Bruna Bellincanta Nicoletto

Effects of obesity on kidney transplantation outcomes: a systematic review and meta-analysis.

Background The effects of obesity on outcomes reported after kidney transplantation have been controversial. The purpose of this systematic review and meta-analysis was to elucidate this issue. Methods MEDLINE, EMBASE, Cochrane Library, and gray literature were searched up to August 6, 2013. Studies that compared obese and nonobese patients who underwent kidney transplantation and evaluated one of these outcomes—delayed graft function (DGF), acute rejection, graft or patient survival at 1 or 5 years after transplantation, or death by cardiovascular disease (CVD)—were included. Two independent reviewers extracted the data and assessed the quality of the studies. Results From 1,973 articles retrieved, 21 studies (9,296 patients) were included. Obesity was associated with DGF (relative risk, 1.41; 95% confidence interval, 1.26–1.57; I2=8%; Pheterogeneity=0.36), but not with acute rejection. Graft loss and death were associated with obesity only in the analysis of studies that evaluated patients who received a kidney graft before year 2000. No association of obesity with graft loss and death was found in the analysis of studies that evaluated patients who received a kidney graft after year 2000. Death by CVD was associated with obesity (relative risk, 2.07; 95% confidence interval, 1.17–3.64; I2=0%; Pheterogeneity=0.59); however, most studies included in this analysis evaluated patients who received a kidney graft after year 2000. Conclusion In conclusion, obese patients have increased risk for DGF. In the past years, obesity was a risk factor for graft loss, death by CVD, and all-cause mortality. However, for the obese transplanted patient today, the graft and patient survival is the same as that of the nonobese patient.

Association between 276G/T adiponectin gene polymorphism and new-onset diabetes after kidney transplantation.

Background New-onset diabetes after transplantation (NODAT) is a well-recognized complication of kidney transplantation and is associated with poor outcomes. Both adiponectin and chemokine ligand 5 (CCL5) proteins are related to glucose metabolism and genetic variations in their genes can lead to development of NODAT. The aim of this study was to investigate the association of adiponectin and CCL5 genes polymorphisms with NODAT in a population of Caucasian kidney transplant recipients. Methods Two hundred seventy Caucasian kidney transplant recipients (83 with NODAT and 187 without NODAT) were included in a nested case-control study. Patients with pretransplantation diabetes mellitus and multiorgan transplantation were excluded. NODAT diagnosis was determined by American Diabetes Association criteria. Subjects were genotyped for 276G/T adiponectin gene polymorphism (rs1501299) and rs2280789 and rs3817655 CCL5 gene polymorphisms by real-time polymerase chain reaction. Results The TT genotype of 276G/T adiponectin gene polymorphism was significantly more frequent in NODAT than non-NODAT patients compared with GG/GT genotypes (recessive model; P=0.031). TT genotype was identified as an independent risk factor for NODAT in Caucasian kidney transplant recipients after adjusting for age at transplantation, pretransplantation body mass index, and use of tacrolimus (TT vs. GG/GT, hazard ratio=1.88, 95% confidence interval=1.03–3.45, P=0.041). There were no differences in genotype distribution and allele frequency of rs2280789 and rs3817655 CCL5 gene polymorphisms between NODAT and non-NODAT groups. Conclusions The 276G/T adiponectin gene polymorphism is associated with NODAT in Caucasian kidney transplant recipients.

The role of progranulin in diabetes and kidney disease.

Progranulin (PGRN) is a cysteine rich secreted protein, expressed in epithelial cells, immune cells, neurons, and adipocytes. It was first identified for its growth factor-like properties, being involved in early embryogenesis and tissue remodeling, acting as an anti-inflammatory molecule. In the central nervous system, PGRN has neurotrophic and neuroprotective actions. There is also evidence of PGRN effects on cancer, contributing to tumor proliferation, invasion and cell survival. Recently, PGRN was recognized as an adipokine related to obesity and insulin resistance, revealing its metabolic function and pro-inflammatory properties. In obesity and type 2 diabetes mellitus, PGRN levels are increased. In renal disease, there is a relevant association, however, it is not known if it could contribute to kidney damage or if it is only a route of PGRN elimination. PGRN is an emerging molecule which demands studies in different fields. Possibly, it plays distinct functions in different tissues/cells and metabolic conditions. Here, we discuss potential mechanisms and recent data of PGRN pro-inflammatory actions, regarding obesity, insulin resistance, type 2 diabetes mellitus and kidney disease.

Leptin, Insulin Resistance, and Metabolic Changes 5 Years After Renal Transplantation

OBJECTIVE To evaluate leptin, insulin resistance (IR), and changes in body composition and lipid profile within 5 years after renal transplantation. DESIGN Longitudinal study. SETTING Hospital de Clínicas de Porto Alegre/RS, Brazil. SUBJECTS Thirty-two renal transplant recipients were followed up for 5 years after transplantation. METHODS Data were collected at transplantation time (T₁) and after 3 months (T₂), 1 year (T₃), and 5 years (T₄). Leptin serum levels, IR assessed by homeostasis model assessment (HOMA) index, lipid profile, and anthropometric measurements were analyzed. Data were compared with a control group at baseline. RESULTS At T₁, pretransplant patients had leptin levels (ng/mL) (11.9 [9.2 to 25.2]) higher than the control group (7.7 [5.2 to 9.9]; P < .0001). After transplantation, levels decreased at T₂ and T₃, but increased at T₄ to values similar to those seen at T₁ (T₄: 9.2 [5.7 to 21]; P = 1). HOMA also decreased at T₂, but increased at T₄ to identical levels (T₁: 2.1 [1.63 to 2.23], T₄: 2.1 [1.6 to 2.85]; P = 1). No significant changes in body fat percentage (BF%) were observed; however, the arm muscle circumference increased significantly at T₄ (P < .0001). At T₂, total cholesterol, triglycerides, and low-density lipoprotein cholesterol increased, whereas at T₄, lipid profile moved toward T₁ levels. By linear regression analysis, gender, BF%, and HOMA were independent predictors of leptin levels. A trend toward higher body mass index was observed in woman who also presented higher leptin and lower HOMA levels. CONCLUSION Leptin levels and HOMA decrease in the immediate posttransplant period and remain reduced for at least 1 year. Five years post transplantation, leptin, IR, BF%, and lipids have a profile similar to those in the pretransplant period. This metabolic profile is possibly associated with the elevated incidence of cardiovascular diseases observed in the late posttransplant period.

Effects of metabolic syndrome on kidney transplantation outcomes: a systematic review and meta-analysis.

Metabolic syndrome (MS) has been associated with proteinuria and reduced glomerular filtration rate. Immunosuppressive agents increase the incidence of traditional risk factors for cardiovascular disease (CVD) and have known effects on MS components after kidney transplantation. The purpose of this meta‐analysis was to evaluate the impact of MS on relevant outcomes after kidney transplantation. MEDLINE, EMBASE, and Cochrane Library were searched up to November 7, 2015. Papers that compared patients with and without MS and assessed one of the following outcomes, graft loss, death by cardiovascular disease, and all‐cause mortality, were included. Of 585 studies identified, five studies including 1269 patients were evaluated. MS was identified as a risk factor for graft loss [relative risk, 3.06; 95% confidence interval (CI), 2.17, 4.32; I² = 0%; P heterogeneity = 0.72] and death by CVD (relative risk, 3.53; 95% CI, 1.27, 9.85; I² = 0%; P heterogeneity = 0.40). Results on the association between MS and all‐cause mortality were inconclusive (relative risk, 2.61; 95% CI, 0.70, 9.81; I² = 58%; P heterogeneity = 0.09). Graft loss and death by CVD were associated with the presence of MS after transplantation. Randomized clinical trials should be conducted to define whether interventions on each MS component would result in better outcomes after transplantation.

Serum and Urinary Progranulin in Diabetic Kidney Disease

Progranulin has been recognized as an adipokine related to obesity, insulin resistance and type 2 diabetes mellitus (T2DM). There are scarce data regarding progranulin and kidney disease, but there are some data linking diabetic kidney disease (DKD) and increased progranulin levels. We aimed to better describe the relationship between serum and urinary progranulin levels and DKD in T2DM. This is a case-control study including four groups of subjects: 1) Advanced DKD cases: T2DM patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2; 2) Albuminuric DKD cases: T2DM patients with urinary albumin excretion (UAE) ≥30 mg/g creatinine and eGFR ≥60 mL/min/1.73m2; 3) Diabetic controls: T2DM patients with UAE <30 mg/g creatinine and eGFR ≥60 mL/min/1.73m2; and 4) Non-diabetic controls: individuals without T2DM. Progranulin was determined by enzyme-linked immunosorbent assay. One hundred and fourteen patients were included (23 advanced DKD cases, 25 albuminuric DKD cases, 40 diabetic controls and 26 non-diabetic controls). Serum progranulin was increased in advanced DKD compared to other groups [70.84 (59.04–83.16) vs. albuminuric cases 57.16 (42.24–67.38), diabetic controls 57.28 (42.08–70.47) and non-diabetic controls 44.54 (41.44–53.32) ng/mL; p<0.001]. Urinary progranulin was decreased in advanced DKD cases compared to albuminuric cases [10.62 (6.30–16.08) vs. 20.94 (12.35–30.22); diabetic controls 14.06 (9.88–20.82) and non-diabetic controls 13.51 (7.94–24.36) ng/mL; p = 0.017]. There was a positive correlation between serum progranulin and body mass index (r = 0.27; p = 0.004), waist circumference (r = 0.25; p = 0.007); body fat percentage (r = 0.20; p = 0.042), high-sensitive C reactive protein (r = 0.35; p<0.001) and interleukin-6 (r = 0.37; p<0.001) and a negative correlation with eGFR (r = -0.22; p = 0.023). Urinary progranulin was positively associated with albuminuria (r = 0.25; p = 0.010). In conclusion, progranulin is affected by a decrease in eGFR, being at a higher concentration in serum and lower in urine of DKD patients with T2DM and eGFR <60 mL/min/1.73m2. It is also associated with markers of obesity and inflammation.

Association between the ENPP1 K121Q polymorphism and risk of diabetic kidney disease : a systematic review and meta-analysis

The potential association between the K121Q (A/C, rs1044498) polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) gene and risk of diabetic kidney disease (DKD) has been investigated. Nevertheless, the effect of this variant on DKD risk is still under debate, and conflicting results have been reported. To this date, no meta-analysis has evaluated the association of the K121Q polymorphism with DKD. This paper describes the first meta-analysis conducted to evaluate whether the ENPP1K121Q polymorphism is associated with DKD. A literature search was conducted to identify all case-control or cross-sectional studies that evaluated associations between the ENPP1K121Q polymorphism and DKD. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for allele contrast, additive, dominant and recessive inheritance models. Seven studies were eligible for inclusion in the meta-analysis, providing data on 3571 type 1 or type 2 diabetic patients (1606 cases with DKD and 1965 diabetic controls without this complication). No significant heterogeneity was observed among the studies included in the meta-analysis when assuming different inheritance models (I² < 50% or P > 0.10 for the entire sample and after stratification by ethnicity). Meta-analysis results revealed significant associations between the K121Q polymorphism and risk of DKD in Asians and Europeans when assuming the different inheritance models analyzed. The most powerful association was observed for the additive model (OR = 1.74, 95% CI 1.27-2.38 for the total sample). In conclusion, the present meta-analysis detected a significant association between the ENPP1K121Q polymorphism and increased susceptibility of DKD in European and Asian populations.

Association between progranulin serum levels and dietary intake

Introduction Progranulin (PGRN) is secreted by adipose tissue and has been linked to obesity, insulin resistance and type 2 diabetes mellitus. There is evidence that a high fat diet increases PGRN expression in rodent adipose tissue. In humans, the relationship between diet composition and concentration of PGRN is still unknown. Objective To investigate the association between dietary intake and serum PGRN levels. Methods This is an exploratory cross-sectional study including 85 subjects. Demographic, clinical, laboratory and anthropometric data were collected. Serum PGRN was determined by enzyme-linked immunosorbent assay after overnight fasting. Dietary intake was assessed by food frequency questionnaire validated for Brazilian southern population. Focused principal component analyses (FPCA) was used to verify the association of dietary components and food groups with PGRN levels. Sensitivity analyses were performed including only subjects with reporting according to the Goldberg and Black cut-offs of energy intake-energy expenditure ratio between 0.76 and 1.24. Results The median PGRN was 51.96 (42.18 to 68.30) ng/mL. Analyzing all sample, the FPCA showed no association of serum PGRN with total energy, protein, carbohydrate, fat and its types, fiber intake and dietary glycemic index; but a significant and positive association between solid fats and PGRN levels (p<0.05). Including only subjects with reporting according cut-off of energy intake-energy expenditure ratio between 0.76 and 1.24, FCPA showed significant and positive association of serum PGRN with saturated fatty acids and solid fats intake (p<0.05). In this subgroup, PGRN correlated with saturated fatty acids (r = 0.341; p = 0.031). Solid fats intake was independently associated to serum PGRN (beta = 0.294; p = 0.004) in multivariate model. Conclusion The dietary intake of solid fats, mainly represented by saturated fatty acids, is associated to serum PGRN concentration in human subjects.

Progranulin serum levels in human kidney transplant recipients: A longitudinal study

Background The adipokine progranulin has metabolic proprieties, playing a role in obesity and insulin resistance. Its levels seems to be dependent of renal function, since higher progranulin concentration is observed in patients with end-stage kidney disease. However, the effect of kidney transplantation on progranulin remains unknown. Objective To assess the serum progranulin levels in kidney transplant recipients before and after kidney transplantation. Methods Forty-six prospective kidney transplant recipients were included in this longitudinal study. They were evaluated before transplantation and at three and twelve months after transplantation. Clinical, anthropometric and laboratorial measurements were assessed. Progranulin was determined with enzyme-linked immunosorbent assays. Results Serum progranulin significantly decreased in the early period after transplantation (from 72.78 ± 2.86 ng/mL before transplantation to 40.65 ± 1.49 ng/mL at three months; p<0.01) and increased at one year (53.15 ± 2.55 ng/mL; p<0.01 vs. three months), remaining significantly lower than before transplantation (p<0.01) (pover time<0.01). At one year after transplantation, there was a significant increase in body mass index, trunk fat and waist circumference compared to immediate period after transplantation. Progranulin was associated with waist circumference and fasting plasma glucose after adjusted for age, gender, study period, glomerular filtration rate, interleukin-6, high sensitivity C reactive protein and adiponectin. Conclusion Progranulin serum levels are increased before transplantation and a reduction is observed in the early period after transplantation, possibly attributed to an improvement in renal function. At one year after transplantation, an increment in progranulin is observed, seems to be independent of glomerular filtration, and remained significantly lower than before transplantation.

Kidney transplantation and obesity: distinct measures at different periods are associated with dissimilar outcomes.

I the Letter to the Editor by Deetman et al, the authors discuss the influence of muscle mass on associations of body mass index (BMI) with outcomes after kidney transplantation. They found that BMI was associated with graft failure and mortality in kidney transplant recipients after adjustment for 24-hour urinary creatinine excretion. The authors suggest that these findings might provide an additional explanation for the absence of increased risk associated with obesity observed after year 2000, as reported in our systematic review and meta-analysis. We agree with the authors that BMI does not represent body composition and fat or muscle mass can influence outcomes after renal transplantation. Therefore, identifying the impact of muscle mass in posttransplantation outcomes is potentially relevant. Deetman et al measured the urinary creatinine excretion to estimate muscle mass in kidney transplant