ABSTRACT
AIM: To examine whether hemodialysis (HD) patients with restless legs syndrome (RLS) are subjects of greater fatigue and impaired quality of life (QoL) compared to HD patients without RLS. METHODS: Eighty five stable HD patients participated in this study. According to their RLS status, the patients were divided into the RLS group (n = 23) and the non-RLS group (n = 62). QoL, fatigue, sleep quality, daily sleepiness and depression symptoms were assessed by using various questionnaires. Finally, biochemical parameters including iron, ferritin, hemoglobin, hematocrit and parathormone were assessed. RESULTS: The HD patients with RLS scored worse in all the questionnaires used in the study (P < 0.05). The patients with RLS were more likely to receive the HD therapy on the morning shift, whilst 43.5% of the RLS patients reported to experience the RLS symptoms also during HD. The severity of RLS was correlated with fatigue, depression score and sleep quality (P < 0.05). CONCLUSION: HD patients with RLS are subject to lower QoL related parameters and greater fatigue compared to HD patients without RLS. RLS should be successfully managed in order to improve the QoL of the sufferers.
ABSTRACT
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.
Subject(s)
Autoantigens/genetics , Collagen Type IV/genetics , Glomerular Basement Membrane/pathology , Glomerulosclerosis, Focal Segmental/genetics , Hematuria/genetics , Adult , Aged , Aging , Base Sequence , Cell Line , Female , High-Throughput Nucleotide Sequencing , Humans , Kidney Failure, Chronic/genetics , Kidney Failure, Chronic/pathology , Male , Middle Aged , Mutation/genetics , Nephritis, Hereditary/genetics , Podocytes/metabolism , Sequence Analysis, DNA , Unfolded Protein Response/geneticsABSTRACT
BACKGROUND AND OBJECTIVES: 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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 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. RESULTS: 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%]). CONCLUSIONS: 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.
Subject(s)
Complement C3/analysis , Complement System Proteins/genetics , Glomerulonephritis/genetics , Kidney/immunology , Mutation , Adolescent , Adult , Aged , Aged, 80 and over , Biopsy , Cyprus , DNA Mutational Analysis , Disease Progression , Female , Founder Effect , Genetic Predisposition to Disease , Glomerulonephritis/complications , Glomerulonephritis/immunology , Glomerulonephritis/pathology , Glomerulonephritis/therapy , Hematuria/genetics , Hematuria/immunology , Humans , Kidney/pathology , Kidney Failure, Chronic/genetics , Kidney Failure, Chronic/immunology , London , Male , Middle Aged , Pedigree , Phenotype , Prospective Studies , Proteinuria/genetics , Proteinuria/immunology , Sex Factors , Time Factors , Young AdultABSTRACT
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.
Subject(s)
Autoantigens/genetics , Collagen Type IV/genetics , Glomerulosclerosis, Focal Segmental/genetics , Hematuria/genetics , Kidney Failure, Chronic/genetics , Proteinuria/genetics , Adolescent , Adult , Age of Onset , Aged , Child , Child, Preschool , Cyprus , Female , Glomerulosclerosis, Focal Segmental/complications , Glomerulosclerosis, Focal Segmental/pathology , Hematuria/complications , Heterozygote , Humans , Kidney Failure, Chronic/etiology , Male , Middle Aged , Mutation , Nephritis, Hereditary/genetics , Pedigree , Proteinuria/etiologyABSTRACT
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.