Defining renal phenotype in Alström syndrome

Abstract

Background Alström syndrome (AS) is a rare autosomal recessive ciliopathy with a wide spectrum of clinical features, including cone–rod retinal dystrophy, neuronal deafness, severe insulin resistance and major organ failure. The characteristics of renal disease in the syndrome have not been systematically described. The aim of this study is to define the onset and progression of renal disease in AS. Method Prospective observational cohort study. Setting and Participants Thirty-two adult subjects from a national specialist clinic in UK and 86 subjects from an international AS registry were studied. Outcomes First, an international registry cross-sectional study across all age groups to determine change in kidney function was performed. Secondly, a detailed assessment was carried out of adult AS patients with serial follow-up to determine incidence, aetiology and progression of renal disease. Analytical approach Generalized estimating equations were used to evaluate the relationship between age and estimated glomerular filtration rate (eGFR). Associations between patient factors and eGFR levels were then assessed in the adult AS cohort. Results The international registry study of the renal function of 118 subjects with AS (median age 21 years) showed a rapid decline with age, at an average of −16.7 and −10.9 mL/min/1.73 m2 per decade in males and females, respectively. In a UK national cohort of 32 patients with AS (median age 22 years), 20/32 (63%) had chronic kidney disease (CKD) Stage 3 or above based on eGFR <60 mL/min/1.73 m2 or evidence of albuminuria. Hyperuricaemia was noted in 25/32 (79%). Structural abnormalities such as nephrocalcinosis without hypercalcaemia and cysts were observed in 20/32 (63%) subjects. Lower urinary tract symptoms were frequent in 17/19 (70%) of AS patients. Histological evidence showed mixed tubulo-interstitial and glomerular disease. Conclusions This is the first study to demonstrate that renal disease is the hallmark of AS, which starts early and progresses with age, leading to a high prevalence of advanced CKD at young age. AS should be considered in the differential diagnosis of rare genetic renal diseases.

Clinical characteristics of individual organ system disease in non-motile ciliopathies

“…Chronic progressive nephropathy is one of the primary manifestations of AS [97][98][99]. Renal failure was found to be the cause of death in 23% of AS patients between the ages of 22 and 48 years [82].…”

“…Renal failure was found to be the cause of death in 23% of AS patients between the ages of 22 and 48 years [82]. Nephropathy in AS is early onset; decline in glomerular function may start as early as 10 years [98]. In adults with AS, renal function declines rapidly, at an average rate of 17 mL/min/1.73 m2 per decade in males, and 11 mL/min/1.73 m2 per decade in females [98].…”

“…Nephropathy in AS is early onset; decline in glomerular function may start as early as 10 years [98]. In adults with AS, renal function declines rapidly, at an average rate of 17 mL/min/1.73 m2 per decade in males, and 11 mL/min/1.73 m2 per decade in females [98]. Approximately two thirds of adults with AS (median age 22 years) meet the criteria for stage 3 or worse chronic kidney disease based on eGFR <60 mL/min/1.73 m2 or evidence of albuminuria [98].…”

“…In adults with AS, renal function declines rapidly, at an average rate of 17 mL/min/1.73 m2 per decade in males, and 11 mL/min/1.73 m2 per decade in females [98]. Approximately two thirds of adults with AS (median age 22 years) meet the criteria for stage 3 or worse chronic kidney disease based on eGFR <60 mL/min/1.73 m2 or evidence of albuminuria [98]. Renal histopathology shows interstitial fibrosis and tubular atrophy associated with varying degrees of glomerular sclerosis but no features of diabetic or reflux nephropathy [82,98,100,101].…”

Nephrocalcinosis in a portuguese pediatric population

“…Moreover, hypercalciuria is present in 10 to 22% of series 19,20 and it can predispose to NC, also described in these patients. NC has also been reported in Klinefelter 21 , Alstrom syndromes 22 , and anecdotal cases of Down syndrome with prolonged excessive calcium intake 23,24 . However, in our patient no metabolic abnormality, medication or supplementation was identified.…”