SIPPET: methodology, analysis and generalizability.

The development of anti-FVIII neutralizing alloantibodies (inhibitors), occurring in about one-third of previously untreated patients (PUPs) with severe haemophilia A, depends on various genetic and environmental risk factors. Several previous studies have reported on the immunogenicity of FVIII concentrates, and due to differences in study design, study period, inhibitor testing frequency and follow-up duration the results were inconclusive. The first randomized trial on this unresolved question (SIPPET) included 251 previously untreated or minimally treated patients with severe haemophilia A treated with either a single plasma-derived FVIII (pdFVIII) containing VWF or a recombinant FVIII (rFVIII). The results showed an 87% higher rate of inhibitor development for rFVIII than pdFVIII during the first 50 exposure days of treatment. These results generated interest by patient organizations, physicians and regulatory agencies. This manuscript summarizes answers to the main questions that arose after the full publication of SIPPET.

Lombardy diagnostic and therapeutic network of thrombotic microangiopathy.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA) requiring urgent treatment. Standardization of its diagnosis and optimal management is challenging. This study aimed to evaluate the role of centralized, rapid testing of ADAMTS13 in patients experiencing acute TMAs requiring plasma-exchange (PEX) and to estimate the incidence of TTP in a large Italian Region. METHODS: We perfomed a cohort study in the frame of the project "Set-up of a Lombardy network for the study and treatment of patients undergoing apheresis", including 11 transfusion centers in the Region. Consecutive patients referred from 2014 to 2016 with acute TMAs requiring PEX were enrolled. Centralized ADAMTS13 activity testing was performed at the Milan Hemophilia and Thrombosis Center within 24 h. RESULTS: Forty-three TMA patients (44 events) were enrolled, of whom 35 (81%) had severe ADAMTS13 deficiency. Patients with severe ADAMTS13 deficiency were younger, mainly women, with a higher prevalence of autoimmune disorders and a lower prevalence of cancer. Clinical and laboratory characteristics of patients with and without severe ADAMTS13 deficiency largely overlapped, with a lower platelet count being the only baseline marker that significantly differed between the two patient groups (ADAMTS13 activity < 10% vs ≥ 10%: median difference of -27 × 109/l, 95% CI - 37 to - 3). PEX treatment was initiated in all patients, but soon discontinued in cases without severe ADAMTS13 deficiency. In this group, the mortality rate was higher and no episode exacerbations or relapses within 6 months occured. The estimated average annual incidence of acute acquired TTP events was 1.17 [0.78-1.55] per million people. CONCLUSIONS: Severe ADAMTS13 deficiency distinguished two groups of patients with largely overlapping clinical features but different treatment and disease course. This study provides a feasible model implemented in a large Italian region for the practical clinical approach to TMAs and underlines the importance of urgent ADAMTS13 activity testing for an accurate differential diagnosis and therapeutic approach.

Timing and severity of inhibitor development in recombinant versus plasma-derived factor VIII concentrates: a SIPPET analysis.

Essentials Recombinant factor VIII (rFVIII) was contrasted with plasma-derived FVIII (pdFVIII). In previously untreated patients with hemophilia A, rFVIII led to more inhibitors than pdFVIII. Inhibitors with rFVIII developed earlier, and the peak rate was higher than with pdFVIII. Inhibitors with rFVIII were more severe (higher titre) than with pdFVIII. SUMMARY: Background The development of neutralizing antibodies (inhibitors) against factor VIII (FVIII) is the most severe complication in the early phases of treatment of severe hemophilia A. Recently, a randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) demonstrated a 2-fold higher risk of inhibitor development in children treated with recombinant FVIII (rFVIII) products than with plasma-derived FVIII (pdFVIII) during the first 50 exposure days (EDs). Objective/Methods In this post-hoc SIPPET analysis we evaluated the rate of inhibitor incidence over time by every 5 EDs (from 0 to 50 EDs) in patients treated with different classes of FVIII product, made possible by a frequent testing regime. Results The highest rate of inhibitor development occurred in the first 10 EDs, with a large contrast between rFVIII and pdFVIII during the first 5 EDs: hazard ratio 3.14 (95% confidence interval [CI], 1.01-9.74) for all inhibitors and 4.19 (95% CI, 1.18-14.8) for high-titer inhibitors. For patients treated with pdFVIII, the peak of inhibitor development occurred later (6-10 EDs) and lasted for a shorter time. Conclusion These results emphasize the high immunologic vulnerability of patients during the earliest exposure to FVIII concentrates, with the strongest response to recombinant FVIII products.

[Intravenous immunoglobulins in the treatment of glomerulopathies]. / Le immunoglobuline EV nella terapia delle glomerulopatie.

Intravenous high-dose immunoglobulin (IVIG) therapy is used in several antibody-mediated diseases including Guillain-Barré syndrome, idiopathic thrombocytopenic purpura, and autoimmune neuropathies. In the last decade, numerous studies have evaluated the application of IVIG therapy in autoimmune glomerulopathies such as lupus nephritis, membranous glomerulonephritis, and transplant-related chronic nephropathy. These studies were conducted on small numbers of patients and varied with respect to IVIG doses and duration of therapy cycles. Furthermore, many of the patients included in the studies did not respond to conventional therapies, were affected by complications, and had impaired renal function. IVIG therapy was able to reduce proteinuria and inflammation and improve renal function in some forms of glomerulonephritis, particularly LES-related forms. IVIG therapy was also tested in patients awaiting kidney transplantation and in patients affected by transplant-related chronic nephropathy: in both groups the results were controversial. Seventy-eight cases of IVIG-related nephrotoxicity have been reported in the literature. In most cases the toxic effect was reversible and observed in patients with pre-existing renal failure treated with IVIG formulations containing saccharose. IVIG could have beneficial effects in many glomerulopathies. Nevertheless, further trials are needed to clarify the potential and the limitations of this therapeutic approach.

Minimal factor XIII activity level to prevent major spontaneous bleeds.

Essentials A strong association between bleeding severity and FXIII activity level (FXIII:C) was shown. The range 5-30 IU dL-1 of FXIII:C was associated with a high variability of bleeding severity. The PROspective study confirmed the association between FXIII:C activity and bleeding severity. A FXIII: C of 15 IU dL-1 is a proposed target to start prophylaxis for prevention of major bleeding. SUMMARY: Background Congenital factor XIII (FXIII) deficiency is a rare bleeding disorder associated with significant bleeding manifestations. The European Network of Rare Bleeding Disorders (EN-RBD) study, performed from 2007 to 2010, showed a strong association between bleeding severity and FXIII activity in plasma of patients with FXIII deficiency. Among these patients, variable levels of FXIII activity, from undetectable to 30%, were associated with a wide range of bleeding severity. Objectives and patients The present cross-sectional study, in the frame of the PRO-RBDD project, a prospective cohort study, analyzed data of 64 patients with FXIII deficiency and different types of clinical and laboratory severity. Results The results of this analysis confirmed that FXIII coagulant activity in plasma is well associated with clinical severity of patients. In addition, 15 IU dL-1 of FXIII activity was identified to be the level under which the probability of spontaneous major bleeding sharply increases (from 50% for levels of 15 IU dL-1 to more than 90% for levels of 5 IU dL-1 or lower). Conclusion The PRO-RBDD study suggests a FXIII coagulant activity level of 15 IU dL-1 as a target to start prophylaxis in order to prevent major bleedings, such as central nervous system or gastrointestinal tract hemorrhages.

Potential misdiagnosis of dysfibrinogenaemia: Data from multicentre studies amongst UK NEQAS and PRO-RBDD project laboratories.

INTRODUCTION: Mutations in fibrinogen (Fgn) genes, causing dysfibrinogenaemia, can result in either a bleeding or thrombophilic diathesis. Dysfibrinogenaemia is infrequently encountered in hospital laboratories, and the utility of different assays in the diagnosis of dysfibrinogenaemia has not previously been explored in a multicentre study. We describe here an exercise in which PRO-RBDD project (prospective data collection on patients with fibrinogen and Factor XIII deficiencies) centres, and UK NEQAS centres, performed investigations for dysfibrinogenaemia. METHODS: Samples from donors with dysfibrinogenaemia (sample 1: gamma p.Arg301Cys, sample 2: Bbeta166Arg3Cys-Fgn Longmont, sample 3: Aalpha p.Arg35His) and a normal donor were sent to laboratories for investigation for possible dysfibrinogenaemia. Median, coefficient of variation and range were determined for each assay method. RESULTS: Results were returned from 62 UK NEQAS and 24 PRO-RBDD centres. PT, APTT, Clauss fibrinogen and thrombin times were performed by >90% of centres, with 51% performing reptilase times, and 31% fibrinogen antigen. All centres identified samples 1 and 3 as abnormal. However, 39% of centres reported a normal or raised fibrinogen for the Fgn Longmont sample, and marked differences in Clauss fibrinogen results with different reagents were noted for this sample (median 1.01 g/L vs 5.10 g/L for the two mostly widely used reagents). CONCLUSION: In-house studies suggest that the method of detection of fibrin clot formation may result in different Clauss fibrinogen measurements with FgnLongmont plasma. It is possible that some widely used methodologies, both using optical and mechanical end-point detection systems, will fail to detect this rare fibrinogen variant.

Detection of Factor XIII deficiency: data from multicentre exercises amongst UK NEQAS and PRO-RBDD project laboratories.

INTRODUCTION: FXIII deficiency is a rare bleeding disorders, and specific FXIII assays are recommended to detect this deficiency. We investigated the performance and accuracy of FXIII investigations in two exercises, comparing centres enrolled in the PRO-RBDD project (prospective data collection on patients with fibrinogen and Factor XIII deficiencies), and UK NEQAS BC centres. METHODS: Samples from a FXIII deficient subject and a normal donor were sent to participating centres, to investigate for FXIII deficiency, and interpret their results. Median, coefficient of variation and range were determined. RESULTS: Results were returned from 98 UK NEQAS BC and 28 PRO-RBDD centres. Up to 40% of UK NEQAS BC and 52% of PRO-RBDD centres reported clot solubility results - with diagnostic errors by two NEQAS BC centres (false negatives for the FXIII deficient sample) and one PRO-RBDD centre (false positive for the normal sample). Over 70% of UK NEQAS BC centres and PRO-RBDD centres performed FXIII assays. Median results were similar between the two groups, with the exception of sample 3 in survey 2 (5.5 vs. 14.0 µ/dl for UK NEQAS BC and PRO-RBDD centres respectively, P < 0.001). Diagnostic errors were made by 2 UK NEQAS BC centres. CONCLUSION: Approximately 70% of centres now employ FXIII assays, complying with international recommendations. However, solubility tests continue to be used. Our data show this can be successful, depending on the sensitivity of the method in use. Diagnostic errors are made by centres using both solubility screens and FXIII assays, and laboratories should ensure good quality assurance procedures to improve diagnostic accuracy.

Role of the 2 adenine (g.11293_11294insAA) insertion polymorphism in the 3' untranslated region of the factor VII (FVII) gene: molecular characterization of a patient with severe FVII deficiency.

Polymorphic variants in the gene encoding factor VII (F7) affect the plasma levels of this coagulation protein and modify the clinical phenotype of FVII deficiency in some patients. In this study we report the in vitro functional analysis of a novel polymorphic variant located in the 3' untranslated region of F7: g.11293_11294insAA. To determine whether this variant regulates FVII expression, we initially compared an expression vector containing FVII cDNA with g.11293_11294insAA with the FVII wild-type (WT) construct. The kinetics of mRNA production showed that the insertion decreases the steady-state FVII mRNA levels. To assess whether the insertion influences the phenotype of FVII-deficient patients, we evaluated its effect on the expression of FVII in a patient with severe FVII deficiency (undetectable FVII activity and antigen) carrying two additional homozygous missense variations (p.Arg277Cys and p.Arg353Gln). The two substitutions alone reduced the expression of FVII activity and antigen in vitro, but with the insertion polymorphism in our expression vector the patient's phenotype of undetectable plasma FVII was recapitulated. The insertion polymorphism in the 3' untranslated region of F7 is another modifier of FVII expression that might explain the poor genotype-phenotype correlation in some FVII-deficient patients.

Effect of captopril on renal function in patients with essential hypertension.

The glomerular filtration rate (creatinine clearance), glomerular permeability (qualitative and quantitative proteinuria), tubular reabsorption (k-lambda chains of immunoglobulins and lysozyme) and indexes of tubular cell lysis (alpha-glucosidase and gamma-glutamyltranspeptidase) were measured in the urine of 10 patients with moderate, uncomplicated essential hypertension during placebo therapy and after captopril given at increasing doses of 25, 50, 100 and 200 mg twice daily, the first three doses being given for 3 days and the last one for 4 weeks in all patients and for an additional 6 months in 5 patients. During placebo therapy, proteinuria was absent in eight patients and detectable (glomerular and selective) in two; selective proteinuria appeared in two and a decrease in selectivity was observed in two patients with previous proteinuria after 4 weeks of captopril therapy. No proteinuria was detectable in the five patients followed up to 6 months, not even in the one in whom a decrease in glomerular selectivity had occurred after 4 weeks. The glomerular filtration rate was unchanged as were lysozyme and gamma-glutamyltranspeptidase values, while light chains were always undetectable. Alpha-glucosidase showed some increase; however, increments were transient and always much lower than those observed with known tubular toxic drugs. These data show that under our experimental conditions captopril caused no evident changes in glomerular and tubular function.

Study of serum 3,5,3'-triiodothyronine sulfate concentration in patients with systemic non-thyroidal illness.

Sulfation is an important pathway of triiodothyronine (T3) metabolism. Increased serum T3 sulfate (T3S) values have been observed during fetal life and in pathological conditions such as hyperthyroidism and selenium deficiency. Similar variations have also been reported in a small number of patients with systemic non-thyroidal illness, but the underlying mechanisms have not been elucidated. In this study, serum T3S concentrations have been measured by a specific radioimmunoassay in 28 patients with end-stage neoplastic disease (ESND) and in 44 patients with chronic renal failure (CRF); 41 normal subjects served as controls. Both ESND and CRF patients had lower serum total T4 (TT4) and total T3 (TT3) than normal controls, while serum reverse T3 (rT3) was increased significantly in ESND (0.7 +/- 0.5 nmol/l; p < 0.001 vs. controls) but not in CRF (0.3 +/- 0.1 nmol/l). The TT3/rT3 ratio, an index of type I iodothyronine monodeiodinase (type I MD) activity, was reduced significantly in both groups of patients. Serum T4-binding globulin (TBG) was decreased in CRF but not in ESND patients. Serum T3S was significantly higher both in ESND (71 +/- 32 pmol/l) and CRF (100 +/- 24 pmol/l) than in controls (50 +/- 16 pmol/l, p < 0.001). Serum T3S values showed a positive correlation with rT3 values and a negative correlation with both TT3 and FT3 values in ESND, but not in CRF. In the latter group a positive correlation was observed between T3S and TBG values. The T3S/FT3 ratio was higher both in CRF (18 +/- 5) and in ESND (23 +/- 18) as compared to controls (10 +/- 4). Serum inorganic sulfate was increased and correlated positively with T3S values in CRF patients. In conclusion, the results of this study in a large series of patients confirm that patients with systemic non-thyroidal illness have increased serum T3S levels. The mechanisms responsible for these changes appear to be different in ESND and CRF patients. In ESND the increase in serum T3S levels is mainly related to reduced degradation of the hormone by type I MD, whereas in CRF it might be driven by the enhanced sulfate ion concentration, and could be partially dependent on the impaired renal excretion of T3S. Because T3S can be reconverted to T3, it is possible that increased T3S concentrations contribute to maintenance of the euthyroid state in systemic non-thyroidal disease.

The link of biocompatibility to cytokine production.

Recent studies suggest that chronic inflammation plays a role in the pathogenesis of cardiovascular disease. Cytokines released from jeopardized tissues stimulate the liver to synthesize acute phase proteins, including C-reactive protein (CRP). Baseline levels of CRP in apparently healthy persons or in persons with unstable angina constitute an independent risk factor for cardiovascular events. More recently, it has been suggested that CRP is useful not only as a marker of the acute phase response, but is also involved in the pathogenesis of the disease. CRP may, in fact, directly interact with the atherosclerotic vessels or ischemic myocardium by activation of the complement system, thereby promoting inflammation and thrombosis. Several studies in uremic patients have implicated CRP as a marker of malnutrition, resistance to erythropoietin, and chronic stimulation in hemodialysis. An increased cytokine production secondary to blood interaction with bioincompatible dialysis components has been reported by several studies; interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and mainly IL-6 are the three proinflammatory cytokines involved in the pathogenesis of hemodialysis-related disease. We have provided evidence for the occurrence of high CRP and IL-6 levels in chronic dialytic patients exposed to contaminate dialysate and suggest that backfiltration may induce a chronic, slowly developing inflammatory state that may be abrogated by avoiding backfiltration of contaminate dialysate. Therefore, CRP is implicated as a marker linking bioincompatibility associated with backfiltration and increased cytokine production with a clinical state of chronic inflammation.

Renal tolerance of rubidium chloride: short-term clinical evaluation.

The rubidium and lithium ions are known to have opposite effects on a wide range of biochemical and behavioral parameters in experimental animals. Based on the proven effectiveness of lithium as an antimanic agent, several trials have been conducted with rubidium in the acute treatment of the depressive phase of bipolar illness. The results to date are promising. However, the 30- to 60-day biologic half-life of rubidium has mandated careful studies of potential toxicity before engaging in long-term administration of this ion to depressive subjects. One area of potential concern is the possibility of renal toxicity, which could be expressed as unexpectedly increased retention of rubidium. The data in this paper show that after 15 days of rubidium administration, there are no changes beyond the normal range in a variety of kidney function tests, including in four enzymes which are specific markers of tubule cell function.

Pretibial myxedema and high-dose intravenous immunoglobulin treatment.

Seven patients affected by Graves' ophthalmopathy and pretibial myxedema (four patients with nodular form, two with diffuse, and one with elephanthiasic form) have been treated with high-dose intravenous immunoglobulins. We have observed (a) clinical improvement of pretibial myxedema and Graves' ophthalmopathy in all patients, (b) a reduction of pretibial skin thickness, by ultrasonography evaluation, in four patients, (c) a reduction of mucopolysaccharide skin content in three patients, (d) disappearance of lymphocytic skin infiltration and IgG deposition in two patients, and (e) a parallel reduction of the titer of circulating autoantibodies as antithyroglobulin, antimicrosomal, anti-TSH receptor, and of non-organ-specific antibodies as antinuclear, anti-smooth muscle cells, and anti-mitochondrial. In comparison two patients with Graves' ophthalmopathy and pretibial myxedema treated with systemic corticosteroids did not present any improvement of the cutaneous ailment. Therefore, this study suggests that intravenous immunoglobulins are effective in the treatment of pretibial myxedema and may have an immunomodulant action in patients with Graves' disease and related disorders.

IgG, IgA and C3 deposits in the extra-thyroidal manifestations of autoimmune Graves' disease: their in vitro solubilization by intravenous immunoglobulin.

OBJECTIVE: To study the involvement of antibodies in the extrathyroidal manifestations of autoimmune Graves' disease, we determined the presence of IgG, IgA and IgM antibodies and C3c in connective tissue samples from patients with Graves' disease and pretibial myxedema (PTM) or thyroid associated ophthalmopathy (TAO). METHODS: Connective orbital tissue samples were obtained from 12 patients undergoing orbital decompression for TAO, and skin samples from lesions on the pretibial area were obtained in 7 patients with PTM. Sections from each tissue sample were stained with fluorescin-isothiocianate conjugated anti-human IgG, IgA, IgM and C3c and were examined by a fluorescence optical instrument. Other serial sections from each sample were incubated with human IgG solutions (concentration 6 mg/ml or 20 mg/ml), human albumin (40 mg/ml), PBS, myoglobin (40 mg/ml), or IgA (20 mg/ml), and were then processed by a standard direct immunofluorescence staining procedure. RESULTS: Among the samples from TAO patients 8/12 (67%) were positive for IgG deposition, 4/9 (44%) were positive for IgA, 1/9 (11%) was positive for IgM and 4/9 (44%) were positive for C3c deposition. Orbital connective samples from 3 non-TAO patients were all negative. Among samples from PTM patients 4/7 (57%) were positive for IgG deposition, 3/ 4 (75%) were positive for IgA, 0/4 was positive for IgM and 3/7 (43%) were positive for C3c deposition. Skin samples from 5 control patients undergoing skin biopsy for non-autoimmune diseases were all negative. Incubation with human IgG (20 mg/ml) resulted in the complete disappearance of IgG and C3c deposition in all positive patients. No significant variation in IgG fluorescent staining after incubation with either 6 mg/ml of IgG solution, human albumin, PBS, myoglobin or IgA was observed. CONCLUSION: The results of our study suggest that different classes of antibodies, mainly IgG and IgA, may be implicated in the disease process in autoimmune TAO and PTM. Activation of the complement cascade, via the classic or the alternative pathway, could take place in about 40% of these patients. IVIG in vitro may solubilize, by a specific mechanism, IgG and complement immune complex deposition in the extrathyroidal manifestations of autoimmune Grave's disease.

Efficacy of intravenous immunoglobulin therapy in a case of autoimmune-mediated chronic active hepatitis.

In a patient suffering from histologically-documented immuno-mediated chronic active hepatitis, intravenous immunoglobulin (IVIG) treatment was initiated as an obligatory alternative therapy because of femur head aseptic necrosis which had followed long-term therapy with steroids. The first cycle of IVIG was followed by remission of most symptoms, normalization of liver enzymes, disappearance of circulating immunecomplexes (CIC), and a negative lupus band test. Improvement in the patient's condition was demonstrated, in liver histology, by the disappearance of peri-portal mononuclear cells infiltrates, while immunohistochemistry showed the disappearance of the intracellular IgG deposits.

Intravenous immunoglobulin therapy of membranous nephropathy: efficacy and safety.

Preliminary results of the efficacy of high-dose intravenous human IgG in patients with biopsy-confirmed idiopathic membranous nephropathy (IMGN) were reported. Five patients with normal renal function (creatinine clearance 125.2 +/- 16 ml/min/1.73 m2 BSA) (Group A) and 4 patients with moderate renal insufficiency (creatinine clearance 65.5 +/- 8.3 ml/min/1.73 m2 BSA) (Group B) received pulse doses of IgG (0.4 g/kg BW) for 3 consecutive days; these 3-day boli were repeated 3 times at 21-day intervals; since then for a 10-month period one bolus once every 3 weeks has been administered. Five responder patients at the end of the trial received a new renal biopsy. In 4 Group A patients complete remission of proteinuria (daily proteinuria less than 0.2 g) was observed, whereas 1 patient showed partial remission (proteinuria 2 g/day). In Group B patients, 1 showed complete remission and 2 partial remission; in 1 patient no variation of proteinuria was noted. In responder patients clinical and biological findings of the nephrotic syndrome disappeared and a statistically significant increase of creatinine clearance was observed. In control biopsies at the end of the trial the immunofluorescence staining failed to find immunodeposits and recovery of glomerular lesions at light microscopy. In conclusion, IgG therapy seems to be of benefit to patients with IMGN but a randomized clinical trial to confirm this preliminary report is needed.

Lack of nocturnal serum thyrotropin (TSH) surge in patients with chronic renal failure undergoing regular maintenance hemofiltration: a case of central hypothyroidism.

Thyrotropin (TSH) secretion was evaluated in a group of patients with chronic renal failure (CRF) undergoing regular maintenance hemofiltration and in normal controls. The study group included 68 patients (39 males and 29 females, age range 39-73 years, mean: 53 years). In all patients blood was drawn at 08:30-09:00 h; in 20 patients the nocturnal (24:00-02:00 h) serum TSH peak was also evaluated; 12 patients underwent stimulation test with synthetic TSH-releasing hormone (TRH). TSH was measured by an ultrasensitive immunoradiometric assay. CRF patients showed a significant decrease in serum total and free thyroxine and triiodothyronine concentrations, which in a substantial proportion of subjects were below the lower normal limit. Serum reverse triiodothyronine and thyroxine-binding globulin values did not differ in the two groups. Despite this trend of thyroid hormones to decrease, no patient had supranormal TSH values as in primary hypothyroidism. While the mean morning TSH concentrations of CRF patients did not differ from those of controls, the mean nocturnal values were significantly reduced in CRF (1.0 +/- 0.2 vs 3.2 +/- 0.4 mU/l, p less than 0.0005) and the nocturnal serum TSH surge was not observed in 18 of the 20 patients (90%) in whom it was evaluated. The mean serum TSH peak value after TSH-releasing hormone (TRH) administration was also reduced in CRF patients, and the TSH response to TRH was blunted in 3 out of 12 patients (25%). The results of this study demonstrate a major impairment of TSH secretion in CRF, which baseline TSH measurements in the morning and the evaluation of the TSH response to TRH may not reveal.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitriol oral therapy for the prevention of secondary hyperparathyroidism in patients with predialytic renal failure.

Secondary hyperparathyroidism is a common feature of chronic renal failure and vitamin D deficiency plays an important role in the development of this abnormality. Several therapeutical calcitriol schedules have been used in treating uremic hyperparathyroidism but recently oral boluses have been proposed as more effective. In this study we compare the efficacy of three different oral calcitriol regimens in suppressing iPTH secretion in predialytic chronic renal failure. Sixteen (16) patients (mean age 51 +/- 16 years; creatinine clearance 22.9 +/- 9.8 ml; range 8-32 ml/min) were treated in a cross-over randomized design with oral daily calcitriol 0.5 micrograms/die (Treatment A), three oral boluses of 2 micrograms of calcitriol a week (Treatment B) and a single oral bolus of 2 micrograms of calcitriol a week (Treatment C). All treatment periods lasted three months and were followed by a wash-out period of one month. Serum iPTH (Allegro Nichols), 1-25 vitamin D (IRMA-MAB), total and ionized calcium (Nova 8 Pabish), serum phosphate, alkaline phosphatase and creatinine clearance were measured every two weeks. Serum iPTH was also determined in a control group of fifteen (15) patients (mean age 47 +/- 12 years, creatinine clearances of 21 +/-12 ml/min) observed for three months without calcitriol treatment. Daily oral intake of 0.5 micrograms of calcitriol prevents an increase of iPTH without causing hypercalcemia, but only oral boluses (B and C) decreased iPTH: from 270 +/- 169 pg/ml to 135 +/- 76 pg/ml (p < 0.01; B) and to 165 +/- 121 pg/ml (p < 0.05; C). Serum iPTH increased from 293 +/- 121 to 323 +/- 129 pg/ml (p = n.s.). No significant differences in renal function were observed during the different study periods. Our results confirm the good efficacy of multiple calcitriol oral boluses but also suggest for the first time a single weekly bolus as a reliable approach to the treatment of secondary hyperparathyroidism in pre-dialytic renal failure.

Protective effect of L-propionylcarnitine on cyclosporine-induced nephrotoxicity.

Nephrotoxicity has represented the major limitation in the use of cyclosporine A (CyA). The structural abnormalities at the level of the proximal tubular cells are necrosis, vacuolisation and lipid droplets, as well as CyA-induced glomerular afferent arteriole constriction and granular juxtaglomerular cell hyperplasia. The mode of action of vasoconstriction is not well known, but there appears to be substantial impairment of endothelial cell function leading to enhanced release of vasoconstrictors such as endothelin and thromboxane. L-propionylcarnitine (PC), one of the most potent analogues of carnitine, is able to correct and to prevent alterations in endothelial membrane permeability and it has been identified in the kidney of various animal species. To investigate a possible reduction of CyA-induced nephrotoxocity, we examined the effects of a pretreatment with PC before administering several doses of CyA in an isolated and perfused rat kidney. The histological findings showed that the perfusion with PC reduces the vasoconstrictive effect of CyA on the glomerular capillaries and preserves the tubular epithelium. The ratio of the diameter between the glomerular capillary tuft and Bowman's capsule was higher, while at the tubular level the ratio internal-diameter/diameter evaluated at the level of the basal membrane was lower in PC + CyA perfused kidneys than in only CyA perfused ones. The final value of perfusion pressure was lower in PC + CyA perfused kidneys than in only CyA perfused ones, confirming the histological findings. The release induced by CyA of alanine aminopeptidase (AAP) and N-acetyl-glucosaminidase (NAG), markers of tubular damage, was significantly reduced by pretreatment with PC. These data suggest that the pretreatment with PC reduces the CyA-induced nephrotoxicity in an isolated and perfused rat kidney.