Patient reported quality of life and medication adherence in Fabry disease patients treated with migalastat: A prospective, multicenter study.

AIMS: Chaperone therapy with migalastat is a novel therapy option in Fabry disease (FD). In contrast to biweekly intravenous enzyme-replacement-therapy in a healthcare setting, oral delivery of migalastat every other day relies on the patient self-administration. Therapy adherence to migalastat and patient reported outcomes have not yet been studied in a real-world scenario. METHODS AND RESULTS: Prospective multicenter 'MigALastat Therapy Adherence among FABRY patients' (MALTA-FABRY) study examined therapy adherence and patient-reported outcomes including quality of life in FD-patients receiving migalastat. Outcome measurements were elicited by the 'Medication Adherence Questionnaire (MAQ)', 'SF-36' and 'Fabry Pain Questionnaire' over a follow-up period of 24 months. Therapy adherence was graded as high (MAQ score of 4), medium (score of 2-3) or low (score 0-1). Within the recruitment period between 2017 and 2021, 40 patients (19 females) from 3 German FD-centers were included in the study. Nearly all patients (n = 37, 92.5%) showed good therapy adherence (MAQ6Mmean:3.93, MAQ12Mmean:3.71 and MAQ24Mmean:3.7). Only one patient fulfilled criteria for low adherence. Patient reported outcomes with completed SF-36 questionnaires were available in 28 patients (14 females). Over 24 months, significant improvement of pain and life role limitations due to physical activity was reported (Pain: change from baseline: 8.57 points, 95%-CI: 1.32-15.82, p = 0.022; role limitations physical: change from baseline: 13.39 points, 95%-CI: 0.61-23.2, p = 0.048). CONCLUSION: Migalastat therapy adherence in FD-patients was high and remained high over a follow-up period of 2 years. Patient reported quality of life remained mostly stable, while pain and physical limitations improved over time.

Defective lysosomal storage in Fabry disease modifies mitochondrial structure, metabolism and turnover in renal epithelial cells.

Fabry disease (FD) is an X-linked lysosomal storage disorder. Deficiency of the lysosomal enzyme alpha-galactosidase (GLA) leads to accumulation of potentially toxic globotriaosylceramide (Gb3) on a multisystem level. Cardiac and cerebrovascular abnormalities as well as progressive renal failure are severe, life-threatening long-term complications. The complete pathophysiology of chronic kidney disease (CKD) in FD and the role of tubular involvement for its progression are unclear. We established human renal tubular epithelial cell lines from the urine of male FD patients and male controls. The renal tubular system is rich in mitochondria and involved in transport processes at high-energy costs. Our studies revealed fragmented mitochondria with disrupted cristae structure in FD patient cells. Oxidative stress levels were elevated and oxidative phosphorylation was upregulated in FD pointing at enhanced energetic needs. Mitochondrial homeostasis and energy metabolism revealed major changes as evidenced by differences in mitochondrial number, energy production and fuel consumption. The changes were accompanied by activation of the autophagy machinery in FD. Sirtuin1, an important sensor of (renal) metabolic stress and modifier of different defense pathways, was highly expressed in FD. Our data show that lysosomal FD impairs mitochondrial function and results in severe disturbance of mitochondrial energy metabolism in renal cells. This insight on a tissue-specific level points to new therapeutic targets which might enhance treatment efficacy.

Dose-Dependent Effect of Enzyme Replacement Therapy on Neutralizing Antidrug Antibody Titers and Clinical Outcome in Patients with Fabry Disease.

BACKGROUND: Use of enzyme replacement therapy (ERT) to treat Fabry disease, caused by deficient lysosomal α-galactosidase A activity, can lead to formation of neutralizing antidrug antibodies (ADAs). These antibodies are associated with increased accumulation of plasma globotriaosylceramide (Gb3) and disease progression. Because agalsidase ERT can saturate ADA-binding sites during infusions (achieving agalsidase/antibody equilibrium), we investigated in this open cohort study whether saturated patients (who have excess agalsidase after infusions) experience better clinical outcomes compared with not saturated patients (who have excess ADAs after infusions). METHODS: We isolated ADAs from sera of 26 men with Fabry disease receiving ERT (for a median of 94 months) and determined the amount of agalsidase necessary for antibody saturation. Clinical and biochemical outcomes included measurements of eGFR, interventricular septum thickness, and lyso-Gb3. RESULTS: ADA titers decreased significantly in all patients during infusion. Agalsidase-α and agalsidase-ß had similar ADA-binding capacity and comparable ADA saturation frequency. Fourteen patients with saturated ADAs presented with mild (but significant) loss of eGFR, stable septum thickness, and significantly decreased lyso-Gb3 levels. The 12 not saturated patients had a more pronounced and significant loss of eGFR, increased septum thickness, and a smaller, nonsignificant reduction in lyso-Gb3, over time. In three patients, dose escalation resulted in partially elevated ADA titers, but importantly, also in reduced lyso-Gb3 levels. CONCLUSIONS: A not saturated ADA status during infusion is associated with progressive loss of eGFR and ongoing cardiac hypertrophy. Dose escalation can result in saturation of ADAs and decreasing lyso-Gb3 levels, but may lead to increased ADA titers.

Epidemiology of autosomal-dominant polycystic kidney disease: an in-depth clinical study for south-western Germany.

BACKGROUND: As we emerge into the genomic medicine era, the epidemiology of diseases is taken for granted. Accurate prevalence figures, especially of rare diseases (RDs, ≤50/100,000), will become even more important for purposes of health care and societal planning. We noticed that the numbers of affected individuals in regionally established registries for mainly hereditary RDs do not align with published estimated and expected prevalence figures. We therefore hypothesized that such non-population-based means overestimate RDs and sought to address this by recalculating prevalence for an important 'common' hereditary disease, autosomal-dominant polycystic kidney disease (ADPKD) whereby presumed-prevalence is 100-250/100,000 METHODS: The Else-Kroener-Fresenius-ADPKD-Study in south-west Germany with a population of 2,727,351 inhabitants was established with the cooperation of all nephrology centres. Furthermore, general practitioners, internists, urologists, human geneticists and neurosurgery centres were contacted with questionnaires for demographic, family and kidney function data. Germline-mutation screening of susceptibility genes PKD1 and PKD2 was offered. Official population data for 2010 were used for overall and kidney function-adjusted prevalence estimations. RESULTS: A total of 891 subjects, 658 index-cases and 233 relatives, aged 10-89 (mean 52), were registered, with >90% response rate, 398 by nephrologists and 493 by non-nephrologists. Molecular-genetic analyses contributed to confirmation of the diagnosis in 57%. The overall prevalence of ADPKD was 32.7/100,000 reaching a maximum of 57.3/100,000 in the 6th decade of life. CONCLUSIONS: Prevalence of ADPKD is overestimated by 2- to 5-fold and close to the limit of RDs which may be of broad clinical, logistic and policy implications.

Renoprotective Effect of Agalsidase Alfa: A Long-Term Follow-Up of Patients with Fabry Disease.

Fabry disease is a rare lysosomal storage disorder caused by mutations in the GLA gene, which, without treatment, can cause significant renal dysfunction. We evaluated the effects of enzyme replacement therapy with agalsidase alfa on renal decline in patients with Fabry disease using data from the Fabry Outcome Survey (FOS) registry. Male patients with Fabry disease aged >16 years at agalsidase alfa start were stratified by low (≤0.5 g/24 h) or high (>0.5 g/24 h) baseline proteinuria and by 'classic' or 'non-classic' phenotype. Overall, 193 male patients with low (n = 135) or high (n = 58) baseline proteinuria were evaluated. Compared with patients with low baseline proteinuria, those with high baseline proteinuria had a lower mean ± standard deviation baseline eGFR (89.1 ± 26.2 vs. 106.6 ± 21.8 mL/min/1.73 m2) and faster mean ± standard error eGFR decline (−3.62 ± 0.42 vs. −1.61 ± 0.28 mL/min/1.73 m2 per year; p < 0.0001). Patients with classic Fabry disease had similar rates of eGFR decline irrespective of baseline proteinuria; only one patient with non-classic Fabry disease had high baseline proteinuria, preventing meaningful comparisons between groups. In this analysis, baseline proteinuria significantly impacted the rate of eGFR decline in the overall population, suggesting that early treatment with good proteinuria control may be associated with renoprotective effects.

Treatment of Fabry Disease management with migalastat-outcome from a prospective 24 months observational multicenter study (FAMOUS).

AIMS: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (GLA/AGAL), resulting in the lysosomal accumulation of globotriaosylceramide (Gb3). Patients with amenable GLA mutations can be treated with migalastat, an oral pharmacological chaperone increasing endogenous AGAL activity. In this prospective observational multicentre study, safety as well as cardiovascular, renal, and patient-reported outcomes and disease biomarkers were assessed after 12 and 24 months of migalastat treatment under 'real-world' conditions. METHODS AND RESULTS: A total of 54 patients (26 females) (33 of these [61.1%] pre-treated with enzyme replacement therapy) with amenable mutations were analysed. Treatment was generally safe and well tolerated. A total of 153 events per 1000 patient-years were detected. Overall left ventricular mass index decreased after 24 months (all: -7.5 ± 17.4 g/m2, P = 0.0118; females: -4.6 ± 9.1 g/m2, P = 0.0554; males: -9.9 ± 22.2 g/m2, P = 0.0699). After 24 months, females and males presented with a moderate yearly loss of estimated glomerular filtration rate (-2.6 and -4.4 mL/min/1.73 m2 per year; P = 0.0317 and P = 0.0028, respectively). FD-specific manifestations/symptoms remained stable (all P > 0.05). A total of 76.9% of females and 50% of males suffered from pain, which has not improved under treatment. FD-specific disease scores (Disease Severity Scoring System and Mainz Severity Score Index) remained stable during treatment. AGAL activities and plasma lyso-Gb3 values remained stable, although some male patients presented with increasing lyso-Gb3 levels over time. CONCLUSIONS: Treatment with migalastat was generally safe and resulted in most patients in an amelioration of left ventricular mass. However, due to the heterogeneity of FD phenotypes, it is advisable that the treating physician monitors the clinical response regularly.

Treatment of Fabry's Disease With Migalastat: Outcome From a Prospective Observational Multicenter Study (FAMOUS).

Fabry's disease (FD) is an X-linked lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme α-galactosidase A (α-Gal A) leading to intracellular accumulation of globotriaosylceramide (Gb3). Patients with amenable mutations can be treated with migalastat, a recently approved oral pharmacologic chaperone to increase endogenous α-Gal A activity. We assessed safety along with cardiovascular, renal, and patient-reported outcomes and disease biomarkers in a prospective observational multicenter study after 12 months of migalastat treatment under "real-world" conditions. Fifty-nine (28 females) patients (34 (57.6%) pretreated with enzyme replacement therapy) with amenable mutations were recruited. Migalastat was generally safe and well tolerated. Females and males presented with a reduction of left ventricular mass index (primary end point) (-7.2 and -13.7 g/m2 , P = 0.0050 and P = 0.0061). FD-specific manifestations and symptoms remained stable (all P > 0.05). Both sexes presented with a reduction of estimated glomerular filtration rate (secondary end point) (-6.9 and -5.0 mL/minute/1.73 m2 ; P = 0.0020 and P = 0.0004, respectively), which was most prominent in patients with low blood pressure (P = 0.0271). α-Gal A activity increased in male patients by 15% from 29% to 44% of the normal wild-type activity (P = 0.0106) and plasma lyso-Gb3 levels were stable in females and males (P = 0.3490 and P = 0.2009). Reevaluation of mutations with poor biochemical response revealed no marked activity increase in a zero activity background. We conclude that therapy with migalastat was generally safe and resulted in an amelioration of left ventricular mass. In terms of impaired renal function, blood pressure control seems to be an unattended important goal.

Alu-Alu recombination underlies the vast majority of large VHL germline deletions: Molecular characterization and genotype-phenotype correlations in VHL patients.

Von Hippel-Lindau disease (VHL) is an autosomal dominant cancer syndrome. Affected individuals are predisposed to multiple tumors, primarily of the central nervous system (CNS), eyes, adrenals, and kidneys. The VHL tumor suppressor gene on chromosome 3p26-25 is partially or completely deleted in 20 to 30% of families with VHL. We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families. In 33 of the index patients, the breakpoints were precisely characterized by DNA sequencing. Of the 66 breakpoints, 90% were located in Alu elements, revealing Alu-mediated recombination as the major mechanism for large germline deletions of the VHL gene, which lies in a region of high Alu density. Interestingly, an AluYa5 element in VHL intron 2, the evolutionarily youngest Alu element and the only such element in the entire region, was found to be the most recombinogenic, involved in 7 out of the 33 deletions. In comparison to VHL patients in general, the 54 index cases and their affected relatives showed a higher occurrence of renal cell carcinomas (RCC) and of CNS hemangioblastomas. We not only noted the association of RCC with retention of the HSPC300 gene, but also observed a significant correlation between retention of HSPC300 and the development of retinal angiomas (AR). This study reveals that germline VHL deletions provide a particularly rich source for the study of Alu-mediated unequal crossover events, and provides evidence for a protective role of the loss of the actin-regulator gene HSPC300 for the development of both RCC and AR.

Agalsidase alfa slows the decline in renal function in patients with Fabry disease.

The aim of this study was to determine the effects of enzyme replacement therapy with agalsidase alpha on renal function in patients with Fabry nephropathy. Serum creatinine data were collected from 165 adult patients during 3 years of treatment. Serum creatinine increased in all men whereas it was stable in women, except in stage II renal disease (Kidney Disease Outcomes Quality Initiative). The estimated glomerular filtration rate (eGFR) declined in males with stage I and II (from 115.0 +/- 22.2 to 98.3 +/- 27.3 and from 76.5 +/- 8.1 to 66.3 +/-21.6 ml/min/1.73 m(2), respectively; both p < 0.01), whereas eGFR was stable in stage III. In females, eGFR was stable in stages I and III, and decreased in stage II (from 72.5 +/- 8.3 to 67.3 +/- 13.6 ml/min/1.73 m(2); p = 0.01). The 24-hour proteinuria was <1 g in all patients, and most patients (96%) were treated with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors. Agalsidase alpha in combination with ACE inhibitors/ARB may be effective in slowing the deterioration in renal function in Fabry nephropathy.

Genetic and clinical investigation of pheochromocytoma: a 22-year experience, from Freiburg, Germany to international effort.

Although deceptively simple, the etio-pathogenesis of pheochromocytoma represents a clinical and molecular genetic investigative challenge. Here, we summarize, from a historical point of view, the 22-year-long studies initiated at the University of Freiburg, which developed from a local experience to a national and finally an international effort. All research activities are translational and clinical and hence, registry based and intended to improve the outcome of the patients, whether by improved detection, prevention, or treatment. Major clinical steps are the prospective study on hormone tests and imaging techniques for adrenal and extra-adrenal abdominal tumors as well as the concept of organ sparing and endoscopic tumor resection. Further, we introduced 18-fluoro-dopa positron emission tomography. Population-based registries were used in order to identify germline mutations in the susceptibility genes VHL, RET, SDHB, and SDHD in non-syndromic pheochromocytoma. We differentiated distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Finally, we identified predictors and prevalence of paraganglioma syndromes associated with mutations of the SDHC gene.

Chronic renal failure and proteinuria in adulthood: Fabry disease predominantly affecting the kidneys.

The prognosis of Fabry disease has changed since enzyme-replacement treatment was introduced. Therefore, early diagnosis is instrumental. We describe a family presenting with chronic renal failure and proteinuria in which classic skin and neurological features were absent and the diagnosis of Fabry disease was difficult and not established until a second family member developed renal abnormalities. A 35-year-old man was admitted because he was overweight and had hypertension, with a serum creatinine level of 1.3 mg/dL (115 micromol/L) and protein excretion of 870 mg/d. Because 1 brother, who died years ago at the age of 32 years of acute myeloid leukemia, also had chronic renal failure and proteinuria, the diagnosis of Fabry disease was entertained. In the index patient, acroparesthesia, hypohidrosis, pain, angiokeratomas of the skin, and cornea verticillata suggesting Fabry disease were absent. Conversely, renal biopsy showed typical globotriaosylceramide deposits, and leukocyte alpha-galactosidase (alpha-GLA) A activity was decreased. Analysis of the alpha-GLA gene showed the mutation E66K. The mutation also was found in another asymptomatic 30-year-old brother who also had chronic renal failure and proteinuria, but normal extrarenal findings. In the brother who died, Fabry disease, missed at autopsy because of cancer-related findings, could be confirmed after repeated review of histological slides. Mutation carriers also included the mother, a sister (both without abnormalities), and a nephew (with episodic pains in his feet). We conclude that familial chronic renal failure combined with proteinuria is suggestive of Fabry disease, and such specific mutations as E66K predominantly may affect the kidneys.

New genetic causes of pheochromocytoma: current concepts and the clinical relevance.

Pheochromocytoma and paraganglioma are tumors of the autonomous nervous system mainly occurring in the adrenal medulla, but also in the extraadrenal paraganglias of the abdomen, thorax, neck and skull basis. The etiology comprises germline mutations of now 6 genes. About 10 years known are the RET gene susceptible for multiple endocrine neoplasia type 2, the VHL gene for von Hippel-Lindau Disease, and the NF 1 gene for neurofibromatosis Recklinghausen (neuro- fibromatosis type 1). Since 2000 the genes for succinatedehydrogenase subunits SDHB, SDHC, and SDHD have been identified for paraganglioma syndromes type 4, type 3, and type 1 respectively. Investigations of series of pheochromocytoma patients identified germline mutations in one of the genes SDHB, SDHD, VHL and RET in 24% to 50% of the patients. Multifocal tumors, young age and positive family history, known features associated with inheritence, have not been present in all patients. Therefore, analyses of blood DNA for mutations in these genes are recommended. Positive tests provide the patients and their relatives with essential platforms for clinical care. Experiences in this field of medicine have shown that optimal management of patients with pheochromocytoma-associated syndromes is a high challenge. National registries may be instrumental in order to provide with adequate facilities.

Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene.

CONTEXT: Paraganglioma syndrome includes inherited head and neck paragangliomas (HNPs) and adrenal or extra-adrenal pheochromocytomas and are classified according to the susceptibility genes SDHB, SDHC, and SDHD. In contrast with those with germline mutations of the SDHB and SDHD genes, clinical and genetic data on patients with mutations of SDHC are scarce. OBJECTIVE: To determine the prevalence and clinical characteristics of SDHC mutation carriers compared with patients with SDHB and SDHD mutations and with sporadic cases. DESIGN, SETTING, AND PATIENTS: Genetic screening for SDHC mutations in an international HNP registry of 121 unrelated index cases and in 371 sporadic cases from a pheochromocytoma registry, conducted January 1, 2001, until December 31, 2004. Identified index cases and affected relatives were clinically evaluated. MAIN OUTCOME MEASURES: Prevalence of and clinical findings for SDHC mutation-associated HNPs vs those with SDHB and SDHD mutations. RESULTS: The prevalence of SDHC carriers was 4% in HNP but 0% in pheochromocytoma index cases. None of the SDHC mutation carriers had signs of pheochromocytoma. We compared HNPs in 22 SDHC mutation carriers with the HNPs of SDHB (n = 15) and SDHD (n = 42) mutation carriers and with 90 patients with sporadic HNPs. Location, number of tumors, malignancy, and age were different: more carotid body tumors were found in SDHC (13/22 [59%]) than in sporadic HNPs (29/90 [32%], P = .03), as well as fewer instances of multiple tumors in SDHC (2/22) than in SDHD (24/42; P<.001), 0 malignant tumors in SDHC vs 6/15 in SDHB (P = .002), and younger age at diagnosis in SDHC than in sporadic HNPs (45 vs 52 years; P = .03). CONCLUSIONS: Patients with HNP, but not those with pheochromocytoma, harbor SDHC mutations in addition to those in SDHB and SDHD. In total, more than one quarter of HNP patients carry a mutation in 1 of these 3 genes. Head and neck paragangliomas associated with SDHC mutations are virtually exclusively benign and seldom multifocal. Analysis for germline mutations of SDHC is recommended in apparently sporadic HNP to identify risk of inheritance.

Renal toxicity after radionuclide therapy.

During the past 10 years, a variety of radiolabeled monoclonal antibodies, antibody fragments, and low-molecular- weight oncophilic peptides have been used to deliver radioactivity to target cells for therapeutic purposes. The high and persistent localization of several of these radiolabeled molecules in the kidneys raised concern about potential renal radiation toxicity compromising therapeutic effectiveness. In particular, radiolabeled peptides, such as yttrium-90-labeled synthetic somatostatin analogues, have initiated a discussion on the safety profiles of the various somatostatin derivatives in recent clinical trials. In general, the toxicity risk seems to depend on the characteristics of the oncophilic molecule, such as the molecular weight, electric charges and clearance pathways as well as the chemical and physical characteristics of the applied radionuclide. Encouraging results for the prevention of radiation-induced renal damage by radiolabeled peptides have been obtained by co-infusion of positively charged amino acids. The available literature on nephrotoxicity after radiolabeled peptide therapy is reviewed, and therapeutic options that have become available as a result of greater insights into putative pathogenic mechanisms are discussed.

Kidney transplantation and enzyme replacement therapy in patients with Fabry disease.

During Fabry disease, progressive glycosphingolipid deposition in the kidney causes gradual deterioration of renal function with proteinuria, uremia and hypertension. This results in end-stage renal disease (ESRD) which is one of the leading causes of morbidity and premature mortality in affected patients. Given the excellent graft and patient survival generally nowadays, kidney transplantation is the first choice to correct renal dysfunction and improve the overall prognosis of patients with renal failure because of Fabry disease. The benefit of enzyme-replacement therapy (ERT) in kidney transplanted Fabry patients has been controversially discussed and long-term trials focusing on the effectiveness of agalsidase in this patient population are needed.

Dysregulated autophagy contributes to podocyte damage in Fabry's disease.

Fabry's disease results from an inborn error of glycosphingolipid metabolism that is due to deficiency of the lysosomal hydrolase α-galactosidase A. This X-linked defect results in the accumulation of enzyme substrates with terminally α-glycosidically bound galactose, mainly the neutral glycosphingolipid Globotriaosylceramide (Gb3) in various tissues, including the kidneys. Although end-stage renal disease is one of the most common causes of death in hemizygous males with Fabry's disease, the pathophysiology leading to proteinuria, hematuria, hypertension, and kidney failure is not well understood. Histological studies suggest that the accumulation of Gb3 in podocytes plays an important role in the pathogenesis of glomerular damage. However, due to the lack of appropriate animal or cellular models, podocyte damage in Fabry's disease could not be directly studied yet. As murine models are insufficient, a human model is needed. Here, we developed a human podocyte model of Fabry's disease by combining RNA interference technology with lentiviral transduction of human podocytes. Knockdown of α-galactosidase A expression resulted in diminished enzymatic activity and slowly progressive accumulation of intracellular Gb3. Interestingly, these changes were accompanied by an increase in autophagosomes as indicated by an increased abundance of LC3-II and a loss of mTOR kinase activity, a negative regulator of the autophagic machinery. These data suggest that dysregulated autophagy in α-galactosidase A-deficient podocytes may be the result of deficient mTOR kinase activity. This finding links the lysosomal enzymatic defect in Fabry's disease to deregulated autophagy pathways and provides a promising new direction for further studies on the pathomechanism of glomerular injury in Fabry patients.

The effectiveness of long-term agalsidase alfa therapy in the treatment of Fabry nephropathy.

BACKGROUND AND OBJECTIVES: Fabry disease is a rare X-linked disease with multisystemic manifestations. This study investigated the effectiveness of long-term enzyme replacement therapy with agalsidase alfa in Fabry nephropathy treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this observational study, data on patients receiving agalsidase alfa (0.2 mg/kg every other week) were extracted from the Fabry Outcome Survey, an international registry of patients with Fabry disease. Serum creatinine and estimated GFR (eGFR) at baseline and after ≥5 years of treatment were assessed; 24-hour urinary protein excretion and BP measurements were also reviewed. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. Patients with an eGFR <30 ml/min per 1.73 m(2) were excluded. RESULTS: Renal function was assessed in 208 patients (mean enzyme replacement therapy, 7.4 years; range, 5.0-11.2 years). Mean yearly change in eGFR was -2.2 ml/min per 1.73 m(2) in men and -0.7 ml/min per 1.73 m(2) in women (95% confidence limits, -2.8; -1.7 and -1.4; 0.0, respectively). Patients with 24-hour protein excretion >1 g/24 h had poorer renal function at baseline and follow-up compared with patients with protein excretion of 500-1000 mg/24 h or with proteinuria <500 mg/24 h. Renal function was worse in patients with baseline arterial hypertension, and there was a more rapid yearly decline compared with normotensive patients. CONCLUSIONS: This study suggests that long-term agalsidase alfa therapy is able to stabilize the rate of Fabry nephropathy progression in women and is associated with a mild to moderate decline of renal function in men.

Adult patients with sporadic polycystic kidney disease: the importance of screening for mutations in the PKD1 and PKD2 genes.

BACKGROUND: ADPKD is one of the most common inherited disorders, with high risk for end-stage renal disease. Numerous patients, however, have no relatives in whom this disorder is known and are unsure whether they may transmit the disease to their offsprings. The aim of this study was to evaluate whether germline mutation analysis adds substantial information to clinical symptoms for diagnosis of ADPKD in these patients. METHODS: Clinical data included renal function and presence of liver or pancreas cysts, heart valve insufficiency, intracranial aneurysms, colonic diverticles, and abdominal hernias. Family history was evaluated regarding ADPKD. Germline mutation screening of the PKD1 and PKD2 genes was performed for intragenic mutations and for large deletions. RESULTS: A total of 324 adult patients with ADPKD including 30 patients without a family history of ADPKD (sporadic cases) were included. PKD1 mutations were found in 24/30 and PKD2 mutations in 6 patients. Liver cysts were present in 14 patients and intracranial aneurysms in 2 patients. Fourteen patients (45%) had no extrarenal involvement. Compared to the 294 patients with familial ADPKD, the clinical characteristics and the age at the start of dialysis were similar in those with sporadic ADPKD. CONCLUSION: The clinical characteristics of patients with sporadic and familial ADPKD are similar, but sporadic ADPKD is often overlooked because of the absence of a family history. Molecular genetic screening for germline mutations in both PKD1 and PKD2 genes is essential for the definitive diagnosis of ADPKD.

Kidney transplantation in patients with Fabry disease.

Little is known about the effects of enzyme replacement therapy (ERT) in kidney transplant recipients with Fabry disease. Clinical characteristics of transplant recipients in the Fabry Outcome Survey (FOS) were therefore examined in patients with Fabry disease with or without ERT. Of the 837 European patients in FOS (March 2006), 34 male patients and two female patients had received kidney transplants. Mean age at transplantation was 37.6 +/- 10.9 years, mean time since transplantation was 7.7 +/- 6.4 years, median estimated glomerular filtration rate (eGFR) was 44.4 ml/min/1.73 m(2), and median proteinuria was 296 mg/24 h. Of 27 patients with baseline data, 59% had hypertension, 74% had left ventricular hypertrophy, 22% had cardiac valve disease, 30% had arrhythmia, and 22% had transient ischaemic attacks and 15% stroke. Twenty patients (74%; two female patients, 18 male patients) were receiving ERT with agalsidase alfa. At enrollment or at the start of ERT, median eGFRs were 59 and 35 ml/min/1.73 m(2) (P = 0.05) and median proteinuria levels were 240 and 420 mg/24 h (not significant) in treated and untreated patients respectively. Renal function remained stable in patients receiving ERT. In conclusion, agalsidase alfa is well tolerated in patients with Fabry disease who have undergone renal transplantation.

When to look for Von Hippel-Lindau disease in gastroenteropancreatic neuroendocrine tumors?

Von Hippel-Lindau (VHL) disease is a progressive autosomal dominant multisystem disorder that is associated with a germ line mutation of the VHL gene on the short arm of chromosome 3. A variety of benign and malignant diseases, including eye and CNS hemangioblastomas, renal cell carcinoma and pheochromocytoma are the major components. Gastroenteropancreatic neuroendocrine tumors are also listed among the typical complications, although these occur seldom. Virtually all such tumors are pancreatic islet cell tumors. VHL-associated islet cell tumors are mostly hormone-inactive. They can be detected during screening investigations according to the multidisciplinary disorder or by workup of space-occupying lesions. There are no specific predictors for malignancy in VHL-associated islet cell neoplasias, but tumors smaller than 3 cm in diameter are believed to be always benign. Gadolinium-enhanced MRI is currently the imaging method of choice, but contrast-enhanced CT is also a diagnostic option. The spectrum of manifestations is illustrated by selected cases.