Analysis on clinicopathology and prognosis of primary IgA nephropathy in children with massive proteinuria / 中华肾脏病杂志

Objective:To investigate the clinicopathological features and the prognosis of IgA nephropathy (IgAN) in children with massive proteinuria.Methods:It was a retrospective cohort study. Clinical data of IgAN children with massive proteinuria admitted to the Department of Nephrology, Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2008 to December 2021 were retrospectively analyzed. Patients were divided into effective group and ineffective group according to whether urine protein turned negative after 6 months of initial treatment. The follow-up endpoint event was defined as a reduction in proteinuria of less than 50% or end-stage renal disease (ESRD) achievement. MedCalc software was used to perform Kaplan-Meier survival analysis, and Log-rank test was used to compare the difference of renal survival between the two groups.Results:A total of 127 patients were diagnosed as primary IgAN by renal biopsy, of whom 57 patients with IgAN showed massive proteinuria. These 57 IgAN patients with macroproteinuria accounted for 44.9% of the total IgAN patients and were enrolled in the study. Among the 57 cases, 33 cases (57.9%) were Lee's grade Ⅲ, 11 cases (19.3%) were below Lee's grade Ⅲ, and 13 cases (22.8%) were above Lee's grade Ⅲ. The follow-up time was 4.0 (3.0,5.8) years. In the initial treatment, among 57 patients, 46 (80.7%) were effective (effective group) and 11 (19.3%) were ineffective (ineffective group). Compared with the effective group, the ineffective group had a higher proportion of concurrent AKI at the onset of disease and longer recovery time of renal function, with significant difference (7/11 vs. 13/46, χ2=4.878, P=0.027). Compared with the effective group, the proportion of Lee grade Ⅲ or above was higher in the ineffective group, and the difference was statistically significant (5/11 vs. 8/46, χ2=3.971, P=0.046). There were significant differences in endocapillary hypercellularity (E1), segmental glomerulosclerosis or adhesion (S1) and cellular/fibrocellular crescents (C2) of Oxford classification between IgAN children with Lee grade Ⅲ or below and those over Lee grade Ⅲ (11/13 vs. 20/44, χ2=6.204, P=0.013; 12/13 vs. 17/44, χ2=11.566, P=0.001; 9/13 vs. 7/44, χ2=14.131, P=0.001). Among 57 patients, endpoint events occurred in 2 patients who both were urinary protein unmitigated, and none of the children progressed to ESRD. There was no significant difference in cumulative renal survival between the two groups by Kaplan-Meier survival analysis and Log-rank test ( χ2=0.537, P=0.460) after addition of calcineurin inhibitors (CNIs) to the initial treatment ineffective group. Conclusions:Macroproteinuria is the prominent manifestation of IgAN in children. The pathological type is mainly Lee grade Ⅲ. Children with macroproteinuria have a good prognosis in the short and medium term after active treatment. For IgAN with macroproteinuria that does not respond well to initial treatment, AKI is more common at onset, and renal function recovery time is longer. The application of CNIs may have a certain effect on improving the renal outcome of IgAN with massive proteinuria.

Optimization of immunosuppressive regimen for kidney transplant recipients / 器官移植

With the maturity and development of surgical techniques, as well as the improvement of perioperative management level, the success rate of kidney transplantation has been significantly improved. However, due to evident differences in heredity and antigenicity between donors and recipients, rejection will occur after kidney transplantation, which will affect the survival of renal grafts. Immunosuppression is an important treatment for rejection, which is of significance to reduce the risk of rejection and enhance graft survival rate. Nevertheless, immunosuppressants may cause multiple complications while lowering the incidence of rejection, such as infection, cardiovascular diseases and tumors, etc., which seriously affect the quality of life of patients and may even lead to their death. Reasonable selection of immunosuppressants and continuous optimization of immunosuppressive regimen for recipients play a critical role in improving the survival of recipients and renal grafts. In this article, the development history of organ transplantation, immune induction therapy and immune maintenance therapy was reviewed, and the progress in the optimization of immunosuppressive regimens for kidney transplant recipients was discussed, aiming to provide reference for improving clinical prognosis of kidney transplant recipients.

Management of immunosuppressive drugs in HIV-positive solid organ transplant recipients / 器官移植

The application of combination antiretroviral therapy (cART) has significantly prolonged the life expectancy of patients infected with human immunodeficiency virus (HIV). However, viral infection and adverse reactions of cART drugs make patients more prone to organ failure. Solid organ transplantation has become a standard treatment for HIV-infected patients with end-stage organ failure. Nevertheless, among HIV-positive soild organ transplant recipients, multiple problems remain to be resolved, such as increased incidence of graft rejection, increased infection risk, drug toxicity and drug interaction between cART therapy and immunosuppressive drugs, etc. It is extremely challenging to deliver appropriate management for HIV-positive soild organ transplant recipients. Therefore, the application of immune induction therapy, calcineurin inhibitors, mammalian target of rapamycin (mTOR) inhibitors and other immunosuppressive drugs in HIV-positive soild organ transplant recipients was reviewed, aiming to provide reference for subsequent management of immunosuppression in HIV-positive soild organ transplant recipients.

Hypomagnesemia and kidney transplantation: research progress in immune effect and infection risk / 器官移植

As a cation with abundant intracellular contents and extensive functions, magnesium plays an active role in immune function and captivates widespread attention. Under the influence of multiple factors, such as use of calcineurin inhibitors, hypomagnesemia post-kidney transplantation is not uncommon. Infection is a common complication post-kidney transplantation and one of the main causes of death of kidney transplant recipients. Recent clinical studies have shown that hypomagnesemia post-kidney transplantation is closely associated with the risk of infection post-transplantation. Emphasizing and monitoring magnesium concentration in kidney transplant recipients may help prevent infection and improve clinical prognosis of both recipients and grafts. Therefore, research progress in magnesium and immune response, the causes of hypomagnesemia post-kidney transplantation and hypomagnesemia and infection post-kidney transplantation was reviewed, aiming to provide reference for the prevention and treatment of infection post-kidney transplantation.

Research progress in risk factors of post-transplantation diabetes mellitus / 器官移植

Solid organ transplantation has significantly prolonged the survival of patients with end-stage diseases. However, long-term use of immunosuppressants will increase the risk of post-transplantation diabetes mellitus (PTDM) in the recipients, thereby elevating the risk of infection, cardiovascular disease and death. In recent years, with persistent improvement of diagnostic criteria of PTDM, clinicians have deepened the understanding of this disease. Compared with type 2 diabetes mellitus, PTDM significantly differs in pathophysiological characteristics and clinical progression. Hence, different treatment strategies should be adopted. Early identification of risk factors of organ transplant recipients, early diagnosis and intervention are of significance for improving the quality of life of recipients, prolonging the survival of grafts and reducing the fatality of recipients. Therefore, the diagnosis, incidence and risk factors of PTDM were reviewed in this article, aiming to provide reference for clinicians to deliver prompt diagnosis and intervention for PTDM.

Audiological follow-up in transplant patients treated with calcineurin immunosuppressants "Calcineurin inhibitors and Ototoxicity" / Seguimiento audiológico en pacientes trasplantados en tratamiento con inmunosupresores inhibidores de calcineurina

BACKGROUND: Ototoxicity is a side effect of drugs and medications that usually leads to bilateral and symmetric sensorineural hearing loss that commonly affects the high-frequency range initially, with or preceded by tinnitus. Possible ototoxic side effects of calcineurin inhibitor immunosuppressants have been suggested, but this remains unclear. Therefore, this study aims to evaluate audiological changes in patients undergoing transplantation receiving immunosuppressive treatment with calcineurin inhibitors. METHODS: Prospective cohort study. Adult patients undergoing liver or kidney transplantation treated with calcineurin inhibitors were included. Pure-tone audiometry, distortion product otoacoustic emissions, and the Tinnitus Handicap Inventory questionnaire were completed at baseline, one, three, and six months after transplantation. Hearing thresholds were compared and correlated with plasma concentrations of calcineurin inhibitors. RESULTS: Seventeen patients were included, 59% males, with a median age of 54.7 years (29-68 years). Twelve patients underwent liver transplantation, four underwent kidney transplantation, and one patient underwent both. The medianfollow-up was 5.8 months (4-8 months). Significant pure-tone average shifts were observed in two patients. Both cases presented fluctuations in their hearing levels, which were not bilateral or symmetrical and affected the higher frequencies. All patients received tacrolimus within the therapeutic range during the follow-up period. Three different patients exceeded the expected range once; however, they were rapidly corrected and did not correlate with any changes in hearing. CONCLUSIONS: It appears that tacrolimus does not cause hearing loss when levels are within the therapeutic range for a follow-up period of six months post-transplantation.

INTRODUCCIÓN: La ototoxicidad corresponde a un efecto secundario a agentes terapéuticos que se manifiesta como hipoacusia sensorioneural bilateral simétrica de frecuencias agudas. Se postulan posibles efectos ototóxicos de los inmunosupresores inhibidores de la calcineurina, pero hasta la fecha es aún incierto. El objetivo de este estudio fue evaluar los cambios audiológicos en pacientes trasplantados en tratamiento inmunosupresor con inhibidores de calcineurina. MATERIAL Y MÉTODO: Cohorte prospectiva. Se incluyeron pacientes adultos sometidos a trasplante hepático o renal tratados con inhibidores de calcineurina. Se realizó una evaluación otorrinolaringo-lógica pre-trasplante con audiometría tonal, emisiones otoacústicas por producto de distorsión y cuestionario Tinnitus Handicap Inventory. Se realizó una evaluación audiológica de seguimiento uno, tres y seis meses después del trasplante. Se compararon los umbrales auditivos antes y después del inicio del tratamiento inmunosupresor y se correlacionaron con las concentraciones plasmáticas de IC. RESULTADOS: Se incluyeron 17 pacientes, 59% hombres, con una mediana de edad de 54,7 años. La mediana de seguimiento fue 5,8 meses. Se observaron cambios en el promedio tonal puro en dos pacientes, los cuales no seguían un patrón audiométrico sugerente de ototoxicidad. Todos los pacientes recibieron Tacrolimus dentro del rango terapéutico durante el seguimiento. Tres pacientes diferentes excedieron el rango esperado una vez sin embargo, se corrigieron rápidamente y no se correlacionaron con cambios auditivos, puntaje de tinnitus o emisiones otoacústicas. DISCUSIÓN: Impresiona que Tacrolimus no se asocia a hipoacusia cuando los niveles están en rango terapéutico durante un período de seguimiento de seis meses post trasplante.

Membranous nephropathy / Nefropatia membranosa

ABSTRACT Membranous nephropathy is a glomerulopathy, which main affected target is the podocyte, and has consequences on the glomerular basement membrane. It is more common in adults, especially over 50 years of age. The clinical presentation is nephrotic syndrome, but many cases can evolve with asymptomatic non-nephrotic proteinuria. The mechanism consists of the deposition of immune complexes in the subepithelial space of the glomerular capillary loop with subsequent activation of the complement system. Great advances in the identification of potential target antigens have occurred in the last twenty years, and the main one is the protein "M-type phospholipase-A2 receptor" (PLA2R) with the circulating anti-PLA2R antibody, which makes it possible to evaluate the activity and prognosis of this nephropathy. This route of injury corresponds to approximately 70% to 80% of cases of membranous nephropathy characterized as primary. In the last 10 years, several other potential target antigens have been identified. This review proposes to present clinical, etiopathogenic and therapeutic aspects of membranous nephropathy in a didactic manner, including cases that occur during kidney transplantation.

RESUMO A nefropatia membranosa é uma glomerulopatia, cujo principal alvo acometido é o podócito, e acarreta consequências na membrana basal glomerular. Tem maior frequência em adultos, principalmente acima dos 50 anos. A apresentação clínica é a síndrome nefrótica, mas muitos casos podem evoluir com proteinúria não nefrótica assintomática. O mecanismo consiste na deposição de complexos imunes no espaço subepitelial da alça capilar glomerular com subsequente ativação do sistema do complemento. Grandes avanços na identificação de potenciais antígenos alvo têm ocorrido nos últimos vinte anos, e o principal é a proteína "M-type phospholipase-A2 receptor" (PLA2R) com o anticorpo anti-PLA2R circulante, o que possibilita avaliar a atividade e o prognóstico dessa nefropatia. Essa via de lesão corresponde aproximadamente a 70% a 80% dos casos da nefropatia membranosa caracterizada como primária. Nos últimos 10 anos vários outros antígenos alvo potenciais têm sido identificados. Esta revisão se propõe a apresentar de modo didático aspectos clínicos, etiopatogênicos e terapêuticos da nefropatia membranosa, incluídos os casos com ocorrência no transplante renal.

Risk factors of new-onset hypertriglyceridemia in kidney transplant recipients: a single-center analysis / 器官移植

Objective To identify the risk factors of new-onset hypertriglyceridemia (HTG) in kidney transplant recipients. Methods Clinical data of 149 kidney transplant recipients were retrospectively analyzed. According to serum triglyceride (TG) level after operation, they were divided into the non-HTG group (TG≤1.7 mmol/L, n=60) and new-onset HTG group (TG>1.7 mmol/L, n=89). Baseline data of all recipients were compared between two groups. The risk factors of HTG in kidney transplant recipients were analyzed by generalized estimating equation (GEE), and validated by multiple regression equations. Results No significant differences were observed in baseline data between two groups (all P>0.05). Multivariate analysis showed that the incidence of HTG in the middle and high tacrolimus (Tac) concentration groups was higher than that in the low Tac concentration group [odds ratio (OR) 3.11, 95% confidence interval (CI) 1.22-7.93, P=0.018 in the middle Tac concentration group; OR 5.11, 95%CI 1.31-19.98, P=0.019 in the high Tac concentration group]. Compared with type-A blood recipients, the risk of new-onset HTG was significantly increased in type-O blood counterparts (OR 2.77, 95%CI 1.14-6.71, P=0.024). The risk of new-onset HTG was decreased along with the increase of preoperative globulin level (OR 0.93, 95%CI 0.87-0.99, P=0.043). At postoperative 3 months, Tac blood concentration in the new-onset HTG group was significantly higher compared with that in the non-HTG group, and significant difference was observed (P<0.05). Multiple regression equations confirmed that the risk of new-onset HTG in type-O blood kidney transplant recipients was higher than that in type-A blood counterparts, and the risk of new-onset HTG in the middle and high Tac concentration groups was higher than that in the low Tac concentration group (all P<0.05). Conclusions Type-O blood kidney transplant recipients are more prone to HTG. It is necessary to strengthen postoperative monitoring and control of blood lipids. The blood concentration of Tac probably affects the new-onset HTG in kidney transplant recipients. Maintaining an appropriate blood concentration of Tac may be beneficial to lowering the risk of HTG.

Research progress on the role of macrophages in renal allograft fibrosis / 器官移植

Ischemia-reperfusion injury, rejection, nephrotoxicity caused by calcineurin inhibitors and other factors cause excessive accumulation of renal extracellular matrix after kidney transplantation, which gradually induce renal fibrosis and eventually lead to renal failure. In recent years, the mechanism of macrophages in renal allograft fibrosis has gradually captivated widespread attention. Studies have shown that some drugs like mammalian target of rapamycin inhibitors may mitigate renal allograft fibrosis through the macrophage. In this article, the main pathogenesis and pathophysiological mechanism of renal allograft fibrosis, the role of different macrophages in the progression of renal allograft fibrosis, the infiltration of peripherally-recruited macrophages and renal resident macrophages into renal injury areas, the induction of myofibroblasts by macrophages and potential treatment regimens of macrophage-associated renal allograft fibrosis were reviewed, aiming to provide reference for investigating the role of macrophages in renal allograft fibrosis.

Clinical characteristics of a case of developmental and epileptic encephalopathy caused by PPP3CA gene mutation and literature review / 中华神经科杂志

Objective:To improve clinicians′ understanding of developmental and epileptic encephalopathy (DEE) caused by PPP3CA gene mutation. Methods:Clinical data of a patient with DEE diagnosed in the First Department of Neurology, Hebei Children′s Hospital in September 2018 were collected. The whole-exome sequencing of the proband′s family was performed, and the characteristics of gene mutation were analyzed. Literature review was carried out based on the reported cases related to PPP3CA gene. Results:The proband, a 3 months and 20 days old girl, was admitted to the hospital with a history of paroxysmal confusion with extremities shaking for 2 days. The clinical manifestations included frequent epilepsy seizures and hypoevolutism. Brain magnetic resonance imaging showed that the bilateral frontotemporal extracerebral space was slightly wider. The video electroencephalography showed hyperarrhythmia and a cluster of spastic seizures. Whole exome sequencing of the family revealed that the proband had a heterozygous de novo frameshift truncating mutation in the PPP3CA gene: c.1255-1256delAG (p.Ser419Cysfs*31). From the establishment of the database to May 2022, 8 foreign literatures and 1 Chinese literature were retrieved, and a total of 21 children with PPP3CA gene mutation were reported, with clinical developmental delay, cognitive dysfunction and abnormal electroencephalography activity. Conclusions:The frameshift truncating mutation of the PPP3CA gene (c.1255-1256delAG) is the hereditary etiology of this patient. For cases of frequent seizures with poor efficacy of antiepileptic drugs, and developmental delay, genetic testing should be performed to confirm diagnosis and treatment.

Dermatite atópica grave: guia prático de tratamento da Associação Brasileira de Alergia e Imunologia e Sociedade Brasileira de Pediatria / Severe atopic dermatitis: a practical treatment guide from the Brazilian Association of Allergy and Immunology and the Brazilian Society of Pediatrics

A dermatite atópica (DA) é uma doença cutânea inflamatória, crônica, comum, complexa e de etiologia multifatorial, que se manifesta clinicamente com prurido muitas vezes incapacitante, lesões recorrentes do tipo eczema, xerose e que pode evoluir para liquenificação. Embora o conhecimento sobre a sua fisiopatologia venham crescendo nos últimos anos, ainda as formas graves são frequentes e representam um desafio para o clínico. Para o presente guia realizou-se revisão não sistemática da literatura relacionada à DA grave refratária aos tratamentos habituais com o objetivo de elaborar um documento prático e que auxilie na compreensão dos mecanismos envolvidos na DA, assim como dos possíveis fatores de risco associados à sua apresentação. A integridade da barreira cutânea é um dos pontos fundamentais para a manutenção da homeostase da pele. Além dos cuidados gerais: evitação dos agentes desencadeantes e/ou irritantes, o uso de hidratantes, suporte emocional, entre outros, o uso de agentes anti-inflamatórios/imunossupressores de uso tópico e/ou sistêmico também foi revisado. A aquisição de novos agentes, os imunobiológicos e as pequenas moléculas, melhorou a terapêutica para os pacientes com formas graves de DA, sobretudo as refratárias aos tratamentos convencionais.

Atopic dermatitis is a chronic, common, and complex inflammatory skin disease with a multifactorial etiology. It manifests clinically with often disabling pruritus, recurrent eczema-like lesions, and xerosis, and can progress to lichenification. Although understanding of the disease's pathophysiology has been growing in recent years, severe forms are still frequent and represent a challenge for clinicians. A non-systematic review of the literature on severe atopic dermatitis refractory to conventional treatment was conducted to develop the present guide, whose purpose is to help clarify the mechanisms involved in the disease and possible risk factors. The integrity of the skin barrier is fundamental for maintaining skin homeostasis. In addition to general care, patients should avoid triggering and/or irritating agents and moisturizers and seek emotional support, etc.; the use of topical and/or systemic anti-inflammatory/immunosuppressive agents was also reviewed. New agents, immunobiologicals, and small molecules have led to a broader range of therapies for patients with severe forms of the disease, especially cases refractory to conventional treatment.

Comparison of effects of m-TOR inhibitors and calcineurin inhibitor on SUPAR and ox-LDL levels in renal transplant recipients / Comparación de los efectos de los inhibidores de m-TOR y el inhibidor de calcineurina sobre los niveles de SUPAR y ox-LDL en receptores de trasplante renal

ABSTRACT Introduction: We aimed to investigate the effect of different immunosuppressive regimens on SUPAR and ox-LDL levels which are early markers of inflammation in renal transplant recipients. Methods: A total number of 83 patients were enrolled in our study. While fourty- eight of those were received mTORi, thirty five patients were been receiving CNI. According to the immunosuppressive regimen patients were divided into CNI and m-TORi receving groups and serum SUPAR and ox-LDL levels were measured. Results: Log-SUPAR values were lower in the group receiving m-TORi (3.40 ± 0.1 vs 3.48 ± 0.4, p=0.010). OxLDL / LDL levels were higher (0.0168± 005 vs 0.0132 ±004, p=0.009) in the CNI group. In linear regression analysis, a statistically significant relationship was detected between the use of m-TORi and log-SUPAR (β = -0.052, 95% CI [-0.224, -0.012], p = 0.041) . A negative and independent relationship was found between HT and log-SUPAR (β = -0.60, 95% CI--0.112, -0.018], p=0.0024) and ox-LDL (β = -0.169 [-0.330, -0.008], p=0.040). Very strong correlation (r=1.0, p=<0.001) and independent relationship (β=0.321 [0.313,0.330], p=<0.001) was detected between ox-LDL and SUPAR. Conclusion: As a result, when compared immunsuppression between m-TORi and CNI, the former was associated with lower SUPAR and oxLDL levels.

RESUMEN Introducción: Nuestro objetivo fue investigar el efecto de diferentes regímenes inmunosupresores sobre los niveles de SUPAR y ox-LDL, que son marcadores tempranos de inflamación en receptores de trasplante renal. Material y métodos: Un total de 83 pacientes se inscribieron en nuestro estudio. Mientras que cuarenta y ocho de ellos recibieron mTORi, treinta y cinco pacientes recibieron CNI. De acuerdo con el régimen inmunosupresor, los pacientes se dividieron en grupos receptores de CNI y m-TORi y se midieron los niveles séricos de SUPAR y ox-LDL. Resultados: Los valores de Log-SUPAR fueron menores en el grupo que recibió m-TORi (3,40 ± 0,1 vs 3,48 ± 0,4, p = 0,010). Los niveles de OxLDL/LDL fueron mayores (0,0168± 005 vs 0,0132 ±004, p=0,009) en el grupo CNI. En el análisis de regresión lineal, se detectó una relación estadísticamente significativa entre el uso de m-TORi y log-SUPAR (β = -0,052, IC del 95% [-0,224, -0,012], p = 0,041). Se encontró una relación negativa e independiente entre HT y log-SUPAR (β = -0.60, 95% IC--0.112, -0.018], p = 0.0024) y ox-LDL (β = -0.169 [-0.330, -0.008], p = 0,040). Se detectó una correlación muy fuerte (r = 1,0, p <0,001) y una relación independiente (β = 0,321 [0,313, 0,330], p <0,001) entre ox-LDL y SUPAR. Conclusión: Como resultado, cuando se comparó la inmunosupresión entre m-TORi y CNI, la primera se asoció con niveles más bajos de SUPAR y oxLDL.

Clinical features and treatment of calcineurin inhibitor-induced pain syndrome in renal transplant recipients / 药学实践杂志

Objective To understand the clinical features and therapeutic methods for calcineurin inhibitor-induced pain syndrome (CIPS) in kidney transplant recipients. Methods The related articles or abstracts from January 1991 to December 2020 were obtained by searching PubMed, Google Scholar, CNKI, Wanfang and VIP databases. The reviews, duplicate literatures and the articles involved in non-kidney transplant recipients were excluded. 11 full papers were included with 15 case reports. Results The average age of patients at the time of diagnosis of CIPS was (44.6±8.31) years, and the 53.3% of the patients was male. The average appearance time of CIPS was (2.42±3.07) months after kidney transplantation. CIPS mainly affected bilateral hands, elbows, wrists, knees, ankles, feet and back. The patients had normal or elevated trough concentrations of calcineurin inhibitors (CNIs) when CIPS occurred. Some patients had elevated alkaline phosphatase, parathyroid hormone, blood calcium, C-reactive protein levels, and abnormal phosphorus levels, while rheumatoid factor and uric acid levels were normal. CIPS symptoms in most patients disappeared with dose reduction of CNIs, change to different class of CNIs, pamidronate IV injection, pregabalin, calcium channel antagonists, etc. The average recovery time was (4.43±3.31) months. Conclusion The most effective treatment for CIPS is to reduce the dose of CNIs and replace immunosuppressants. Other treatments include GABA analogs, intravenous pamidronate, calcium channel blockers and conservative therapy.

Research progress on kidney injury-related complications after heart transplantation / 器官移植

In recent years, significant progress has been achieved in heart transplantation, perioperative management and application of immunosuppressants. Nevertheless, complications after heart transplantation are still main risk factors affecting the survival of recipients. Among them, acute kidney injury is a common complication during the early stage following heart transplantation. It may lead to secondary chronic kidney diseases after heart transplantation and progress into end-stage renal diseases, severely affecting the quality of life and long-term survival of recipients. Therefore, it is of significance to identify the risk factors of kidney injury after heart transplantation and deliver prompt interventions to improve clinical prognosis of heart transplant recipients. In this article, research progress on the incidence, risk factors, prevention and treatment strategies of kidney injury-related complications after heart transplantation was reviewed, aiming to provide reference for the prevention, diagnosis and treatment of kidney injury-related complications after heart transplantation and enhance clinical prognosis of recipients undergoing heart transplantation.

Advances in clinical determinants and mechanisms of calcineurin inhibitor pharmacokinetic disposition in vivo / 中国药理学通报

Tacrolimus and cyclosporine are both calcineurin inhibitors ( CNI) that widely used for immunosuppression and have the characteristics of great intra-and inter-variabilities in phar-macokinetics and pharmacodynamics.CNI undergoes extensive first-pass metabolism and is substrate for cytochrome P450 (CYP) 3A4, CYP3A5 and P-glycoprotein in intestine and liver.'Hie functions of the enzyme and transporter are determined by complex interactions including gene polymorphisms, induction or inhibition of drugs and endogenous substances ( such as inflam-matory factors).This review summarizes the clinical determinants of CNI treatment variability, including food intake, diarrhea and other intestinal diseases, anemia, hypoproteinemia, hyperlipidemia, liver and kidney disease and combination medications.The underlying mechanisms are also discussed.

Incidência de reações adversas associadas ao uso de inibidores de calcineurina em pacientes submetidos ao transplante pulmonar / Incidence of adverse reactions associated with the use of calcineurin inhibitors in patients undergoing lung transplantation

Introdução: O uso de terapia imunossupressora é de extrema importância no transplante pulmonar, entretanto existem diversas reações adversas (RAMs) associadas ao seu uso. Neste trabalho buscamos descrever a incidência de perda de função renal (FR), diabetes mellitus (DM), hipertensão arterial sistêmica (HAS) e hipercolesterolemia associadas ao uso de ICN na população de transplantados pulmonares do Hospital de Clínicas de Porto Alegre após 1 ano de transplante.Metodologia: Estudo de coorte retrospectivo, conduzido no Hospital de Clínicas de Porto Alegre. Foram incluídos os pacientes transplantados de pulmão no período de 2016 a 2018.Resultados: Após um ano do transplante 56,5% (13/23) tiveram uma perda de FR em comparação ao basal, mas com valores ainda dentro da normalidade e 30,4% (7/23) perderam FR. A diferença de FR antes e após o transplante foi estatisticamente significativa com p < 0,001, no entanto não foi observado diferença entre os ICN (p = 0,499). Entre as variáveis: DM, HAS e Hipercolesterolemia, apenas o desenvolvimento de HAS foi estaticamente significativo quando comparado ao período pré-transplante (p < 0,001).Conclusão: Nossos dados demonstraram importante perda de FR após uso de imunossupressores ICN, corroborando com dados já publicados, no entanto, não foi possível identificar associação com ICN específico, sugerindo que benefícios na intercambialidade de terapias entre os ICN na tentativa de preservação da FR devem ser melhor estudados. Diante da possibilidade de desenvolvimento de RAMs associadas ao uso de imunossupressores, destacamos a importância da inserção do farmacêutico clínico nas equipes de transplante.

Introduction: Immunosuppressive therapy is extremely important in lung transplantation, but there are several adverse drug reactions (ADRs) associated with its use.Objective: To report the incidence of loss of renal function (RF), diabetes mellitus (DM), systemic arterial hypertension (SAH), and hypercholesterolemia associated with the use of calcineurin inhibitors (CNIs) in the population of lung transplant recipients at Hospital de Clínicas de Porto Alegre at 1 year after transplant. Methods: We conducted a retrospective cohort study of patients undergoing a lung transplant at Hospital de Clínicas de Porto Alegre from 2016 to 2018.Results: At 1 year after transplant, 56.5% (13/23) had loss of RF compared with baseline, but the values remained within the normal range, whereas 30.4% (7/23) had complete loss of RF. There was a statistically significant difference in RF before and after transplant (p < 0.001), but not in CNIs (p = 0.499). Among the variables DM, SAH, and hypercholesterolemia, only the development of SAH was statistically significant compared with the pre-transplant period (p < 0.001).Conclusion: Our data demonstrated an important loss of RF after the use of CNI immunosuppressants, which is consistent with published data. However, no association was identified with the type of CNI, suggesting that the benefits of the interchangeability of CNI therapies aimed at preserving RF should be further studied. Given the potential occurrence of ADRs associated with the use of immunosuppressants, we highlight the importance of the presence of a clinical pharmacist in the transplant team.

Alternative Oral Mucous Membrane Pemphigoid Therapy Using Tacrolimus: A Case Report

ABSTRACT: Mucous membrane pemphigoid (MMP) is a blistering disease that predominantly involves the mucous membranes and that can lead to major negative impacts on patient quality of life. The first-line MMP treatment is based on the use of topical and systemic corticosteroids. In this report, we presented a 45-year-old female patient presented blisters in the inferior gingiva for over 8-months. The patient reported being allergic to corticosteroids. Under the clinical hypothesi s of oral lichen planus and MMP, an incisional biopsy was performed, and the histopathological diagnosis of MMP was established. Thus, it was instituted an alternative therapy with tacrolimus 0.03 %. The patient showed an excellent clinical outcome with no recurrence five months after the end of therapy. Tacrolimus 0.03 % may represent an effective therapeutic alternative in MMP treatment and may be used in cases of hypersensitivity to standard therapy.

RESUMEN: El penfigoide de la membrana mucosa (PMM) es una enfermedad ampollosa que afecta predominantemente a las membranas mucosas y que puede provocar importantes impactos negativos en la calidad de vida del paciente. El tratamiento de primera línea de PMM se basa en el uso de corticosteroides tópicos y sistémicos. En este informe, presentamos un caso de una paciente femenina de 45 años que presentó ampollas en la encía inferior durante más de 8 meses. La paciente informó ser alérgica a los corticosteroides. Bajo la hipótesis clínica de liquen plano oral y PMM, se realizó una biopsia incisional y se estableció el diagnóstico histopatológico de PMM. Por lo tanto, se instituyó una terapia alternativa con tacrolimus tópico al 0,03 %. La paciente mostró un excelente resultado clínico sin recurrencia después de 5 meses de la terapia final. Tacrolimus 0,03 % puede representar una alternativa terapéutica efectiva en el tratamiento de PMM y se puede usar en casos de hipersensibilidad a la terapia estándar.

Regulatory control of the Na-Cl co-transporter NCC and its therapeutic potential for hypertension

Hypertension is the largest risk factor for cardiovascular disease, the leading cause of mortality worldwide. As blood pressure regulation is influenced by multiple physiological systems, hypertension cannot be attributed to a single identifiable etiology. Three decades of research into Mendelian forms of hypertension implicated alterations in the renal tubular sodium handling, particularly the distal convoluted tubule (DCT)-native, thiazide-sensitive Na-Cl cotransporter (NCC). Altered functions of the NCC have shown to have profound effects on blood pressure regulation as illustrated by the over activation and inactivation of the NCC in Gordon's and Gitelman syndromes respectively. Substantial progress has uncovered multiple factors that affect the expression and activity of the NCC. In particular, NCC activity is controlled by phosphorylation/dephosphorylation, and NCC expression is facilitated by glycosylation and negatively regulated by ubiquitination. Studies have even found parvalbumin to be an unexpected regulator of the NCC. In recent years, there have been considerable advances in our understanding of NCC control mechanisms, particularly

Establishment of a blood concentration detection system for everolimus in recipients after liver transplantation / 器官移植

Objective To establish a detection system of ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for everolimus concentration in whole blood of liver transplant recipients. Methods The proteins of samples were precipitated with methanol and zinc sulfate, and everolimus-D4 was used as the internal standard. Phenomenex Kinetex PFP column was used. The mobile phase A was water (containing 2 mmol/Lammonium formate and 0.1% formic acid), and the mobile phase B was methanol (containing 2 mmol/L ammonium formate and 0.1% formic acid). The gradient elution was performed with the flow rate of 1 mL/min, the column temperature of 50 ℃ and the injection volume of 1 μL. The multi-reaction monitoring mode was used to quantitatively analyze with electrospray positive ionization. The UPLC-MS/MS detection system required only 100 μL of whole blood, and could achieve a sufficient lower limit of quantification without complicated sample preparation. The total running time was within 4.5 min. Linear regression (1/x2) analysis was performed using peak area of everolimus / peak area of everolimus-D4 (y) and concentration of everolimus/concentration of everolimus-D4 (x) to calculate the calibration function and analyze its accuracy and linear relationship. UPLC-MS/MS was used to detect the trough blood concentration of everolimus in blood samples of 5 recipients after liver transplantation. Results The accuracy of quality control was within 15%, and the linear relationship of everolimus was good in the blood concentration range of 1-100 ng /mL(R2 > 0.990). Trough blood concentration of everolimus measured in blood samples of 5 liver transplant recipients ranged from 3.77 to 9.27 ng/mL. Conclusions The detection system of UPLC-MS/MS in this study is suitable for monitoring the concentration of everolimus in whole blood of liver transplant recipients because of its high accuracy, simple sample processing method and short detection time.

Recent progress on diabetes mellitus after liver transplantation / 器官移植

Diabetes mellitus is one of the most common complications after liver transplantation. The survival rate of recipients after liver transplantation with diabetes mellitus and the long-term survival rate of grafts are significantly lower than those of their counterparts without diabetes mellitus. In recent years, diabetes mellitus after liver transplantation has attracted widespread attention along with the rapid development of liver transplantation in China. Although post-transplantation diabetes mellitus (PTDM) has been extensively investigated in the past two decades, multiple problems remain to be further resolved. The study was designed to review the latest research progress upon diabetes mellitus after liver transplantation, covering the definition and diagnostic criteria of PTDM, risk factors, prevention and treatment of diabetes mellitus after liver transplantation, aiming to deepen the understanding of diabetes mellitus following liver transplantation, deliver effective prevention and management, improve the long-term survival rate and enhance the quality of life of the recipients.