Co-transplantation of Xenogeneic Bone Marrow-derived Mesenchymal Stem Cells Alleviates Rejection of Pancreatic Islets in Non-obese Diabetic Mice.

Bone marrow-mesenchymal stem cells (BM-MSCs) have generated a great perspective in the field of regenerative medicine, and also in the treatment of inflammatory and autoimmune diseases in the past decade due to their immunomodulatory and anti-inflammatory properties. Here, we investigated the effect of xenogeneic BM-MSCs and pancreatic islets co-transplantation obtained from Wistar rats in preventing rejection or inducing tolerance to islet transplantation in non-obese diabetic mice. Non-obese diabetic mice were treated with co-transplantation of pancreatic islets and BM-MSCs (islet + MSCs group) or pancreatic islets only (islet group). Compared to the islet group, islet + MSCs had a lower expression of inflammatory markers, such as, tumor necrosis factor- α (13.40 ± 0.57 vs. 9.90 ± 0.12, P = .01), monocyte chemoattractant protein 1 (51.30 ± 6.80 vs. 9.00 ± 1.80, P = .01), and interleukin 1ß (IL-1ß) (16.2 ± 1.65 vs. 6.80 ± 1.00, P = .04). Comparing the expression of immune tolerance markers, it is noted that animals receiving the co-transplantation showed a significantly higher expression than the islet group of IL-4 (25.60 ± 1.96 vs. 2.80 ± 0.20, P = .004), IL-10 (188.40 ± 4.60 vs. 4.55 ± 0.12, P = .0001), and forkhead box P3 (34.20 ± 1.3 vs. 1.30 ± 0.2, P = .004), respectively. These results suggest an immunomodulatory action of BM-MSC in islet xenotransplantation showing that these stem cells have the potential to mitigate the early losses of grafts, due to the regulation of the inflammatory process of transplantation.

Elevated levels of plasma osteoprotegerin are associated with all-cause mortality risk and atherosclerosis in patients with stages 3 to 5 chronic kidney disease

Osteoprotegerin (OPG) regulates bone mass by inhibiting osteoclast differentiation and activation, and plays a role in vascular calcification. We evaluated the relationship between osteoprotegerin levels and inflammatory markers, atherosclerosis, and mortality in patients with stages 3-5 chronic kidney disease. A total of 145 subjects (median age 61 years, 61% men; 36 patients on hemodialysis, 55 patients on peritoneal dialysis, and 54 patients with stages 3-5 chronic kidney disease) were studied. Clinical characteristics, markers of mineral metabolism (including fibroblast growth factor-23 [FGF-23]) and inflammation (high-sensitivity C-reactive protein [hsCRP] and interleukin-6 [IL-6]), and the intima-media thickness (IMT) in the common carotid arteries were measured at baseline. Cardiac function was assessed by color tissue Doppler echocardiography. After 36 months follow-up, the survival rate by Kaplan-Meier analysis was significantly different according to OPG levels (χ 2=14.33; P=0.002). Increased OPG levels were positively associated with IL-6 (r=0.38, P<0.001), FGF-23 (r=0.26, P<0.001) and hsCRP (r=0.0.24, P=0.003). In addition, OPG was positively associated with troponin I (r=0.54, P<0.001) and IMT (r=0.39, P<0.0001). Finally, in Cox analysis, only OPG (HR=1.07, 95%CI=1.02-1.13) and hsCRP (HR=1.02, 95%CI=1.01-1.04) were independently associated with increased risk of death. These results suggested that elevated levels of serum OPG might be associated with atherosclerosis and all-cause mortality in patients with chronic kidney disease.

Elevated levels of plasma osteoprotegerin are associated with all-cause mortality risk and atherosclerosis in patients with stages 3 to 5 chronic kidney disease.

Osteoprotegerin (OPG) regulates bone mass by inhibiting osteoclast differentiation and activation, and plays a role in vascular calcification. We evaluated the relationship between osteoprotegerin levels and inflammatory markers, atherosclerosis, and mortality in patients with stages 3-5 chronic kidney disease. A total of 145 subjects (median age 61 years, 61% men; 36 patients on hemodialysis, 55 patients on peritoneal dialysis, and 54 patients with stages 3-5 chronic kidney disease) were studied. Clinical characteristics, markers of mineral metabolism (including fibroblast growth factor-23 [FGF-23]) and inflammation (high-sensitivity C-reactive protein [hsCRP] and interleukin-6 [IL-6]), and the intima-media thickness (IMT) in the common carotid arteries were measured at baseline. Cardiac function was assessed by color tissue Doppler echocardiography. After 36 months follow-up, the survival rate by Kaplan-Meier analysis was significantly different according to OPG levels (χ ² =14.33; P=0.002). Increased OPG levels were positively associated with IL-6 (r=0.38, P<0.001), FGF-23 (r=0.26, P<0.001) and hsCRP (r=0.0.24, P=0.003). In addition, OPG was positively associated with troponin I (r=0.54, P<0.001) and IMT (r=0.39, P<0.0001). Finally, in Cox analysis, only OPG (HR=1.07, 95%CI=1.02-1.13) and hsCRP (HR=1.02, 95%CI=1.01-1.04) were independently associated with increased risk of death. These results suggested that elevated levels of serum OPG might be associated with atherosclerosis and all-cause mortality in patients with chronic kidney disease.

Raising awareness of chronic kidney disease in a Brazilian urban population.

The incidence and prevalence of chronic kidney disease have been increasing in recent years in developing countries. The aim of this study was to report the results of a general chronic kidney disease awareness program applied to an urban population in a large Brazilian city. From January 2002 to January 2005 a total of 8883 individuals in the city of Curitiba (PR, Brazil) were screened for hypertension, body mass index, hematuria, and proteinuria. A family history and previous medical diagnosis of hypertension and diabetes mellitus (DM) were also recorded. Of the 8883 individuals assessed, 56% were women, subject median age was 47 years (range: 17-93 years) and more than 90% were Caucasian. Thirty percent had signs of hematuria, 6% had proteinuria, and 3% had hematuria and proteinuria. The median of mean arterial pressure values was 93 mmHg (range: 71-135 mmHg) and 16% of the population screened had a history of hypertension. A significant positive family history of both hypertension or DM was present in 42% (P < 0.0001; chi-square = 83.18) and 7% (P < 0.0001; chi-square = 161.31) of the hypertensive group, respectively. Finally, the prevalence of hypertension and DM was significantly higher in older individuals with proteinuria. In the present study, a higher prevalence of hematuria and proteinuria was found in older individuals with hypertension and diabetes compared to the general population. These data confirm the need for public awareness of renal disease in high-risk individuals.

Raising awareness of chronic kidney disease in a Brazilian urban population

The incidence and prevalence of chronic kidney disease have been increasing in recent years in developing countries. The aim of this study was to report the results of a general chronic kidney disease awareness program applied to an urban population in a large Brazilian city. From January 2002 to January 2005 a total of 8883 individuals in the city of Curitiba (PR, Brazil) were screened for hypertension, body mass index, hematuria, and proteinuria. A family history and previous medical diagnosis of hypertension and diabetes mellitus (DM) were also recorded. Of the 8883 individuals assessed, 56% were women, subject median age was 47 years (range: 17-93 years) and more than 90% were Caucasian. Thirty percent had signs of hematuria, 6% had proteinuria, and 3% had hematuria and proteinuria. The median of mean arterial pressure values was 93 mmHg (range: 71- 135 mmHg) and 16% of the population screened had a history of hypertension. A significant positive family history of both hypertension or DM was present in 42% (P < 0.0001; chi-square = 83.18) and 7% (P < 0.0001; chi-square = 161.31) of thehypertensive group, respectively. Finally, the prevalence of hypertension and DM was significantly higher in older individuals with proteinuria. In the present study, a higher prevalence of hematuria and proteinuria was found in older individuals with hypertension and diabetes compared to the general population. These data confirm the need for public awareness of renal disease in high-risk individuals.

Increased plasma and endothelial cell expression of chemokines and adhesion molecules in chronic kidney disease.

Chemokines and adhesion molecules are involved in early events of atherogenesis. In the present study, we investigated the effects of the uremic milieu on the expression of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) and their relationship to cardiovascular status. Plasma samples were obtained from patients in different stages of chronic kidney disease (CKD). Cardiovascular status was evaluated by intima-media thickness and endothelial dysfunction by flow mediation dilatation and proteinuria. In vitro studies were performed using human umbilical endothelial cells exposed to uremic plasma or plasma from healthy subjects. MCP-1, IL-8, sVCAM-1 and sICAM-1 levels in plasma and in supernatant were analyzed by enzyme-linked immunosorbent assay. The population consisted of 73 (mean age 57 years; 48% males) CKD patients with glomerular filtration rate (GFR) of 37 +/- 2 ml/min. MCP-1 and sVCAM-1 plasma levels were negatively correlated with GFR (rho = -0.40, p < 0.0005 and rho = -0.42, p < 0.0005, respectively). Fibrinogen was positively correlated with MCP-1, sICAM-1 and sVCAM-1 (rho = 0.33, p < 0.005, rho = 0.32, p < 0.05 and rho = 0.25, p < 0.05, respectively) and ultra-high-sensitivity C-reactive protein was positively correlated with sICAM-1 (rho = 0.25, p < 0.0005). Plasma IL-8 had a significant positive correlation with proteinuria (rho = 0.31, p < 0.01). There was a time- and CKD-stage-dependent MCP-1, IL-8 and sVCAM-1 endothelial expression (p < 0.05). In summary, plasma levels of markers of endothelial cell activation (MCP-1 and sVCAM-1) are increased in more advanced CKD. Exposure of endothelial cells to uremic plasma results in a time- and CKD-stage-dependent increased expression of MCP-1, IL-8 and sVCAM-1, suggesting a link between vascular activation, systemic inflammation and uremic toxicity. Future studies are necessary to investigate whether these biomarkers add predictive value in comparison to the previously described ones. Also, endothelial response to uremic toxicity should be viewed as a potential target for intervention in order to reduce morbidity and mortality in CKD-related cardiovascular disease.

Analysis of the association of polymorphism in the osteoprotegerin gene with susceptibility to chronic kidney disease and periodontitis.

BACKGROUND AND OBJECTIVE: Chronic kidney disease (CKD) is a complex disorder, which results in several complications involving disturbance of mineral metabolism. Periodontal disease is an infectious disease that appears to be an important cause of systemic inflammation in CKD patients. Periodontal disease is characterized by clinical attachment loss (CAL) caused by alveolar bone resorption around teeth, which may lead to tooth loss. Osteoprotegerin (OPG) is a key regulator of osteoclastogenesis. Polymorphisms are the main source of genetic variation, and single nucleotide polymorphisms (SNPs) have been reported as major modulators of disease susceptibility. The aim of this study was to investigate the association of a polymorphism located at position -223 in the untranslated region of the OPG gene, previously known as -950, with susceptibility to CKD and periodontal disease. MATERIAL AND METHODS: A sample of 224 subjects without and with CKD (in hemodialysis) was divided into groups with and without periodontal disease. The OPG polymorphism was analyzed by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: No association was found between the studied OPG polymorphism and susceptibility to CKD or periodontal disease. CONCLUSION: It was concluded that polymorphism OPG-223 (C/T) was not associated with CKD and periodontal disease in a Brazilian population. Studies on other polymorphisms in this and other genes of the host response could help to clarify the involvement of bone metabolism mediators in the susceptibility to CKD and periodontal disease.

The Brazilian Peritoneal Dialysis Multicenter Study (BRAZPD) : characterization of the cohort.

The Brazilian Peritoneal Dialysis Multicenter Study (BRAZPD) was launched in December 2004 aiming to collect data monthly and continuously from a representative cohort, allowing for a continuous snapshot of the peritoneal dialysis (PD) reality in the country. This is an observational study of PD patients comprising follow-up from December 2004 to February 2007 (mean follow-up of 13.6 months-ranging from 1 to 26 months) in 114 Brazilian centers. All centers report data through a central web-based database. After an initial baseline retrospective data collection, all patients are followed prospectively every month until they drop out from the PD program. Total number of patients recruited until February 2007 was 3226 (2094 incident patients). Mean age was 54+/-19 years (37% above 65 years old), with 55% females and 64% Caucasians. The more frequent causes of renal failure were diabetic nephropathy (34%), renal vascular disease associated with hypertension (26%), and glomerulopathies (13%). The most common comorbidities were hypertension (76%), diabetes (36%), and ischemic heart disease (23%). Automated PD (APD) was the modality utilized in 53%. The estimated overall peritonitis rate was 1 episode per 30 patient-months (most frequently due to Staphylococcus aureus). The total dropout rate was 33%, mainly due to deaths, whereas 20% of dropouts were due to renal transplant. The gross mortality was 17.6% and the main causes of mortality were cardiovascular diseases (40%) and infections (15%). The initial results of this first Brazilian PD registry provide a unique opportunity to develop future clinical studies addressing specific PD questions in the Brazilian reality and context.

Early graft function in kidney transplantation: comparison between laparoscopic donor nephrectomy and open donor nephrectomy.

Laparoscopic donor nephrectomy (LN) offers less postoperative pain and early recovery in living kidney donors, but graft kidney function in the recipients can be delayed due to prolonged warm ischemic time (WIT) and adverse effects of pneumoperitoneum. We compared the early function of the grafted kidney and the complications in kidney recipients after LN versus open nephrectomy (ON). We analyzed 109 kidney recipients from living donors, including 60 LN and 49 ON, comparing immediate diuresis after surgery, glomerular filtration rate (GFR) by MDRD formula (modification of diet in renal disease) at day 5, and complications. The recipient age among the LN group was 20 to 73 years with 51% men among whom 95% of patients had immediate diuresis with GFR at day 5 varying from 4.85 to 99.45 mL/min/1.73 m(2) by MDRD Surgical complications were renal artery stenosis (5%) and urinary leakage (5%). The recipient among age ON cases varied from 18 to 63 years with 63% men and immediate diuresis observed in 87% and GFR at day 5 varied from 4.75 to 101.1 mL/min/1.73 m(2) by MDRD. Renal artery stenosis was observed in 8.16%. The WIT was longer (P < .05) among the LN (1.4 to 11 minutes) compared with the ON group (1 to 4 minutes). GFR at day 5 showed no difference between the two groups. In conclusion, WIT was higher among LN compared with ON but did not seem to influence early function of the grafted kidney.

Hand-assisted laparoscopic donor nephrectomy: comparison to pure laparoscopic donor nephrectomy.

Hand-assisted laparoscopic surgery is assumed to be easier to learn than the standard approach and simplifies intact kidney removal. Herein we have presented our experience performing hand-assisted laparoscopic donor nephrectomy (HALDN) compared with contemporary pure laparoscopic donor nephrectomy (LDN). We retrospectively analyzed 55 patients who underwent LDN. Among the procedures, 21 were HALDN and 34 were pure LDN. We compared the two groups with regard to operative time, warm ischemic time (WIT), estimated blood loss, conversion rate, postoperative stay, and complications. For the HALDN group, the mean operative time was 191 minutes, WIT varied from 2 to 11 minutes, and bleeding estimates varied from 100 to 4000 mL. The overall complication rate of 28.6% included: vessel injury, urinary leakage, and paralytic ileus. In the LDN group, the mean operative time was 184 minutes, WIT varied from 2 to 10 minutes, and bleeding estimated varied 100 to 3000 mL. Three patients (8.8%) had complications including ureteral obstruction (n = 1) and vessel injury (n = 2). There was no significant difference between the two groups about the procedure and the complications. Our series suggested that HALDN and LDN were similar, with a tendency toward better results in LDN group, which also shows lower costs.

Hand-assisted laparoscopic nephrectomy in living donors.

Hand-assisted laparoscopic nephrectomy (HLN) in living donors is a minimally invasive surgical modality that uses classic laparoscopic techniques either combined or not with the use of the surgeon's hand as a support tool during renal dissection maneuvers. The purpose of this study was to describe the initial experience with HLN technique in renal donors. Among 58 hand-assisted laparoscopic nephrectomies, the left kidney was removed in 39 donors (67%) and the right in 19 (33%). Surgery time ranged from 55 to 270 minutes (mean 156.9 +/- 49.5). Warm ischemia time ranged from 2 to 11 minutes (mean 4.38 +/- 2.31 min), with an estimated mean blood loss during the intraoperative period of 268 mL. Conversion to open surgery was required for four (6.8%) patients due to a vascular lesion. Upon graft evaluation, we observed immediate diuresis in 56 (96.3%) cases, with a mean serum creatinine on postoperative day 7 of 1.74 +/- 1.61 mg/dL. Renal vein thrombosis requiring graft removal occurred in one (1.7%) patient. Lymphocele was observed in three recipients (5.1%), and urinary leakage due to ureteral necrosis in three cases (5.1%). HLN for living donors is a safe procedure and an effective alternative to open nephrectomy. In this series, the procedure displayed low morbidity after surgery, providing a good morphological and functional quality of the graft for the recipient.

Effect of hepatitis C serology on C-reactive protein in a cohort of Brazilian hemodialysis patients.

Hepatitis C (HCV) is not an uncommon feature in hemodialysis (HD) patients and may be a cause of systemic inflammation. Plasma cytokine interleukin-6 (IL-6) is mainly produced by circulating and peripheral cells and induces the hepatic synthesis of C-reactive protein (CRP), which is the main acute phase reactant. The aim of this study was to investigate the influence of HCV on two markers of systemic inflammation, serum CRP and IL-6, in HD patients. The study included 118 HD patients (47% males, age 47 +/- 13 years, 9% diabetics) who had been treated by standard HD for at least 6 months. The patients were divided into two groups depending on the presence (HCV+) or absence (HCV-) of serum antibodies against HCV. Serum albumin (S-Alb), plasma high sensitivity CRP (hsCRP), IL-6, and alanine aminotransferase (ALT) were measured and the values were compared with those for 22 healthy controls. Median hsCRP and IL-6 values and hsCRP/IL-6 ratio were: 3.5 vs 2.1 mg/l, P < 0.05; 4.3 vs 0.9 pg/ml, P < 0.0001, and 0.8 vs 2.7, P < 0.0001, for patients and controls, respectively. Age, gender, S-Alb, IL-6 and hsCRP did not differ between the HCV+ and HCV- patients. However, HCV+ patients had higher ALT (29 +/- 21 vs 21 +/- 25 IU/l) and had been on HD for a longer time (6.1 +/- 3.0 vs 4.0 +/- 2.0 years, P < 0.0001). Moreover, HCV+ patients had a significantly lower median hsCRP/IL-6 ratio (0.7 vs 0.9, P < 0.05) compared to the HCV- group. The lower hsCRP/IL-6 ratio in HCV+ patients than in HCV- patients suggests that hsCRP may be a less useful marker of inflammation in HCV+ patients and that a different cut-off value for hsCRP for this population of patients on HD may be required to define inflammation.

Effect of hepatitis C serology on C-reactive protein in a cohort of Brazilian hemodialysis patients

Hepatitis C (HCV) is not an uncommon feature in hemodialysis (HD) patients and may be a cause of systemic inflammation. Plasma cytokine interleukin-6 (IL-6) is mainly produced by circulating and peripheral cells and induces the hepatic synthesis of C-reactive protein (CRP), which is the main acute phase reactant. The aim of this study was to investigate the influence of HCV on two markers of systemic inflammation, serum CRP and IL-6, in HD patients. The study included 118 HD patients (47 percent males, age 47 ± 13 years, 9 percent diabetics) who had been treated by standard HD for at least 6 months. The patients were divided into two groups depending on the presence (HCV+) or absence (HCV-) of serum antibodies against HCV. Serum albumin (S-Alb), plasma high sensitivity CRP (hsCRP), IL-6, and alanine aminotransferase (ALT) were measured and the values were compared with those for 22 healthy controls. Median hsCRP and IL-6 values and hsCRP/IL-6 ratio were: 3.5 vs 2.1 mg/l, P < 0.05; 4.3 vs 0.9 pg/ml, P < 0.0001, and 0.8 vs 2.7, P < 0.0001, for patients and controls, respectively. Age, gender, S-Alb, IL-6 and hsCRP did not differ between the HCV+ and HCV- patients. However, HCV+ patients had higher ALT (29 ± 21 vs 21 ± 25 IU/l) and had been on HD for a longer time (6.1 ± 3.0 vs 4.0 ± 2.0 years, P < 0.0001). Moreover, HCV+ patients had a significantly lower median hsCRP/IL-6 ratio (0.7 vs 0.9, P < 0.05) compared to the HCV- group. The lower hsCRP/IL-6 ratio in HCV+ patients than in HCV- patients suggests that hsCRP may be a less useful marker of inflammation in HCV+ patients and that a different cut-off value for hsCRP for this population of patients on HD may be required to define inflammation.

Nutrition for the post-renal transplant recipients.

An adequate nutritional status may improve outcomes after renal transplantation. This review article presents the impact of major nutritional risk factors, such as malnutrition, obesity, dislipidemia, and other associated or independent metabolic complications on the results of renal transplantation. Malnutrition that exists prior to transplant may be associated with an increased risk of infection, delayed wound healing, and muscle weakness. Obesity, which may also be preexisting or developing after transplantation, can lead to adverse effects, such as poor wound healing or increased risk of cardiovascular disease, although some recent studies suggest no major consequences. Hypercholesterolemia and hypertrigliceridemia (risk factors for cardiovascular disease) are common post-renal transplantation complications. All of these possible complications may be prevented or treated through early nutritional intervention and follow-up. This article reviews important nutritional recommendations to provide guidelines for adult posttransplant recipients.