Rannveig Skrunes

Familial Clustering of ESRD in the Norwegian Population

BACKGROUND AND OBJECTIVES Studies and clinical experience suggest that kidney disease clusters in families, but few population-based studies have been performed. This study investigates risks and causes of ESRD in Norwegians with and without a first-degree relative with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS On the basis of data from the Norwegian Population Registry, first-degree relatives for most Norwegians were identified. All Norwegians with ESRD (defined as chronic RRT) since 1980 have been registered in the Norwegian Renal Registry. All Norwegians born in Norway who were alive in 1980 and had at least one registered relative were included. For this study, data on ESRD were available through 2009, and individuals without ESRD were censored at December 31, 2009. Data were analyzed in a cohort design, with ESRD in a first-degree relative of the included person as the main explanatory variable. Risks of ESRD and different causes of ESRD were analyzed using Cox regression statistics. RESULTS In total, 5,119,134 individuals were included, of whom 8203 individuals developed ESRD during follow-up and 27,046 individuals had a first-degree relative with ESRD. Compared with individuals without a first-degree relative with ESRD, individuals with a first-degree relative with ESRD had a relative risk of ESRD of 7.2 (95% confidence interval, 6.5 to 8.1). Similar analyses showed that relative risk of ESRD caused by nonhereditary causes was 3.7 (95% confidence interval, 3.1 to 4.4), relative risk of ESRD caused by glomerular disease was 5.2 (95% confidence interval, 4.1 to 6.6), relative risk of ESRD caused by interstitial disease was 4.7 (95% confidence interval, 3.1 to 7.3), relative risk of ESRD caused by diabetic nephropathy was 2.6 (95% confidence interval, 1.6 to 4.1), and relative risk of ESRD caused by hypertensive nephrosclerosis was 2.6 (95% confidence interval, 1.6 to 4.1). Relative risk of nonhereditary parenchymal renal disease was 3.8 (95% confidence interval, 3.1 to 4.7). CONCLUSIONS As expected, ESRD clusters in families. Interestingly, ESRD without known hereditary cause also clusters in families.

Reaccumulation of globotriaosylceramide in podocytes after agalsidase dose reduction in young Fabry patients

Background Agalsidase-α 0.2 mg/kg every other week (eow) and agalsidase-β 1.0 mg/kg/eow are licensed in Europe as equipotent treatment of the α-galactosidase deficiency in Fabry disease. This case series describes the effects of agalsidase dose adjustments in serial kidney biopsies in switch patients. Methods All treatment-naïve patients with classical Fabry disease in our centre started on agalsidase-β 1.0 mg/kg/eow and subsequently switched to agalsidase-α 0.2 mg/kg/eow were included ( n = 3). The median age at enzyme replacement therapy start was 11 (range 7-18) years. Kidney biopsies were performed at baseline, after 5 years of agalsidase-β 1.0 mg/kg/eow and after 3 subsequent years of agalsidase-α 0.2 mg/kg/eow. One patient was re-biopsied 2 years after reswitch to agalsidase-β 1.0 mg/kg/eow. The scoring system of the International Scoring Group of Fabry Nephropathy was used. Results The patients completely cleared globotriaosylceramide (GL3) from mesangial and endothelial cells and partly cleared podocytes on agalsidase-β 1.0 mg/kg/eow. Reaccumulation of GL3 in podocytes, but not in the mesangium or endothelium, occurred after 3 years of agalsidase-α 0.2 mg/kg/eow. Subsequent reduction of podocyte GL3 was observed in the single patient rebiopsied 2 years after reswitch to agalsidase-β 1.0 mg/kg/eow. Conclusion Partial clearance, reaccumulation and renewed partial clearance of podocyte GL3 deposits in serial kidney biopsies over 8-10 years were seen in parallel with agalsidase dose adjustments. Repeated kidney biopsies may impact therapeutic choices in Fabry disease.

Familial Factors, Low Birth Weight, and Development of ESRD: A Nationwide Registry Study.

BACKGROUND Previous studies have demonstrated that low birth weight (LBW) is associated with higher risk for end-stage renal disease (ESRD). However, both LBW and ESRD cluster in families. The present study investigates whether familial factors explain the association between LBW and ESRD. STUDY DESIGN Retrospective registry-based cohort study. SETTING & PARTICIPANTS Since 1967, the Medical Birth Registry of Norway has recorded medical data for all births in the country. Sibling data are available through the Norwegian Population Registry. Since 1980, all patients with ESRD in Norway have been registered in the Norwegian Renal Registry. Individuals registered in the Medical Birth Registry with at least 1 registered sibling were included. PREDICTOR LBW in the participant and/or LBW in at least 1 sibling. OUTCOME ESRD. RESULTS Of 1,852,080 included individuals, 527 developed ESRD. Compared with individuals without LBW and with no siblings with LBW, individuals without LBW but with a sibling with LBW had an HR for ESRD of 1.20 (95% CI, 0.91-1.59), individuals with LBW but no siblings with LBW had an HR of 1.59 (95% CI, 1.18-2.14), and individuals with LBW and a sibling with LBW had an HR of 1.78 (95% CI, 1.26-2.53). Similar results were observed for individuals who were small for gestational age (SGA). Separate analyses for the association of age 18 to 42 years and noncongenital ESRD showed stronger associations for SGA than for LBW, and the associations were not statistically significant for age 18 to 42 years for LBW. LIMITATIONS Follow-up only until 42 years of age. CONCLUSIONS LBW and SGA are associated with higher risk for ESRD during the first 40 years of life, and the associations were not explained by familial factors. Our results support the hypothesis that impaired intrauterine nephron development may be a causal risk factor for progressive kidney disease.

Long-Term Dose-Dependent Agalsidase Effects on Kidney Histology in Fabry Disease

BACKGROUND AND OBJECTIVES Dose-dependent clearing of podocyte globotriaosylceramide has previously been shown in patients with classic Fabry disease treated with enzyme replacement. Our study evaluates the dose-dependent effects of agalsidase therapy in serial kidney biopsies of patients treated for up to 14 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Twenty patients with classic Fabry disease (12 men) started enzyme replacement therapy at a median age of 21 (range =7-62) years old. Agalsidase-α or -β was prescribed for a median of 9.4 (range =5-14) years. The lower fixed dose group received agalsidase 0.2 mg/kg every other week throughout the follow-up period. The higher dose group received a range of agalsidase doses (0.2-1.0 mg/kg every other week). Dose changes were made due to disease progression, suboptimal effect, or agalsidase-β shortage. Serial kidney biopsies were performed along with clinical assessment and biomarkers and scored according to recommendations from the International Study Group of Fabry Nephropathy. RESULTS No statistical differences were found in baseline or final GFR or albuminuria. Kidney biopsies showed significant reduction of podocyte globotriaosylceramide in both the lower fixed dose group (-1.39 [SD=1.04]; P=0.004) and the higher dose group (-3.16 [SD=2.39]; P=0.002). Podocyte globotriaosylceramide (Gb3) reduction correlated with cumulative agalsidase dose (r=0.69; P=0.001). Arterial/arteriolar intima Gb3 cleared significantly in the higher dose group, all seven patients with baseline intimal Gb3 cleared the intima, one patient gained intimal Gb3 inclusions (P=0.03), and medial Gb3 did not change statistically in either group. Residual plasma globotriaosylsphingosine levels remained higher in the lower fixed dose group (20.1 nmol/L [SD=11.9]) compared with the higher dose group (10.4 nmol/L [SD=8.4]) and correlated with cumulative agalsidase dose in men (r=0.71; P=0.01). CONCLUSIONS Reduction of podocyte globotriaosylceramide was found in patients with classic Fabry disease treated with long-term agalsidase on different dosing regimens, correlating with cumulative dose. Limited clearing of arterial/arteriolar globotriaosylceramide raises concerns regarding long-term vascular effects of current therapy. Residual plasma globotriaosylsphingosine correlated with cumulative dose in men.

Pathomechanisms of renal Fabry disease

Fabry disease, also known as Anderson-Fabry disease, is a clinically heterogeneous, X-linked lysosomal storage disorder first described in 1898 by Johannes Fabry and William Anderson (Anderson 1898; Fabry 1898). The disease is caused by defects in the lysosomal enzyme, alphagalactosidase A (Brady et al. 1967; Sweeley and Klionsky 1963). Various mutations in the GLA-gene give rise to this rare form of lysosomal storage disease (Bishop et al. 1986; Germain 2010). Fabry disease is characterized by multi-organ involvement (e.g., skin, heart, kidneys, eyes, blood vessels and central/peripheral nervous system) with a wide variety of symptoms (Germain 2010; Wise et al. 1962) due to accum u l a t i o n o f g l y c o s p h i n g o l i p i d s , p r i m a r i l y globotriaosylceramide (abbreviated as Gb3 or GL-3), in several different cell types. Fabry disease is a slowly progressing systemic disorder characterized by a variable disease course in affected patients (Germain 2010). The initial disease process starts early (Vedder et al. 2006), yet most patients display no symptoms during infancy. Usually, clinical signs appear between 3 and 10 years of age (Hopkin et al. 2008) in classically affected males, with a later onset of symptoms in non-classical patients as well as in many female patients with classical mutation (Wilcox et al. 2008). Classical Fabry patients typically develop chronic kidney disease (CKD) culminating in end-stage renal disease (ESRD) before the fifth decade (Fogo et al. 2010). Enzyme replacement therapy (ERT), available for more than 15 years, has been shown to reduce GL-3 deposits and halt or attenuate progression of Fabry nephropathy in many patients. Disease progression is highly variable in females, ranging from nonprogressive asymptomatic carriers to classical Fabry disease. Clinically evident Fabry disease with kidney involvement, such as proteinuria and/or reduced glomerular filtration rate (GFR), beginning at an average age of 37 years has been reported in 40% of 248 investigated female patients registered in the Fabry Outcome Survey (Europe), including development of ESRD in three cases (Deegan et al. 2006). Male patients may present as early as in their second decade with evidence of chronic kidney disease (Branton et al. 2002a), while nephropathy was diagnosed at the mean age of 27 years in another study (Donati et al. 1987). In an NIH series, it was shown that 50 % of the male patients had chronic renal insufficiency at 43 years of age and half of the patients had reached ESRD 10 years later (Branton et al. 2002a). The renal aspects of Fabry disease contribute largely to the total burden of * Øystein Eikrem oystein.eikrem@uib.no

Bedside Stereomicroscopy of Fabry Kidney Biopsies: An Easily Available Method for Diagnosis and Assessment of Sphingolipid Deposits

Background/Aims: A previous case report found stereomicroscopic changes typical for Fabry disease in a kidney biopsy. This case series evaluates an expanded diagnostic capacity of the method. Methods: Bedside stereomicroscopy was performed in a cross-sectional prospective study of 31 consecutive enzyme-treated or treatment-naïve male (n = 14) and female Fabry disease patients. The burden of glomerular storage material was scored semiquantitatively on a visual analog scale (range 0-3) and a blinded comparison was done with a reference histologic method. Results: Significant correlations (p < 0.001) were found between the stereomicroscopic scoring of glomerular characteristic white storage material and the amount of podocyte globotriaosylceramide (Gb3) deposits scored by standardized light microscopy. The bedside method correctly identified the variability of podocyte Gb3 accumulation after 10 years of identical agalsidase therapy in 2 brothers aged 24 and 27 years, and also identified tubular cell deposits. Stereomicroscopy correctly verified the absence of sphingolipid deposits in the biopsy of a female index patient with a genetic variant of unknown significance, and the diagnosis of Fabry disease was finally discarded. Conclusions: Bedside stereomicroscopy of kidney biopsies is an easily available, low-cost microscopy method handled by the clinician. The method carries a high diagnostic sensitivity for Fabry disease, reducing the risk of misdiagnosis in previously unknown cases. An expanded yield of the method is suggested, including the grading of the podocyte Gb3 burden and assessment of effectiveness of enzyme replacement therapy. We recommend the method as complementary to current standard histologic evaluation of Fabry kidney biopsies.

End Stage Renal Disease Predicts Increased Risk of Death in First Degree Relatives in the Norwegian Population

Background Increased risk of end stage renal disease (ESRD) and death in Norwegian living kidney donors has been reported, most of the donors were related to the recipient. The present study investigates risk of death in first degree relatives of ESRD patients. Methods The Norwegian Population Registry, The Norwegian Cause of Death Registry and the Norwegian Renal Registry were linked. All citizens born in Norway, alive in 1960 and with at least one registered first degree relative were included; individuals who died during the first year of life were excluded. A cohort-design was used, ESRD in a first degree relative was the main exposure variable and death and causes of death were the main outcome variables. Cox regression statistics were used to investigate mortality risks. Results 5 130 600 individuals were included, 27 508 had at least one first degree relative with ESRD. 828 022 died during follow-up, of whom 4105 had a first degree relative with ESRD. Adjusted hazard ratio (aHR) for death was 1.13 (1.09–1.16) in individuals with a relative with ESRD compared to those without a relative with ESRD. Excluding known hereditary renal disease, aHR decreased to 1.12 (1.09–1.15). Cardiovascular death aHR was 1.15 (1.10–1.21), of which cerebrovascular death 1.34 (1.22–1.50). aHR for death due to non-hereditary renal/ureteric disease was 2.29 (1.81–2.91) with renal failure 1.80 (1.26–2.56) and glomerular disease 5.69 (3.88–8.34) as main contributors. Diabetes mellitus death aHR was 1.68 (1.35–2.10). Absolute mortality risks increased most for the oldest cohorts with excess mortality of 148 per 100.000 person years for the cohort born 1920–39 and 218 for the cohort born 1900–1919. Conclusions ESRD in first degree relatives was associated with increased hazard ratio for death. Death due to cardiovascular disease, renal disease and diabetes mellitus increased the most.