High prevalence of subclinical hypothyroidism in patients with Anderson-Fabry disease.

Anderson-Fabry disease is a rare lysosomal storage disorder. It results from a deficiency of the lysosomal alpha-galactosidase A and leads to progressive accumulation of globotriaosylceramide in the endothelium and tissue cells of various organs. Some of the typical clinical findings such as tiredness, dry skin, myalgia and arthralgia as well as vague gastrointestinal complaints are also symptoms of hypothyroidism. Therefore, we studied the thyroid function in patients with Anderson-Fabry disease. Thyroid function was studied in 11 patients (6 female, 5 male) with Anderson-Fabry disease by measuring thyroid-stimulating hormone (TSH) and free thyroxine serum levels. Nine patients had chronic kidney disease with stage 1 and two with stage 5. Subclinical hypothyroidism (normal serum free thyroxine concentrations along with elevated serum TSH levels) was found in 4 of 11 patients (36.4%). Subclinical hypothyroidism was observed in both male and female patients as well as in patients with stage 1 and stage 5 kidney disease. Subclinical hypothyroidism is a common finding in patients with Anderson-Fabry disease, showing an excess prevalence as compared to the normal population. The high frequency seems to be relevant regarding the potential consequences of a hypothyroid state.

Hormonal profile and fertility in patients with Anderson-Fabry disease.

Anderson-Fabry disease is a glycosphingolipid storage disorder with an X-linked recessive inheritance. The alpha-galactosidase A deficiency leads to a progressive accumulation of globotriaosylceramide in the endothelium and tissue cells of various organs. The kidney, heart and brain are predominantly affected. Reports on endocrine function and fertility rates in patients with Anderson-Fabry disease are sparse. In the present study, we assessed ovarian, testicular and adrenal function in a cohort of patients with Anderson-Fabry disease. Plasma follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, testosterone, sex hormone-binding globulin, somatotropin, insulin-like growth factor-I and serum cortisol were measured in 13 patients (six female and seven male), currently observed in an outpatient clinic. The profile revealed an undisturbed hormonal function and a normal fertility rate in both male and female Anderson-Fabry patients when compared with the corresponding Austrian population.

Measurement of renal function in patients with Fabry disease.

UNLABELLED: Appropriate measurement of the glomerular filtration rate (GFR) is important for the assessment of renal function. This paper reviews the methods used to assess GFR in clinical trials of enzyme replacement therapy (ERT) in patients with Fabry disease, which include inulin clearance, 24-hour creatinine clearance, chromium ethylene diamine tetraacetate (51Cr-EDTA) clearance and cystatin C concentrations. GFR has also been estimated using calculations based on creatinine clearance (the Cockcroft-Gault formula) and the Modification of Diet in Renal Disease (MDRD) equation. Analysis of the results of these studies shows that there are striking discrepancies between estimated and measured GFR. For example, the MDRD equation overestimates GFR in patients with Fabry disease who have normal renal function. In addition, cystatin C has been shown to be of limited use for measuring renal function during ERT, because it is influenced by other factors such as age, gender and weight. CONCLUSION: The use of exact methods, such as inulin clearance, 124I-iothalamate, 99mTc-DTPA, 51Cr-EDTA and iohexol, appears to be mandatory for a robust evaluation of the effects of ERT on GFR in patients with Fabry disease.

The expanding clinical spectrum of Anderson-Fabry disease: a challenge to diagnosis in the novel era of enzyme replacement therapy.

Anderson-Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient alpha-galactosidase A activity. The conception of the disease has changed within the last decade. Studies of the last years have shown that the disease is not limited to the classical full-blown manifestation in affected males, which is well known since more than a century, but may also occur in carrier females. The phenomenology may differ in severity and kind of organ manifestation. Cardiac and renal variants with solely disease manifestation of these organs have also been described in an increasing number. It is likely that a spectrum exists regarding alpha-galactosidase A activity in both genders on the one hand, and an additional one regarding the severity and the number of organs affected on the other. The purpose of this review is to sharpen physicians' perception of this disease. Early and accurate diagnosis is mandatory considering that this disorder is now, after introduction of the novel enzyme replacement therapy, a treatable disease.

Fibrinolytic therapy with rt-PA in a patient with paroxysmal nocturnal hemoglobinuria and Budd-Chiari syndrome.

Paroxysmal nocturnal hemoglobinuria (PNH) is associated with a high risk of thrombosis, particularly in the peripheral, cerebral, and abdominal veins. We report a patient with an occlusion of the hepatic veins and a slit shape narrowing of the cava inferior consistent with the Budd-Chiari syndrome in whom intravenous fibrinolytic therapy with recombinant tissue plasminogen activator (rt-PA) was applied. Systemic rt-PA was given in a dose of 25 mg rt-PA over 3 h and 25 mg rt-PA as constant intravenous infusion over the next 21 h leading to an incomplete recanalization. The same protocol was applied again 2 days later, resulting in a complete recanalization of the hepatic veins and the vena cava inferior. Our case shows that exclusive systemic application of rt-PA can result in full anatomic and clinical restoration.

[Angiotensin II type-1-receptor antagonists from the viewpoint of nephrology]. / Angiotensin-II-Typ-1-Rezeptor-Antagonisten aus nephrologischer Sicht.

ACE (Angiotensin Converting Enzyme) inhibitors and angiotensin II type 1 receptor antagonists increase the effective renal plasma flow dose dependently, whereas glomerular filtration rate does not change. Both substances reduce dose dependently arterial blood pressure, glomerular capillary pressure and proteinuria and are probably comparably renoprotective due to haemodynamic and non-haemodynamic (e.g. antiproliferative) effects. These data indicate that the renoprotective effects of ACE inhibitors and angiotensin II receptor antagonists are the results of inhibition of angiotensin II and not due to inhibition of bradykinin degradation. Several studies suggest an additive renoprotective effect of ACE inhibitors and angiotensin II receptor antagonists. However, controlled clinical studies are lacking. Experimental data suggest that the combination of AT1 and AT2 receptor blockers or treatment with ACE inhibitors reduce more effectively inflammatory cell infiltration into the kidney than angiotensin II type 1 receptor antagonists alone. Long-term clinical trials using angiotensin II type 1 receptor antagonists are needed before these substances can be recommended as comparably renoprotective as ACE inhibitors.

Efficacy of folinic versus folic acid for the correction of hyperhomocysteinemia in hemodialysis patients.

The effectiveness of intravenous folinic acid or intravenous folic acid for the treatment of hyperhomocysteinemia of hemodialysis patients is unknown. In a randomized, controlled, double-blind trial, 66 hemodialysis patients were administered either 15 mg of folic acid or an equimolar amount (16.1 mg) of folinic acid intravenously three times weekly. Normalization of total homocysteine (tHcy) plasma levels after 4 weeks of treatment was achieved in 10 patients (30.3%) in the folic-acid group and 6 patients (18.2%; P: = 0.389) in the folinic-acid group (normalization at any time during the study period in 39.4% and 33.3% of the patients; P: = 0.798). The relative reduction in tHcy plasma levels at week 4 was 32.2% in the folic-acid group and 34.1% in the folinic-acid group. A high baseline tHcy plasma concentration (P: = 0.00001), methylenetetrahydrofolate reductase (MTHFR) 677TT/1298AA genotype (P: = 0.03540), and low red blood cell folate concentrations (P: = 0.02285) were associated with a better relative response to treatment. Normalization of tHcy plasma levels was dependent on a lower baseline tHcy level (P: = 0.01976), younger age (P: = 0.00896), and MTHFR 677TT/1298AA or 677CT/1298AC genotypes (P: = 0.00208 and P: = 0.02320, respectively). A 4-week course of intravenous folinic acid is not superior to intravenous folic acid in reducing elevated tHcy plasma levels in hemodialysis patients. The response to treatment is predicted by tHcy plasma level, red blood cell folate content, and MTHFR genotype.

Prevalence of preterminal pulmonary thromboembolism among patients on maintenance hemodialysis treatment before and after introduction of recombinant erythropoietin.

The prevalence of pulmonary thromboembolism at autopsy was assessed in a retrospective study of a cohort of 185 patients undergoing maintenance hemodialysis treatment who died in the last decade. The overall frequency of thromboembolism was 12.43% in the dialysis population, which statistically was significantly less than in a control group of 8,051 nondialysis patients (21.77%; P = 0.0023). Moreover, pulmonary thromboembolism was less frequently fatal or contributing to death in the dialysis group than in the control group (P = 0.039). The prevalence of pulmonary thromboembolism in the dialysis group remained statistically unchanged over the 10-year period and was independent of a steady increase in the percentage of patients receiving recombinant erythropoietin therapy and the average hematocrit values. The occurrence of preterminal pulmonary thromboembolism was associated with a shorter period since onset of hemodialysis treatment and with infection as cause of death (P = 0. 031; P = 0.029, respectively). No statistically significant influence of the type of basic renal disease, type of dialysis anticoagulation, or dialysis access could be found. Our data suggest that, at least in the preterminal stage, the introduction of recombinant erythropoietin within the last decade had no substantial influence on the prevalence of pulmonary thromboembolism.

Inappropriately high plasma leptin levels in obese haemodialysis patients can be reduced by high flux haemodialysis and haemodiafiltration.

1. Blood leptin levels are increased in obese subjects and seem to play a major role in the hypothalamic regulation of appetite and energy expenditure. 2. We measured plasma leptin levels in a cohort of 46 patients on maintenance haemodialysis treatment and 26 control subjects. 3. Higher body mass indices were associated with higher plasma leptin levels in both groups. 4. The increase was more pronounced in the dialysis group than in the control group (P = 0.001), leading to inappropriately high plasma levels. 5. Haemodialysis with low flux cellulosic dialysers did not result in a decrease in plasma levels, while dialysis with high flux dialysers and haemodiafiltration led to a substantial reduction of the initial value to 76.95 +/- 14.89% (P = 0.013) and 62.90 +/- 24.94% (P = 0.001) respectively. 6. Our data suggest that high flux dialysis membranes can decrease plasma leptin levels and that inappropriately high plasma leptin levels may play a role in the nutrition of haemodialysis patients.

Sufentanil plasma concentrations following lower extremity tourniquet release.

STUDY OBJECTIVE: To investigate whether release of a tourniquet on the lower extremity affects plasma concentrations of sufentanil, as previously demonstrated with fentanyl and midazolam. DESIGN: Prospective. SETTING: University tertiary-care institution with residency program. PATIENTS: 20 ASA status I, II, and III patients undergoing total knee arthroplasty under a tourniquet using a sufentanil, nitrous oxide, relaxant regimen. INTERVENTIONS: Each patient received sufentanil 1 to 2 micrograms/kg at induction of anesthesia and in 12.5 to 25 microgram increments as needed thereafter, until 15 minutes prior to tourniquet release. MEASUREMENTS AND MAIN RESULTS: Plasma sufentanil concentrations were determined before tourniquet inflation, immediately before tourniquet deflation, and 1, 2, 5, 10, 20, 30, and 40 minutes following deflation. A 15% elevation of plasma sufentanil concentration above that predicted by elimination pharmacokinetics defined a secondary peak. Although the aggregate data did not indicate an overall statistically significant rise in plasma concentrations after deflation, 9 (45%) patients exhibited a secondary peak in sufentanil plasma concentration following tourniquet deflation (range of secondary peaks, 16% to 89% above predicted values). No patient experienced clinically significant respiratory depression. CONCLUSION: Release of a tourniquet on the lower extremity may yield a detectable rise in plasma sufentanil concentration.

Decreased postheparin lipolytic activity in renal transplant recipients with cyclosporin A.

The patterns of hyperlipidemia in renal transplant recipients (RTRs) are more variable than in the uremic state, showing increases in both very low-density lipoprotein (VLDL) and low density lipoprotein (LDL). This has been attributed, at least in part, to immunosuppressive therapy, especially to treatment with corticosteroids. Postheparin lipolytic activity (PHLA) was determined in 28 RTRs. Sixteen patients presenting with hyperlipidemia comprised group A, who were aged 49.8 +/- 13.5 years, and had a cholesterol of 8.24 +/- 1.86 mmol/liter, triglycerides of 6.02 +/- 3.33 mmol/liter. Twelve patients presenting cholesterol and triglyceride values within the normal range were in group B, and were aged 48.6 +/- 13.3 years. All RTRs received cyclosporin A (CsA) twice daily orally, which were divided in two equal doses and adjusted to provide CsA blood trough levels (RIA) in a range of 250 to 350 ng/ml. Twenty-one RTRs were additionally treated by alternate-day corticosteroids, whereas seven patients had CsA on their sole immunosuppressive agent. PHLA (mumol free fatty acids/ml/hr, given 10 and 20 min after 100 U/heparin kg body wt intravenously) was commonly reduced in RTRs (group A at 10/20 min: 5.6 +/- 1.1/5.26 +/- 1.2; group B: 8.26 +/- 2.91/8.38 +/- 3.44) as compared to the values obtained in healthy controls (15.3 +/- 2.9/17.2 +/- 5.0). This was mainly due to a reduction of the activity of the hepatic triglyceride lipase, and to a minor extent to a reduced activity of peripheral lipoprotein lipase. There was no statistically significant difference of PHLA in RTRs with or without corticosteroid treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Progression of renal insufficiency in analgesic nephropathy: impact of continuous drug abuse.

Twenty-three patients with analgesic nephropathy and apparent cessation of drug abuse were tested for blood acetaminophen and salicylate on the occasion of routine renal control examinations. In 12 patients (mean creatinine level 2.74 +/- 1.09 mg/dl) no deterioration of renal function was noted within a 1-year observation period (Group 1). In 11 patients a significant progression of renal insufficiency was observed (mean creatinine level rose from 3.86 +/- 1.06 to 6.40 +/- 3.18 mg/dl within the same observation period; Group 2). Blood tests for acetaminophen and salicylate were positive in 2 patients of Group 1 and in 9 patients of Group 2 (chi 2 = 7.326), p less than 0.01). Our data emphasize the importance of a continuous analgesic abuse hidden from the medical staff with regard to the progression of renal insufficiency in analgesic nephropathy.

[Beta-N-acetylglucosaminidase (beta-NAG) as a parameter in the diagnosis and evaluation of primary glomerular and tubulointerstitial kidney diseases]. / Beta-N-Acetylglucosaminidase (beta-NAG) als Parameter in der Diagnose und Bewertung von primär glomerulären und primär tubulointerstitiellen Nierenerkrankungen.

beta-N-acetylglucosaminidase (beta-NAG) and beta 2-microglobulin were assessed in two cohorts of patients with glomerular or tubulointerstitial diseases respectively. While beta-NAG activities did not differ statistically significantly between both groups, beta 2-microglobulin excretion was statistically highly significantly increased in the setting of tubulointerstitial diseases. On the whole mean beta-NAG activity at 37 degrees C and beta 2-microglobulin urinary excretion were elevated in both groups, when compared to normal controls. Increased beta-NAG activities above 10 U/g creatinine were associated with a marked increase of creatinine serum levels within 6 months in both, patients with glomerular and tubulointerstitial basic renal diseases. beta-NAG and beta 2-microglobulin are useful tools in diagnosis and assessment of renal diseases elucidating different aspects.

Generation of the membrane attack complex during haemodialysis: impact of classical and alternative pathway components.

1. The generation of the plasma SC5b-9 complex (the soluble form of the membrane attack complex) during haemodialysis was studied in 29 patients together with markers of the classical (C4d fragment) and alternative (Bb fragment) pathways and the common iC3b fragment. 2. In the patients dialysed with Hemophan and Cuprophan membranes, a rapid increase in the plasma levels of SC5b-9 complex, Bb fragment and iC3b fragment occurred within 15 min of the initiation of the haemodialysis procedure. The SC5b-9 complex and the Bb fragment concentrations remained at a plateau until 120 min thereafter. The iC3b fragment level showed a continual decline. 3. The C4d fragment concentrations remained unchanged, indicating that generation of the membrane attack complex is most likely due only to activation of the alternative pathway. 4. The generation of the membrane attack complex occurred throughout the full haemodialysis period. In patients treated with Polysulfon membranes no statistically significant variation in these components was noted. 5. The study shows that the membrane attack complex may be generated during the full period of the haemodialysis session and is a stable index of biocompatibility. 6. Moreover, it seems be involved directly in haemodialysis-associated phenomena.

["Membrane attack complex" formation in hemodialysis treatment]. / Die "Membrane attack complex"-Bildung während der Hämodialysebehandlung.

The behaviour of plasma concentrations of the membrane attack complex (MAC) during haemodialysis was studied in 23 patients. An increase in the levels up to 250% of the initial value was noted when Hemophan or Cuprophan membranes were used. Patients dialyzed, with Polysulfon membranes showed only a slight increase in MAC levels. In the Hemophan and Cuprophan group a plateau developed lasting from 15 to 120 minutes after onset of the haemodialysis session. The MAC may serve as marker of biocompatibility. Furthermore, it seems to be involved in many untoward effects of haemodialysis treatment.

Transient hyperoxaluria after ingestion of chocolate as a high risk factor for calcium oxalate calculi.

In 6 male subjects the diurnal variation of urinary oxalic acid excretion was studied after ingestion of chocolate, a food stuff rich in oxalic acid. The ingestion of chocolate caused a striking but transient increase in urinary oxalic acid excretion due to its absorption in the upper gastrointestinal tract. The peak excretion rates occurred 2-4 h after the intake of the chocolate. The peak values were 235% of the fasting excretion rate in the trial with 50 g chocolate and 289% in the trial with 100 g chocolate and reached the amounts found in cases with primary hyperoxaluria. The administration of ranitidine had no influence on oxalic acid absorption. The transient hyperoxaluria observed seems to be an important factor for the formation of calcium oxalate calculi in patients on risk for stone disorders.