Absence of interaction between rivaroxaban, tacrolimus and everolimus in renal transplant recipients with deep vein thrombosis or atrial fibrillation.

No data are available on rivaroxaban use in renal transplant recipients and on its surmised interaction with immunosuppressants. The aim was to investigate potential interactions between rivaroxaban and immunosuppressants in this setting. Renal transplant recipients with a stable renal function treated with rivaroxaban and tacrolimus with or without everolimus were investigated. All drugs and creatinine concentrations were determined daily for 2 weeks after the start of anticoagulation. Blood samples were drawn at 8.00 am and 3-4 h later for trough and peak concentrations, respectively. Bleeding and thrombotic events were recorded during a minimum follow-up of 6 months. In 8 renal transplant patients, rivaroxaban levels showed a predictable pharmacokinetic trend, both at Ctrough (30-61 µg/L) and at Cpeak (143-449 µg/L), with limited variability in the 25th-75th percentile range. Tacrolimus (Ctrough 3-13 µg/L; Cpeak 3-16 µg/L), everolimus (Ctrough 3-11 µg/L; Cpeak 5-17 µg/L) and creatinine concentrations were stable as well. Immunosuppressors variability before and after rivaroxaban were 30% and 30% for tacrolimus, 27% and 29% for everolimus, respectively, as well as 14% and 3% for creatinine. For rivaroxaban monitoring, the reference change value better performed in identifying significant variations of its concentration. No patient had bleeding or thrombotic events, worsening of renal graft function, and signs of immunosuppressants toxicity during a mean follow-up of 23 (9-28) months. In conclusion, rivaroxaban does not seem to interact with tacrolimus and everolimus in renal transplant recipients. Both anticoagulant and immunosuppressive effects seem warranted, without major bleeding complications and effect on the graft function.

Coronary Microvascular Dysfunction Predicts Long-Term Outcome in Simultaneous Pancreas-Kidney Transplantation.

BACKGROUND: Patients with diabetes are at increased cardiovascular risk. Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice in patients with type 1 diabetes mellitus and diabetic nephropathy. We assessed coronary flow reserve (CFR) by transthoracic echocardiography as a marker of major adverse cardiac events (MACE) in SPKT patients. METHODS: We studied 48 consecutive SPKT patients (28 male, age at SPKT 54 ± 8 years). Time from transplantation was 8.5 ± 3 years. Follow-up was 4.6 ± 1.8 years. Coronary flow velocity in the left anterior descending coronary artery was detected by Doppler echocardiography at rest and during adenosine infusion. CFR was the ratio of hyperemic diastolic flow velocity (DFV) to resting DFV. A CFR ≤ 2 was considered abnormal and a sign of coronary microvascular dysfunction. MACE were cardiac death, myocardial infarction, and heart failure. RESULTS: CFR was 2.55 ± 0.8. CFR was ≤2 in 13 (27%) patients. CFR was lower in SPKT patients with MACE (2.1 ± 0.7 vs 2.7 ± 0.8, P = .03) and patients with MACE had a higher incidence of CFR ≤ 2 (P = .03). Time from transplantation was shorter in patients with MACE (P < .0001). Patients with CFR ≤ 2 had a lower MACE-free survival (P = .03). CFR ≤ 2 predicted the risk of MACE (P = .007) independently from coronary artery disease and metabolic control. However, this predicted role is lost when adjusted for the time from transplantation, which plays a protective role (P = .001). CONCLUSIONS: In SPKT, CFR ≤ 2 may be a reliable marker for MACE, independent of coronary artery disease diagnosis. However, this role seems to be reduced over time. This finding suggests a gradual reduction of cardiovascular risk in SPKT patients.

Estresse osmótico na germinação de sementes de Petiveria alliacea L / Osmotic stress on seed germination of Petiveria alliacea L

RESUMOO trabalho teve como objetivo verificar os efeitos dos estresses hídrico e salino na germinação de sementes de Petiveria alliacea , bem como definir os limites máximos de tolerância da espécie a esses estresses. As sementes foram submetidas aos agentes osmóticos NaCl, CaCl2 e PEG nos potenciais à 0; -0,1; -0,2; -0,3; -0,4; -0,5; -0,6; -0,7; -0,8; -0,9 e -1,0 MPa sob temperatura constante de 25˚C e fotoperíodo de 12 horas, com avaliações diárias durante 30 dias. As variáveis analisadas foram porcentagem de germinação, índice de velocidade de germinação, tempo médio de germinação, índice de sincronização e frequência relativa da germinação. As sementes de P. alliacea sob estresse osmótico apresentam menor porcentagem e velocidade de germinação com a redução dos potencias osmóticos, principalmente com CaCl2. Em potenciais osmóticos mais negativos que -0,4; -0,5 e -0,7 MPa, respectivamente nos agentes CaCl2, NaCl, e PEG, não ocorre germinação. O padrão de distribuição da frequência relativa aumentou a polimodalidade, o tempo médio de germinação e o índice de sincronização da germinação com a redução dos potencias osmóticos.

ABSTRACTThe study aimed to investigate the effects of water and salt stress on seed germination of Petiveria alliacea, as well as to define the limits of tolerance of the species to these stresses. The seeds were subjected to osmotic agents NaCl, CaCl2 and PEG in the potential 0; -0.1; -0.2; -0.3; -0.4; -0.5; -0.6; -0.7; -0.8; -0.9 and -1.0 MPa at a constant temperature of 25˚C and a photoperiod of 12 hours, with daily assessments for 30 days. The variables studied were germination percentage, germination velocity index, middle fear germination, synchronization index and relative frequency of germination. The seeds of P. alliacea under osmotic stress had lower percentage and speed of germination with the reduction of the the osmotic potential, especially with CaCl2. At more negative osmotic potentials than -0.4; -0.5 and -0.7 MPa, respectively in the CaCl2, NaCl, and PEG agents, the germination does not occur. The distribution pattern of the relative frequency increased the several modalities, , the average time of germination and the germination index of synchronization with the reduction of osmotic potential.

Everolimus associated with low-dose calcineurin inhibitors, an option in kidney transplant recipients of very old donors.

BACKGROUND: Despite potential renal and cardiovascular advantages of proliferation signal inhibitors, their de novo use in kidney transplantation (KT) from elderly donors (ED) is poorly documented. We retrospectively analyzed two consecutive cohorts of KT from ED: low-dose extended-release tacrolimus (Tac) was used from 2010 to 2012 and cyclosporine (Csa) was used from 2008 to 2010. METHODS: Associated maintenance drugs were everolimus (Eve) and steroids. Outcomes were compared between groups over a 12-month follow-up. Fifty-six patients were analyzed in the Tac-Eve group and 54 in the Csa-Eve group. RESULTS: There were no significant differences at baseline with the exception of older donors age in the Tac-Eve cohort (74 vs 71 years, P = .002). There were no deaths, primary non functions, or graft losses. Eight (14%) Tac-Eve and 15 (28%) Csa-Eve patients had delayed graft function (P = .10). Renal function was fairly stable over time (median cGFR 36-49 mL/min and 51-55 mL/min in single kidney transplantation and dual kidney transplantation patients, respectively) with no significant differences between groups at month 12. Surgical complications were infrequent and observed mostly in dual kidney transplantation recipients. Thirty-nine (70%) and 30 (56%) patients remained under their initial Tac-Eve or Csa-Eve regimen, respectively. CONCLUSIONS: Induction with Thymoglobuline and maintenance with Eve and low-dose extended-release Tac and steroids is safe and effective in renal transplant from ED.

Desensitization with plasmapheresis and anti-Cd20 for ABO incompatible kidney transplantation from living donor: experience of a single center in Italy.

OBJECTIVE: Blood group incompatibility in kidney transplants from a living donor can be successfully overcome by using various desensitization protocols: intravenous immunoglobulin, plasmapheresis (PP), immunoadsorption, and double filtration PP. PATIENTS AND METHODS: From July 2010 to October 2013, we performed 10 ABO incompatible kidney transplantation (KT) procedures from a living donor. The desensitization protocol was based on rituximab and PP+cytomegalovirus immune globulin. All patients received induction with basiliximab, except 1 case treated with Thymoglobuline® (ATG) for the simultaneous presence of donor-specific antibody. Tacrolimus and mycophenolate mofetil were initiated at the time of desensitization and continued after the transplant. RESULTS: After a mean follow-up of 11.6±10.4 months, all patients are alive with a functioning graft. The mean serum creatinine concentration at 1 month, 3 months, 6 months, and 1 year was 1.48±0.29, 1.47±0.18, 1.47±0.27, and 1.5±0.27 mg/dl. Three episodes of acute cellular rejection occurred in 2 patients. There was only 1 case of BK virus infection, treated with reduction of immunosuppressive therapy. The protocol biopsy specimens at 1, 3, and 6 months were C4d positive in the absence of acute rejection. CONCLUSIONS: Desensitization with rituximab, PP, and anti-cytomegalovirus immune globulin allowed us to perform transplants from living donors to ABO incompatible recipients with excellent results and reduced costs.

[A case of Kaposi's sarcoma in the rapamycin era]. / Un caso di sarcoma di Kaposi nell'era della Rapamicina.

We report a case of Kaposi's sarcoma in a patient who received a double kidney transplant in 2005. Immunosuppression was induced with rapamycin and antilymphocyte serum while maintenance therapy consisted of rapamycin, corticosteroids and mycophenolic acid. The patient developed delayed graft function but no rejection. In November 2006 and March 2007 two graft biopsies were taken because of a significant rise in serum creatinine; they revealed chronic allograft nephropathy and polyomavirus infection. Meanwhile a skin biopsy of the leg was performed to determine the nature of a discolored lesion. The morphohistological diagnosis was Kaposi's sarcoma. For this reason rapamycin was stopped and steroid treatment gradually reduced. Specific therapy with doxorubicin was started; radiological and endoscopic examination excluded disseminated disease while serological tests were positive for antibodies to HHV-8, a virus known to cause Kaposi's sarcoma. Unfortunately, withdrawal of antirejection therapy caused loss of the graft, so the patient had to start dialysis. In this report we stress the possible development of malignancy in transplanted patients who are given rapamycin. Rapamycin is known to be an antirejection drug and to have antineoplastic activity; the major risk of malignancy is probably related to immunosuppression rather than the type of drugs used to obtain it.

Medullary sponge kidney (Lenarduzzi-Cacchi-Ricci disease): a Padua Medical School discovery in the 1930s.

The introduction of radiological contrast media and intravenous (i.v.) urography in clinical diagnostics in the 1930s enabled the discovery of several diseases, including the medullary sponge kidney (MSK). MSK is a renal malformation characterized by cystic anomalies of precalyceal ducts, which is frequently associated with nephrocalcinosis and renal stones. Although it was first recognized by G Lenarduzzi in 1939, its thorough description was the result of the ante litteram multidisciplinary cooperation between a radiologist (Lenarduzzi), a urologist (Cacchi), and a pathologist (Ricci), all at the Padua University Hospital. These authors 'established' the paradigm for its diagnosis that is still used today. I.v. urography is the gold standard for the diagnosis of MSK, but as the technique is used less and less, there is a concrete possibility of this renal condition being forgotten in the future. Although the pathogenesis of MSK has yet to be elucidated, its association with different malformative conditions supports the idea that it is a developmental disorder. Recent findings suggest that MSK may be the consequence of a disruption of the ureteral-bud/metanephric-blastema interface.

Advanced glycation end products/peptides: an in vivo investigation.

Advanced glycation end products/peptides (AGE/peptides) originate by in vivo enzymatic digestion of nonenzymatically glycated proteins, which are produced by reaction of glucose with primary amino groups present in the protein chain following the Maillard pattern. AGE/peptides are highly reactive species and can interact with tissue and circulating proteins, leading to tissue modification and impaired protein functionality. Serum levels of AGE/peptides are reported to be particularly high in diabetes (in terms of higher production) or in end-stage renal disease (in terms of accumulation). For these reasons, their structural identification is of high interest, giving information on their relationship with the pathological state and allowing the design of possible therapeutic interventions. We report here some preliminary results obtained by liquid chromatography/electrospray ionization/mass spectrometry (LC/ESI/MS) and matrix-assisted laser desorption ionization MS (MALDI-MS) investigations carried out on the low-molecular-weight serum peptide fraction from 10 healthy subjects, 10 patients with poorly controlled diabetes, and 10 patients with end-stage nephropathy.

[Proliferative response of peripheral blood mononuclear cells to the recombinant allergen BtM of the Blomia tropicalis housedust mite]. / Respuesta proliferativa de células mononucleares de sangre periférica frente al alergeno recombinante BtM del ácaro del polvo casero Blomia tropicalis.

Allergic diseases are triggered when individuals genetically predisposed to developing an allergy (atopy) are exposed to sensitizing allergens. These allergens are captured and processed by antigen-presenting cells (APC) which presents them to T lymphocytes. Some of these allergens have a significant influence on the development of this type of disease and cause most of the symptoms in allergic individuals around the world. They are found in the feces of house dust mites, which have diverse and varied origin in several species, for example the Blomia tropicalis (Bt) mite. In Cartagena (Colombia), this highly prevalent mite has been a central object of study by the Institute of Immunological Research of the University of Cartagena, where several of its allergens have been cloned, sequenced and expressed as recombinant allergens. Moreover, their capacity to bind to IgE and the frequency of this process has been studied. The aim of the present study was to analyze the lymphoproliferative response of peripheral blood mononuclear cells (PBMC) in healthy and allergic individuals to one of the recombinant allergens of B. tropicalis, BtM. This response was studied in PBMC from six patients with allergy to Bt (positive cutaneous test to Bt extract), using a cellular proliferation technique, with incorporation of 3H thymidine at days 3 and 6 days of culture, and at three different concentrations of BtM. Notable among the results was the high proliferation produced by cells from patient JF018 at 3 days of stimulus (41.7 IE), with the lowest concentration of protein (100 microg/mL). Moreover, in all the experiments this concentration was the cause of most of the cell proliferation. In addition, some response to control LAC012 against glutathione-S-transferase (GST) was induced. In conclusion, the results of the present study demonstrate that the recombinant allergen BtM is able to induce a cellular response in the PBMC of patients allergic to Bt. Moreover, it is able to induce a response similar to that produced by natural allergens, because its pattern of response is similar to that shown by cells stimulated with Bt extract. These results also show that a process of anergy can be produced in cells when excess antigen is present. In some individuals (both allergic and nonallergic), GST is able to cause a proliferative response, indicating its sensitizing potential in these individuals.

Respuesta proliferativa de células mononucleares de sangre periférica frente al alergeno recombinante BtM del ácaro del polvo casero Blomia tropicalis / Proliferative response of peripheral blood mononuclear cells to the recombinant allergen BtM of the Blomia tropicalis mite

Las enfermedades alérgicas se desencadenan cuando los individuos que tienen predisposición genética a desarrollar algún tipo de alergia (atópicos), se exponen a alergenos sensibilizantes. Estos alergenos son captados y procesados por las células presentadoras de antígenos (CPA), que de igual forma los presentan a los linfocitos T. Algunos de estos alergenos tienen una mayor incidencia en el desarrollo de este tipo de patologías y son causantes de las mayores molestias en individuos alérgicos alrededor del mundo, son ellos los encontrados en las heces de los ácaros del polvo casero, los cuales tienen un origen diverso y variado en varias especies, como por ejemplo el ácaro Blomia tropicalis. En Cartagena de Indias, este ácaro de alta prevalencia, ha sido objeto central de estudio por el instituto de investigaciones inmunológicas de la Universidad de Cartagena, en donde se han logrado clonar, secuenciar y expresar varios de sus alergenos como proteínas recombinantes, además se les ha estudiado su capacidad y frecuencia de unión a la IgE. El presente estudio se realizó con el objetivo de analizar la respuesta linfoproliferativa de las células mononucleares de sangre periférica (CMSP) de individuos alérgicos y sanos, a uno de los alergenos recombinantes de Blomia tropicalis, el BtM. Dicha respuesta se estudió en CMSP de 6 pacientes alérgicos a Bt (con prueba cutánea positiva al extracto de la misma), utilizando una la técnica de proliferación celular, con incorporación de timidina tritiada, a 3 y 6 días de cultivo y a tres diferentes concentraciones de BtM. De los resultados obtenidos se destaca, la alta proliferación causada por las células del paciente JF018 a los 3 días de estímulo (41,7 IE), con la concentración más baja de proteína (100 g/mL), además, sobresale el hecho que esta concentración fue la causante de la mayor proliferación, de las células, en todos los experimentos. También, se indujo alguna respuesta del control LAC012, contra la glutation-S-transferasa (GST). En conclusión, los resultados del presente estudio demostraron que el alergeno recombinante BtM, es capaz de inducir una respuesta celular en CMSP de pacientes alérgicos a Bt, además, tiene la capacidad de inducir una respuesta similar a la producida por los alergenos naturales, pues su patrón de respuesta se asemeja al mostrado por las células estimuladas con el extracto del ácaro. Además estos resultados muestran, que se puede estar desarrollando un proceso de anergia en las células cuando estas se encuentran en presencia de exceso de antígeno. También es de resaltar que en algunos individuos (tanto alérgicos como sanos), la GST es capaz de causar respuesta proliferativa indicando su potencial poder sensibilizante en estos individuos (AU)

Allergic diseases are triggered when individuals genetically predisposed to developing an allergy (atopy) are exposed to sensitizing allergens. These allergens are captured and processed by antigen-presenting cells (APC) which presents them to T lymphocytes. Some of these allergens have a significant influence on the development of this type of disease and cause most of the symptoms in allergic individuals around the world. They are found in the feces of house dust mites, which have diverse and varied origin in several species, for example the Blomia tropicalis (Bt) mite. In Cartagena (Colombia), this highly prevalent mite has been a central object of study by the Institute of Immunological Research of the University of Cartagena, where several of its allergens have been cloned, sequenced and expressed as recombinant allergens. Moreover, their capacity to bind to IgE and the frequency of this process has been studied. The aim of the present study was to analyze the lymphoproliferative response of peripheral blood mononuclear cells (PBMC) in healthy and allergic individuals to one of the recombinant allergens of B. tropicalis, BtM. This response was studied in PBMC from six patients with allergy to Bt (positive cutaneous test to Bt extract), using a cellular proliferation technique, with incorporation of 3H timidine at days 3 and 6 days of culture, and at three different concentrations of BtM. Notable among the results was the high proliferation produced by cells from patient JF018 at 3 days of stimulus (41.7 IE), with the lowest concentration of protein (100μg/mL). Moreover, in all the experiments this concentration was the cause of most of the cell proliferation. In addition, some response to control LAC012 against glutathione-S-transferase (GST) was induced. In conclusion, the results of the present study demonstrate that the recombinant allergen BtM is able to induce a cellular response in the PBMC of patients allergic to Bt. Moreover, it is able to induce a response similar to that produced by natural allergens, because its pattern of response is similar to that shown by cells stimulated with Bt extract. These results also show that a process of anergy can be produced in cells when excess antigen is present. In some individuals (both allergic and nonallergic), GST is able to cause a proliferative response, indicating its sensitizing potential in these individuals (AU)

[Gout and kidney during XVII and XIX centuries]. / Gotta e rene tra XVII e XIX secolo.

The authors briefly describe the history of gout, mainly focusing their attention on the renal involvement. They report some works and theories on gout of great ancient physicians, such as Paracelsus, Sydenham, Boerhaave, Van Swieten and Morgagni.

[Arterial hypertension and oxidative stress induced by cyclosporin. Effect of carvedilol]. / Ipertensione arteriosa e stress ossidativo indotti dalla ciclosporina. Effetto del carvedilolo.

Cyclosporin-induced hypertension and endothelial dysfunction have been attributed to the effects of cyclosporin on factors controlling vasomotor tone. Endothelial nitric oxide (NO) regulates basal vasodilation, and an NO-mediated protective mechanism from cyclosporin-induced vasoconstriction has been proposed. In transplanted patients with cyclosporin-induced hypertension, we have recently demonstrated upregulation of the NO system and superoxide and free radical overproduction, which, by increasing NO metabolism, could induce hypertension, vascular remodeling and chronic rejection. In the present work, we have evaluated endothelial constitutive NO synthase (ecNOS), transforming growth factor beta and heme oxygenase-1 (protective against oxidative stress), mRNA production and plasma NO metabolites, peroxynitrite and antioxidant power in 15 kidney transplanted patients before and after 4 months of treatment with carvedilol alpha 1-beta-blocker and potent antioxidant. Our aim was to study the efficacy of the reduction of oxidative stress on complications such as endothelial dysfunction and fibrogenesis. Monocyte ecNOS and plasma NO metabolites remained higher versus those of control subjects and were unchanged by carvedilol, while antioxidant power and heme oxygenase-1 mRNA production increased. Peroxynitrite, as well as transforming growth factor beta mRNA, were reduced by carvedilol. It also normalized blood pressure. In conclusion, carvedilol reduces oxidative stress and normalizes blood pressure; ecNOS remains upregulated while mRNA for transforming growth factor beta, a key fibrogenic cytokine, is reduced by carvedilol, which seems to preserve protective mechanisms such as NO and heme oxygenase-1 against long-term complications of oxidative stress, e.g., endothelial dysfunction, fibrogenesis and chronic rejection.

Alendronate prevents further bone loss in renal transplant recipients.

The aim of this study was to investigate the effects of alendronate, calcitriol, and calcium in bone loss after kidney transplantation. We enrolled 40 patients (27 men and 13 women, aged 44.2 +/- 11.6 years) who had received renal allograft at least 6 months before (time since transplant, 61.2 +/- 44.6 months). At baseline, parathyroid hormone (PTH) was elevated in 53% of the patients and the Z scores for bone alkaline phosphatase (b-ALP) and urinary type I collagen cross-linked N-telopeptide (u-NTX) were higher than expected (p < 0.001). T scores for the lumbar spine (-2.4 +/- 1.0), total femur (-2.0 +/- 0.7), and femoral neck (-2.2 +/- 0.6) were reduced (p < 0.001). After the first observation, patients were advised to adhere to a diet containing 980 mg of calcium daily and their clinical, biochemical, and densitometric parameters were reassessed 1 year later. During this period, bone density decreased at the spine (-2.6 +/- 5.7%;p < 0.01), total femur (-1.4 +/- 4.2%; p < 0.05), and femoral neck (-2.0 +/- 3.0%; p < 0.001). Then, the patients were randomized into two groups: (1) group A-10 mg/day of alendronate, 0.50 microg/day of calcitriol, and 500 mg/day of calcium carbonate; and (2) group B-0.50 microg/day of calcitriol and 500 mg/day of calcium carbonate. A further metabolic and densitometric reevaluation was performed after the 12-month treatment period. At the randomization time, group A and group B patients did not differ as to the main demographic and clinical variables. After treatment, bone turnover markers showed a nonsignificant fall in group B patients, while both b-ALP and u-NTX decreased significantly in alendronate-treated patients. Bone density of the spine (+5.0 +/- 4.4%), femoral neck (+4.5 +/- 4.9%), and total femur (+3.9 +/- 2.8%) increased significantly only in the alendronate-treated patients. However, no trend toward further bone loss was noticed in calcitriol and calcium only treated subjects. No drug-related major adverse effect was recorded in the two groups. We conclude that renal transplanted patients continue to loose bone even in the long-term after the graft. Alendronate normalizes bone turnover and increases bone density. The association of calcitriol to this therapy seems to be advantageous for better controlling the complex abnormalities of skeletal metabolism encountered in these subjects.

Chronic renal failure, end-stage renal disease, and peritoneal dialysis in Gitelman's syndrome.

The chronic state of hypovolemia, hypotension, and hypokalemia found in Bartter's syndrome has been shown to lead to a chronic nephropathy, which then can progress toward end-stage renal disease and dialysis. This progression, however, has never been reported for Gitelman's syndrome, a variant of Bartter's syndrome that shows a milder clinical picture. This report is the first to document this progression (ie, the development of end-stage renal disease in Gitelman's syndrome) as well as the first report of the use of peritoneal dialysis in either Bartter's syndrome or Gitelman's syndrome. The clinical course highlights the importance of and the need for careful control of hemodynamic status in these patients to slow the progression of renal injury. The hemodynamic alterations that characterize Bartter's syndrome and Gitelman's syndrome patients suggest that for patients requiring renal replacement therapy, peritoneal dialysis is a more appropriate treatment because of its less severe impact on these parameters.

Urinary excretion of vasoactive substances in chronic renal failure.

To investigate the pathophysiological role of vasoactive substances in the progression of chronic renal disease, we measured the 24-hour urinary excretion of prostaglandin 6-keto F1alpha, thromboxane B2, NOx, cGMP and ET-1 in 26 patients with chronic renal failure under conservative treatment and in 40 control subjects. Urinary 6-keto PgF1alpha, TxB2 and cyclic GMP were evaluated by RIA, and ET-1 was assayed by EIA. NOx were evaluated using a colorimetric assay as nitrate/nitrite. Urinary excretion of prostaglandin 6-keto F1alpha averaged 18.1 +/- 20.9 ng/g Ucreat in patients vs. 240.9 +/- 257.3 in controls (p < 0.0001), thromboxane B2 422 +/- 374 ng/g Ucreat in patients vs. 967 +/- 589 in controls (p < 2x 10(-5)), NOx 7.07 +/- 5.54 mg/g Ucreat in patients vs. 9.79 +/- 3.77 in controls (p < 0.01), cGMP 310 +/- 200 pg/g Ucreat in patients vs. 488 +/- 241 in controls (p < 0.001). In contrast, ET-1 urinary excretion was almost doubled in patients (13.45 +/- 5.84 ng/g of Ucreat) in comparison with controls (6.84 +/- 2.81 p < 1x10(-5)). While in control subjects significant correlations between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.69, p < 0.001) or NOx and ET-1 (r = 0.54, p < 0.001) were present, in patients only the relationship between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.53, p < 0.01) was retained. Our data suggest that in the normal kidney a balance between prostaglandin I2 and thromboxane A2, or nitric oxide and endothelin-1 is present, which contributes to hemodynamic regulation and protects this organ from ischemic damage. This balance is abolished in CRF, where a large increment of vasopressor agent endothelin is present, which, joined to a prevalent decrease of prostaglandin I2 synthesis, could contribute to the ischemic and fibrogenetic damage of the kidney, leading to progression of renal disease.

Oxidative stress and nitric oxide system in post-transplant hypertension.

BACKGROUND: CsA-induced endothelial dysfunction and CsA-induced hypertension have been attributed to CsA effects on the endothelial-derived factors controlling vasomotor tone, but the mechanisms responsible are unclear. Endothelial nitric oxide (NO) is known to maintain a state of basal vasodilation and recently a NO mediated counterregulatory mechanism protective from CsA-induced vasoconstriction has been suggested. PATIENTS AND METHODS: Our study evaluates ecNOS gene status and NO metabolites in kidney transplanted patients under chronic CsA treatment with CsA-induced hypertension. Since CsA increases superoxide production, which metabolizes NO, plasma hydroperoxides and peroxynitrite were also evaluated as index of the presence of "oxidative stress". RESULTS: Quantification of monocyte ecNOS mRNA and NO metabolites plasma level from patients and control subjects (C) demonstrated NO system up regulation in patients notwithstanding hypertension. The mean ecNOS to beta-actin ratio was 2.00 +/- 0.87 vs 0.29 +/- 0.08 in C, p < 0.04. NO metabolite plasma level was 30.03 +/- 9.62 mM vs 9.37 +/- 3.86, p < 0.001. Hydroperoxides were also increased in patients: 3.6 +/- 1.6 i.a.u. vs 1.4 +/- 0.8, p < 0.007 (from cholesterol esters) and 10.8 +/- 6.6 vs 1.5 +/- 0.9, p < 0.008 (from triglycerides) as well as peroxynitrite plasma level: 0.36+/- 0.14 mM/L vs undetectable in C. CONCLUSIONS: This study confirms a NO system up-regulation in transplanted patients. However, the counterregolatory system to CsA-induced vasoconstriction, could be cancelled by CsA induced superoxide and free radicals production which, increasing NO metabolism could contribute to CsA induced vasoconstriction and hypertension.

Parathyroid hormone and bone metabolism in kidney-transplanted patients.

BACKGROUND: Decreases in bone mass and increased susceptibility to fractures are well-recognized complications in organ transplants. SUBJECTS AND METHODS: We performed a cross-sectional study on 60 patients (40 males, 20 females, mean age 43.2 +/- 1.06, SE range 22 - 70) who underwent kidney transplantation (KTX) 55.6 +/- 4.5 months before. Blood and 24-hour urine samples were analyzed for the main parameters of mineral metabolism, and also for osteocalcin (BGP), bone alkaline phosphatase (b-ALP, urine N-telopeptid (u-NTx) and urine galactosyl-hydroxylysine (u-Ghyl). DEXA scan of the lumbar spine (LS) and proximal femur (PF) and ultrasound determination of the heel (stiffness) was also performed. RESULTS: T-score values for bone density (BD) were 2.14 +/- 0.11 SD's for LS, -2.56 +/- 0.09 for PF and 2.49 +/- 0.15 for stiffness. There were 29 peripheral fractures in 16 patients. The rate of fractures before KTX were 0.0011 per patient/year and 0.0005 after transplantation (p < 0.02). When expressed as number of SD's with respect to normal controls, BGP (1.48 +/- 0.23), b-ALP (0.95 +/- 0.19), u-NTx excretion correlated negatively with BD at the femoral neck (p < 0.02) and trochanter (p < 0.03). Cumulative steroids intake were negatively correlated with b-ALP positively (p < 0.05). Current CsA was positively correlated with b-ALP (p < 0.001). Both cumulative steroid (p < 0.02) and CSA (p < 0.01) intakes were negatively correlated with BD at Wards triangle. CONCLUSIONS: Our data demonstrate an important bone depletion at each stage KTX. PTH plays a major role in the observed increase in bone turnover, exacerbating the negative effects on the bone on immunosuppressive treatment. Glucocorticosteroid therapy is an important risk factor for osteoporosis in this setting also.