A case-control study to assess the role of polyomavirus in transplant complications: Where do we stand?

PURPOSE: The study's aim was to assess whether polyomavirus DNAemia screening was associated with different outcomes in patients with positive viremia compared with negative viremia. METHODS: Case-control retrospective study of patients with polyomavirus DNAemia (viremia > 1000 copies/mL) matched 1:1 with controls. Control group consists of the patient who received a transplant immediately before or after each identified case and did have nil viremia. FINDING: Ultimately, 120 cases of BK polyomavirus (BKPyV) were detected and matched with 130 controls. Of these, 54 were adult kidney transplant recipients (KTRs), 43 were pediatric KTRs, and 23 were undergoing hemato-oncologic therapy, of which 20 were undergoing hematopoietic stem cell transplantation. The odds ratio (OR) for overall risk of poorer outcomes in cases versus controls was 16.07 (95% CI: 5.55-46.54). The unfavorable outcome of switching the immunosuppressive drug (ISD) (14/40,35%) was no different from that of those treated with reduced ISD doses (31/71, 43.6%, P = .250). Acute rejection or graft-versus-host disease, previous transplant, and intensity of immunosuppression (4 ISDs plus induction or conditioning) were risk factors for BKPyV-DNAemia (OR: 13.96, 95% CI: 11.25-15.18, P < .001; OR: 6.14, 95% CI: 3.91-8.80, P < .001; OR: 5.53, 95% CI: 3.37-7.30, P < .001, respectively). CONCLUSIONS: Despite viremia screening, dose reduction, and change in therapeutic protocol, patients with positive BKPyV-DNAemia present poorer outcomes and unfavorable results.

La infección por citomegalovirus postrasplante renal y pérdida del injerto a largo plazo / Cytomegalovirus infection after kidney transplantation and long-term graft loss

Antecedentes: A pesar del uso de estrategias de prevención y la mejora en los métodos diagnósticos, el citomegalovirus (CMV) continúa siendo la complicación viral más frecuente después del trasplante renal y su impacto en los resultados a largo plazo se sigue debatiendo. Objetivo: Conocer la incidencia de infección/enfermedad por CMV bajo estrategias de prevención y analizar su asociación con la supervivencia del paciente y del injerto y con otros eventos clínicos relacionados con el CMV. Métodos: Revisión de las historias clínicas de 377 pacientes trasplantados de riñón entre enero de 1998 y diciembre del 2008. Se analizó la supervivencia por el método de Kaplan-Meier en función de la presencia o ausencia de infección/enfermedad CMV y se usó el modelo de Cox para identificar factores asociados con infección/enfermedad por CMV y para evaluar su impacto en la mortalidad y la pérdida del injerto. Resultados: La incidencia de infección por CMV fue del 34,7% y de enfermedad del 9,5%. La supervivencia del paciente y del injerto fue significativamente inferior en los pacientes con infección/enfermedad CMV. La infección/enfermedad por CMV se asoció de forma significativa a mayor riesgo de pérdida del injerto (HR 1,91, IC del 95% 1,09-3,36, p=0,023) pero no con más riesgo de mortalidad (HR 1,29, IC del 95% 0,7-2,38, p=0,4). Conclusión: La replicación viral después del trasplante es un factor de riesgo de pérdida del injerto pero no de mortalidad a largo plazo. Las estrategias de prevención disminuyen la incidencia de infección y enfermedad por CMV postrasplante (AU)

Background: Despite the use of prevention strategies, cytomegalovirus (CMV) infection is the most common viral complication after renal transplant and its impact on long-term outcomes is still open to debate. Objective: To evaluate the incidence of CMV infection and disease during the use of prevention strategies in our centre and to analyse the association between CMV infection and long-term patient and graft survival and other potentially clinical events related with CMV. Methods: We reviewed the medical records of 377 recipients of kidney transplants performed between January 1998 and December 2008. Kaplain-Meier survival curve analysis was performed to analyse graft and patient survival by CMV infection/disease and Cox proportional hazards regression was used to identify factors associated with CMV infection/disease, graft loss and mortality. Results: The incidence of CMV infection was 34.7% and CMV disease was 9.5%. Patient and graft survival was significantly lower in patients with CMV infection/disease. CMV infection/disease was associated with a higher risk of graft loss (HR 1.91, 95% CI 1.09-3.36, p=0.023), but not with a higher mortality (HR 1.29, 95% CI 0.7-2.38, p=0.4). Conclusion: CMV replication after renal transplant is a risk factor for long-term graft loss but not mortality. Prevention strategies decrease post-transplant CMV infection and disease (AU)

Cytomegalovirus infection after kidney transplantation and long-term graft loss. / La infección por citomegalovirus postrasplante renal y pérdida del injerto a largo plazo.

BACKGROUND: Despite the use of prevention strategies, cytomegalovirus (CMV) infection is the most common viral complication after renal transplant and its impact on long-term outcomes is still open to debate. OBJECTIVE: To evaluate the incidence of CMV infection and disease during the use of prevention strategies in our centre and to analyse the association between CMV infection and long-term patient and graft survival and other potentially clinical events related with CMV. METHODS: We reviewed the medical records of 377 recipients of kidney transplants performed between January 1998 and December 2008. Kaplain-Meier survival curve analysis was performed to analyse graft and patient survival by CMV infection/disease and Cox proportional hazards regression was used to identify factors associated with CMV infection/disease, graft loss and mortality. RESULTS: The incidence of CMV infection was 34.7% and CMV disease was 9.5%. Patient and graft survival was significantly lower in patients with CMV infection/disease. CMV infection/disease was associated with a higher risk of graft loss (HR 1.91, 95% CI 1.09-3.36, p=0.023), but not with a higher mortality (HR 1.29, 95% CI 0.7-2.38, p=0.4). CONCLUSION: CMV replication after renal transplant is a risk factor for long-term graft loss but not mortality. Prevention strategies decrease post-transplant CMV infection and disease.

Pretransplant CD8 T-cell response to IE-1 discriminates seropositive kidney recipients at risk of developing CMV infection posttransplant.

BACKGROUND: Cytomegalovirus (CMV) infection is an ongoing clinical problem in solid-organ transplantation (SOT). Pretransplant CMV serology is currently the only tool for assessing the risk of CMV infection, although cellular immune responses driven by CMV-specific CD4 and CD8 T lymphocytes are important for controlling viral replication. Therefore, the analysis of CMV-specific T cells may be useful for estimating the risk of infection. METHODS: This is a prospective study of patients with kidney transplants and no prophylactic treatment for CMV replication. CD4 and CD8 T-cell responses to the major CMV pp65 and IE-1 antigens in 15 seropositive patients at intermediate risk of CMV infection were investigated, according to current algorithms. Intracellular flow cytometry was employed to determine IFN-γ production as a functional readout. The response was analyzed in pretransplant samples and prospectively at 1 and 6 months and at 1 year posttransplant. RESULTS: It was observed that the CD8 responses to IE-1 antigen were practically absent pretransplant in patients who developed CMV infection posttransplant. Within the group of patients free of infection, CD8 responses to IE-1 were detected more frequently and were significantly higher (P=0.0083). In a receiver operating characteristics curve analysis (AUC=0.929; P=0.010; 95% CI: 0.078-1.0), low CD8 responses to IE-1 (≤0.05%) pretransplant predicted the development of CMV infection under the immunosuppressive regime after transplant with 100% specificity and 85.7% sensitivity. CONCLUSIONS: Assessment of IE-1-specific CD8 T-cell frequencies pretransplant may be a useful tool for identifying seropositive SOT patients at risk of developing CMV infection posttransplant.

[Progression factors in chronic kidney disease. Non-immunological mechanisms]. / Factores de progresión de la enfermedad renal crónica. Mecanismos no inmunológicos.

Non-immunological factors in the progression of kidney disease in transplant patients are the following: high blood pressure, proteinuria, dislypidemia, etc. 1. Arterial hypertension treatment: Blood pressure must be measured periodically in all transplant patients. Similarly to native kidneys, in renal transplant patients arterial hypertension is a risk factor in the progression of kidney disease. Arterial hypertension represent a clinical marker of chronic allograft nephropathy and contributes to graft loss and to the morbid- mortality of these patients (Evidence level C). Blood pressure control should be < 130/80 mm Hg for renal transplant patients without proteinuria and 125/75 mm Hg for proteinuric patients (> 1 g/24 hours). Hypertension and proteinuria are frequently associated in the same patients, a global treatment of both seems more rational (Evidence level C). General measures should be instigated first with pharmacological therapy. All antihypertensive drugs are useful in renal transplant patients and the majority of patients will need two or more drugs. In proteinuric patients an angiotensin receptor antagonist or an ACE-inhibitor should be initiated. It is advisable to monitor the serum potassium and creatinine after the start of this drugs or during the treatment periodically, especially in patients with chronic kidney disease stage IV-V. 2. Proteinuria treatment: Proteinuria has been strongly correlated with reduced function and graft survival. Lowering proteinuria to values as near to normal as possible (< 0.5 g/24 hours). To reduce proteinuria, an angiotensin receptor antagonist, an ACE-inhibitor or a combination of both are required, with serum potassium or creatinine monitoring, especially in patients with chronic kidney disease stage IV-V. 3. Dyslipidemia treatment: For kidney transplant recipients the assessment of dyslipidemias should include a complete fasting lipid profile with total cholesterol, LDL, HDL, and triglycerides. Evidence from the general population indicates that treatment of dyslipidemias reduces cardiovascular disease and evidence in kidney transplant patients suggests that judicious treatment can be safe and effective in improving dyslipidemia. Therapeutic goal must be LDL < 100 mg/dl. (Evidence level C). 4. Others: Cigarette smoking, glucose intolerance or diabetes control and obesity should be assessed.

[Managing anaemia in kidney transplant patients with chronic kidney disease]. / Manejo de la anemia en la enfermedad renal crónica del paciente trasplantado renal.

DEFINITION: The definition of anemia is established by the World Health Organization and was subsequently adopted by the American Society of Transplantation, which defines anemia as hemoglobin concentration <12 g/dl in women and <13 g/dl in men. PREVALENCE OF ANEMIA POSTTRANSPLANTATION: Varies throughout the posttransplantation period and is associated with the degree of renal graft function. The relationship between hemoglobin levels and glomerular filtration does not behave the same way as in the population with chronic kidney disease. The results of various studies show a high prevalence in the first months after transplantation (<6 months), which decreases from the first year posttransplantation and then increases related to loss of graft function. European study on the management of anemia showed a prevalence of anemia in 38.6% and only 18% of patients with severe anemia were treated with erythropoietin (EPO). PATHOPHYSIOLOGY: There is a decrease in the synthesis of erythropoietin (EPO) or an increase in resistance to EPO. There are many factors that can cause anemia post-transplantation. Some of these factors are specific to transplanted patients whilst others are common to all patients with chronic kidney disease. Among the common factors there are: the degree of renal function and iron deficiency and among the factors of transplantation there are acute rejection, post-transplantation medications, infections and malignancies. CLINICAL RESULTS: The available data evaluating the association of anemia with morbidity and mortality of the patient and graft survival are scarce. Most studies are retrospective and analyze experiences of individual centers. They showed a higher mortality and morbidity among patients with a hemoglobin <11 g/dl. (Evidence B). TREATMENT OF POST-TRANSPLANTATION ANEMIA: Erythropoiesis-stimulating agents (ESA) and replenishment of iron deposits (Evidence A). RESPONSE TO TREATMENT: In transplant patients there may be some resistance to treatment with erythropoiesis- stimulating agents (ESA) due to the use of myelosuppressive medications, chronic inflammation and other factors. - Adverse effects of treatment with ESA: There are few controlled studies failed to show respect to the ESA that are effective and unlikely to accelerate the deterioration of renal function but may aggravate hypertension.

[Changes in bone and mineral metabolism in kidney transplant patients with chronic kidney disease]. / Alteraciones del metabolismo óseo mineral en la enfermedad renal crónica del paciente trasplantado renal.

DESCRIPTION: Recently, the Foundation has proposed new definitions KDIGO to refer to the alterations of bone - mineral metabolism in patients with chronic renal disease (CRD), relegating the traditional term of renal osteodystrophy (ODR). RECOMMEND: The term ODR exclusively to define alterations in bone morphology and architecture characteristic of the ERC. - And the term of bone-mineral alteration associated with the CRD to describe biochemical changes, and skeletal calcifications that occur as a result of alterations in mineral metabolism in the CRD. PATHOPHYSIOLOGY: The different metabolic abnormalities are secondary to the progressive loss of renal mass and renal function that leads to retention of phosphorus and a decrease in the levels of calcitriol which are responsible for the skeletal resistance to the action of PTH. CLINICAL FEATURES: The main clinical manifestations of abnormal bone mineral metabolism are posttransplantation osteoporosis and osteopenia producing an increase in fractures, osteonecrosis, and bone pain. DIAGNOSTIC METHODS: Biochemical parameters (calcium, phosphorus, PTH, 25 hydroxyvitamin D), X-ray bone densitometry and bone biopsy. (Evidence B). THERAPEUTIC ALTERNATIVES: It is recommended for the treatment and prevention of osteopenia - osteoporosis in transplant patients based on data from clinical evidence available from other study populations, such as in patients with chronic kidney disease. In addition to specific treatment, we must take into account the preventive measures to reduce the risk of fractures. Treatment includes specific measures for the prevention of bone loss (active metabolite of vitamin D analogues and bisphosphonates) and the treatment of persistent hyperparathyroidism (calcimiméticos). (Evidence B).

Mesangial C4d deposition: a new prognostic factor in IgA nephropathy.

BACKGROUND: It has been shown that patients with IgA nephropathy can be divided into two groups on the basis of the pattern of complement activation. Activation of the lectin pathway of complement is associated with more severe renal disease. Glomerular deposition of C4d is a marker of activation of the lectin pathway of complement. The aim of our study was to determine whether C4d staining at the time of the renal biopsy could identify patients with a different long-term prognosis in IgA nephropathy. METHODS: This retrospective cohort study included all patients with IgA nephropathy who underwent renal biopsy at our centre from January 1992 to December 2006. We evaluated baseline age, sex, presence of macroscopic haematuria, hypertension, serum creatinine and glomerular filtration rate (GFR), urine protein, mesangial C4d staining, glomerulosclerosis, interstitial fibrosis and extracapillary proliferation. Kaplan-Meier survival and Cox proportional hazards analyses were performed, with end-stage renal disease (ESRD) being defined as onset of dialysis or transplantation. RESULTS: Nineteen patients (32.2%) were C4d positive and 40 patients (67.8%) C4d negative. Age, hypertension, absence of macroscopic haematuria, serum creatinine levels, GFR, glomerular sclerosis, interstitial fibrosis and C4d-positive staining were all univariately associated with evolution to ESRD. Renal survival at 10 years was 43.9% in C4d-positive patients versus 90.9% in C4d-negative patients (log-rank, P = 0.0005). CONCLUSION: Negative mesangial C4d staining in glomeruli in patients with IgA nephropathy helps to identify patients with a good long-term prognostic for whom aggressive treatments are not justified.

Manejo de la anemia en la enfermedad renal crónica del paciente trasplantado renal / Managing anaemia in kidney transplant patients with kidney disease

Definición: La definición de anemia más extendida es la establecida por la Organización Mundial de la Salud y que posteriormente fue adoptada por la Sociedad Americana de Trasplantes, que define como anemia la concentración de hemoglobina <12 g/dl en mujeres y <13 g/dl en varones. Prevalencia de anemia postrasplante: Varía a lo largo del período postrasplante y se asocia con el grado de función del injerto renal. La relación entre niveles de hemoglobina y filtrado glomerular no se comporta de la misma manera que en la población con enfermedad renal crónica (ERC). Los resultados de los diversos estudios muestran una prevalencia elevada en los primeros meses postrasplante (<6 meses), que disminuye a partir del año postrasplante y posteriormente se incrementa relacionándose con la pérdida de función del injerto. El estudio europeo sobre manejo de la anemia mostró una prevalencia de anemia del 38,6%, y sólo el 18% de los pacientes con anemia grave estaban en tratamiento con eritropoyetina (EPO). Fisiopatología: Se produce una disminución de la síntesis de EPO o un incremento en la resistencia a la EPO. Existen múltiples factores que pueden causar anemia postrasplante. Algunos de estos factores son únicos de los pacientes trasplantados y otros son comunes a otros pacientes con ERC. Entre los factores comunes se encuentran: el grado de función renal y el déficit de hierro, y entre los factores propios del trasplante están el rechazo agudo, la medicación postrasplante, infecciones y neoplasias. Resultados clínicos: Los datos disponibles que evalúan la asociación de anemia con la morbimortalidad del paciente y la supervivencia del injerto son escasos. La mayoría de los estudios son retrospectivos y analizan experiencias de centros aislados. En ellos se demuestra una mayor mortalidad y morbilidad entre los pacientes con una hemoglobina <11 g/dl (evidencia B). Tratamiento de la anemia postrasplante: - Agentes estimulantes de la eritropoyesis (AEE) y reposición de los depósitos férricos (evidencia A). - Respuesta al tratamiento: en los pacientes trasplantados puede existir cierta resistencia al tratamiento con AEE debido al uso de medicación mielosupresora, inflamación crónica y otros factores. - Efectos adversos del tratamiento con AEE: existen pocos estudios no controlados al respecto que muestran que los AEE son eficaces y probablemente no aceleran el deterioro de función renal, pero pueden agravar la hipertensión arterial (AU)

Definition: The definition of anemia is established by the World Health Organization and was subsequently adopted by the American Society of Transplantation, which defines anemia as hemoglobin concentration <12 g/dl in women and <13 g/dl in men. Prevalence of anemia posttransplantation: Varies throughout the posttransplantation period and is associated with the degree of renal graft function. The relationship between hemoglobin levels and glomerular filtration does not behave the same way as in the population with chronic kidney disease. The results of various studies show a high prevalence in the first months after transplantation (<6 months), which decreases from the first year posttransplantation and then increases related to loss of graft function. European study on the management of anemia showed a prevalence of anemia in 38.6% and only 18% of patients with severe anemia were treated with erythropoietin (EPO). Pathophysiology: There is a decrease in the synthesis of erythropoietin (EPO) or an increase in resistance to EPO. There are many factors that can cause anemia post-transplantation. Some of these factors are specific to transplanted patients whilst others are common to all patients with chronic kidney disease. Among the common factors there are: the degree of renal function and iron deficiency and among the factors of transplantation there are acute rejection, post-transplantation medications, infections and malignancies. Clinical Results: The available data evaluating the association of anemia with morbidity and mortality of the patient and graft survival are scarce. Most studies are retrospective and analyze experiences of individual centers. They showed a higher mortality and morbidity among patients with a hemoglobin <11 g/dl. (Evidence B) Treatment of post-transplantation anemia: - Erythropoiesis-stimulating agents (ESA) and replenishment of iron deposits (Evidence A) - Response to treatment: In transplant patients there may be some resistance to treatment with erythropoiesis- stimulating agents (ESA) due to the use of myelosuppressive medications, chronic inflammation and other factors. - Adverse effects of treatment with ESA: There are few controlled studies failed to show respect to the ESA that are effective and unlikely to accelerate the deterioration of renal function but may aggravate hypertension (AU)

Alteraciones del metabolismo óseo mineral en la enfermedad renal crónica del paciente transplantando renal / Changes in bone and mineral metabolism in kidney transplant patient with chronic kidney disease

Definición: Recientemente, la Fundación KDIGO (Kidney Disease: Improving Global Outcomes) ha propuesto nuevas definiciones para referirse a las alteraciones del metabolismo óseo-mineral de los pacientes con enfermedad renal crónica (ERC), relegando el término tradicional de «osteodistrofia renal» (ODR). Recomiendan: - El término de ODR para definir exclusivamente las alteraciones de la morfología y la arquitectura ósea propias de la ERC. - Y el término de alteración óseo-mineral asociada a la ERC para describir las alteraciones bioquímicas, esqueléticas y calcificaciones extraesqueléticas que ocurren como consecuencia de las alteraciones del metabolismo mineral en la ERC. Fisiopatología: Las diferentes alteraciones metabólicas son secundarias a la pérdida progresiva de masa renal y función renal, que conlleva una retención de fósforo y descenso de los niveles de calcitriol que son responsables de la resistencia esquelética a la acción de la PTH Manifestaciones clínicas: Las manifestaciones clínicas principales de las alteraciones del metabolismo óseo mineral postrasplante son la osteoporosis y la osteopenia, que producen un incremento de las fracturas, osteonecrosis y dolor óseo. Métodos diagnósticos: Parámetros bioquímicos (calcio, fósforo, PTH y 25 hidroxivitamina D), radiología ósea, densitometría y biopsia ósea (evidencia B). Alternativas terapéuticas: Para el tratamiento y la prevención de la osteopenia-osteoporosis en pacientes trasplantados se recomienda basarse en los datos de evidencia clínica disponibles de otras poblaciones de estudio, como la de los pacientes con ERC. Además del tratamiento específico, hay que tener en cuenta las medidas preventivas para reducir el riesgo de fracturas. El tratamiento específico incluye medidas para la prevención de pérdida de masa ósea (metabolitos activos de la vitamina D, activadores selectivos de los receptores de la vitamida D y bifosfonatos) y el tratamiento del hiperparatiroidismo persistente (calcimiméticos) (evidencia B) (AU)

Description: Recently, the Foundation has proposed new definitions KDIGO to refer to the alterations of bone - mineral metabolism in patients with chronic renal disease (CRD), relegating the traditional term of renal osteodystrophy ODR). Recommend: - The term ODR exclusively to define alterations in bone morphology and architecture characteristic of the ERC. - And the term of bone-mineral alteration associated with the CRD to describe biochemical changes, and skeletal calcifications that occur as a result of alterations in mineral metabolism in the CRD. Pathophysiology: The different metabolic abnormalities are secondary to the progressive loss of renal mass and renal function that leads to retention of phosphorus and a decrease in the levels of calcitriol which are responsible for the skeletal resistance to the action of PTH. Clinical features: The main clinical manifestations of abnormal bone mineral metabolism are posttransplantation osteoporosis and osteopenia producing an increase in fractures, osteonecrosis, and bone pain. Diagnostic methods: Biochemical parameters (calcium, phosphorus, PTH, 25 hydroxyvitamin D), X-ray bone densitometry and bone biopsy. (Evidence B) Therapeutic alternatives: It is recommended for the treatment and prevention of osteopenia - osteoporosis in transplant patients based on data from clinical evidence available from other study populations, such as in patients with chronic kidney disease. In addition to specific treatment, we must take into account the preventive measures to reduce the risk of fractures. Treatment includes specific measures for the prevention of bone loss (active metabolite of vitamin D analogues and bisphosphonates) and the treatment of persistent hyperparathyroidism (calcimiméticos). (Evidence B) (AU)