[Fabry disease and cystinosis, two lysosomal diseases: similarities and differences]. / Maladie de Fabry et cystinose, deux maladies lysosomales: similitudes et différences.

Fabry disease and cystinosis are both lysosomal diseases. Some clinical features (such as renal and corneal involvement) are shared by both diseases whereas many other features are different (mode of inheritance, rate of progression, mechanism of lysosomal storage, therapeutic modalities etc.). Intermediary mechanisms that lead from lysosomal overload to lesions and disease are still incompletely understood.

Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies.

Cardiovascular events (CVEs) are the leading cause of death in chronic hemodialysis patients. Results of trials in non-end-stage renal disease (ESRD) patients cannot be extrapolated to patients with ESRD. It is critical to test cardiovascular therapies in these high-risk patients who are usually excluded from major cardiovascular trials. The study objective was to evaluate the effect of fosinopril on CVEs in patients with ESRD. Eligible patients were randomized to fosinopril 5 mg titrated to 20 mg daily (n=196) or placebo (n=201) plus conventional therapy for 24 months. The primary end point was combined fatal and nonfatal first major CVEs (cardiovascular death, resuscitated death, nonfatal stroke, heart failure, myocardial infarction, or revascularization). No significant benefit for fosinopril was observed in the intent to treat analysis (n=397) after adjusting for independent predictors of CVEs (RR=0.93, 95% confidence interval (CI) 0.68-1.26, P=0.35). The per protocol secondary supportive analysis (n=380) found a trend towards benefit for fosinopril (adjusted RR=0.79 (95% CI 0.59-1.1, P=0.099)). In the patients who were hypertensive at baseline, systolic and diastolic blood pressures were significantly decreased in the fosinopril as compared to the placebo group. After adjustment for risk factors, trends were observed suggesting fosinopril may be associated with a lower risk of CVEs. These trends may have become statistically significant had the sample size been larger, and these findings warrant further study.

Increase of circulating neutrophil and platelet microparticles during acute vasculitis and hemodialysis.

Release of microparticles (MPs) from blood cells may occur upon various activation signals. MPs from neutrophil and platelet have been studied in systemic infectious diseases and cardiovascular diseases, respectively. They are here investigated in common nephropathies including vasculitis and dialysis, two conditions characterized by neutrophil activation. Flow cytometry analysis of neutrophil-derived (CD66b-positive) and platelet-derived (CD41a-positive) MPs was performed on 213 plasma samples from patients with various nephropathies, including 46 patients with vasculitis and 40 hemodialysis patients. MPs released ex vivo, during neutrophil activation in whole blood, were also measured in these patients. Correlations with clinical parameters and creatinine clearance were evaluated. The results show that MPs present in plasma from patients or healthy controls are from various origins: platelet-derived (38+/-22%), neutrophil-derived (2.8+/-3.8%) MPs, mixed aggregates of neutrophil/platelet MPs (28+/-15%) or neither from neutrophil or platelet (null) 31+/-20%. Acute vasculitis showed the highest level of all types of MPs, while other nephropathies did not result in significant changes of MP levels. A significant increase was observed during hemodialysis sessions. In patients with renal failure, no correlation was seen between MP levels and creatinine clearance. In conclusion, neutrophil and platelet MP levels are non-specific markers of neutrophil activation during vasculitis acute phase and dialysis-induced inflammation. Circulating aggregates of neutrophil/platelet MPs co-express adhesion molecules of both cell types and may be thus endowed with inflammation and coagulation- thus modulating properties.

[Progressive renal failure caused by lithium nephropathy]. / Insuffisance rénale évolutive par néphropathie au lithium.

OBJECTIVES: Study the renal consequences of lithium therapy and find out whether lithium-induced chronic renal toxicity can provoke a progressive nephropathy, leading to advanced renal failure, requiring periodical dialysis. METHODS: Fifty-three patients treated with long-term lithium salts were included in the study. They had developed chronic renal failure (creatinine clearance inferior to 80 ml/min) not due to any other cause. RESULTS: These patients had received lithium salts for a mean period of 17.7 years. The mean reduction in creatinine clearance was of 2.23 ml/min/year. Final clearance correlated negatively with the duration of lithium administration. In 7 patients treated a mean of 22 years, progression towards terminal kidney failure required periodical dialysis. Around 30% of patients exhibited mild hypercalcemia. CONCLUSION: Lithium nephropathy inducing progressive renal failure is a reality. Its prevalence in patients treated long-term with lithium should be assessed.

Arterial remodelling in Fabry disease.

AIM: The enzymatic defect in Fabry disease results in the slow systemic deposition of uncleaved glycosphingolipids in the lysosomes of vascular endothelium and smooth muscle cells, leading to ischaemic strokes, cardiomyopathy and renal failure. Whereas it is known that Fabry disease affects small blood vessels, little is known about its effects on peripheral large arteries. We therefore set out to compare parameters of arterial wall structure and function in a cohort of patients with Fabry disease and an age-matched control group. METHODS: Large artery phenotype was non-invasively investigated in 21 hemizygous patients with Fabry disease and 24 age-matched male controls. Common carotid and radial artery diameter, intima-media thickness (IMT) and distensibility were determined with high-definition echotracking systems and aplanation tonometry. RESULTS: Patients with Fabry disease had a significant twofold increase in radial artery IMT and distensibility, independent of body surface area, age and mean blood pressure. In both groups, older age at the time of examination was significantly associated with larger radial artery IMT. The relationship between age and radial IMT was 2.3-fold higher in patients with Fabry disease than in controls (p < 0.01). Carotid IMT was mildly but significantly increased in patients with Fabry disease (+18%), whereas distensibility was unchanged. CONCLUSION: This study presents evidence of a major increase in arterial wall thickness and distensibility, measurable at the site of a medium-sized artery, in a cohort of patients with classic Fabry disease.

Longer duration of predialysis nephrological care is associated with improved long-term survival of dialysis patients.

BACKGROUND: Late nephrological referral of chronic renal failure patients has been shown to be associated with high morbidity and short-term mortality on dialysis. However, the impact of predialysis nephrological care duration (PNCD) on the long-term survival of dialysis patients had not been evaluated. METHODS: We studied data from all 1057 consecutive patients who started dialysis treatment at the Necker Hospital from 1989 to 1998 (mean age at start of dialysis 53.8+/-17.2 years (range 18-91 years), excluding from analysis patients who presented with acute renal failure (n=60) or advanced malignancy (n=35). We evaluated the effects of PNCD and clinical risk factors on all-cause mortality after long-term follow-up on dialysis. RESULTS: Among the 1057 patients analysed (13.2% diabetics), PNCD was <6 months in 258 patients, 6-35 months in 267 patients, 36-71 months in 227 patients and >or=72 months in 307 patients. Cardiovascular (CV) morbidity, namely a history of myocardial or cerebral infarction, peripheral arteriopathy, and/or cardiac failure, before starting dialysis was 39.6% and 37.4%, respectively, in patients followed for <6 months or 6-35 months, compared with 24.4% in those followed for 36-71 months and 19.9% in those followed for >or=72 months (P<0.001). Five-year survival was significantly lower in patients with a PNCD of <6 months (59+/-4.1%) than for 36-71 months or >or=72 months (77.1+/-3.7 and 73.3+/-3.6%, respectively, P<0.001), but similar to those followed for 6-35 months (65.3+/-3.9%, NS). By Cox proportional hazard analysis, PNCD <6 months, age, diabetes and prior CV disease were independent predictive factors of all-cause death on dialysis. CONCLUSIONS: This study provides suggestive evidence that longer duration of regular nephrological care in the predialysis period, at least for several years prior to the start of dialysis, is associated with a better long-term survival on dialysis. Such data strongly support the argument for early referral and regular nephrological care of chronic renal failure patients.

Autosomal recessive polycystic kidney disease in adulthood.

BACKGROUND: Renal cysts arising from collecting ducts, congenital hepatic fibrosis, and recessive inheritance characterize autosomal recessive polycystic kidney disease (ARPKD). The disorder usually manifests in infancy, with a high mortality rate in the first year of life. For the patients who survive the neonatal period, the probability of being alive at 15 years of age ranges from 50 to 80%, with 56--67% of them not requiring renal replacement therapy at that stage. Some develop portal hypertension. Long-term outcome of adults escaping renal insufficiency above age 18 is largely unknown. METHOD: In consecutive patients with ARPKD and autonomous renal function at age 18, clinical course of kidney and liver disease in adulthood and status at last follow-up were evaluated. Progression of renal insufficiency was assessed by the rate of decline of creatinine clearance, according to Schwartz's formula before age 18 and Cockcroft and Gault formula thereafter. Severity of liver involvement was estimated by imaging techniques, liver function tests, and endoscopy. RESULTS: Sixteen patients from 15 families were included. ARPKD was diagnosed between 1 day and 13 years of age. From diagnosis, mean follow-up period lasted 24+/-9 years. Before age 18, nine patients (56%) were hypertensive, nine (56%) had renal failure, and four (25%) had portal hypertension. Beyond age 18, no additional patient became hypertensive, and another five developed progressive renal insufficiency; altogether, the mean yearly decline of creatinine clearance was 2.9+/-1.6 ml/min. Portal hypertension was recognized in two additional patients. Four patients experienced gastro-oesophageal bleeding, while recurrent cholangitis or cholangiocarcinoma developed in one case each. At the end of follow-up, 15/16 patients (94%) were alive at a mean age of 27 (18--55) years. Two patients had a normal renal function, 11 had chronic renal insufficiency, one was on regular dialysis, and two had functioning kidney grafts. Four patients had required a porto-systemic shunt. CONCLUSIONS: A subset of ARPKD patients with autonomous renal function at age 18 experiences slowly progressive renal insufficiency. With prolonged renal survival, complications related to portal hypertension are not rare, requiring careful surveillance and appropriate management.

[Course of chronic renal failure epidemiology and prediction of maintenance dialysis needs in France]. / Evolution de l'épidémiologie de l'insuffisance rénale chronique et prévision des besoins en dialyse de suppléance en France.

Epidemiology of diseases leading to end-stage renal disease (ESRD) in France has greatly changed over the past decades, with the disappearance of type 1 primary membranoproliferative glomerulonephritis, and the increased incidence of both vascular and diabetic nephropathies. The incidence of ESRD is continuously growing, by about 4% per year, with a present rate of more than 100 new patients per million population (pmp) per year. The rise in incidence is mainly observed in older subjects. As a consequence, one may predict a relentless increase in the next years, in parallel with the relentless ageing of the population. The number of ESRD patients on maintenance dialysis is also growing, by nearly 4% per year. The present prevalence is 433 pmp in the Ile de France area, ranging from 268 pmp in subjects aged 15-59 years, to as high as 980 pmp in the population aged 60 years or more. Whereas the number of in-center treated patients has remained quite stable over the past five years, the total number and proportion of out-center treated patients is continuously increasing, as expected, thanks to the development of self-care hemodialysis and of peritoneal dialysis. These data may help predict logistic requirements for maintenance dialysis in the next years.

Clinical outcome following coronary angioplasty in dialysis patients: a case-control study in the era of coronary stenting.

BACKGROUND: Balloon coronary angioplasty has been reported to be ineffective in patients treated for end stage renal disease because of a high restenosis rate. OBJECTIVE: To compare the clinical outcome following coronary angioplasty with provisional stenting in dialysis versus non-dialysis patients. DESIGN: A case-control study. PATIENTS: Of 1428 consecutive patients who underwent coronary angioplasty, 100 (7%) were being treated for end stage renal disease. These were compared with 100 control patients matched for age, sex, coronary lesions, presence of diabetes mellitus, and rate of coronary stenting (40%). MAIN OUTCOME MEASURES: In-hospital and one year clinical outcome. RESULTS: The rates of procedural success (90% v 93%), in-hospital mortality (1% v 0%), stent thrombosis (0% v 0%), and Q wave myocardial infarction (0% v 1%) were similar in dialysis and non-dialysis patients. One year clinical outcome after coronary angioplasty was similar in the two groups in terms of clinical restenosis (31% v 28%) and myocardial infarction (6% v 2%), but cardiac death was more common in dialysed patients (11% v 2%, p < 0.03). CONCLUSIONS: Dialysis does not increase the risk of clinical restenosis after coronary angioplasty with provisional stenting. Coronary angioplasty is a safe and effective therapeutic procedure in selected dialysis patients with culprit lesions accessible to stenting. However, the one year survival is reduced in this high risk population.

[Refractory ascites in hemodialysis: treatment by paracentesis- reinjection during dialysis]. / Ascite réfractaire en hémodialyse: traitement par ponction-réinjection en cours de dialyse.

Two hemodialysis patients, one male and one female, aged 46 and 54 years, were treated with preceed respectively for refractory ascites secondary to hepatic cirrhosis and for large polycystic liver. Preceed was decided because of the rapid reappearance of effusion following repeated puncture and albumin infusion, the poor tolerance to ultrafiltration (UF) and the poor nutritional status of the patients, with severe hypoalbuminemia. Abdominal paracentesis was performed on initiation of the dialysis session. Reinjection of the ascites fluid was made into the arterial line, allowing its UF and control of its flow. The procedure was performed whenever necessary, i.e., when inter-dialysis weight gain and ascites volume were high. In both cases, improvement was quickly obtained, with less rapid and less severe reappearance of the effusion and correction of albuminemia. Dialysis sessions with UF were better tolerated. No notable side effect was observed. The first patient was treated for 2 months, when he died of an unrelated cause. The other patient was treated for 6 months and then could be transferred to a dialysis center near her home. Twenty five months after start of dialysis treatment, kidney and liver transplantation were performed in this same patient. After transplantation, reappearance of moderate ascites and oedema is attributed to e degradation of renal function, without liver dysfunction. Five weeks after transplantation, improvement of renal function and ascites regression were noted. Preceed is an effective method of treating refractory ascites in the hemodialysis patient. Compared to classical paracentesis, it has the advantage of good tolerance, patient comfort and moderate cost.

[Clinical genetics at the crossroads: the example of hereditary kidney diseases]. / La génétique clinique à la croisée des chemins: l'exemple des maladies rénales génétiques.

Clinical genetics has reached a crossroads. Indeed recent progress in molecular genetics has generated great hope. This progress has consequences beyond genetic diseases, leading to the understanding of much more general mechanisms of disease. This progress has also permitted a better classification of genetic entities, such as Alport's syndrome, based on the molecular mechanisms involved. Lastly this progress allows us to design pharmacologic therapeutic approaches. Enzyme replacement therapy in Fabry's disease is a recent example of this approach. Difficulties are much greater in diseases such as autosomal dominant polycystic kidney disease. To reach these goals, height collaboration between molecular genetics and cell biology in the post-gene era, and between clinical genetics and other medical specialties, is required not only in the field of pediatric diseases, but also in late-onset genetic diseases.

Renal disease in Fabry patients.

Renal dysfunction is a major complication in hemizygous males with Fabry disease. This often results in end-stage renal failure (ESRF), requiring dialysis or transplantation, on average 10 years after the start of renal impairment. ESRF usually occurs between 40 and 50 years of age, but may occur much earlier. Although progression of renal disease can be rapid, it is variable and may depend on whether there is residual alpha-galactosidase enzyme activity and on environmental or genetic factors. Significant renal disease is much less common in women carriers of the disease. However, renal changes do occur, which may progress to ESRF as in male patients.