Familial nephropathy in Bracchi Italiani: 8 cases (2012–2019)

OBJECTIVE To characterize the signalment, clinical signs, clinical pathological and histologic findings, and outcome in 8 related Bracchi Italiani with proteinuric kidney disease. ANIMALS 8 client-owned Bracchi Italiani. PROCEDURES Health records submitted to the Bracco Italiano Health Foundation and the Bracco Italiano Club of America between 2012 and 2019 were reviewed for dogs with evidence of nephropathy for which histologic diagnoses were obtained. Pedigree, signalment, clinical signs, diagnostic test results (including microscopic examination of kidney tissue samples collected ante- or postmortem), and outcome were acquired. Results were presented as descriptive statistics. RESULTS The most common clinical sign in affected dogs was inappetence. All dogs were proteinuric, and 4 dogs were azotemic. Seven dogs developed clinical signs of kidney disease and were euthanized a median of 75 days postdiagnosis. Six dogs had glomerular amyloidosis, and 1 dog each had nephrosclerosis and nonamyloidotic fibrillar glomerulopathy. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the clinical presentation may vary in affected dogs, and proteinuria in young or middle-aged Bracchi Italiani should raise the concern for hereditary nephropathy. Prognosis is likely poor once clinical signs are noted.

Small RNA sequencing evaluation of renal microRNA biomarkers in dogs with X-linked hereditary nephropathy

Dogs with X-linked hereditary nephropathy (XLHN) are an animal model for Alport syndrome in humans and progressive chronic kidney disease (CKD). Using mRNA sequencing (mRNA-seq), we have characterized the gene expression profile affecting the progression of XLHN; however, the microRNA (miRNA, miR) expression remains unknown. With small RNA-seq and quantitative RT-PCR (qRT-PCR), we used 3 small RNA-seq analysis tools (QIAGEN OmicSoft Studio, miRDeep2, and CPSS 2.0) to profile differentially expressed renal miRNAs, top-ranked miRNA target genes, and enriched biological processes and pathways in CKD progression. Twenty-three kidney biopsies were collected from 5 dogs with XLHN and 4 age-matched, unaffected littermates at 3 clinical time points (T1: onset of proteinuria, T2: onset of azotemia, and T3: advanced azotemia). We identified up to 23 differentially expressed miRNAs at each clinical time point. Five miRNAs (miR-21, miR-146b, miR-802, miR-142, miR-147) were consistently upregulated in affected dogs. We identified miR-186 and miR-26b as effective reference miRNAs for qRT-PCR. This study applied small RNA-seq to identify differentially expressed miRNAs that might regulate critical pathways contributing to CKD progression in dogs with XLHN.

MO064ASSESSMENT OF KIDNEY SURVIVAL IN PATIENTS AFFECTED BY ADPKD

Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary nephropathy that causes kidney failure and the need for renal replacement therapy (RRT). It has recently been established that there is a genotype-phenotype relationship for this disease, with differences in the age of access to TRS if the involvement occurs in the PKD1 or PKD2 gene and if the variant is truncating or not. Identifying patients at high risk for rapid progression has become increasingly important given the emergence of potential new treatments such as tolvaptan. Method Studies are carried out in 23 families affected in which a genetic study has previously been the variant identified. For the survival analysis, the Kaplan-Meier test was performed. Data are expressed in terms of mean ± SD, median and %. Results The data described in Table 1 show that there is huge variability of access to RRT according to the type of variant found in the family. We found families in which the age at which kidney failure occurred ranged from 48.03 (28.38-67.68) years to families in which RRT began with 78.04 (65.06-91.03). We observed that those families that present a variant with a stop or frameshift codon suffer a loss of kidney function before those that present a missense variant. In the variants with a stop or frameshift codon, we observed that they ranged from 48.03 (28.38-67.68) for the variant c.7480G> T (p.Glu2494 *) to 73.75 (61.52-85, 98) in variant c.9616C> T p.Gln3203 *. In those missense variants, the age of access to RRT ranges from 62.17 (60.43-63.91) to 77.13 (71.56-82.71) Conclusion Advances in studies of the genes involved in ADPKD are expanding the identification of new variants and the knowledge about their involvement in the progression of the disease. The correlation between genotype and kidney disease will provide a useful clinical prognosis for ADPKD and will allow us to establish current and future treatments.

Abnormal Expression of miR-21 in Kidney Tissue of Dogs With X-Linked Hereditary Nephropathy: A Canine Model of Chronic Kidney Disease

MicroRNAs (miRNAs) are a group of small noncoding RNAs that act as regulators of posttranslational gene/protein expression and are known to play a key role in physiological and pathological processes. The objective of our study was to compare expression of miR-21 in renal tissue from dogs affected with chronic kidney disease (CKD) caused by X-linked hereditary nephropathy (XLHN), a disease equivalent to human Alport syndrome, to that from unaffected dogs. Additionally, we sought to characterize changes in relative mRNA expression of various genes associated with miR-21 function. miRNA was isolated from kidney tissue collected from both affected dogs and unaffected, age-matched littermates at defined milestones of disease progression, including end-stage renal disease (ESRD). Additionally, autopsy samples from affected dogs at ESRD and corresponding unaffected dogs were evaluated. Samples were scored based on histological changes, and relative expression of miR-21 and kidney disease-related genes was determined using quantitative real-time polymerase chain reaction. In affected dogs, significant upregulation of kidney miR-21 was first detected at the milestone corresponding with increased serum creatinine. Furthermore, miR-21 expression correlated significantly with urine protein: urine creatinine ratio, serum creatinine concentration, glomerular filtration rate, and histologic lesions (glomerular damage, tubular damage, chronic inflammation, and fibrosis). At end-stage disease, COL1A1, TGFB1 and its receptor, TGFB2, and Serpine1 were upregulated, while PPARA, PPARGC1A, ACADM, SOD1, and EGF were downregulated. In conclusion, miR-21 is abnormally upregulated in the kidneys of dogs with CKD caused by XLHN, which may play an important pathologic role in the progression of disease by dysregulating multiple pathways.