu868ArgfsTer22) classified as "pathogenic" according to the American College of Medical Genetics and Genomics (ACMG) guidelines.ConclusionTo our best knowledge, this is the first Tunisian study involving familial cases of KIN with mutations in the FAN1 gene. We hypothesize that these findings can expand the mutational spectrum of KIN and provide valuable information on the genetic cause of KIN.

MO004PRIMARY BILIARY CHOLANGITIS PRESENTING WITH RENAL FANCONI SYNDROME: A FORGOTTEN PHENOTYPE

Abstract Background and Aims Primary biliary cholangitits (PBC) is an autoimmune liver disease, leading to liver fibrosis and cirrhosis. It is a rare disease affecting 1 in 3-4000 people and is more common in females. Symptoms may go unnoticed and include itch and fatigue. Most patients have anti-mitochondrial antibodies (AMA) as well as raised gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) levels. First line treatment for PBC is ursodeoxycholic acid and is usually continued lifelong. It improves liver biochemistry, histological progression of liver disease and liver transplant-free survival. Renal complications of PBC include distal renal tubular acidosis (RTA), tubule-interstitial nephritis (TIN) and renal Fanconi syndrome. Method We reviewed a case of PBC presenting with renal Fanconi syndrome. Results A 48-year-old female was referred to the renal clinic due to progressive decline in renal function since she was diagnosed with type 2 diabetes in 2007. She was also known to have AMA (&amp;gt;1:640) and previously had transient transaminitis. She was clinically well with no major symptoms but reported that she had had a few episodes of urinary tract infection in the previous year. Her diabetes was managed with lifestyle modifications in the past until a few months ago when Metformin was introduced. However, her HbA1c level had never been greater than 55 mmol/mol. Urine dipstick in the clinic showed pH of 6, blood+, glucose+++, protein+++ and ketone trace. The severity of glycosuria was inconsistent with her glycaemic control. There was a disparity between her urine albumin/creatinine ration (ACR) of 18.8g/mol and protein/creatinine ratio (PCR) of 124mg/mmol. Myeloma screen was negative and further urine analysis showed generalised aminoaciduria. She also had hypouricaemia, intermittent hypophosphataemia and non-anion gap metabolic acidosis. These results are in keeping with renal Fanconi syndrome. Her eGFR was 48 ml/min/1.72m2 in 2007 and was 21 ml/min/1.72m at the time of review. A renal biopsy was undertaken, and the appearances were suggestive of mild tubulo-interstitial nephritis; the glomeruli were unremarkable; there was mild chronic tubulo-interstitial damage. She was started on oral steroid, sodium bicarbonate and ursodeoxycholic acid. The course of steroid had a slight transitory beneficial effect on the renal function. Conclusion Distal RTA is the usual renal feature of PBC, occurring in 1/3 of cases with advanced disease. In contrast, proximal RTA associating with renal Fanconi syndrome occurs rarely. Like our case, the cases that have been previously reported show that Fanconi syndrome occurred during the early phase of PBC in the absence of marked hepatic abnormalities, and were associated with CKD. Fanconi syndrome and TIN are renal features of mitochondrial cytopathies and are perhaps a forgotten association of PBC. Antimitochondrial antibodies may play a role in the onset of tubulo-interstitial nephritis and Fanconi syndrome.

MO454A NEW AKI TO CKD PROGRESSION IN VIVO EXPERIMENTAL MODEL

Abstract Background and Aims Chronic kidney disease (CKD) represents an enormous problem for healthcare systems. It is estimated that in USA more than 37 million people suffer from this disease. Risk factors include hypertension, diabetes mellitus, older age, proteinuria and previous episodes of acute kidney injury (AKI). Indeed, several studies have shown that AKI increases the risk of CKD, independently of other risk factors, especially when the episode is severe or recurrent. Under these circumstances, maladaptive responses may occur leading to structural and functional abnormalities. Renal fibrosis is the hallmark for maladaptive repair and is considered the final common outcome of progressive kidney disease. We hypothesized that after multiple renal insults, the mechanisms of adaptive repair could be less effective generating a progressive accumulation of extracellular matrix and a progressive deterioration of kidney function. Method We used 8 weeks old male Wistar rats and we analyse their evolution during 9 months. Animals were subdivided into 4 experimental groups: Control group: SHAM operated rats, saline solution, i.p.; “CDDP5-I/R60-I/R60” group: 5 mg/kg cisplatin i.p., after renal function normalization, 60-minute ischemia-reperfusion (I/R60) on left kidney, and 2 weeks later 60-minute ischemia-reperfusion (I/R60) on right kidney; “5/6 RMR” group: 5/6 renal mass reduction; “UNX” group: nephrectomy. Blood and urine were collected at: day 0 (basal); day 4 (AKI development); day 8 (normalized renal function after AKI and induction of renal ischemia); day 9 (1 day after ischemia); day 13, day 20 and monthly thereafter. Renal function was analyzed by sCr, creatinine clearance, blood urea nitrogen and proteinuria determination using colorimetric methods. Tissue samples were stained with Masson´s trichrome and Sirius Red at days 13, 20, 56, 165 and 270 and renal fibrosis was quantified using Image J program. Results The addition of several AKI episodes induces a progressive accumulation of extracellular matrix. In addition, the “CDDP5-I/R60-I/R60” group presented an initial reduction in renal function that remained stable in the last 6 months of the study. On the contrary, we observed a spontaneous and progressive decline of kidney function in the “5/6 RMR” group, which nevertheless presented a significant lower degree of interstitial fibrosis than the “CDDP5-I/R60-I/R60” group. Conclusion We have generated a new in vivo experimental model of AKI to CKD transition combining nephrotoxic and ischemic AKI. We demonstrate that after recurrent episodes of AKI, kidneys show progressive interstitial fibrosis which however does not correlate with a progressive decline of renal function.

Rhabdomyolysis-induced acute kidney injury in a patient with non-compliance to levothyroxine therapy.

SummaryHypothyroidism is a common medical condition and is often easily managed with excellent outcomes, when treated adequately. Compliance with levothyroxine (LT4) therapy is often compromised because of the need for a daily and lasting schedule. Overt rhabdomyolysis due to under-treatment or non-compliance is a rare occurrence. We report a case of rhabdomyolysis leading to acute kidney injury (AKI) on chronic kidney disease (CKD) requiring hemodialysis (HD) in a 68-year-old Caucasian male due to non-compliance with levothyroxine (LT4) therapy. Our patient 'ran out of levothyroxine' for approximately 4 weeks and developed gradually progressive muscle pain. The diagnosis of severe AKI due to rhabdomyolysis was made based on oliguria, elevated creatinine kinase (CK), and renal failure. Resuming the home dose of LT4 failed to correct CK levels, and there was a progressive decline in renal function. Although increasing doses of LT4 and three cycles of HD improved CK levels, they remained above baseline at the time of discharge. The patient recovered gradually and required HD for 4 weeks. CK levels normalized at 6 weeks. Through this case report, we highlight that non-compliance with LT4 therapy can lead to life-threatening complications such as renal failure and hence the need to educate patients on the significance of compliance with LT4 therapy should be addressed.Learning points Non-compliance to levothyroxine therapy is common and can lead to serious complications, including rhabdomyolysis. Rhabdomyolysis is an uncommon presentation of hypothyroidism and severe rhabdomyolysis can result in renal failure requiring hemodialysis. Rhabdomyolysis associated with hypothyroidism can be further exacerbated by concomitant use of statins.

Vascular growth factors as potential new treatment in cardiorenal syndrome in diabetes.

Cardiorenal syndrome in diabetes is characterised by alterations of the cardiovascular system paralleled by kidney disease with progressive renal function decline. In diabetes, chronic metabolic and haemodynamic perturbations drive endothelial dysfunction, inflammation, oxidative stress and progressive tissue fibrosis which, in turn, lead to heart and renal anatomo-functional damage. In physiology, vascular growth factors have been implicated in vascular homeostasis; their imbalance, in disease setting such as diabetes, leads to vascular dysfunction and cardiorenal damage. To define the role of vascular growth factors and angiopoietins in cardiorenal syndrome. We will focus on the two most studied vascular growth factors, vascular endothelial growth factor (VEGF) and angiopoietins (Angpt). The balance and crosstalk between these growth factors are important in organ development and in the maintenance of a healthy vasculature, heart and kidney. The observed alterations in expression/function of these vascular growth factors, as seen in diabetes, are a protective response against external perturbations. The chronic insults driving diabetes-mediated cardiorenal damage results in a paradoxical situation, whereby the vascular growth factors imbalance becomes a mechanism of disease. Studies have explored the possibility of modulating the expression/action of vascular growth factors to improve disease outcome. Experimental work has been conducted in animals and has been gradually translated in humans. Difficulties have been encountered especially when considering the magnitude, timing and duration of interventions targeting a selective vascular growth factor. Targeting VEGF in cardiovascular disease has been challenging, while modulation of the Angpt system seems more promising. Future studies will establish the translatability of therapies targeting vascular growth factors for heart and kidney disease in patients with diabetes.