Minimal Proteinuria Research Articles

#3084 Familial nephropathy associated with a combined mutations of Alport and Nail Patella syndrome genes in the same family

Abstract Introduction Alport syndrome is a genetic condition stemming from mutation in Type IV collagen and is characterized by kidney disease and frequently hearing loss and ocular abnormalities. Renal involvement is from an abnormality of the glomerular basement membrane with hematuria and proteinuria progressing eventually to renal failure. In the vast majority, the inheritance is X- linked affecting the alpha 5 chain of type IV collagen while in about 15 percent of the patients the inheritance is autosomal recessive or dominant with mutations affecting alpha 3 or 4 chains of type IV collagen. Sensorineural deafness is common and ocular abnormalities may include lenticonus, corneal opacities, fleck retinopathy and temporal retinal thinning. Nail Patella syndrome (NPS) is a rare genetic condition from mutation in the LMX1B gene on chromosome 9 with an autosomal dominant inheritance. Glomerular disease is from characteristic glomerular basement membrane changes and is associated with nail, pelvic girdle and limb abnormalities. A forme fruste with glomerular lesions but lacking extrarenal features is recognized but uncommon. We present a family with mutations in both COL4A5 and LMX1B presenting with hematuria and proteinuria Case Presentation A 23 year old female was evaluated for hematuria and proteinuria. Her history was notable for kidney biopsy at the age thirteen showing focal and segmental glomerulosclerosis (FSGS). She was treated with tacrolimus for four years from age thirteen through seventeen. Patient was reportedly diagnosed with Nail Patella Syndrome after genetic testing. Her family history was notable for hematuria in her brother and hematuria and proteinuria in her mother. On physical examination she was noted to have no nail or skeletal abnormalities associated with Nail Patella Syndrome. Her labs were notable for a serum creatinine of 0.6 mg/dl and proteinuria of 155 mg/g creatinine of proteinuria. Urine microscopy revealed dysmorphic hematuria. Radiological imaging did not show skeletal abnormalities observed in Nail Patella Syndrome but genetic testing identified a pathogenic variant in COL4A5 c.919G>A (p.Gly307Ser) in addition to a variant of uncertain significance in LMX1B c.349G>A (p.Gly117Ser). Her brother aged 20 had a creatinine of 0.87 mg/dl with dysmorphic hematuria and no proteinuria. Genetic testing showed the same pathogenic variant in COL4A5 as in his sibling. His mother aged 55 was subsequently evaluated and had a creatinine 0.73 mg/dl with dysmorphic hematuria and 152 mg/g of proteinuria. Genetic testing was with the same variant in COL4A5 noted in her two children. Renal biopsy was extensive thinning and segmental lamellation of the glomerular basement membrane with eight percent FSGS. The typical “moth-eaten” appearance of the glomerular basement membrane characteristic of NPS was not evident. Segmental staining was observed with alpha 5 unit of Type IV collagen. Audiology and retinal optical coherence optometry studies are pending. Discussion Alport syndrome and Nail Patella Syndrome are rare genetic disorders that cause variable degrees of renal insufficiency from glomerular base membrane defects and are associated with characteristic extra renal manifestations. This is the first report of an inherited nephritis with combined mutations in COL4A5 and LMX1B. The clinical features and renal biopsy are compatible with Alport Syndrome and the significance of the mutation in LMX1B is uncertain. Conclusion This is the first case report of a combined mutation in COL4A5 and LMX1B gene presenting with hematuria and minimal proteinuria with preserved kidney function.

Autosomal dominant chronic tubulointerstitial nephropathy: do not forget amyloidosis

Amyloidosis is a rare cause of inherited kidney disease, with most variants responsible for prominent glomerular involvement. In this issue, Kmochová etal. reported the first description of autosomal dominant medullary amyloidosis due to apolipoprotein A4 variants, resulting in slowly progressive chronic kidney disease with minimal proteinuria. Combining next-generation sequencing with histopathological studies incorporating Congo red staining and mass spectrometry should be considered in the diagnostic workup of hereditary tubulointerstitial disorders not identified after routine genetic testing.

Sodium-Glucose Cotransporter-2 Inhibitors Utilization and Outcomes in Patients with Chronic Kidney Disease at a Tertiary Centre

Sodium-glucose cotransporter-2 (SGLT2) inhibitor is an antidiabetic agent with cardiac and renal protective properties. Its renal protective property is a result of the inhibition of tubular sodium reabsorption and reduction in the intraglomerular pressure. The use of SGLT2 inhibitor in chronic kidney disease (CKD) independent of diabetic status is emerging. However, the real-world data of SGLT2 inhibitor utilisation in CKD is limited. We conducted a descriptive study of patients with CKD, who were prescribed with SGLT2 inhibitor in our Nephrology Clinic. A total of 156 patients were initiated on SGLT2 inhibitor from 2017 to 2022. Among them, 58.3% were male, with a mean age of 61 + 13 years, and 86.5% had diabetes mellitus, with estimated mean glomerular filtration rate (eGFR) of 46.41 + 21.14 ml/min/1.73m2, and proteinuria of 2.22 + 2.62 g/day. A total of 85.9% of patients were on renin-angiotensin-system (RAS) blockers, whereby those who were not prescribed with RAS were mostly CKD stage 4. Among the non-diabetic patients, 81% had glomerulonephritis, half of which was IgA nephropathy, and 42.9% were on immunosuppressants. There was a significant retardation of eGFR decline over a six-month-duration after the initiation of SGLT2 inhibitor from -3.46 + 6.56 ml/min/1.73m2 to -0.77 + 7.97 ml/min/1.73m2 (p=0.001). The retardation of eGFR decline was more pronounced in more advanced CKD stages. However, the proteinuria reduction was insignificant over a six-month-duration (-0.03 + 2.31 g/day). There were no adverse events reported. In conclusion, SGLT2 inhibitor retarded the eGFR decline with minimal proteinuria reduction in short-term. Nonetheless, long-term efficacy and safety data of SGLT2 inhibitor in local populations requires further evaluation.

Clinico-Epidemiological Profile of Patients with Chronic Kidney Diseases of Unknown Etiology: A Hospital-Based, Cross-Sectional Study from Central India.

Chronic kidney disease (CKD) not associated with known risk factors, called CKD of unknown etiology (CKDu), has been reported from several geographically distinct regions across the world. This study reports the clinical and epidemiological profile of patients with CKDu from a new hotspot in central India. This cross-sectional study describes the sociodemographic, clinical, and laboratory profile of the patients diagnosed with CKDu visiting a tertiary care public hospital in the state of Chhattisgarh in central India between June 2019 and June 2021. CKDu was diagnosed as progressive CKD, minimal proteinuria, absence of hematuria, diabetes, severe hypertension, systemic illness, glomerulonephritis or other urinary tract diseases, and presence of symmetrically contracted kidneyon ultrasound. A total of 166 (3.1%) out of 5365 patients with CKD were diagnosed with CKDu. The mean age was 53.6 ± 11.8 years. The patients were predominantly male (n = 113, 68.1%), belonged to rural areas (n = 147, 88.6%), and were engaged in farming (n = 105, 63.3%). The estimated glomerular filtration rate (eGFR) at presentation was 21.5 ± 15.1 ml/min/1.73m2. Forty-four (26.5%) had stage 3 CKD, 57 (34.3%) had stage 4 CKD, and 65 (39.2%) had stage5 CKD. There was an over-representation of CKDu cases in patients with CKD from Gariyaband (36.0%) and Mahasamund (25%) districts of Chhattisgarh and Nuapada (35.0%) and Balangir (30.0%) districts of Odisha. The study suggests clustering of cases of CKDu in certain districts of Orissa and Chhattisgarh.

"Idiopathic" minimal change nephrotic syndrome: a podocyte mystery nears the end.

The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human minimal change nephrotic syndrome (MCNS). Recently, uncovered genomic defects upstream of ZHX2 induce a ZHX2 hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In ZHX2 hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4Rα. During disease relapse, high plasma soluble IL-4Rα (sIL-4Rα) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4Rα toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of ANGPTL4, resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hyposialylated ANGPTL4, and hyposialylation-related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human minimal change disease (MCD), including massive and selective proteinuria, podocyte foot process effacement, and loss of glomerular basement membrane charge. Administration of glucocorticoids reduces ANGPTL4 upregulation, which reduces hyposialylation injury to improve the clinical phenotype. Improving sialylation of podocyte-secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-α, IL-6, or sIL-4Rα after the induction of the cytokine storm in Zhx2 hypomorph mice reduces albuminuria, suggesting potential new therapeutic targets for clinical trials to prevent MCD relapse. These studies collectively lay to rest prior suggestions of a role of single cytokines or soluble proteins in triggering MCD relapse.

IgA nephropathy in children with minimal proteinuria: to biopsy or not to biopsy?

Tubulointerstitial lesions and glomerular inflammation severity have been shown to correlate with proteinuria in children with IgA nephropathy (cIgAN). However, there is a lack of data regarding severity of histopathologic findings in cIgAN in patients with minimal to absent proteinuria since kidney biopsy indications are not well defined in these cases. Twenty-eight cIgAN patients with kidney biopsy from 4 different centers in Paris (France) and Montreal (Canada) with a urine protein/creatinine ratio (UPCr) ≤ 0.03g/mmol and a normal estimated glomerular filtration rate (eGFR > 90ml/min/1.73 m2) on the day of kidney biopsy prior to treatment were included. Median age was 11.82 (9.32-13.45) years, and median follow-up was 4years (2.87-6.53). At time of biopsy, median eGFR was 116 (102.3-139.7) ml/min/1.73 m2, and median UPCr was 0.02 (0.011-0.03) g/mmol. Microscopic or macroscopic hematuria was present in 35.7% and 64.3% of cases, respectively. Kidney biopsy microscopy analysis showed mesangial (M1), endocapillary (E1), or extracapillary (C1) hypercellularity in 53.5%, 32.1%, and 7.1% of patients, respectively. Chronic histological lesions were also present: glomerulosclerosis (S1) in 42.8% and tubular atrophy/interstitial fibrosis in 7.1%. Podocytopathic features were detected in 21.4%. An ACE inhibitor or immunosuppressive therapy (IS) was prescribed in 42.8% and 21.4% of these patients respectively. One-third (35.7%) received no treatment. At last follow-up, median eGFR was 111.9 (90.47-136.1) ml/min/1.73 m2, and median UPCr was 0.028 (0.01-0.03) g/mmol. cIgAN with minimal proteinuria at time of biopsy might be linked with acute and chronic glomerular lesions.

Umbilical artery ultrasound haemodynamics combined with serum adiponectin levels can aid in predicting adverse pregnancy outcomes in patients with severe pre-eclampsia

Severe pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality. This retrospective study explored pregnancy outcome predictive values of umbilical artery Doppler with serum adiponectin in severe pre-eclampsia. Fasting elbow venous blood was collected from 118 severe pre-eclampsia patients [maternal systolic pressure ≥ 160 mmHg and/or diastolic pressure ≥ 110 mmHg + minimal proteinuria, 56; mild hypertension + heavy proteinuria (≥2 g/24 h or random urinary protein ≥ 2+), 42; no proteinuria but new-onset hypertension + diseases of heart/lung/liver/kidney/other organs or abnormalities in blood/digestive/nervous systems, placental foetus involved, 20] and 90 controls (18.5-24.9 kg/m2) in the first morning of admission. Serum adiponectin and resistance/pulsatility indexes were separately measured and correlatively analysed by Pearson’s coefficient analysis. Adverse outcomes included maternal primary postpartum haemorrhage and placental abruption, neonatal asphyxia, low birth weight, foetal distress, foetal growth restriction. In severe pre-eclampsia, serum adiponectin (downregulated) was negatively-correlated with resistance/pulsatility indexes (upregulated). The area under the curve of umbilical artery Doppler with serum adiponectin for predicting adverse outcomes of severe pre-eclampsia was 0.6545 (specificity 60.27%, sensitivity 60.00%). In conclusion, umbilical artery Doppler with serum adiponectin predicts adverse pregnancy outcomes in severe pre-eclampsia. Impact statement What is already known on this subject? Sad levels were lowered in sPE patients. UA ultrasound hemodynamic parameters can predict adverse pregnancy outcomes. What do the results of this study add? Our study revealed that ultrasonic hemodynamic indexes of UA combined with Sad levels had better efficacy in predicting pregnancy outcomes in patients with sPE, and our study is expected to improve the accuracy of clinical prediction of adverse outcomes in sPE patients. What are the implications of these findings for clinical practice and/or further research? Through the combined detection of multiple indicators of the foetus in the mother, our study expects to be able to monitor and predict the growth of the foetus in the mother more accurately in clinical practice, avoid excessive intervention or untimely intervention, and reduce the incidence of perinatal adverse pregnancy outcomes.

APOL1 Genotype, Proteinuria, and the Risk of Kidney Failure: A Secondary Analysis of the AASK (African American Study of Kidney Disease and Hypertension) and CRIC (Chronic Renal Insufficiency Cohort) Studies

Patients with a high-risk Apolipoprotein L1 (APOL1) genotype are more likely to develop chronic kidney disease and kidney failure. It is unclear whether this increased risk is entirely mediated by the development of proteinuria. Retrospective observational study of the African American Study of Kidney Disease and Hypertension cohort and Chronic Renal Insufficiency Cohort. Self-identified race (Black/non-Black) and presence of high-risk APOL1 genotype. The primary model was adjusted for age, sex, diabetes, estimated glomerular filtration rate, and urinary protein-creatinine ratio. Time to kidney failure defined as time to dialysis or transplantation. We used Cox proportional hazard models to study how proteinuria mediates the association between APOL1 and kidney failure. We modeled proteinuria at baseline and as a time-varying covariate. A high-risk APOL1 genotype was associated with a significantly higher risk of kidney failure, even for patients with minimal proteinuria (HR, 1.87; 95% CI, 1.23-2.84). The association was not significant among patients with high proteinuria (HR, 1.22; 95% CI, 0.93-1.61). When modeling proteinuria as a time-varying covariate, a high-risk APOL1 genotype was associated with higher kidney failure risk even among patients who never developed proteinuria (HR, 2.04; 95% CI, 1.10-3.77). Compared to non-Black patients, Black patients without the high-risk genotype did not have higher risk of kidney failure (HR, 0.96; 95% CI, 0.85-1.10). Two datasets were combined to increase statistical power. Limited generalizability beyond the study cohorts. Residual confounding common to observational studies. A high-risk APOL1 genotype is significantly associated with increased kidney failure risk, especially among patients without baseline proteinuria. Although our results suggest that the risk is partially mediated through proteinuria, higher kidney failure risk was present even among patients who never developed proteinuria. Providers should consider screening for the high-risk APOL1 genotype, especially among Black patients without proteinuria in populations with chronic kidney disease.

MO030: Familial clustering of a rare UMOD variant in undiagnosed hereditary nephropathy suggests the presence of a common ancestral founder mutation

Abstract BACKGROUND AND AIMS ADTKD–UMOD (Autosomal dominant tubulointerstitial kidney disease–UMOD) is a rare genetic disease due to a heterozygous mutation in the UMOD gene encoding uromodulin. It is classically characterized by minimal proteinuria, slowly progressive CKD, hyperuricemia and early-onset gout. With increasing awareness and testing, pathogenic variants in UMOD are being identified more frequently although the nonspecific nature of most symptoms makes clinical diagnosis difficult. We report the surprising finding of a rare UMOD variant in 11 seemingly unrelated families referred to Sheffield or Nottingham renal genetics services over a 15-year period with undiagnosed hereditary kidney disease. METHOD The probands identified were initially referred to renal genetics services based in Sheffield and Nottingham between 2006 and 2021, where they underwent genetic testing and a comprehensive renal workup. All had a family history of ESRD. A pathogenic variant of UMOD, c.278_289delinsCCGCCTCCT was identified in 11 probands by gene or panel-based sequencing. Family members of the affected probands were invited for genetic testing and clinical follow-up. A retrospective review of all patients screened or with ESRD at both renal genetic clinics was conducted. Molecular modeling of the variant was performed using in-silico tools. RESULTS Clinical data from 60 members (11 pedigrees) was obtained. All individuals were born in the United Kingdom and of White British ethnicity. A total of 37 tested positive for the variant, 3 were negative and 19 were not tested due to being deceased (n = 13) and for unknown reasons (n = 6). The median age of ESRD was 52 (range 32, 76) years. More females had ESRD comprising 67% (20/30). Of patients with available data, 68% (30/44) had hypertension, 7.3% (3/41) had proteinuria >30 mg/g and 18% (7/40) had mild hematuria. A total of 11% (6/57) had experienced ≥1 episode of gout with a median onset of 42.5 (range 29–61) years. Only one patient had asymptomatic renal calculi. All patients with CKD who carried the UMOD mutation (n = 22) had hypertension, apart from two who had unknown hypertensive status (n = 1) or reflux nephropathy causing kidney scarring (n = 1). Renal histology where available (8) showed glomerulosclerosis and tubulointerstitial fibrosis. Ultrasound kidney lengths were normal or reduced and renal cysts were only occasionally detected. Molecular modeling of the variant showed structural changes in the cysteine-rich (C6) with EGFII-like Ca2+ binding domain of UMOD, predicted to disrupt disulfide-bond formation (fifth cysteine C94–sixth cysteine C106) as well as by altering the loop (93–97) between two β-sheets of EGFII domain (AlphaFold), possibly altering calcium ion binding (DeepFRI). This variant was initially reported as a recurrent mutation in four apparently unrelated families [1] and has since been noted in a further 11 families [2], all of White British ethnicity. CONCLUSION We have identified a rare pathogenic UMOD variant shared by 11 apparently unrelated families with familial ESRD within a contiguous geographical region of England. The nonspecific symptoms associated with this variant (especially the rarity of gout) were atypical from those with more classical UMOD variants leading to a delay in diagnosis. Our findings and those of others suggest that this is likely to represent a common ancestral variant rather than a recurrent variant within the UK population. 1. Smith GD, Robinson C, Stewart AP et al. Characterization of a recurrent in-frame UMOD indel mutation causing late-onset autosomal dominant end-stage renal failure. Clin J Am Soc Nephrol 2011; 6: 2766–2774. 2. Kidd K, Vylet'al P, Schaeffer C et al. Genetic and clinical predictors of age of ESKD in individuals with autosomal dominant tubulointerstitial kidney disease due to UMOD mutations. Kidney Int Rep 2020; 5:1472–1485.

Chronic inflammation and progression of chronic kidney disease in patients with type 2 diabetes

Chronic inflammation, atherosclerosis, tubulointerstitial fibrosis, and vascular damage play a crucial role in the progression of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus (DM). However, specific biomarkers that can determine the progression of diabetic kidney disease, including patients with minimal albuminuria, remain undefined.
 The present study aimed to determine markers of chronic inflammation as indicators of CKD progression in patients with type 2 DM.
 Methods. 45 patients with type 2 DM and stage 1-3 CKD were involved in this cross-sectional observational study. Analysis of cellular mechanisms of CKD progression was performed on the concentrations of endothelin-1 (ET-1), fibronectin (FN), tumor necrosis factor-alpha (TNF-α), transforming growth factor beta-1 (TGF-β1), and monocyte chemoattractant protein (MCP) -1) in the serum.
 Results. In patients with type 2 DM, an increasing trend in the majority of endothelial and proinflammatory mediators was found according to the CKD stages despite normal albuminuria.
 Conclusions. Concentrations of TNF-α, ET, TGF-β1 and MCP-1 can be used to assess the progression of CKD in patients with type 2 DM with normal albuminuria. Further researches are needed to determine early indicators of diabetic kidney disease progression.

Expression of human CD47 in pig glomeruli prevents proteinuria and prolongs graft survival following pig-to-baboon xenotransplantation.

Nephrotic syndrome is a common complication of pig-to-baboon kidney xenotransplantation (KXTx) that adversely affects outcomes. We have reported that upregulation of CD80 and down-regulation of SMPDL-3b in glomeruli have an important role in the development of proteinuria following pig-to-baboon KXTx. Recently we found induced expression of human CD47 (hCD47) on endothelial cells and podocytes isolated from hCD47 transgenic (Tg) swine markedly reduced phagocytosis by baboon and human macrophages. These observations led us to hypothesize that transplanting hCD47 Tg porcine kidneys could overcome the incompatibility of the porcine CD47-baboon SIRPα interspecies ligand-receptor interaction and prevent the development of proteinuria following KXTx. Ten baboons received pig kidneys with vascularized thymic grafts (n=8) or intra-bone bone marrow transplants (n=2). Baboons were divided into three groups (A, B, and C) based on the transgenic expression of hCD47 in GalT-KO pigs. Baboons in Group A received kidney grafts with expression of hCD47 restricted to glomerular cells (n=2). Baboons in Group B received kidney grafts with high expression of hCD47 on both glomerular and tubular cells of the kidneys (n=4). Baboons in Group C received kidney grafts with low/no glomerular expression of hCD47, and high expression of hCD47 on renal tubular cells (n=4). Consistent with this hypothesis, GalT-KO/hCD47 kidney grafts with high expression of hCD47 on glomerular cells developed minimal proteinuria. However, high hCD47 expression in all renal cells including renal tubular cells induced an apparent destructive inflammatory response associated with upregulated thrombospondin-1. This response could be avoided by a short course of weekly anti-IL6R antibody administration, resulting in prolonged survival without proteinuria (mean 170.5 days from 47.8 days). Data showed that transgenic expression of hCD47 on glomerular cells in the GalT-KO donor kidneys can prevent xenograft nephropathy, a significant barrier for therapeutic applications of xenotransplantation. The ability to prevent nephrotic syndrome following KXTx overcomes a critical barrier for future clinical applications of KXTx.

UK experience of ofatumumab in recurrence of focal segmental glomerulosclerosis post-kidney transplant

BackgroundSteroid-resistant nephrotic syndrome (SRNS), commonly caused by focal segmental glomerulosclerosis (FSGS), is associated with progression to stage 5 chronic kidney disease, requirement for kidney replacement therapy and a risk of disease recurrence post-kidney transplantation. Ofatumumab (OFA) is a fully humanised monoclonal antibody to CD20, with similar mechanisms of action to rituximab (RTX).MethodsWe report a case series of seven UK patients (five paediatric, two adult), all of whom developed FSGS recurrence after kidney transplantation and received OFA as part of their therapeutic intervention. All also received concomitant plasmapheresis. The 2-year outcome of these seven patients is reported, describing clinical course, kidney function and proteinuria.ResultsFour patients (all paediatric) achieved complete urinary remission with minimal proteinuria 12 months post-treatment. Three of those four also had normal graft function. Two patients showed partial remission—brief improvement to non-nephrotic proteinuria (197 mg/mmol) in one patient, maintained improvement in kidney function (estimated glomerular filtration rate 76 ml/min/1.73 m2) in the other. One patient did not demonstrate any response.ConclusionsOFA may represent a useful addition to therapeutic options in the management of FSGS recurrence post-transplantation, including where RTX has shown no benefit. Concomitant plasmapheresis in all patients prevents any definitive conclusion that OFA was the beneficial intervention.

Nephrosclerosis impacts time trajectory of renal function and outcomes in elderly individuals with chronic kidney disease

Despite hypertension ranks among the leading causes of chronic kidney disease (CKD), the impact of chronic hypertensive nephropathy, the so-called ‘nephrosclerosis’ (NS), on CKD progression is often unpredictable, particularly in...

MO462TIME-TRAJECTORIES OF RENAL FUNCTION AND OUTCOMES IN ELDERLY INDIVIDUALS WITH CKD OF VARIOUS ETIOLOGY

Abstract Background and Aims Despite hypertension ranks among the leading causes of chronic kidney disease (CKD), the impact of chronic hypertensive nephropathy, the so-called “nephrosclerosis” (NS), on CKD progression towards end-stage kidney disease (ESKD) is often unpredictable, particularly in older populations. We run a prospective, observational study to define renal function patterns and outcomes in elderly individuals with or without NS-related CKD. Method 304 elderly patients with already established CKD (mean age 69±4 y; mean eGFR 44.2±19.6 mL/min/1.73 m2; male= 64.1%), followed in our outpatients’ clinic were categorized according to the etiology of CKD. NS was defined as the presence of CKD associated with long-term essential hypertension, hypertensive retinopathy, left ventricular hypertrophy and minimal proteinuria. Time-trajectories in eGFR (CKD-Epi) were computed over a 4-year follow-up. In addition, we analysed the occurrence of a composite outcome of doubling of serum creatinine, eGFR reduction≥ 25% and/or ESKD needing dialysis or kidney transplantation. Results CKD was secondary to nephrosclerosis (CKD-NS) in 220 (72.3%) patients. Among the remaining 84 (27.7%), glomerular/diabetic diseases were the most frequent cause of CKD (47.6%). In the whole cohort, the average estimated annual GFR slope was of 1.8 mL/min/1.73 m2. eGFR decline was slower in CKD-NS as compared with the one of others (1.4 vs. 3.4 mL/min/1.73 m2; p<0.001. Figure 1). The composite renal outcome during follow-up (median 36 mo.; range 6-48) occurred less frequently among elderly with CKD-NS (16/204 vs 14/70; p=0.01 Crude HR 0.43, 95%CI 0.22-0.85) and was associated at logistic analyses with etiology of CKD, serum total cholesterol, serum LDL cholesterol levels and glycemia (p ranging from 0.01 to 0.04). Conclusion Despite being highly prevalent in the elderly, NS is associated with a more favorable renal disease course as compared with other conditions. Therapeutic efforts to delay CKD progression in older populations should go beyond just optimizing blood pressure control and focus more on concomitant diseases.

POS-475 GRANULOMATOUS INTERTITIAL NEPHRITIS : A SERIE OF FIVE PATIENTS

Granulomatous interstitial nephritis (GIN) is a rare histologic diagnosis.The cause is often difficult to establish and the studies are limited.This serie reported the presenting features, associated conditions, treatment, and outcomes of patients with a diagnosis of GIN. From 2005 to 2020 , we analysed cases of acute intertitial nephritis in the departement of nephrology of Fatouma Bourguiba Monastir University Hospital. From 17 cases of acute intertitial glomerulonephritis, five patients had granulomatous interstitial nephritis : three cases were associated with sarcoidosis, two were idiopathic. All the patients were femele.The median age of patients was 57 years [34- 77 years]. All patients presented with advanced renal failure (median estimated creatinine clearance 9 ml/min) and minimal proteinuria ( the mean was 0.9 g/day ) without hematuria. Hypercalcemia was present in 2 patients. Pulmonary involvement was present in one case, uveitis and pancreatitis were identified respectively in two cases and one case. Renal biopsy revealed granulomatous interstitial nephritis lesions in all patients. Corticosteroid therapy using prednisolone 1 mg/kg per day was used in all patients. Two patients had methylprednisolone pulse before oral corticosteroid therapy. MMF was associated with corticosteroids in one case. All patients improved their renal function. The median estimated creatinine clearance was 25 ml/min after 6 months. Two patients had normalized their renal fonction. Granulomatous interstitial nephritis may be the first manifestation of a systemic disease . Histologic features do not seem to distinguish the underlying cause of GIN. Corticosteroids therapy seems to be efficient and must be introduced early to prevent progression to chronic renal failure and it is associated with a good prognosis.

Risk of sarcopenia among older persons with Type 2 diabetes mellitus with different status of albuminuria: A dose-responsive association

BackgroundThe association between type 2 diabetes mellitus (T2DM) and sarcopenia has been reported before, but little was known regarding associations between albuminuria status in the development of sarcopenia. This study aimed to explore the associations between albuminuria status and sarcopenia among older patients with T2DM. MethodsThis cross-sectional study recruited T2DM patients aged 65 years and older from the DM shared care center in a regional hospital who were grossly absent from functional impairment. Demographic characteristics were collected and functional assessments were performed for all participants. Urinary albumin-to-creatinine ratio (UACR) was obtained by spot urine exams, whereas UACR ≥ 30 mg/g was defined as microalbuminuria, and UACR > 300 mg/g as macroalbuminuria. Appendicular lean mass (ASM) was measured by the dual X-ray absorptiometry, and the relative appendicular muscle mass (RASM) was calculated as the ASM divided by height square (kg/m2).The definition of sarcopenia was made according to the Asian Working Group for Sarcopenia and muscle quality was defined as handgrip strength (kg) divided by RASM. ResultsOverall, 180 participants (mean age: 72.5±5.3 years, 53.3% males) were enrolled for study. Higher HbA1c levels and poorer renal function were significantly associated with more severe albuminuria status.Besides, sarcopenia and low handgrip strength also showed dose-responsive associations with albuminuria status, which was similar in muscle quality.The receiver operating characteristic curve determine that the UACR of 13.7 mg/g was the optimal cutoff for sarcopenia diagnosis, which was lower than the conventionally definition of microalbuminuria (<30 mg/g). ConclusionsAlbuminuria status was dose-responsively associated with sarcopenia among older persons with T2DM, and the risk started to escalate from minimal albuminuria (UACR 9.18 mg/g in men and 18.4 mg/g in women). Further intervention studies are needed to evaluate potential benefits of better diabetes control in preventing sarcopenia and its outcomes.

The unresolved epidemic of chronic kidney disease of uncertain origin (CKDu) around theworld: A review and new insights.

An increasing number of inhabitants of Central America have developed a form of chronic kidney disease of unknown cause, named Mesoamerican nephropathy (MeN). Because similar epidemics have been reported in other parts of the world, such as Sri Lanka, India, Egypt, and Tunisia, this condition is currently called chronic kidney disease of uncertain origin (CKDu). This disease is characterized by minimal proteinuria, leukocyturia, hyperuricemia, hypokalemia reduced glomerular filtration rate, and renal tubular dysfunctions. Pathology: The kidneys manifest tubulo-interstitial nephritis and glomerulosclerosis. Electron microscopy shows large dimorphic lysosomes with dark electron-dense aggregates. Potential causes: The cause(s) of this disease remain largely unknown. Several hypotheses have been proposed including infections, dehydration, global warming, hyperuricemia, exposure to agro-chemicals or heavy metals, and genetic susceptibility. This review addresses a mounting body of evidence suggesting that the disease may be the result of exposure to a variety of water contaminants combined with volume depletion. Absent a clear understanding of the causes of the disease, no specific therapeutic interventions can be recommended. Preliminary studies suggest that reduction of working hours, frequent rest in shaded area, and administration of purified water may reduce the risk of CKDu.

Status of chronic kidney disease of unknown aetiology in Pakistan.

The incidence of chronic kidney disease (CKD) is rising all over the world. Developing countries like Pakistan will be most affected due to the prevalence of risk factors associated with CKD, such as diabetes, hypertension, kidney stone, and infections. Chronic kidney disease of unknown aetiology (CKDu) is an emerging CKD recently recognised in agricultural communities all around the world. CKDu is recognised, mostly in men between 20 and 50 years of age, with no symptoms, having normal or borderline elevated blood pressure with normal blood glucose levels. Their ultrasonography manifests small kidneys. Urine examinations reveal no or minimal proteinuria, few red blood cells and leukocytes. The actual prevalence in Pakistan is unknown but it is not infrequent for nephrologists and physicians to see these patients in hospitals. There is a need to look into this entity at the community level.

Long-term renal outcomes of IgA nephropathy presenting with different levels of proteinuria

Proteinuria is a strong prognostic factor in IgA nephropathy (IgAN). However, the risk threshold of proteinuria for kidney disease progression remains in debate. This study aimed to evaluate the risk of different levels of proteinuria on renal outcomes in Chinese patients with IgAN. Patients with biopsy-proven primary IgAN were recruited and divided into four groups based on their proteinuria levels: ≤ 0.30 g/d, 0.31-0.50g/d, 0.51-1.00g/d, and >1.00 g/d. The primary outcomes were composed by doubling of baseline serum creatinine (Scr) and end-stage renal disease (ESRD, defined as eGFR <15 mL/min/1.73m2, initiation of dialysis or transplantation). A total of 921 IgAN patients were enrolled in this study. During a median follow-up duration of 48 (34-62) months, higher risks of doubling of baseline Scr developed in patients with proteinuria 0.31-0.50g/d (HR=2.87, p=0.04), 0.51-1.00 g/d (HR=4.26, p=0.002), and >1.00g/d (HR=14.56, p<0.001), while increased risks for ESRD were observed in patients with proteinuria 0.51-1.00g/d (HR=3.00, p=0.02) and >1.00g/d (HR=13.03, p<0.001) in unadjusted Cox regression models. After adjusted for potential confounders, proteinuria 0.31-0.50 g/d (HR=3.70, p=0.04), 0.51-1.00 g/d (HR=3.67, p=0.02), and >1.00 g/d (HR=8.20, p<0.001) remained to be significantly associated with higher risks of doubling of Scr, while only those with proteinuria >1.00g/d (HR=6.04, p=0.001) exhibited a markedly increased risk of ESRD. Patients with proteinuria levels > 0.30g/d already have a higher risk of doubling of baseline Scr, suggesting the necessity of early intervention in patients presenting with minimal proteinuria.

Abstract P028: Activation Of The Renin-angiotensin System Drives Renal Metabolic Abnormalities In Diabetic Nephropathy

Activation of the renin-angiotensin system (RAS) is a major contributor to the pathogenesis of diabetic nephroathy (DN). However, the precise mechanisms of renoprotection associated with RAS blockade in DN are not entirely clear. The aim of this study is to examine whether metabolic effects of RAS blockade might contribute to renoprotection. We utilized a mouse model of DN combining severe type I diabetes (the Akita mutation) with a single-copy renin transgene (ReninTG) driven by the albumin promoter. Akita-ReninTG mice on a 129/Sv background (DN-susceptible mice) develop clinical features of human DN including high-grade albuminuria, renal interstitial inflammation and glomerulosclerosis, while Akita-ReninTG mice on a C57BL/6 background (DN-resistant mice) do not develop significant kidney disease. These two experimental groups were treated with the angiotensin receptor blocker (ARB) losartan 10 mg/kg/day for 12 weeks, and metabolic profiles in kidney tissues were examined using a targeted metabolomics assay. The DN-susceptible mice exhibited high-grade albuminuria that was significantly attenuated by ARB (Vehicle vs ARB: 1480±562 vs 193±42 μg/day, p =0.045), while DN-resistant mice had minimal albuminuria that was not affected by ARB (Vehicle vs ARB: 80±14 vs 75±14 μg/day, p =0.801). The metabolomics profiles of the DN-resistant mice were similar to C57BL/6 wild-type controls. By contrast, DN-susceptible mice exhibited broad reductions in even-chain acyl-carnitines and an abnormal profile of TCA cycle intermediates compared to 129/Sv wild-type controls, suggesting substantial impairments of renal mitochondrial fuel oxidation including altered fatty acid metabolism. RAS blockade had broad effects to correct this profile by increasing acetyl-carnitines generated from acetyl-CoA and concomitantly normalizing expression of genes associated with mitochondrial fatty acid metabolism including PPAR-α, PGC-1α, CPT1 and CPT2. ARB treatment restored TCA cycle activity to normal. These findings suggest that effects of RAS blockade re-establish normal fuel metabolism and mitochondrial fatty acid oxidation in kidney and may contribute to renoprotection.