Novel pathogenic OCRL mutations and genotype–phenotype analysis of Chinese children affected by oculocerebrorenal syndrome: two cases and a literature review

Background Oculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by congenital cataracts, mental retardation, and proximal tubulopathy. This condition is caused by a mutation of OCRL gene (located at chromosome Xq26.1), which encodes an inositol polyphosphate 5-phosphatase. Case presentation We identified two novel OCRL mutations in two unrelated Chinese boys, each with a severe phenotype of Lowe syndrome. A novel de novo deletion (hemizygous c.659_662delAGGG, p.E220Vfs*29) was present in patient 1 and a novel splicing mutation (hemizygous c.2257-2A > T) that was maternally inherited was present in patient 2. A renal biopsy in patient 2 indicated mild mesangial proliferative glomerulonephritis, mild focal mononuclear cells infiltration, and interstitial focal fibrosis. Moreover, renal expression of OCRL-1 protein in patient 2 was significantly reduced compared to a control patient with thin basement membrane disease. Conclusions This study reports two novel OCRL variants associated with severe ocular and neurologic deficiency, despite only mild renal dysfunction. Based on our two patients and a literature review, the genotype–phenotype correlation of OCRL mutations with this severe phenotype of Lowe syndrome suggest a possible clustering of missense, deletion, and nonsense mutations in the 5-phosphatase domain and Rho-GAP domain in the Chinese population.

How genomics reclassifies diseases: the case of Alport syndrome

In this issue, Matthews et al. provide a comprehensive review of published cohorts with heterozygous pathogenic variants in COL4A3 or COL4A4, documenting the wide spectrum of the disease. Due to the extreme phenotypes that patients with heterozygous pathogenic variants in COL4A3 or COL4A4 may show, the disease has been referred to in a variety of ways, including ‘autosomal dominant Alport syndrome’, ‘thin basement membrane disease’, ‘thin basement membrane nephropathy’, ‘familial benign hematuria’ and ‘carriers of autosomal dominant Alport syndrome’. This confusion over terminology has prevented nephrologists from being sufficiently aware of the relevance of the entity. Nowadays, however, next-generation sequencing facilitates the diagnosis and it is becoming a relatively frequent finding in haematuric–proteinuric nephropathies of unknown origin, even in non-familial cases. There is a need to raise awareness among nephrologists about the disease in order to improve diagnosis and provide better management for these patients.

Heterozygous Urinary Abnormality–Causing Variants of COL4A3 and COL4A4 Affect Severity of Autosomal Recessive Alport Syndrome

BackgroundAutosomal recessive Alport syndrome (ARAS) is an inherited renal disorder caused by homozygous and compound heterozygous mutations in COL4A3 or COL4A4, but the prognostic predictors for this disorder are not yet fully understood. Recently, the magnitude of the clinical spectrum of the COL4A3 and COL4A4 heterozygous state has attracted attention. This spectrum includes asymptomatic carriers of ARAS, benign familial hematuria, thin basement membrane disease, and autosomal dominant Alport syndrome.MethodsWe retrospectively analyzed 49 patients with ARAS from 41 families with a median age of 19 years to examine the clinical features and prognostic factors of ARAS, including the associated genotypes.ResultsThe median age of patients with ARAS at ESKD onset was 27 years. There was no significant association between the presence or absence of hearing loss or truncating mutations and renal prognosis. However, there was a statistically significant correlation between renal prognosis and heterozygous variants that cause urinary abnormalities. Where the urinary abnormality–causing variant was absent or present in only one allele, the median age of ESKD onset was 45 years, whereas the same variant present on both alleles was associated with an age of onset of 15 years (P<0.001).ConclusionsThis study was the first to demonstrate the clinical importance in ARAS of focusing on variants in COL4A3 or COL4A4 that cause urinary abnormalities in both the homozygous or heterozygous state. Although heterozygous mutation carriers of COL4A3 and COL4A4 comprise a broad clinical spectrum, clinical information regarding each variant is important for predicting ARAS prognosis.

P0433AGE-RELATED DIFFERENCES IN THE SPECTRUM OF BIOPSY-PROVEN GLOMERULONEPHRITIS

Background and Aims The proportion of geriatric population is increasing globally and age-related changes, as kidney ageing and decline in immunocompetence, might interfere with frequency of various glomerulopathies (GP). Thus, it is conceivable that the spectrum of biopsy-proven GP varies across different age categories. Accordingly, we aimed to describe age-related variation in clinical presentation and the in prevalence of GP diagnosed by kidney biopsy (KB) in adults. Method This retrospective study enrolled 1254 subjects selected from the KB database of a large tertiary academic Nephrology center (which provides specialized care for the south-eastern part of our country), over a ten-year span (01.01.2008-31.12.2017). Inclusion criteria were age &gt;18 years, native kidney biopsy, availability of data from light, immunofluorescence, and electron microscopy, and a histologic diagnosis of GP. Repeated biopsies and inadequate tissue samples were excluded. Demographic (age, gender), clinical and laboratory data at the time of biopsy were extracted from medical records for all the selected subjects. To investigate the possible influence of age on the spectrum of biopsy-proven GP, the cohort was divided into 4 categories: young adults (18 to 30 years, n=156), adults (31 to 64 years, n=868), elderly (65 to 74 years, n=176) and very elderly (≥75 years, n=54), and the collected data were compared by non-parametric methods (Mann-Whitney, Chi2 and Fisher exact tests). Results The nephrotic syndrome was the most common presentation form in all age groups but had a higher prevalence in very elderly (62%) and elderly (55%) as compared to adults (37%, p=0.01) and young adults (41%, p&lt;0.001). In the groups below age of 65, the chronic nephritic syndrome was the second most common indication for KB (31% and 28%, respectively), followed by chronic renal failure in adults (13%) and acute nephritic syndrome in young adults (10%). Lupus nephritis (LN) and IgA nephropathy (IgAN) were the most commonly diagnosed GP in young adults (22% each), followed by minimal change disease (MCD, 14%), membranous nephropathy (MN, 8%), focal and segmental glomerulosclerosis (FSGS, 8%), and thin basement membrane disease (6%). In adults, the most common GP were: IgAN (23%), MN (15%), diabetic nephropathy (DN, 11%) and MCD (10 %). Conversely, in both the elderly and the very elderly, the most common biopsy-proven GP was MN (26% each). Elderly had renal amyloidosis as the second most prevalent histological diagnosis (17%), followed by DN (11%), and by IgAN and MCD (≈10% each). Crescentic glomerulonephritis (CGN) occurred in 7.5% of the elderly, but it was the second pathology (17%) in subjects aged 75+ years, followed by MCD (15%) and DN (13%). IgAN and amyloidosis were identified in about 5% of this group. It appears that the prevalence of both clinical presentation and histologically diagnosed GP showed some similarities between the first two and, respectively, last two age categories. Conclusion Biopsy-proven GP have different frequencies depending on the patient’s age, with some pathologies predominantly found at older ages (such as membranous nephropathy, amyloidosis and crescentic GN) or, on the contrary, typical for young adults (lupus nephritis and IgAN). These differences account for the distinct clinical presentations at the time of KB.

P0102A REVIEW OF RENAL BIOPSIES IN A LARGE UK RENAL CENTRE- A 20 YEAR EXPERIENCE

Background and Aims Percutaneous renal biopsy is the mainstay of renal pathological diagnosis. Not only does it secure an accurate diagnosis, but also lends itself to guiding the prognosis of a myriad of renal disorders. An important diagnostic modality for nephrologists, they have contributed greatly to the field of nephrology, both in terms of the classification of diseases and assisting in understanding their pathogenesis. Adequacy of the tissue samples of at least ten to fifteen glomeruli is generally preferred. The aim of our retrospective study was to review the renal biopsies done in one large UK renal centre, namely Salford Royal Foundation Trust, over the last twenty years. This Trust covers a catchment area that serves approximately 1.5 million people. Method A list of all renal biopsies performed at Salford Royal Foundation Trust between January 2000 to January 2020 was generated by our pathology department. Following this, each individual biopsy report was reviewed. In addition to this, certain information was collated from individual patient records; namely patient demographics, the indication for biopsy, tissue type (native or transplant), histological diagnosis and outcomes. Our centre has an excellent electronic patient record (EPR). This enabled us to analyse full clinical data retrospectively for each case. Results Between January 2000 and January 2020 a total of 3555 renal biopsies were performed at Salford Royal Foundation Trust. These biopsies were performed solely by nephrology specialists and supervised trainees, under ultrasound guidance. 177.5 biopsies were performed on average, per year, ranging between 140 – 203. 90% of biopsies were performed on native kidneys, with 10% being performed on transplanted kidneys. 10% of biopsies had normal histology morphologically when reviewed by light microscopy. There diagnoses of these included entities minimal change disease and thin basement membrane disease most commonly. IgA nephropathy was the most common glomerular pathology identified, in keeping with the wealth of published literature. There were over 525 biopsies done confirming IgAN as the primary pathology. 7% of biopsies had a crescentic glomerular pathology when examined histologically. The main causes included crescentic IgA nephropathy and anca-associated vasculitis. Conclusion Kidney biopsies have long been regarded as safe, minimally invasive procedures are of paramount importance to our diagnostic armamentarium. Our data echoes that of already published pathology series, IgAN being the most common glomerular pathology in our series. We further plan to analyse the various conditions and their outcomes in further detail.

Prevalence of clinical, pathological and molecular features of glomerular basement membrane nephropathy caused by COL4A3 or COL4A4 mutations: a systematic review

Background Patients heterozygous for COL4A3 or COL4A4 mutations show a wide spectrum of disease, extending from familial isolated microscopic haematuria, as a result of thin basement membranes (TBMs), to autosomal dominant Alport syndrome (ADAS) and end-stage renal disease (ESRD). Many patients are mentioned in the literature under the descriptive diagnosis of TBM nephropathy (TBMN), in which case it actually describes a histological finding that represents the carriers of autosomal recessive Alport syndrome (ARAS), a severe glomerulopathy, as most patients reach ESRD at a mean age of 25 years. Methods We performed a systematic literature review for patients with heterozygous COL4A3/A4 mutations with the aim of recording the spectrum and frequency of pathological features. We searched three databases (PubMed, Embase and Scopus) using the keywords ‘Autosomal Dominant Alport Syndrome’ OR ‘Thin Basement Membrane Disease’ OR ‘Thin Basement Membrane Nephropathy’. We identified 48 publications reporting on 777 patients from 258 families. Results In total, 29% of the patients developed chronic kidney disease (CKD) and 15.1% reached ESRD at a mean age of 52.8 years. Extrarenal features and typical Alport syndrome (AS) findings had a low prevalence in patients as follows: hearing loss, 16%; ocular lesions, 3%; basement membrane thickening, 18.4%; and podocyte foot process effacement, 6.9%. Data for 76 patients from 54 families emphasize extensive inter- and intrafamilial heterogeneity, with age at onset of ESRD ranging between 21 and 84 years (mean 52.8). Conclusions The analysis enabled a comparison of the clinical course of patients with typical ARAS or X-linked AS with those with heterozygous COL4A mutations diagnosed with TBMN or ADAS. Despite the consequence of a potential ascertainment bias, an important outcome is that TBM poses a global high risk of developing severe CKD, over a long follow-up, with a variable spectrum of other findings. The results are useful to practicing nephrologists for better evaluation of patients.

Clinicopathologic and ultrastructural findings of hereditary nephritis; a 16-year single center survey in Iran

Introduction: Hereditary nephritis is an umbrella term for a group of congenital childhood diseases including but not limited to Alport syndrome, thin basement membrane disease, and Fabry disease. Objectives: The purpose of this study was a clinicopathologic investigation of Alport syndrome, thin basement membrane disease, and Fabry disease with a focus on the role of electron microscopy and toluidine blue staining in diagnosis. Patients and Methods: In this cross-sectional study, we investigated kidney biopsies with a final diagnosis of either Alport syndrome, thin basement membrane disease or Fabry disease from 2001 to 2016. Electron microscopy and light microscopy were done and the clinical and paraclinical data were extracted from the patients’ medical charts. Electron microscopy role was assessed in terms of necessary, helpful or non-necessary, while correlations between clinical and para-clinical data were determined using appropriate statistical tests. Results: Among the 2865 kidney biopsies, there were 22 patients of hereditary nephritis including 15 (0.52%) Alport syndrome, 5 (0.17%) thin basement membrane disease and 2 (0.07%) Fabry disease diagnosed by electron microscopy. Electron microscopy was essential for the diagnosis of 19 (86.4%) cases, helpful for 3(13.6%) and there was no case for which electron microscopy was non-necessary. The patients’ mean age was 16.1 ± 9.0 years. The most common finding in Alport syndrome was proteinuria (86.7%) followed by hematuria (60.0%). Conclusion: Considering the rate of misdiagnosis of hereditary nephritis using light microscopy and clinical findings alone, electron microscopy study and toluidine blue staining has an essential role in the precise diagnosis in these patients. With regard to the progressive nature of these diseases, prompt diagnosis using electron microscopy is pertinent for therapeutic decisions.

Non-visible haematuria in a military setting

Asymptomatic non-visible haematuria is a common finding at routine military medical examinations. This article briefly reviews the possible causes, which include malignancy, structural causes, exertion haematuria, hereditary nephritis, thin basement membrane disease (TBMD), immunoglobulin A nephropathy (IgAN), tuberculosis (TB) and schistosomiasis. This paper discusses how these conditions may affect potential military recruits as well as currently serving members of the Armed Forces, and offers a general approach to the management of a patient with non-visible haematuria.