Case Report: A Novel In-Frame Deletion of GLIS2 Leading to Nephronophthisis and Early Onset Kidney Failure

Variants in the GLIS family zinc finger protein 2 (GLIS2) are a rare cause of nephronophthisis-related ciliopathies (NPHP-RC). A reduction in urinary concentration and a progressive chronic tubulointerstitial nephropathy with corticomedullary cysts are the major characteristic features of NPHP. NPHP demonstrates phenotypic and genetic heterogeneity with at least 25 different recessive genes associated with the disease. We report a female, from a consanguineous family, who presented age 9 years with echogenic kidneys with loss of cortico-medullary differentiation and progressive chronic kidney disease reaching kidney failure by 10 years of age. A novel homozygous in-frame deletion (NM_032,575.3: c.560_574delACCATGTCAACGATT, p.H188_Y192del) in GLIS2 was identified using whole exome sequencing (WES) that segregated from each parent. The five amino acid deletion disrupts the alpha-helix of GLIS2 zinc-finger motif with predicted misfolding of the protein leading to its predicted pathogenicity. This study broadens the variant spectrum of GLIS2 variants leading to NPHP-RC. WES is a suitable molecular tool for children with kidney failure suggestive of NPHP-RC and should be part of routine diagnostics in kidney failure of unknown cause, especially in consanguineous families.

Combined protective effects of icariin and selenomethionine on novel chronic tubulointerstitial nephropathy models in vivo and vitro

Chronic tubulointerstitial nephropathy (CTIN) is one of the most common kidney diseases. However, treatment for CTIN has multiple limits. Adjuvant therapy through nutritional regulation has become a hot research topic at present. Icariin (ICA), an extraction of Chinese herbal medicine epimedium, has many pharmacological functions including anti-inflammation and tonifying kidney. Selenomethionine (SeMet) possesses the effects of antioxidant and lightening nephrotoxicity. However, little is known about the combined nephroprotection of them. This study was investigated to evaluate the joint effects of ICA and SeMet on CTIN and explore the mechanism. Based on a novel CTIN model developed in our previous study, mice were randomly divided into five groups (a: control; b: model; c: model+ICA; d: model+SeMet; e: model+ICA+SeMet). Renal tubule epithelial cells were treated with cyclosporine A and ochratoxin A without/with ICA or/and SeMet. The results showed ICA or/and SeMet ameliorated CTIN by inhibiting the uptrends of blood urine nitrogen, serum creatinine, urine protein, urine gravity, histopathological damage degree and collagen Ⅰ deposition. ICA or/and SeMet also increased cell proliferation and decreased apoptosis and the expression of TGF-β1 and α-SMA. Emphatically, ICA and SeMet joint had better nephroprotection than alone in most indexes including fibrosis. Furthermore, ICA and SeMet joint decreased the activation of toll like receptor 4 (TLR4)/NFκB pathway induced by CTIN. TLR4 overexpression counteracted the joint protection of ICA and SeMet. Therefore, ICA and SeMet in combination could protect against CTIN through blocking TLR4/NFκB pathway. The study will provide novel insights to explore an adjuvant therapeutic orientation.

Local and Systemic Oxidative Stress in Balkan Endemic Nephropathy Is Not Associated with Xanthine Oxidase Activity

Balkan endemic nephropathy (BEN) represents a chronic tubulointerstitial nephropathy which is followed by the progression of kidney fibrosis to end-stage kidney failure. The critical involvement of poisons in food (aristolochic acid (AA), ochratoxin, and heavy metals) and selenium deficiency are among nutritive factors which contribute to the pathogenesis of BEN, due to reactive oxygen species (ROS) liberation and/or decreased antioxidative defence system. The aim of the study is to distinguish a possible systemic and local origin of ROS through the measurement of xanthine oxidase (XO) activity in urine and plasma, along with the determination of the oxidative changes in lipids and proteins. The study included 50 patients with BEN and 38 control healthy subjects. We noted increased levels of both thiobarbituric acid-reactive substances (TBARS) and advanced oxidation protein products (AOPPs) in the plasma of patients with BEN, compared to the control group (p<0.001). The urinary levels of AOPPs were higher in patients with BEN in comparison to the control (p<0.001). The specific activity of XO was significantly lower in plasma and urine in BEN samples, compared to controls (p<0.005). Based on these results, we hypothesize that XO might not be considered a direct systemic or local contributor to ROS production in BEN, most probably because of the diminished kidney functional tissue mass and/or AA-induced changes in purine nucleotide conformation. The increased AOPP and TBARS level in both plasma and urine in BEN may predict ROS systemic liberation with toxic local effects.

P0282SARCOIDOSIS WITH RENAL INVOLVEMENT: APPROACH TO DIAGNOSIS AND MANAGEMENT

Background and Aims Renal involvement in sarcoidosis is rare. It is most often the consequence of calcium metabolism disorders, interstitial granulomatous damage or secondary glomerular damage. It can progress to kidney failure in around 3% of cases. In this study, we determined the clinical presentation of sarcoidosis with renal involvement and we described the histological lesions. We report our experience about the management and the follow-up. Method we analyzed all cases of renal failure caused by sarcoidosis in our department during the period of 13 years (2006-2019). There were five patients (one man and four women) at the time of diagnosis. The middle age was 53.8 years. Results The renal involvement was revealing in 60% of the cases. The extrarenal localizations were: pulmonary (100%), cutaneous (knotty erythema 20%), ocular (dry eye syndrome (60%) and anterior uveitis (20%)), the reticuloendothelial system (adenitis (20%) and medullary (20%)), exocrine glands (sialadenitis (40%), nasal (20%), nervous (optic neuritis 20%)). The middle renal clearance (eGFR) at the time of diagnosis of renal involvement was 33ml / min / 1.73 m. Moderate proteinuria was observed in four patients (median: 0.99 g / 24 hours), aseptic leukocyturia in one patient. No patient had microscopic hematuria. Hypercalcemia was noted in 60% of patients with hyper calciuria (median: 3 mmol / kg / 24 hours). Nephrolithiasis was noted in only one patient. No cases of nephrocalcinosis was noted. Renal biopsy showed tubulointerstitial nephropathy with granulomatous in 2 cases (40%), absence of granuloma in one case, extra-membranous glomerulonephritis in one patient and moderate interstitial fibrosis with tubular atrophy in two patients, fibrous andarteritis in a single case. A granuloma without caseous necrosis was objectified on the osteo-medullary biopsy in a single case. All patients received oral corticosteroids (Prednisone: 1 mg / kg / day for 4 patients; 0.5 mg / kg / day for one patient) associated with the treatment of hypercalcemia (hydration and diuretics). The follow-up varied from 2 to 156 months with an median of 56.4 months. 3 patients improved their renal function with a middle clearance : M0: 29 ml / min, M1: 42 ml / min, M3: 68 ml / min, M6: 67 ml / min, M12: 95 ml / min. A non-recovery of renal function was noted in only one patient. An end-stage renal disease was observed in two patients. A renal and extrarenal (lymph node) relapse was noted in a single patient with an interval of 7 years after the initial presentation. Conclusion Renal involvement in sarcoidosis is probably underestimated. Treatment is based on corticosteroid, which must be introduced early to prevent progression to renal failure.

P0437IS RENAL BIOPSY NEEDED FOR THE DIAGNOSIS OF NEPHROPATHIES OR IT IS SUFFICIENT WITH A CLINICAL DIAGNOSIS?

Background and Aims Percutaneous renal biopsy (PRB) guided by ultrasound is the gold standard for the diagnosis of nephropathies and glomerulopathies. Sometimes, comorbidity and relative contraindications for PRB could condition us to consider clinical diagnosis as sufficient to treat renal pathology. This is a continuous challenge for the nephrologist due to the prognostic and therapeutic diversity of the different types of nephropathies. Therefore, we wonder if in most cases it is still necessary to perform PRB, or clinical diagnosis would be enough in a significant number of them. We decided to assess our PRB series over 15 years, comparing clinical and biopsy diagnosis, and learning about the complications associated with the technique. Method Cross-sectional analysis of the 262 PRB conducted between January 2003 and December 2018. In our department, before performing the PRB, doctors always make a clinical report with different diagnostic possibilities that facilitates the pathologist's work. For this study the first diagnostic option, being the most clinically compatible with the patient, was always taken. We also collected socio-demographic data, clinical data (hypertension and diabetes mellitus), pre and post-biopsy diagnosis, and complications associated with the technique. For the statistical analysis, the SPSS 15 program was used to calculate frequencies, and the Kappa coefficient for diagnostic concordance. Results 262 PRB were performed, of which 149 (56.9%) were performed in men and 113 (43.1%) in women. Average age: 58.6 ± 19.2 years. 173 patients were hypertensive (66%) and 50 had DM (19.1%). Renal pathologies by age are similar to the data reported by Spanish Society. The table shows the concordance measured by the kappa coefficient in the pre and post-PRB diagnosis of the most frequent nephropathies. There were 15 PRB with complications (5.8%): 12 minors (4.6%, haematuria and hematoma); and 3 major: 2 haemorrhages (0.8%) and 1 nephrectomy (0.4%). 33 PRB (12.6%) were inconclusive due to insufficient material. Conclusion From the data obtained, a high mismatch was observed in very common nephropathies in our environment, such as IgA nephropath and pauci-immune focal and segmental necrotizing glomerulonephritis. In contrast, PRB showed more cases of diabetic nephropathy and tubulointerstitial nephropathy. In the case of the pathologies due to nephrotic syndrome (table) we find a high discordance. This may be due to the fact that in all of those cases there was an initial nephrotic syndrome, and our clinical diagnosis was partly based on the frequency of glomerulopathies in the adult. In conclusion, the different concordances between pre and post-biopsy diagnoses show us that clinical diagnosis is not enough to obtain a final diagnosis. In most cases PRB is necessary for the definitive diagnosis. In addition, after the introduction of the ultrasound, complications have decreased, especially when the biopsy is performed by the nephrologist.

The modern spectrum of biopsy-proven renal disease in Chinese diabetic patients—a retrospective descriptive study

Background Renal biopsies performed in diabetic patients are increasing and becoming more complex. Comprehensive data on modern spectrum of biopsy-proven renal disease in Chinese diabetic patients are lacking. Methods In a nationwide renal biopsy survey including 71,151 native biopsies from 2004 to 2014, diabetic patients were identified according to the clinical diagnosis from referral records. The clinical data were extracted from referral records and pathological reports. Results A total of 1,604 diabetic patients, including 61 patients with T1DM, were analyzed in this study. The median age is 51.39 ± 11.37 years. Male patients accounted for 58% of the population. We found that only 44.7% of diabetic patients had the isolated pathological diagnosis of diabetic nephropathy (DN), while 49.1% had non-diabetic renal disease (NDRD) alone, and 6.2% had NDRD superimposed on DN. Nephrotic syndrome (n = 824, 51.4%) was the most common clinical indication for renal biopsy. Among 887 patients with NDRD, membranous nephropathy (n = 357) was the leading diagnosis, followed by IgA nephropathy (n = 179). Hypertensive renal disease (n = 32), tubulointerstitial nephropathy (n = 27) and acute tubular necrosis (n = 16) accounted for 3.5%, 2.9%, 1.7% of the NDRD cases respectively. Nearly a half (49.2%) of patients with T1DM had NDRD. Discussion Over 55% diabetic patients with kidney disease were diagnosed as non-diabetic renal disease, among which MN and IgAN were the most common two pathological types.