Mutations in the COL4A3/COL4A4 genes of type IV collagen have been found in approximately 40% of cases of thin basement membrane nephropathy, which is characterized by microscopic hematuria and is ...classically thought to cause proteinuria and chronic renal failure rarely. Here we report our observations of 116 subjects from 13 Cypriot families clinically affected with thin basement membrane nephropathy. These families first came to our attention because they segregated microscopic hematuria, mild proteinuria, and variable degrees of renal impairment, but a dual diagnosis of focal segmental glomerulosclerosis (FSGS) and thin basement membrane nephropathy was made in 20 biopsied cases. Molecular studies identified founder mutations in both COL4A3 and COL4A4 genes in 10 families. None of 82 heterozygous patients had any extrarenal manifestations, supporting the diagnosis of thin basement membrane nephropathy. During follow-up of up to three decades, 31 of these 82 patients (37.8%) developed chronic renal failure and 16 (19.5%) reached end-stage renal disease. Mutations G1334E and G871C were detected in seven and three families, respectively, and were probably introduced by founders. We conclude that these particular COL4A3/COL4A4 mutations either predispose some patients to FSGS and chronic renal failure, or that thin basement membrane nephropathy sometimes coexists with another genetic modifier that is responsible for FSGS and progressive renal failure. The findings presented here do not justify the labelling of thin basement membrane nephropathy as a benign condition with excellent prognosis.
Thin-basement-membrane nephropathy (TBMN) and Alport syndrome (AS) are progressive collagen IV nephropathies caused by mutations in COL4A3/A4/A5 genes. These nephropathies invariably present with ...microscopic hematuria and frequently progress to proteinuria and CKD or ESRD during long-term follow-up. Nonetheless, the exact molecular mechanisms by which these mutations exert their deleterious effects on the glomerulus remain elusive. We hypothesized that defective trafficking of the COL4A3 chain causes a strong intracellular effect on the cell responsible for COL4A3 expression, the podocyte. To this end, we overexpressed normal and mutant COL4A3 chains (G1334E mutation) in human undifferentiated podocytes and tested their effects in various intracellular pathways using a microarray approach. COL4A3 overexpression in the podocyte caused chain retention in the endoplasmic reticulum (ER) that was associated with activation of unfolded protein response (UPR)-related markers of ER stress. Notably, the overexpression of normal or mutant COL4A3 chains differentially activated the UPR pathway. Similar results were observed in a novel knockin mouse carrying the Col4a3-G1332E mutation, which produced a phenotype consistent with AS, and in biopsy specimens from patients with TBMN carrying a heterozygous COL4A3-G1334E mutation. These results suggest that ER stress arising from defective localization of collagen IV chains in human podocytes contributes to the pathogenesis of TBMN and AS through activation of the UPR, a finding that may pave the way for novel therapeutic interventions for a variety of collagenopathies.
Complement factor H and related proteins (CFHR) are key regulators of the alternative complement pathway, where loss of function mutations lead to a glomerulopathy with isolated mesangial C3 deposits ...without immunoglobulins. Gale et al. (12) reported on 26 patients with the first familial, hematuric glomerulopathy caused by a founder mutation in the CFHR5 gene in patients of Cypriot descent living in the United Kingdom. CFHR5 nephropathy is clinically characterized by continuous microscopic hematuria whereas some patients present with additional episodes of synpharyngitic macrohematuria, associated with infection and pyrexia. A subgroup of patients, particularly men, develop additional proteinuria, hypertension, and chronic renal disease or ESRD.
We herewith expand significantly on the study by Gale et al., reporting on histologic, molecular, and clinical findings in 91 patients from 16 families with the same founder mutation.
Eighty-two patients (90%) exhibited microscopic hematuria; 51 (62%), exhibited only microscopic hematuria, whereas the remaining 31 additionally had proteinuria (38%); 28 proteinuric patients developed chronic renal failure (CRF). Among carriers of CFHR5 mutation aged >50 years, 80% of the men and 21% of the women developed CRF; 18 developed ESRD (14 men 78%, 4 women 22%).
The diagnosis of CFHR5-related, isolated C3 glomerulopathy was established in 2009 using newly described mutation analysis after decades of follow-up with unclear diagnoses, occasionally confused with IgA nephropathy. This larger patient cohort establishes the clinical course, significant variable expressivity, and marked gender difference regarding the development of CRF and ESRD.
Tissue dispersion could be used as a marker of early disease changes to further improve the diagnostic potential of optical coherence tomography (OCT). However, most methods to measure dispersion, ...described in the literature, rely on the presence of distinct and strong reflectors and are, therefore, rarely applicable
. A novel technique has been developed which estimates the dispersion-induced resolution degradation from the image speckle and, as such, is applicable
. This method was verified experimentally
and was applied to the classification of a set of normal and cancerous colon OCT images resulting in 96% correct classification.
Autosomal-dominant medullary cystic kidney disease type 1: Clinical and molecular findings in six large Cypriot families.
Autosomal-dominant medullary cystic kidney disease (ADMCKD), a hereditary ...chronic interstitial nephropathy, recently attracted attention because of the cloning or mapping of certain gene loci, namely NPHP1, NPHP2 and NPHP3 for familial juvenile nephronophthisis (NPH) and MCKD1 and MCKD2 for the adult form of medullary cystic kidney disease. Our aim was to present and discuss the clinical, biochemical, sonographic and histopathological findings in six large Cypriot families in whom molecular analysis has confirmed linkage to the MCKD1 locus on chromosome 1q21.
The clinical, biochemical, sonographic and histopathological findings in 186 members of six large Cypriot families with ADMCKD-1 are presented. Creatinine clearance was calculated according to the Cockroft-Gault formula and was corrected to a body surface area (BSA) of 1.73m2. DNA linkage analysis was performed with previously identified flanking polymorphic markers.
This disease is characterized by the absence of urinary findings in the vast majority of patients, leading to end-stage renal failure (ESRF) at a mean age of 53.7 years. Hypertension and hyperuricemia are common, especially in males, the former encountered more frequently in advanced chronic renal failure (CRF). Gout has been noted in a small percentage of male patients. Loss of urinary concentrating ability was not a prominent early feature of the disease, while severe natriuresis was observed in a few males toward ESRF. Renal cysts are mainly corticomedullary or medullary, and they are present in about 40.3% of patients and appear more frequently near ESRF.
ADMCKD type 1 is a common cause of ESRF among our dialysis population. The disease is difficult to diagnose clinically, particularly in the early stage when renal cysts are not usually present, making them a weak diagnostic finding. A dominant pattern of inheritance and DNA linkage analysis are helpful in the diagnosis of this disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Background: The EndoPredict 12-gene prognostic assay is validated to predict distant recurrence-free survival (DRFS) and response to chemotherapy in post-menopausal women with ER+, ...HER2- breast cancer. This study evaluated the performance of EndoPredict in pre-menopausal women. Methods: Stored tumor samples from women with ER+, HER2- primary breast cancer who were pre-menopausal at the time of diagnosis and were systemically treated with endocrine therapy alone were obtained from two sites (University of Nottingham and University of Cyprus). These samples were tested with EndoPredict to produce a 12-gene molecular score (EP). Pathologic tumor size and nodal status were algorithmically combined with the EP score to produce the clinicomolecular EPclin score. Cases with tumors > pT3, which were treated with chemotherapy, or for whom the EPclin score was missing or invalid were excluded. Associations of EP and EPclin with 10-year DRFS were evaluated in terms of hazard ratios (HRs) from Cox proportional hazards models stratified by cohort. 10-year DRFS was estimated for EPclin high-risk and low-risk women by Kaplan-Meier analysis. Results: Out of 411 eligible cases, 385 had a valid EPclin score and were included in the analysis. Mean age at breast cancer diagnosis was 46.5 years (standard deviation 4.7). Most women (N = 239, 62.6%) had grade II tumors and 16.1% (N = 62) had node-positive disease. Over the observation period (median 9.7 years, interquartile range 6.6-13.9 years), 35 women had a distant recurrence within 10 years. Both the molecular EP score and the molecular-clinicopathologic EPclin score were associated with increased risk of distant recurrence HR 1.3, 95% confidence interval (CI) 1.2-1.5; p < 0.001 and HR 3.6, 95% CI 2.3-5.7; p < 0.001, respectively. Of these patients, 249 (64.7%) were categorized as low risk by EPclin score while the remaining 136 (35.3%) were categorized as high risk. Compared to EPclin low-risk women, EPclin high-risk patients were more likely to experience distant recurrence (HR 4.6, 95% CI 1.4-15.2; p = 0.004). At 10 years post-diagnosis, EPclin low-risk women who received endocrine therapy alone had a DRFS of 97% (95% CI 93-99%). Conversely, EPclin high-risk women had a DRFS of only 76% (95% CI 67-82%). Conclusions: The EPclin score is highly associated with DRFS in pre-menopausal women who received adjuvant endocrine therapy alone. Based on these data, pre-menopausal women with EPclin low-risk breast cancer may safely forgo adjuvant chemotherapy in addition to endocrine therapy.
The EndoPredict prognostic assay is validated to predict distant recurrence and response to chemotherapy primarily in post-menopausal women with estrogen receptor-positive (ER+), HER2- breast cancer. ...This study evaluated the performance of EndoPredict in pre-menopausal women.
Tumor samples from 385 pre-menopausal women with ER+, HER2- primary breast cancer (pT1-3, pN0-1) who did not receive chemotherapy in addition to endocrine therapy were tested with EndoPredict to produce a 12-gene EP molecular score and an integrated EPclin score that includes pathologic tumor size and nodal status. Associations of molecular and EPclin scores with 10-year distant recurrence-free survival (DRFS) were evaluated by Cox proportional hazards models and Kaplan-Meier analysis.
After a median follow-up of 9.7 years, both the EP molecular score and the molecular-clinicopathologic EPclin score were associated with increased risk of distant recurrence HR, 1.33; 95% confidence interval (CI), 1.18-1.50; P = 7.2 × 10-6; HR, 3.58; 95% CI, 2.26-5.66; P = 9.8 × 10-8, respectively. Both scores remained significant after adjusting for clinical factors in multivariate analysis. Patients with low-risk EPclin scores (64.7%) had significantly improved DRFS compared with high-risk patients (HR, 4.61; 95% CI, 1.40-15.17; P = 4.2 × 10-3). At 10 years, patients with low-risk and high-risk EPclin scores had a DRFS of 97% (95% CI, 93%-99%) and 76% (95% CI, 67%-82%), respectively.
The EPclin score is strongly associated with DRFS in pre-menopausal women who received adjuvant endocrine therapy alone. On the basis of these data, pre-menopausal women with EPclin low-risk breast cancer may be treated with endocrine therapy only and safely forgo adjuvant chemotherapy.
Background. Heterozygous mutations in the COL4A3/ COL4A4 genes are currently thought to be responsible for familial benign microscopic haematuria and maintenance of normal long-term kidney function. ...Methods. We report on 11 large Cypriot pedigrees with three such mutations. A total of 236 at-risk family members were genetically studied, and 127 (53.8%) carried a heterozygous mutation. Clinico-pathological correlations were available in all of these patients. Renal biopsies in 21 of these patients all showed various stages of focal, segmental glomerulosclerosis (FSGS). Thirteen of these biopsies were also studied with EM and showed thinning of the glomerular basement membrane. Results. Mutation G1334E (COL4A3) was found in six pedigrees, mutation G871C (COL4A3) in four and mutation 3854delG (COL4A4) in one pedigree. Clinical and laboratory correlations in all 127 mutation carriers (MC) showed that microscopic haematuria was the only urinary finding in patients under age 30. The prevalence of ‘haematuria alone’ fell to 66% between 31 and 50 years, to 30% between 51 and 70 and to 23% over age 71. Proteinuria with CRF developed on top of haematuria in 8% of all MC between 31 and 50 years, to 25% between 51 and 70 years and to 50% over 71 years. Altogether 18 of these 127 MC (14%) developed ESRD at a mean age of 60 years. Two members with different mutations married, and two of their children inherited both mutations and developed adolescent, autosomal recessive Alport syndrome (ATS), confirming that these mutations are pathogenic. Conclusions. Our data confirm for the first time a definite association of heterozygous COL4A3/COL4A4 mutations with familial microscopic haematuria, thin basement membrane nephropathy and the late development of familial proteinuria, CRF, and ESRD, due to FSGS, indicating that the term ‘benign familial haematuria’ is a misnomer, at least in this cohort. A strong hypothesis for a causal relationship between these mutations and FSGS is also made. Benign familial haematuria may not be so benign as commonly thought.
Familial glomerular hematuria(s) comprise a genetically heterogeneous group of conditions which include Alport Syndrome (AS) and thin basement membrane nephropathy (TBMN). Here we investigated 57 ...Greek-Cypriot families presenting glomerular microscopic hematuria (GMH), with or without proteinuria or chronic kidney function decline, but excluded classical AS. We specifically searched the COL4A3/A4 genes and identified 8 heterozygous mutations in 16 families (28,1%). Eight non-related families featured the founder mutation COL4A3-p.(G1334E). Renal biopsies from 8 patients showed TBMN and focal segmental glomerulosclerosis (FSGS). Ten patients (11.5%) reached end-stage kidney disease (ESKD) at ages ranging from 37-69-yo (mean 50,1-yo). Next generation sequencing of the patients who progressed to ESKD failed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD. Although this could be viewed as a milder and late-onset form of autosomal dominant AS, we had no evidence of ultrastructural features or extrarenal manifestations that would justify this diagnosis. Functional studies in cultured podocytes transfected with wild type or mutant COL4A3 chains showed retention of mutant collagens and differential activation of the unfolded protein response (UPR) cascade. This signifies the potential role of the UPR cascade in modulating the final phenotype in patients with collagen IV nephropathies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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