São Paulo lung transplantation waiting list: patient characteristics and predictors of death.

INTRODUCTION: Nowadays, lung transplantation (LTx) allocation in Brazil is based mainly on waiting time. There is a need to evaluate the equity of the current lung allocation system. OBJECTIVES: We sought to (1) determine the characteristics of registered patients on the waiting list and (2) identify predictors of death on the list. MATERIALS AND METHODS: We analyzed the medical records as well as clinical and laboratory data of 164 patients registered on the waiting list from 2001 to June 2008. Predictors of mortality were obtained using Cox proportional hazards analysis. RESULTS: Patients who were registered on the waiting list showed a mean age of 36.1 +/- 15.0 vs. 42.2 +/- 15.7 years, considering those who did versus did not, die on the list, respectively (P = .054). Emphysema was the most prevalent underlying disease among the patients who did not die on the list (28.8%); its prevalence was low among the patients who died on the list (6.5%; P = .009). The following variables correlated with the probability of death on the waiting list: emphysema or bronchiectasis diagnosis (hazard ratio [HR] = 0.15; P = .002); activated partial thromboplastin time > 30 seconds (HR = 3.28; P = .002); serum albumin > 3.5 g/dL (HR = 0.41; P = .033); and hemoglobin saturation > 85% (HR = 0.44; P = .031). CONCLUSIONS: Some variables seemed to predict death on the LTx waiting list; these characteristics should be used to improve the LTx allocation criteria in Brazil.

The quality of life of patients on the lung transplantation waiting list.

INTRODUCTION: Lung transplantation (LTx) candidates present incapacitating symptoms related to their mobility and activities of daily living, thereby affecting their work, social and emotional relations, and quality of life (QoL). OBJECTIVE: To study the QoL of LTx candidates, seeking to identify domains that suffer the greatest impact and verify if there are differences among these impairments according to the original lung disease. METHODS: We applied the Short Form-36 questionnaires and St George's Respiratory Questionnaire (SGRQ). All data were analyzed by one-way analysis of variance and the Kruskal Wallis test for the probability with significance at P < 0.05. RESULTS: Fifty patients were divided into groups of emphysema (n = 16), bronchiectasis (n = 12), idiopathic pulmonary fibrosis (n = 7), and cystic fibrosis (n = 15). The functional capacity, physical aspects, general status, and vitality domains showed average values below 50 points. The cystic fibrosis group showed higher functional capacity scores (46 +/- 23) than the emphysema (12 +/- 13) or idiopathic pulmonary fibrosis cohort (7 +/- 5). The limitation caused by pain affected the bronchiectasis more than the cystic fibrosis group (52 +/- 28 vs 81 +/- 25, respectively). The SGRQ scores showed impairment among all groups in all domains with average values over 50. The activities domain shows the highest score value; the emphysema (92 +/- 10) and idiopathic pulmonary fibrosis cohorts (91 +/- 9) were extremely affected compared with the cystic fibrosis (69 +/- 21) and bronchiectasis subjects (79 +/- 16). The impact domain show that subjects with cystic fibrosis were less emotionally affected by the disease. CONCLUSION: LTx candidates showed great impairment of their QoL due to their health problems, above all in the physical-functional aspects; the cystic fibrosis patients were the least affected by their health status.

The need for early predictors of diabetic nephropathy risk: is albumin excretion rate sufficient?

Initial studies showing an approximately 80% rate of progression from microalbuminuria (MA) to proteinuria in type 1 diabetic patients led to the broad acceptance of MA as a useful clinical predictor of increased diabetic nephropathy (DN) risk. Some MA patients, however, have quite advanced renal structural changes, and MA may, in these cases, be a marker rather than a predictor of DN. More recent studies have observed only about a 30-45% risk of progression of MA to proteinuria over 10 years, while about 30% of type 1 diabetic patients with MA became normoalbuminuric and the rest remained microalbuminuric. The finding that some MA patients have only mild diabetic renal lesions is consistent with the lower than originally estimated risk of progression from MA to proteinuria and with the notion that some MA patients revert to normoalbuminuria. To increase the complexity of the scenario, some normoalbuminuric long-standing type 1 diabetic patients have well-established DN lesions and approximately 40% of all patients destined to progress to proteinuria are normoalbuminuric at initial screening, despite many years of diabetes. A similar picture is emerging in type 2 diabetic patients, although fewer studies have been conducted. Thus, the predictive precision for MA to progress to overt nephropathy over the subsequent decade or so is considerably less than originally described. It is unclear whether this is due to changes in the natural history of DN resulting from improved glycemia and blood pressure control, or whether there were overestimates of risk in the original studies due to the small sample sizes, post hoc analyses, and variable MA definitions. Albumin excretion rate (AER) remains the best available noninvasive predictor of DN risk and should be regularly measured according to established guidelines. However, AER may be unable to define patients who are safe from or at risk of DN with an accuracy that is adequate for optimal clinical decision making or for the design of certain clinical trials. Investigations into new risk markers or into the combined use of several currently available predictive parameters are needed.

Glomerular filtration rate, urinary albumin excretion rate, and blood pressure changes in normoalbuminuric normotensive type 1 diabetic patients: an 8-year follow-up study.

OBJECTIVE: To analyze the changes in glomerular filtration rate (GFR), urinary albumin excretion rate (UAER), and blood pressure (BP) levels in a cohort of normoalbuminuric and normotensive type 1 diabetic patients. RESEARCH DESIGN AND METHODS: This is an 8.4+/-2.1-year prospective study of 33 normotensive normoalbuminuric (24-h UAER <20 microg/min) type 1 diabetic patients. UAER (radioimmunoassay), GFR (51Cr-EDTA single-injection technique), and GHb (ion-exchange chromatography) were measured at baseline and at 1- to 2-year intervals. RESULTS: The GFR decreased (137.6+/-16.5 to 116.4+/-21.3 ml x min(-1) x 1.73 m(-2) P < 0.05) during the follow-up period. GFR reduction (-0.20+/-0.29 ml x min(-1) x month(-1); P < 0.05) was associated with baseline GFR and mean GHb (R2 = 0.30; beta = 0.072; F = 6.54; P = 0.004). UAER was higher at the end of the study (3.7-7.1 microg/min; P = 0.017). Microalbuminuria was observed in two patients, while macroalbuminuria was observed in one. No changes in UAER were observed when these three patients were excluded from the analysis. Mean blood pressure (MBP) increased during the study (85.8+/-9.7 to 99.6+/-11.6 mmHg; P < 0.001). MBP at the end of the study was associated with age and GFR at baseline (R2 = 0.39; beta = 0.074; F = 9.64; P = 0.001). CONCLUSIONS: In this cohort of normoalbuminuric normotensive type 1 diabetic patients, GFR decreased and BP levels increased during the follow-up period. The predictors for the GFR change were baseline GFR level and metabolic control. For end-of-study MBP, the predictor was baseline GFR level.

Risk factors and survival impact of primary graft dysfunction after lung transplantation in a single institution.

BACKGROUND: Lung transplantation has become a standard procedure for some end-stage lung diseases, but primary graft dysfunction (PGD) is an inherent problem that impacts early and late outcomes. The aim of this study was to define the incidence, risk factors, and impact of mechanical ventilation time on mortality rates among a retrospective cohort of lung transplantations performed in a single institution. METHODS: We performed a retrospective study of 118 lung transplantations performed between January 2003 and July 2010. The most severe form of PGD (grade III) as defined at 48 and 72 hours was examined for risk factors by multivariable logistic regression models using donor, recipient, and transplant variables. RESULTS: The overall incidence of PGD at 48 hours was 19.8%, and 15.4% at 72 hours. According multivariate analysis, risk factors associated with PGD were donor smoking history for 48 hours (adjusted odds ratio [OR], 4.83; 95% confidence interval [CI], 1.236-18.896; P = .022) and older donors for 72 hours (adjusted OR, 1.046; 95% CI, 0.997-1.098; P = .022). The operative mortality was 52.9% among patients with PGD versus 20.3% at 48 hours (P = .012). At 72 hours, the mortality rate was 58.3% versus 21.2% (P = .013). The 90-days mortality was also higher among patients with PGD. The mechanical ventilation time was longer in patients with PGD III at 48 hours namely, a mean time of 72 versus 24 hours (P = .001). When PGD was defined at 72 hours, the mean ventilation time was even longer, namely 151 versus 24 hours (P < .001). The mean overall survival for patients who developed PGD at 48 hours was 490.9 versus 1665.5 days for subjects without PGD (P = .001). Considering PGD only at 72 hours, the mean survival was 177.7 days for the PGD group and 1628.9 days for the other patients (P < .001). CONCLUSION: PGD showed an important impacts on operative and 90-day mortality rates, mechanical ventilation time, and overall survival among lung transplant patients. PGD at 72 hours was a better predictor of lung transplant outcomes than at 48 hours. The use of donors with a smoking history or of advanced age were risk factors for the development of PGD.

Cytokine profile in pleural fluid and serum after lung transplantation.

BACKGROUND: Lung transplantation is the procedure of choice in several end-stage lung diseases. Despite improvements in surgical techniques and immunosuppression, early postoperative complications occur frequently. OBJECTIVE: To evaluate the pleural inflammatory response after surgery. PATIENTS AND METHODS: Twenty patients aged 18 to 63 years underwent unilateral or bilateral lung transplantation between August 2006 and March 2008. Proinflammatory cytokines interleukin (IL)-1beta, IL-6, and IL-8 and vascular endothelial growth factor in pleural fluid and serum were analyzed. For cytokine evaluation, 20-mL samples of pleural fluid and blood (right, left, or both chest cavities) were obtained at 6 hours after surgery and daily until removal of the chest tube or for a maximum of 10 days. Data were analyzed using analysis of variance followed by the Holm-Sidak test. RESULTS: All effusions were exudates according to Light's criteria. Pleural fluid cytokine concentrations were highest at 6 hours after surgery. Serum concentrations were lower than those in pleural fluid, and IL-1beta, IL-6, and IL-8 were undetectable at all time points. CONCLUSIONS: There is a peak concentration of inflammatory cytokines in the first 6 hours after transplantation, probably reflecting the effects of surgical manipulation. The decrease observed from postoperative day 1 and thereafter suggests the action of the immunosuppression agents and a temporal reduction in pleural inflammation.

Impact of cytomegalovirus infection in lung transplant patients under universal prophylaxis: single-center experience in Brazil.

INTRODUCTION: Cytomegalovirus (CMV) infection, a common complication in lung transplant (LT) patients, is associated with worse outcomes. Therefore, prophylaxis and surveillance with preemptive treatment is recommended. OBJECTIVES: Describe the epidemiology and impact on mortality of CMV infection in LT patients receiving CMV prophylaxis. METHODS: Single-center retrospective cohort of LT recipients from August 2003 to March 2008. We excluded patients with survival or follow-up shorter than 30 days. We reviewed medical charts and all CMV pp65 antigen results. RESULTS: Forty-seven patients met the inclusion criteria and 19 (40%) developed a CMV event: eight CMV infections, seven CMV syndromes, and 15 CMV diseases. The mean number of CMV events for each patient was 1.68 +/- 0.88. Twelve patients developed CMV events during prophylaxis (5/12 had CMV serology D+/R-). Forty-six of the 47 patients had at least one episode of acute rejection (mean 2.23 +/- 1.1). Median follow-up was 22 months (range = 3-50). There were seven deaths. Upon univariate analysis, CMV events were related to greater mortality (P = .04), especially if the patient experienced more than two events (P = .013) and if the first event occurred during the first 3 months after LT (P = .003). Nevertheless, a marginally significant relationship between CMV event during the first 3 months after LT and mortality was observed in the multivariate analysis (hazards ratio: 7.46; 95% confidence interval: 0.98-56.63; P = .052). Patients with CMV events more than 3 months post-LT showed the same survival as those who remained CMV-free. CONCLUSION: Prophylaxis and preemptive treatment are safe and effective; however, the patients who develop CMV events during prophylaxis experience a worse prognosis.

The kidney in diabetes: dynamic pathways of injury and repair. The Camillo Golgi Lecture 2007.

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD). The natural history of diabetic nephropathy has changed over the last decades, as a consequence of better metabolic and blood pressure management. Thus, it may now be possible to delay or halt the progression towards ESRD in patients with overt diabetic nephropathy, and the decline of renal function is not always inexorable and unavoidable. Also, the rate of progression from microalbuminuria to overt nephropathy is much lower than originally estimated in the early 80s. Furthermore, there is now evidence that it is possible, in humans, to obtain reversal of the established lesions of diabetic nephropathy. This review focuses on the contribution of kidney biopsy studies to the understanding of the pathogenesis and natural history of diabetic nephropathy and the identification of patients at high risk of progression to ESRD. The classic lesions of diabetic nephropathy and the well-established structural-functional relationships in type 1 diabetes will be briefly summarised and the renal lesions leading to renal dysfunction in type 2 diabetes will be described. The relevance of these biopsy studies to diabetic nephropathy pathogenesis will be outlined. Finally, the evidence and the possible significance of reversibility of diabetic renal lesions will be discussed, as well as future directions for research in this field.

Risk predictors in patients with diabetic nephropathy.

Diabetic nephropathy is currently the most common cause of end-stage renal disease in the Western countries. Only approximately one third of patients with type 1 diabetes develop nephropathy; thus, because it is not feasible to aggressively treat all patients, it becomes very important to find early markers in order to identify patients at high nephropathy risk. To date the best available predictor of overt nephropathy is microalbuminuria. In this article we review the validity of microalbuminuria as a predictor of overt nephropathy and consider other markers of nephropathy risk.

Cellular basis of diabetic nephropathy: III. In vitro GLUT1 mRNA expression and risk of diabetic nephropathy in type 1 diabetic patients.

AIMS/HYPOTHESIS: Altered glucose transporter expression has been implicated in the pathogenesis of diabetic nephropathy. There is increasing evidence that genetic factors convey risk of, or protection from, diabetic nephropathy and that the behaviour of cultured skin fibroblasts from type 1 diabetic patients may reflect these genetic influences. This study aimed to compare GLUT1 mRNA expression levels in skin fibroblasts from type 1 diabetic patients with either rapid ("fast-track", n=25) or slow ("slow-track", n=25) development of diabetic nephropathy and from non-diabetic normal control subjects (controls, n=25). METHODS: Skin fibroblasts were cultured in Dulbecco's Modified Eagle's Medium with 25 mmol/l glucose for 36 h. Total RNA was isolated, and GLUT1 mRNA levels were estimated by microarray analysis and RT-PCR. RESULTS: Levels of GLUT1 mRNA expression in skin fibroblasts from "slow-track" patients were greater than those from "fast-track" patients (p=0.02), as initially detected by microarray. GLUT1 mRNA expression levels were confirmed by RT-PCR to be higher in skin fibroblasts from "slow-track" patients (4.59+/-2.04) than in those from "fast-track" patients (3.34+/-1.2, p=0.02), and were also higher than in skin fibroblasts from control subjects (3.52+/-1.66, p=0.03). There was no statistically significant difference between levels of expression in the "fast-track" patients and the control subjects. CONCLUSIONS/INTERPRETATION: This finding is consistent with the presence of cellular protection factors against diabetic nephropathy in the "slow-track" patients. These factors could be associated with the regulation of the GLUT1 pathway and may be genetically determined.

Post-partum thyroiditis in South Brazil presenting as thyrotoxicosis: prevalence and risk factors.

The prevalence of post-partum thyroiditis (PPT) has been reported in several countries (1.9 to 16.7%) but is not known in Brazil. Several factors have been associated to its development, such as a female sex of the newborn, PPT in a previous pregnancy, a family history of thyroid disease and cigarette smoking. To investigate the prevalence of PPT and its risk factors in a southern Brazilian city, a three-cross-sectional observation study was performed. PPT was diagnosed in 14/284 subjects (5.3%) and all cases had thyrotoxicosis (13 sub-clinical and one clinical). Serum total T4 and free T4 were higher and serum TSH was lower in PPT subjects. Anti-thyroid antibodies were positive in 16.7% of PPT subjects and in 4.5% of those with no thyroid dysfunction. Goiter was identified in 14.3% of PPT subjects and in 15% of no PPT subjects. Thyroid was hardened more frequently in PPT subjects (21.4%) than in others (5.2%). Male sex of the newborn was associated to PPT, increasing 11 times the risk of PPT. Cigarette smoking was associated to PPT in group II subjects. There was no clinical sign or symptom able to contribute to this diagnosis, except the presence of hardened thyroid. Based on these findings, PPT, manifesting itself as mild thyrotoxicosis, is a common problem in southern Brazil and is associated to male sex of the newborn.