Immunotolerance in liver transplantation: a primer for the clinician.

The use of immunosuppressive medications for solid organ transplantation is associated with cardiovascular, metabolic, and oncologic complications. On the other hand, the development of graft rejection is associated with increased mortality and graft dysfunction. Liver transplant recipients can withdraw from immunosuppression without developing graft injury while preserving an adequate antimicrobial response - a characteristic known as immunotolerance. Immunotolerance can be spontaneously or pharmacologically achieved. Contrary to the classic dogma, clinical studies have elucidated low rates of true spontaneous immunotolerance (no serologic or histological markers of immune injury) among liver transplant recipients. However, clinical, serologic, and tissue biomarkers can aid in selecting patients in whom immunosuppression can be safely withdrawn. For those who failed an immunosuppression withdrawal trial or are at high risk of rejection, pharmacological interventions for immunotolerance induction are under development. In this review, we provide an overview of the mechanisms of immunotolerance, the clinical studies investigating predictors and biomarkers of spontaneous immunotolerance, as well as the potential pharmacological interventions for inducing it.

Calculated Versus Measured Urine Osmolarity: Accuracy of Estimated Urine Density.

BACKGROUND: Urine osmolarity (OsmU) is the gold standard for the evaluation of the kidney's urine concentration capacity; nevertheless, urinary density (UD) is often used as a surrogate for its estimation. OBJECTIVE: The objective of this study was to analyze the accuracy of UD in estimating OsmU. MATERIALS AND METHODS: A transversal study including patients with simultaneous determination of UD measured with refractometry and OsmU measured by osmometer (OsmUm). We multiplied the last two digits of the UD by 35, 30, 32, 33.5, and 40 to estimate OsmU; the estimates were considered precise if the value was ± 30 mOsm/kg from the OsmUm. A Bland-Altman analysis was conducted. RESULTS: Among 205 patients, there was no difference between OsmUm and the estimated form when using a factor of 33.5 (p = 0.578). When analyzing by the absence or presence of proteinuria and/or glycosuria, there were no differences when using the factors 35 (p = 0.844) and 32 with adjusted UD (p = 0.898). In the linear correlation analysis, values for Pearson's r = 0.788 and r2 = 0.621 were obtained (p < 0.001). The areas under the curve obtained by the receiver operating characteristics curves to estimate urine osmolarity values < 100 and > 600 mOsm/kg were > 0.90. CONCLUSION: The estimation of the OsmU from UD showed adequate performance. If an osmometer is unavailable, we recommend using the factor 35 for clean samples and 32 with adjusted UD for samples with proteinuria and/or glycosuria.

C-reactive protein (CRP) polymorphisms and haplotypes are associated with SLE susceptibility and activity but not with serum CRP levels in Mexican population.

To evaluate the association of C-reactive protein (CRP) polymorphisms with risk of development SLE in a group of Mexican individuals. Five CRP polymorphisms (rs3093059, rs3093062, rs1800947, rs1130864, and rs1205) were determined by PCR-restriction fragment length polymorphism and SNP rs3093061 by refractory mutation system PCR assay in 126 SLE patients and 131 controls. Four of the polymorphisms showed differences between patients and controls. rs3093061 polymorphism was associated with a lower risk of developing lupus principally in the codominant 2 (OR = 0.219, 95% CI 0.108-0.785, P = 0.015) model. rs1130864 was associated with decreased risk mainly under codominant 1 (OR = 0.288, 95% CI 0.143-0.581, P = 0.001) model. rs1205 was associated under the over-dominant model (OR = 0.504, 95% CI 0.270-0.942, P = 0.032). The rs3091244 polymorphism was associated with decreased risk of SLE mostly under additive (OR = 0.605, 95% CI 0.393-0.931. P = 0.022) model. Our study establishes that rs3093061, rs1130864, rs1205, and rs3091244 polymorphisms are associated with decreased risk of developing SLE.

Vß T cell receptor (TCR) genes in circulating cells of patients with systemic lupus erythematosus and their healthy relatives / Genes del receptor variable beta de células T en células circulantes de pacientes con lupus eritematoso generalizado y sus familiares sanos.

Objective: We investigated the proportion of Vß T cell receptor (TCR) gene expression in peripheral CD3+ lymphocytes in familial and non-familial systemic lupus erythematosus (SLE) patients. Method: The Vß TCR repertoire was studied in 14 families in which several members had SLE. The Vß TCR usage in SLE patients (n = 27) was compared with that in healthy members of these multiplex families (n = 47), in 37 sporadic SLE patients who had no relatives with SLE, and in 15 healthy unrelated controls. Vß TCR repertoire expression was studied by multiparameter flow cytometry with the use of an array of 24 different Vß TCR gene family-specific monoclonal antibodies. Results: We found the same Vß TCR expression profile in the comparisons between sporadic SLE and familial SLE cases and healthy relatives, which included increased expression of Vß 5.2, Vß 11 and Vß 16, and lower expression of Vß 3, Vß 4, Vß 7.1 and Vß 17. Interestingly, solely Vß 17 was differentially expressed among sporadic and familial SLE. Also, increased expression of Vß 9 was the hallmark among familial SLE (casesand h ealthy relatives) in comparison to controls. Conclusion: These results highlight the notion that the final profile of the Vß TCR repertoire seen in familial and non-familial SLE seems to arise from the interaction of genetic, environmental, and immunoregulatory factors. Furthermore, it may contribute to the immunologic abnormalities affecting relatives of SLE patients.

Objetivo: Se investigó la proporción de la expresión génica del receptor variable beta de células T (Vß TCR) en linfocitos periféricos CD3+ en pacientes con lupus eritematoso generalizado (LEG) familiar y no familiar. Método: El repertorio de Vß TCR se estudió en 14 familias que presentaban más de un miembro con LEG. El uso de Vß TCR en pacientes con LEG (n = 27) se comparó con el de los miembros sanos de estas familias (n = 47), con 37 pacientes con LEG esporádico y con 15 controles sanos. La expresión del repertorio de Vß TCR se estudió por citometría de flujo multiparamétrica utilizando un arreglo de 24 diferentes anticuerpos monoclonales específicos de genes familiares para Vß TCR. Resultados: Se encontró el mismo perfil de expresión en las comparaciones entre los casos de LEG esporádico y familiar, así como en los consanguíneos sanos de las familias multicasos, que incluía una expresión incrementada de Vß 5.2, Vß 11 y Vß 16, y una menor expresión de Vß 3, Vß4, Vß 7.1 y Vß 7. De manera interesante, solo Vß 17 se expresó de modo diferente entre casos familiares y esporádicos de LEG. Igualmente, la expresión incrementada de Vß 9 fue el distintivo entre los casos de LEG familiar (casos y consanguíneos sanos) y los controles sanos. Conclusiones: Estos resultados refuerzan la noción de que el perfil final del repertorio Vß TCR observado en LEG familiar y no familiar parece surgir de la interacción de factores genéticos, ambientales e inmunorreguladores, además de que pueden explicar las alteraciones inmunitarias que se observan en los consanguíneos sanos de pacientes con LEG.

Electrolyte and Acid-Base Disturbances in End-Stage Liver Disease: A Physiopathological Approach.

Electrolyte and acid-base disturbances are frequent in patients with end-stage liver disease; the underlying physiopathological mechanisms are often complex and represent a diagnostic and therapeutic challenge to the physician. Usually, these disorders do not develop in compensated cirrhotic patients, but with the onset of the classic complications of cirrhosis such as ascites, renal failure, spontaneous bacterial peritonitis and variceal bleeding, multiple electrolyte, and acid-base disturbances emerge. Hyponatremia parallels ascites formation and is a well-known trigger of hepatic encephalopathy; its management in this particular population poses a risky challenge due to the high susceptibility of cirrhotic patients to osmotic demyelination. Hypokalemia is common in the setting of cirrhosis: multiple potassium wasting mechanisms both inherent to the disease and resulting from its management make these patients particularly susceptible to potassium depletion even in the setting of normokalemia. Acid-base disturbances range from classical respiratory alkalosis to high anion gap metabolic acidosis, almost comprising the full acid-base spectrum. Because most electrolyte and acid-base disturbances are managed in terms of their underlying trigger factors, a systematic physiopathological approach to their diagnosis and treatment is required.

Perioperative management of patients with antiphospholipid syndrome: a single-center experience.

The objective was to describe the management and risk factors for complications of antiphospholipid syndrome (APS) patients who underwent a surgical procedure in a single center. We reviewed medical records of all patients with primary or secondary APS who underwent an elective surgery during a 6-year period. Demographical data, management of anticoagulation and complications were recorded. We identified 43 patients, mean age 37.9 ± 8.9 years, who underwent a total of 48 elective surgeries. All patients had history of at least one thrombotic event and were under vitamin K antagonists. Before surgery, all patients received bridging therapy with intravenous infusion of heparin or low molecular weight heparin (LMWH). Among the LMWH group, 36 had a full anticoagulation regimen and nine prophylactic doses. In 62% of the surgeries, we identified an optimal management of periprocedural anticoagulation according to guidelines. Overall six patients had severe bleeding and three thrombotic complications (full anticoagulation regimen n = 2 and prophylactic dose group n = 1). Patients with optimal management of anticoagulation experienced less thrombotic and hemorrhagic complications (7 vs. 33%; OR 0.14, 95% CI 0.02-0.81; p = 0.040) and patients with INR ≤1.5 at surgery had fewer episodes of major bleeding (6 vs. 29%; OR 0.19, 95% CI 0.02-0.98; p = 0.050). All three thrombotic events occurred in patients with INR ≤1.5. Proper management of anticoagulation based on guidelines is associated with less complications in patients with APS. Notwithstanding the proper use of bridging therapy, some patients may develop thrombotic complications.

Sarcoidosis: a single hospital-based study in a 24-year period.

BACKGROUND: Clinical presentation of sarcoidosis varies according to race and geographical area. We describe the clinical spectrum and outcome of sarcoidosis in Mexican patients compared with other populations. METHODS: We reviewed the medical charts of 21 patients with sarcoidosis seen at a referral hospital in 1989-2012; organ involvement was assessed using the ACCESS instrument. We compared our results with the ACCESS and Latin American studies. We used descriptive statistics and reported odd ratios with 95% CI. RESULTS AND CONCLUSION: Fifty-two percent were women; median age was 31 years; median time to diagnosis, 5.5 months. Frequency of organ involvement was: constitutional symptoms 62%, lungs 66.6%, skin 42.8%, bone marrow 23.4%, lymph node 19%, liver 19%, and eye 19%. After one year of follow-up, 47.5% of patients were asymptomatic without treatment, 38% asymptomatic on treatment, and 14.2% symptomatic on treatment. In our patients, pulmonary involvement was lower (66.6 vs. 94.9%; p = 0.001) and cutaneous (42.8 vs. 15.8%; p = 0.003) and bone marrow (23.4 vs. 4.7%; p = 0.001) were higher than in the ACCESS cohort. Data regarding Latin American populations was scarce. The clinical spectrum of sarcoidosis in our population differed from other studies, with a higher frequency of cutaneous sarcoidosis and less pulmonary involvement.

Persistent hepatic encephalopathy secondary to portosystemic shunt occluded with Amplatzer device.

Hepatic encephalopathy is a frequent complication of cirrhosis, when this event becomes persistent, treatment compliance should be verified and any precipitating factor need to be identified. Also the presence of portosystemic shunts, which are a rare cause of decompensation or persistence hepatic encephalopathy need to be ruled out. In this paper we report the case of a 57 year old man with persistent hepatic encephalopathy secondary to the presence of a porto-onfalo-femoral shunt successfully closed with the placement of an Amplatzer device.

Clinical and Immunopathologic Profile of Mexican Patients with IgG4 Autoimmune Pancreatitis.

Autoimmune pancreatitis is part of the spectrum of IgG4-associated diseases. Its diagnostic criteria and histological subtypes have been formally proposed recently and although based on current data it has been suggested that there are differences in clinical presentation among populations, more research is needed to properly establish if this heterogeneity exists. In this paper, we describe 15 cases of autoimmune pancreatitis diagnosed at a Mexican centre of reference, all of them associated to the lymphoplasmocytic sclerosing pancreatitis variant. The mean age at the onset of symptoms was 47.5 ± 14.4 years, and 53% of patients were male. The main manifestations were weight loss (87%), obstructive jaundice (53%), and acute (27%) and chronic (27%) pancreatitis. Only 20% of patients had high IgG4 serum levels at the time of diagnosis. All patients receiving prednisone responded favourably, both in their pancreatic and extrapancreatic manifestations. Clinical manifestations of Mexican patients showed certain differences with respect to those usually reported.

An unusual multiplex systemic lupus erythematosus family with high prevalence of nephropathy, late-onset disease, and one member with disease-onset post-HIV therapy.

In the present study, we report the clinical characteristics of a unique systemic lupus erythematosus (SLE) multiplex family with 6 of its members affected by the disease, 1 of them being male. Four patients showed nephropathy, 2 of them with late-onset SLE (52 and 55-year-old), one with cutaneous and articular involvement, and another one developing lupus after 5 years undergoing highly active antiretroviral therapy (HAART) due to acquired immunodeficiency syndrome. Notwithstanding the genetic load, the fact that 2 patients showed late-onset disease, and the extreme delay of the appearance of SLE after HAART in the proband suggest that not only genetic, but other--mainly environmental--factors are necessarily required for the development of SLE.

Deficiency of red cell bound CD55 and CD59 in patients with systemic lupus erythematosus.

CD55 and CD59 are glycosylphosphatidylinositol-anchored proteins with complement inhibitory properties. Autoimmune hemolytic anemia (AIHA) has been associated with antiphospholipid antibodies (APLA). The aim of this study was to evaluate the presence of APLA and its possible correlation with diminished CD55 and CD59 in red blood cells from patients with primary AIHA or secondary to systemic lupus erythematosus (SLE). Flow cytometric analyses were performed on CD55 and CD59 stained erythrocytes from 24 patients (primary AIHA, n=8; AIHA plus SLE, n=11; and SLE without AIHA, n=5) and 20 healthy controls. Antibodies to several phospholipids were detected in the sera by ELISA. Most patients with AIHA plus SLE and few with primary AIHA showed deficiency of either or both CD55 and CD59 expression and was not associated to the presence of APLA, while SLE patients exhibited a normal expression of these molecules. Although our findings showed CD55 and CD59 deficiency in primary or secondary AIHA, it appears that this defect plays a facilitator rather than a triggering role for the hemolytic process. Additionally, a role of anti-phospholipid antibodies as causative of this acquired defect is questionable.

Tratamiento del síndrome de sjögren primario con ciclosporina-A: efectos clínicos y biológicos / Treatment of primary sjogren syndrome with ciclosporine-A: clinical an biological effects

Objetivo: Evaluar el efecto de la ciclosporina A (CsA) en el tratamiento del síndrome de Sjögren primario (SSP). Métodos: Se incluyeron nueve pacientes con SSP. Se les suministró CsA (2 mg/kg de peso) durante seis meses. Todos los pacientes fueron evaluados clínicamente cada mes. Se realizó la prueba de Schirmer y la respuesta a CsA se registró por medio de la escala visual análoga durante y después del tratamiento. En suero se determinó el factor reumatoide y los niveles de inmunoglobulinas por nefelometría y los anticuerpos anti-Ro y anti-La por análisis inmunoenzimático. En sobrenadantes de células mononucleares cultivadas por 24 y/o 48 horas. Se cuantificó la producción espontánea de IL-10 e inmunoglobulinas. La IL-10 intracelular en las subpoblaciones CD4+, CD8+, CD19+ y CD14+ fue detectada mediante citometría de flujo. Resultados: El tratamiento fue bien tolerado y sin efectos colaterales. Las manifestaciones oculares mejoraron notablemente en cinco pacientes, en forma moderada en dos, en una no hubo respuesta y en otra no fue evaluable. Las manifestaciones orales mejoraron notablemente en tres pacientes, moderadamente en cinco y en otra no hubo respuesta. Los niveles de inmunoglobulinas tanto en suero como en sobrenadante, se normalizaron en los cinco pacientes que presentaron hipergamaglobulinemia al inicio del estudio. Los niveles de IL-10 disminuyeron en siete pacientes a expensas de las células CD19+. Conclusiones: El tratamiento del SSP con CsA mostró efectos benéficos en la xerostomía y xeroftalmia, aunado a la corrección de los parámetros biológicos estudiados. Por ello la CsA podría ser una alternativa terapéutica promisoria para pacientes con SSP.