Secular Trends in Infection-Related Mortality after Kidney Transplantation.

BACKGROUND AND OBJECTIVES: Infections are the most common noncardiovascular causes of death after kidney transplantation. We analyzed the current infection-related mortality among kidney transplant recipients in a nationwide cohort in Finland. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Altogether, 3249 adult recipients of a first kidney transplant from 1990 to 2012 were included. Infectious causes of death were analyzed, and the mortality rates for infections were compared between two eras (1990-1999 and 2000-2012). Risk factors for infectious deaths were analyzed with Cox regression and competing risk analyses. RESULTS: Altogether, 953 patients (29%) died during the follow-up, with 204 infection-related deaths. Mortality rate (per 1000 patient-years) due to infections was lower in the more recent cohort (4.6; 95% confidence interval, 3.5 to 6.1) compared with the older cohort (9.1; 95% confidence interval, 7.6 to 10.7); the incidence rate ratio of infectious mortality was 0.51 (95% confidence interval, 0.30 to 0.68). The main causes of infectious deaths were common bacterial infections: septicemia in 38% and pulmonary infections in 45%. Viral and fungal infections caused only 2% and 3% of infectious deaths, respectively (such as individual patients with Cytomegalovirus pneumonia, Herpes simplex virus meningoencephalitis, Varicella zoster virus encephalitis, and Pneumocystis jirovecii infection). Similarly, opportunistic bacterial infections rarely caused death; only one death was caused by Listeria monocytogenes, and two were caused by Mycobacterium tuberculosis. Only 23 (11%) of infection-related deaths occurred during the first post-transplant year. Older recipient age, higher plasma creatinine concentration at the end of the first post-transplant year, diabetes as a cause of ESKD, longer pretransplant dialysis duration, acute rejection, low albumin level, and earlier era of transplantation were associated with increased risk of infectious death in multivariable analysis. CONCLUSIONS: The risk of death due to infectious causes after kidney transplantation in Finland dropped by one half since the 1990s. Common bacterial infections remained the most frequent cause of infection-related mortality, whereas opportunistic viral, fungal, or unconventional bacterial infections rarely caused deaths after kidney transplantation.

Transferrin receptor expression on reticulocytes as a marker of iron status in dialyzed patients.

BACKGROUND: Erythropoietin therapy should be accompanied by an adequate iron supply in order to avoid functional iron deficiency (FID) related to enhanced erythropoiesis. Therefore, accurate monitoring of the body's iron homeostasis is needed. This study was conducted to investigate whether transferrin receptor (TfR) expression on reticulocytes can reflect iron status in patients with chronic renal failure (CRF). METHODS: TfR expression [antibody binding capacity (ABC)] and the proportion of TfR positive reticulocytes (%TfR+ Ret) relative to all reticulocytes were measured by a quantitative flow cytometric method at baseline and at 3 weeks in 34 dialysis patients. Iron status (plasma ferritin and soluble TfR) and hemoglobin (Hb) with advanced cellular indices, such as the percentage of hypochromic reticulocytes (%HYPOr) and cellular Hb in reticulocytes (CHr), were also analyzed. RESULTS: Patients with FID had significantly higher TfR ABC and %TfR+ Ret compared with patients with replete iron status (p=0.034 and p=0.006, respectively). In patients whose Hb concentrations showed a reduction, the mean increase (3 weeks- baseline) in TfR ABC was four-fold higher and %TfR(+)Ret was three-fold higher when compared with patients whose Hb was stable or had increased. The changes in TfR expression correlated significantly with the changes in reticulocyte indices [CHr (negatively), %HYPOr (positively)] and plasma ferritin (negatively). CONCLUSIONS: Reticulocyte TfR expression reflected the changes in the Hb level and the iron availability at the cellular level, and therefore it might be useful in the assessment of iron status in patients with CRF.

Improved survival of type 2 diabetic patients on renal replacement therapy in Finland.

BACKGROUND: Survival of type 2 diabetes mellitus patients on maintenance dialysis therapy is poor mainly due to cardiovascular events. The aim was to examine whether survival of type 2 diabetes patients on renal replacement therapy (RRT) in Finland has improved during 1995-2005. METHODS: Patients who entered RRT because of type 2 diabetes mellitus in 1995-99 (n = 314) and 2000-05 (n = 583) were identified within the Finnish Registry for Kidney Diseases. The two cohorts were followed up from start of RRT until death or end of follow-up on 31 December 2006. Survival probabilities and probabilities of receiving a kidney transplant were calculated using Kaplan-Meier curves. Multivariate modelling was performed using Cox regression. RESULTS: Patients who entered RRT in 2000-05 had lower risk of dying than those who entered in 1995-99; hazard ratio (HR) was 0.76 (95% CI 0.65-0.89) and 0.74 (95% CI 0.63-0.87) with adjustment for age and gender. The decreased risk of death was most obvious in age groups 55-64 (HR 0.67, 95% CI 0.49-0.92) and 65-74 years (HR 0.69, 95% CI 0.56-0.87). Adjustment for albumin in addition to age and gender only slightly weakened the effect of study periods (HR 0.83, 95% CI 0.69-1.01). The patients in 2000-05 were more obese, had lower total and LDL cholesterol and higher HDL cholesterol and albumin concentration in serum than patients in 1995-99. Patients' probability to receive a kidney transplant was low in both groups. CONCLUSIONS: Survival of type 2 diabetes patients on RRT improved during the time period 1995-2005 in Finland while the probability of receiving a kidney transplant remained low and unchanged.

Infrapopliteal balloon angioplasty for chronic critical limb ischemia in diabetic patients with uremia: when is it worth the effort?

PURPOSE: To assess the utility of infrapopliteal percutaneous transluminal angioplasty (PTA) in diabetic patients with end-stage renal disease and chronic critical limb ischemia. MATERIALS AND METHODS: Between 1994 and 2003, 20 consecutive diabetic patients with uremia (mean age, 59 years; age range, 39-73 years) underwent infrapopliteal PTA (total of 26 limbs). Additional infrainguinal lesions were treated in 12 limbs. Three limbs (12%) were classified as having Rutherford category 4 ischemia, 19 (73%) as having category 5 ischemia, and four (15%) as having category 6 ischemia. The mean length of the 58 treated infrapopliteal lesions was 8.8 cm. RESULTS: Angiographic success (<30% residual stenosis) was achieved in 22 of the 26 limbs (85%) and primary clinical success (at least one Rutherford category improvement) was achieved in nine (35%). One major complication was encountered. PTA was successful in producing a patent artery to the ankle level in 18 limbs. Primary clinical success was achieved in eight of those 18 limbs (44%) versus only one of the eight limbs (13%) with no patent artery after angioplasty (P = .01). When including the four repeated interventions, the clinical patency at 1 year (based on physical findings) was 38% (10 of 26 limbs). The rate of major amputations at 3, 6, and 12 months was 23%, 31%, and 35%, respectively, with a tendency of increased frequency among patients treated for more severe ischemia (Rutherford 4 vs 5 vs 6, P = .10). CONCLUSIONS: In diabetic patients with uremia, infrapopliteal PTA should be restricted to limbs without extensive tissue loss with lesions estimated to facilitate accomplishment of at least one patent artery to the ankle level.

Endovascular salvage of nonmaturing autogenous hemodialysis fistulas: comparison with endovascular therapy of failing mature fistulas.

PURPOSE: To evaluate the utility of endovascular salvage of nonmaturing autogenous hemodialysis fistulas in a prospective trial of consecutive patients compared with a historical group of patients who underwent treatment of failing mature autogenous fistulas. MATERIALS AND METHODS: During a 12-year period, angiography revealed anatomic lesions in 75 fistulas with maturing problems (72 radiocephalic and three brachiocephalic). Endovascular therapy through antegrade arterial access was attempted in 72 fistulas. A series of 45 consecutive patients who underwent endovascular salvage of failing mature fistulas was used as a control group. RESULTS: A technical success rate of 88% (66 of 75) and a clinical success rate of 87% (65 of 75) were achieved for the nonmaturing fistulas. Including the secondary interventions, the rate of complications was 6.1% (eight of 131). By Kaplan-Meier analysis, the primary clinical patency rates were 43% +/- 6% (+/-SEM), 36% +/- 6%, and 23% +/- 6%, and the secondary patency rates were 76% +/- 5%, 68% +/- 6%, and 57% +/- 8% at 6, 12, and 36 months, respectively. A small inflow artery (<3 mm in diameter) predicted a poorer primary patency rate (28% +/- 10% vs 48% +/- 9% at 1 year; P = .01). The secondary patency rate of nonmaturing fistulas at 3 years was worse than that of mature fistulas, at 57% +/- 8% versus 79% +/- 8% (P = .02). CONCLUSIONS: A functional fistula was achieved in 87% of nonmaturing fistulas. Although the functional time gained in these fistulas is shorter than that gained in failing mature fistulas, more than half of nonmaturing fistulas are functional after 3 years.

Discontinuation of dialysis treatment: experience of a single dialysis centre.

OBJECTIVE: Discontinuation of dialysis is a common cause of death in end-stage renal disease (ESRD) patients in the USA and UK, but is less common in the rest of Europe and in Japan. The aim of this study was to describe the discontinuation pattern in a single dialysis unit in eastern Finland. MATERIAL AND METHODS: We retrospectively analysed the case history and cause of death of 146 dialysis patients in whom dialysis treatment was started between 1992 and 2001 and who had died by March 2003. We compared patients who died after withdrawal from dialysis and those who continued dialysis until death. RESULTS: In 53 patients (36.3%) dialysis treatment was discontinued before death (withdrawal group). In the rest of the patients (control group; n=93) dialysis was continued until death. The patients in the withdrawal group were older (median 69 vs 65 years at the onset of ESRD), more often institutionalized before death (49% vs 11.8%) and more often had dementia diagnosed before death (20.8% vs 2.2%) than those in the control group. They were also less rehabilitated before death (54.7% vs 76.7%) and their treatment more often lasted for <3 months (20.8% vs 7.6%). The patients in the withdrawal group died less often of cardiac disease (11.3% vs 39.8%), whereas kidney disease was the commonest cause of death (41.5 vs 19.4%). The commonest reason for discontinuation of dialysis was severe medical illness (86.5%). In most cases the nephrologist or the renal team raised the issue of stopping dialysis. Nearly 70% of patients were incompetent at the time of the decision. Patient refusal to stop dialysis was uncommon. CONCLUSIONS: Stopping dialysis before death is a common practice in our unit. Dialysis was mostly discontinued in severely ill patients who were near the end of their life. The nephrologist or the renal team decided to stop treatment. Our results should encourage renal teams to raise the issue of stopping dialysis when a patient's illness has become terminal. More studies and discussion of this difficult field are needed.

The Val103Ile polymorphism of melanocortin-4 receptor regulates energy expenditure and weight gain.

OBJECTIVE: The melanocortin-4 receptor (MC4R) regulates energy intake. On the basis of animal studies, it may also regulate energy expenditure. RESEARCH METHODS AND PROCEDURES: The effect of the Val103Ile polymorphism of the MC4R gene on energy metabolism was studied in 229 middle-aged nondiabetic subjects (Group 1, age 51.2 +/- 9.8 years, BMI 26.8 +/- 4.5 kg/m2) and on weight gain in 1013 elderly subjects (Group 2, age 69.9 +/- 2.9 years, BMI 27.4 +/- 4.1 kg/m2) during a 3.5-year follow-up study. In Group 1, insulin sensitivity, energy expenditure, and substrate oxidation were measured with the hyperinsulinemic euglycemic clamp combined with indirect calorimetry. RESULTS: In Group 1, the Val103Ile genotype was associated with high rates of energy expenditure (63.42 +/- 13.40 in eight subjects with the Val103Ile genotype vs. 59.86 +/- 7.33 J/kg per minute in 221 subjects with the Val103Val genotype, p = 0.007), high rates of glucose oxidation (8.90 +/- 6.15 vs. 6.07 +/- 4.38 micromol/kg per minute, p = 0.020), and low levels of free fatty acids (0.45 +/- 0.18 vs. 0.56 +/- 0.23 mM, p = 0.029) in the fasting state, and with high rates of glucose oxidation during the clamp (18.88 +/- 4.63 vs. 17.60 +/- 3.24 micromol/kg per minute, p = 0.031). In Group 2, the 103Ile allele was associated with an increase in weight gain during the follow-up (0.78 +/- 3.98 vs. -0.82 +/- 3.98 kg, p = 0.038). DISCUSSION: The Val103Ile polymorphism of the MC4R gene is associated with energy expenditure in humans. Furthermore, it may associate with glucose oxidation, free fatty acid levels, and weight gain.

The effect of the -308A allele of the TNF-alpha gene on insulin action is dependent on obesity.

OBJECTIVE: Promoter polymorphisms of the tumor necrosis factor alpha (TNF-alpha) gene are associated with insulin sensitivity and BMI. We investigated whether the effect of the G-308A polymorphism of the TNF-alpha gene on insulin action depends on BMI. RESEARCH METHODS AND PROCEDURES: The effects of the G-308A polymorphism on the rates of glucose and lipid oxidation and free fatty acid (FFA) levels were studied using the hyperinsulinemic euglycemic clamp combined with indirect calorimetry in 129 healthy subjects. RESULTS: The -308A allele of the TNF-alpha gene was associated with high rates of glucose oxidation (p = 0.008 adjusted for age, gender, and BMI) and lipid synthesis (p = 0.037) and suppression of FFA levels (p = 0.023) during hyperinsulinemia. In normal weight subjects (BMI < 26 kg/m(2)), the -308 allele was associated with high rates of glucose oxidation (p = 0.036) during the clamp but not with high rates of lipid synthesis (p = 0.896) or FFA suppression (p = 0.464). In overweight subjects (BMI >or= 26 kg/m(2)), high rates of lipid synthesis and FFA suppression (p = 0.010 and p = 0.042, respectively) but not the rates of glucose oxidation during the clamp (p = 0.193) were associated with the -308A allele. DISCUSSION: The -308A allele of the promoter of the TNF-alpha gene is associated with high rates of glucose oxidation in normal weight subjects and with effective lipid storage in overweight subjects. These findings suggest an interaction of the polymorphism with obesity.

The Leu7Pro polymorphism of the neuropeptide Y gene regulates free fatty acid metabolism.

The Leu7Pro polymorphism in the signal peptide of the preproneuropeptide Y (NPY) has been associated with dyslipidemias and free fatty acid (FFA) levels during exercise. The association of this polymorphism with insulin sensitivity has not been studied. In this study, the Leu7Pro polymorphism was determined in 2 groups of nondiabetic middle-aged subjects (n = 266 and n = 295). Insulin sensitivity was measured with the hyperinsulinemic euglycemic clamp (n = 266) or with an intravenous glucose tolerance test (IVGTT, n = 295). First-phase insulin secretion was determined as insulin area under the curve (AUC) during the first 10 minutes of the IVGTT. FFAs were measured both in the fasting state and during the hyperinsulinemic clamp. The Leu7Pro polymorphism of the NPY gene was not associated with the rates of whole body glucose uptake, insulin sensitivity index, insulin secretion during the IVGTT, or insulin AUC during the oral glucose tolerance test. However, the Pro7 allele was associated with low FFA levels both in the fasting state (P =.043) and during the hyperinsulinemic clamp (P =.003). In conclusion, the Leu7Pro polymorphism of the NPY gene associates with alterations in FFA metabolism but does not have an impact on insulin sensitivity, insulin secretion, or glucose metabolism.

The K121Q polymorphism of the PC-1 gene is associated with insulin resistance but not with dyslipidemia.

OBJECTIVE: To investigate the relationship of the K121Q polymorphism of the plasma cell glycoprotein 1 (PC-1) gene with insulin resistance, insulin secretion, and lipids and lipoproteins. RESEARCH DESIGN AND METHODS: Altogether, 110 normoglycemic subjects (group I) underwent a hyperinsulinemic-euglycemic clamp for evaluation of insulin sensitivity. The first-phase insulin secretion was determined by the intravenous glucose tolerance test (IVGTT) in a separate sample of 295 normoglycemic subjects (group II). RESULTS: The 121Q allele (genotypes K121Q and Q121Q) compared with the K121K genotype was related to higher fasting insulin levels (group I: 69.6 +/- 45.6 vs. 51.9 +/- 28.4 pmol/l [mean +/- SD], P = 0.050; group II: 66.6 +/- 38.8 vs. 53.8 +/- 26.6 pmol/l, P = 0.009). In group I, subjects carrying the 121Q allele compared with subjects with the K121K genotype had lower rates of whole-body glucose uptake (51.17 +/- 12.07 vs. 60.12 +/- 14.86 micro mol x kg(-1) x min(-1), P = 0.012) and nonoxidative glucose disposal (33.71 +/- 10.51 vs. 41.51 +/- 13.36 micro mol x kg(-1) x min(-1), P = 0.015) during the clamp. In group II, there was no significant difference between the 121Q allele carriers and subjects with the K121K genotype in total first-phase insulin secretion during the first 10 min of the IVGTT (2,973 +/- 2,224 vs. 2,520 +/- 1,492 pmol. l(-1). min(-1), P = 0.415). No association of the K121Q polymorphism with serum lipids and lipoproteins was found. CONCLUSIONS: In healthy normoglycemic Finnish subjects, the K121Q polymorphism of the PC-1 gene is associated with insulin resistance but not with impaired insulin secretion or dyslipidemia.

The C-174G promoter polymorphism of the IL-6 gene affects energy expenditure and insulin sensitivity.

Interleukin-6 (IL-6) is a pleiotropic cytokine expressed in many tissues. IL-6 null mice show low energy expenditure, but the effect of the variants of the IL-6 gene on energy expenditure has not been previously studied in humans. Therefore, we investigated the effect of the C-174G promoter polymorphism of the IL-6 gene on energy expenditure, measured by indirect calorimetry in healthy Finnish subjects (n = 124). We also measured insulin sensitivity by the hyperinsulinemic-euglycemic clamp. Subjects with the C-174C genotype of the IL-6 gene had significantly lower energy expenditure than subjects with the G-174C or G-174G genotypes both in fasting (CC 13.68 +/- 1.98, CG 14.73 +/- 1.57, GG 14.81 +/- 2.01 kcal x kg(-1) x min(-1); P = 0.012) and during the euglycemic-hyperinsulinemic clamp (CC 15.24 +/- 2.05, CG 16.62 +/- 2.06, GG 16.66 +/- 2.50 kcal x kg(-1) x min(-1); P = 0.007). Moreover, subjects homozygous for the C allele had lower rates of whole-body glucose uptake than carriers of the G allele (CC 50.95 +/- 13.91, CG 59.40 +/- 14.17, GG 59.21 +/- 15.93 micro mol x kg(-1) x min(-1); P = 0.016). The rates of both oxidative (P = 0.013) and nonoxidative (P = 0.016) glucose disposal were significantly affected by the IL-6 promoter polymorphism. In conclusion, the C-174C promoter polymorphism of the IL-6 gene influences energy expenditure and insulin sensitivity in healthy normoglycemic subjects. Whether this polymorphism is a risk factor for obesity or type 2 diabetes can be estimated only in prospective population-based studies.