Nonuremic Patients Research Articles

A Multi-Modal Approach to Islet and Pancreas Transplantation With Calcineurin-Sparing Immunosuppression Maintains Long-Term Insulin Independence in Patients With Type I Diabetes.

Long-term success in beta-cell replacement remains limited by the toxic effects of calcineurin inhibitors (CNI) on beta-cells and renal function. We report a multi-modal approach including islet and pancreas-after-islet (PAI) transplant utilizing calcineurin-sparing immunosuppression. Ten consecutive non-uremic patients with Type 1 diabetes underwent islet transplant with immunosuppression based on belatacept (BELA; n = 5) or efalizumab (EFA; n = 5). Following islet failure, patients were considered for repeat islet infusion and/or PAI transplant. 70% of patients (four EFA, three BELA) maintained insulin independence at 10years post-islet transplant, including four patients receiving a single islet infusion and three patients undergoing PAI transplant. 60% remain insulin independent at mean follow-up of 13.3 ± 1.1years, including one patient 9years after discontinuing all immunosuppression for adverse events, suggesting operational tolerance. All patients who underwent repeat islet transplant experienced graft failure. Overall, patients demonstrated preserved renal function, with a mild decrease in GFR from 76.5 ± 23.1mL/min to 50.2 ± 27.1mL/min (p = 0.192). Patients undergoing PAI showed the greatest degree of renal impairment following initiation of CNI (56% ± 18.7% decrease in GFR). In our series, repeat islet transplant is ineffective at maintaining long-term insulin independence. PAI results in durable insulin independence but is associated with impaired renal function secondary to CNI dependence.

Pancreas Transplantation Alone for Brittle Diabetes Mellitus

Only about 8% of all pancreas transplants for insulin-dependent diabetes mellitus are performed in the Pancreas Transplant Alone (PTA) category. PTAs are primarily performed in diabetic, non-uremic patients with unstable glucose control, hypoglycemia unawareness, and an increased risk of diabetes-related mortality, and who have failed all of the more traditional approaches to glycemic control. Tremendous, yet not widely noticed, progress in PTA outcome has been made over the past two decades. PTA is a very safe procedure with 1-and 5-year patient survival rates of 98.3% and 90.5% according to International Pancreas Transplant Registry (IPTR) data. Since the introduction of tacrolimus and mycophenolate mofetil maintenance therapy in the 1990s and the use of depleting antibody induction therapy, PTA graft survival rates at 1-and 5-years posttransplant are 87.2% and 65.0%. To avoid the need for a future kidney after pancreas (KAP) transplant due to impaired pretransplant native kidney function and the posttransplant use of calcineurin inhibitors, the estimated Glomerular Filtration Rate (eGFR) of PTA candidates should be well within the normal range and preferably > 80 mL/min/1.73m². PTAs with stable, long-term function have been shown to have a positive impact on secondary complications of diabetes mellitus. Considering the significantly improved outcome results, PTA should become the pancreas transplant option of choice before the manifestation of devastating secondary complications (kidney failure, cardio-cerebrovascular events, and blindness) that require simultaneous pancreas and kidney (SPK) transplants in qualified candidates, but with higher morbidity and mortality risks. It is important for diabetologists, endocrinologists, and other health professionals involved in the care of diabetic patients to learn about these positive PTA outcome results. Despite improvements in intensive insulin therapy, insulin-delivering devices, bioartificial pancreas, and islet transplantation, a successful PTA is the only treatment option for patients with brittle diabetes that consistently restores normal glucose homeostasis long-term without exposing recipients to the risks of severe hypoglycemia and prevents, halts, or reverses the development or progression of secondary diabetes complications.

214.1: Strategies to Achieve Long-term Insulin Independence Using a Multimodal Approach to Beta-cell Replacement in Patients With Type I Diabetes

Purpose: Beta cell replacement, via islet or solid organ pancreas transplant, remains the best strategy to restore insulin independence in patients with Type 1 diabetes mellitus (T1DM). Insulin independence beyond ten years is limited, with calcineurin inhibitors (CNI) contributing to beta cell toxicity and impairing renal function. Here, we report long-term results for multimodal beta cell replacement including islet and pancreas after islet (PAI) transplant with CNI-free immunosuppression (IS) regimens based on Belatacept (BELA) and Efalizumab (EFA). Methods: Ten non-uremic patients with severe T1DM received their first islet cell transplant between 2007 and 2009 with CNI-sparing IS based on BELA (n=5) or EFA (n=5). Patients were monitored for a mean of 12.9 ± 1.1 years from islet transplant for beta cell function and renal function. Following islet failure, patients were considered for repeat islet infusion and/or PAI transplant. Circulating immunologic phenotype was characterized in the first year. Results: Seven of 10 patients (70%) maintained insulin independence with normalization of HbA1c (3 BELA, 4 EFA) at 10 years post-islet transplant; four patients (2 EFA, 2 BELA) achieved long-term insulin independence after one islet infusion and three additional patients (2 EFA, 1 BELA) following PAI transplantation (Figure 1, Figure 2). Six of 10 (60%) remain insulin independent currently, at a mean follow-up of 13.3 ± 1.1 years from islet transplant. Eight of 10 patients (80%) maintained renal function with less than 30% decrease in GFR and without progression to stage 4 or stage 5 CKD (Figure 2). One patient progressed to stage 4 CKD following initiation of tacrolimus for PAI, and another progressed to stage 5 CKD after islet failure and return to full insulin dependence. Patients receiving EFA demonstrated profound expansion of circulating CD4+Foxp3+ regulatory T cells (Tregs). One patient (EFA-4) demonstrated Tregs comprising 68% of all circulating CD4+ T cells, and remains insulin independent despite discontinuing all immunosuppression, thus demonstrating the first reported case of operational tolerance in islet transplantation. Conclusions: Our results describe a multi-modal, personalized approach to beta-cell replacement. In our series, repeat islet transplant is ineffective at maintaining long-term insulin independence. PAI results in durable insulin independence but is associated with deterioration of renal function secondary to CNI dependence. EFA-based immunosuppression resulted in significant expansion of Tregs following transplantation, with one islet recipient establishing operational tolerance.Juvenile Diabetes Research Foundation (4-2004-372). NIH P30 (DK63720). NIH UO1 (AIO65193). CRC UL1 (RR024131). NIH T32 (AI125222).

Evaluation of Natural Killer Cells in HCV Patients undergoing Hemodialysis

ABSTRACT Background Hepatitis C virus (HCV) is a hepatotropic virus and one of the major causes of liver disease and a potential cause of substantial morbidity and mortality worldwide. Patients on hemodialysis are at high risk for HCV, with frequency of infection several times higher than that in non-uremic patients. Natural killer (NK) cells are best appreciated for innate defense against viral infections and in tumor cell surveillance. Objective To study the percentage of peripheral blood natural killer cells among chronic hepatitis C patients undergoing hemodialysis compared to chronic HCV patients with normal kidney functionsby flowcytometry immunophenotyping. Methodology Frequency of CD3- CD56+ cells was assessed in two distinct groups. Group I: 35 chronic HCV patients with end stage renal disease and undergoing hemodialysis, group II: 35 age and sex matched chronic HCV patients with no kidney disease. Results No significant difference was observed between HCV hemodialysis patients with ESRD and HCV patients with normal kidney function regarding the frequency of both NK cells (CD3CD56+) and NKT cells (CD3+CD56+). However, group I had significantly higher percentage of CD3+ cells than group II. Conclusion no difference was found in this study between HCV patients on hemodialysis and HCV with normal kidney function regarding NK cell frequency. However, assessment of NK cell function in future studies might reveal differences.

168-OR: Five-Year Follow-up after Islet Transplantation in Nonuremic Patients with Type 1 Diabetes Mellitus and Hypoglycemia Unawareness: Favorable Long-Term Outcomes of Multicenter Trial at University of Chicago

Introduction: Prospective randomized multicenter trial did not find advantage of CXCR1/2 blocker (Reparixin) over placebo in islet transplantation in patients with type 1 diabetes mellitus and problematic hypoglycemia at 1 year follow-up. We note favorable metabolic outcomes at 5-year follow-up in trial cohort from our center. Material and Methods: 12 patients with type 1 diabetes and problematic hypoglycemia received a total 19 islet transplants (max 2 per patient) within one year. Eight patients were randomly assigned and received Reparixin and 4 received placebo within first week after each transplant in addition to standard immunosuppression (anti-thymocyte globulin, tacrolimus, and mycophenolate). Results: 11/12 patients achieved insulin independence during the study period. At 5-year follow-up 4/8 (50%) remained insulin free with HbA1c <6.0 % in Reparixin group vs. 1/4 (25%) in placebo group. One patient had partial islet function without severe hypoglycemic episodes (SHE). Diabetic neuropathy and renal function remained unchanged while retinopathy improved in 3/6 (50%) patients. 6/12 (50%) patients left the study: 3/6 proceeded with pancreas transplant and remain off insulin, the remaining 3/6 stopped immunosuppression with decline of islet graft function, deterioration of glucose control (HbA1c > 7.0 %), and recurrence of SHE. No patients experienced any cardiovascular events nor became persistently sensitized (current PRA 0%). Conclusions: Repeat islet transplantation led to insulin independence in 91% of patients; 50% of patients in Reparixin group and 25% in placebo. Secondary diabetic complications did not progress. No patients became persistently sensitized. Subsequent pancreas transplantation was feasible and effective in patients with decline of islet graft function. Disclosure P. J. Bachul: None. A. Perez-gutierrez: None. A. C. Lucander: None. J. Fung: None. P. Witkowski: None. G. S. Generette: None. P. Borek: None. J. S. Pyda: None. R. Anteby: None. L. Basto: None. L. Perea: None. K. Golab: None. M. Tibudan: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (P30DK02059); Kovler Family Fund; Dompé farmaceutici S.p.A.

Management of Cutaneous Calciphylaxis

Calciphylaxis is a deadly, painful disease with a 1-year mortality of up to 50%. The disease is commonly associated with patients with end-stage kidney disease (ESKD), but it can manifest in non-uremic patients as well. In patients who are undergoing dialysis, the incidence of calciphylaxis can range from 0.04% to 4%. The progressive arterial calcification seen in calciphylaxis can affect multiple body organs, including the skin, brain, lungs, and muscle. In cutaneous calciphylaxis, painful and non-healing nodules, plaques, and ulcers may appear, increasing morbidity for patients. Diagnosis can be difficult, and the condition can clinically appear similar to other dermatological diseases, especially in non-uremic patients. Currently, skin biopsy with histological analysis is the most reliable method to help diagnose the condition. In certain cases, the use of medical imaging may be helpful. Treatment of pain in this condition can be difficult and should be multimodal and include wound care as well as modification of risk factors. Analgesic options include opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), as well as analgesic options that are targeted for specific patients. There are currently multiple clinical trials underway that are studying targeted therapies for this condition.

Prevalence of dynapenic obesity and sarcopenic obesity and their associations with cardiovascular disease risk factors in peritoneal dialysis patients.

BackgroundDynapenic obesity and sarcopenic obesity increase cardiovascular disease (CVD) and mortality in nonuremic patients. The present study was designed to determine the prevalence of dynapenic obesity and sarcopenic obesity and their associations with CVD risk factors in peritoneal dialysis (PD) patients.MethodsAll eligible PD patients in Tehran peritoneal dialysis centers were included in this cross-sectional study. Skeletal muscle mass and fat mass were assessed using bioelectrical impedance analysis. Muscle strength and physical performance were determined using hand grip strength and a 4-meter walk gait speed test, respectively. In addition, a 5-mL blood sample was obtained from each patient.ResultsThe prevalence of dynapenic obesity and sarcopenic obesity were 11.4% and 3.8% in PD patients, respectively. Serum high-sensitive C-reactive protein (hs-CRP), soluble intercellular adhesion molecule type 1, triglyceride, total cholesterol, and low-density lipoprotein cholesterol were significantly higher in PD patients with dynapenic obesity than in dynapenic nonobese and nondynapenic nonobese patients. Similarly, serum concentrations of CVD risk factors in PD patients with sarcopenic obesity were higher than in nonsarcopenic nonobese patients, but these differences were statistically significant only for serum hs-CRP and triglyceride. In addition, muscle strength and skeletal muscle mass percentage were negatively associated with markers of inflammation and dyslipidemia, whereas body fat percentage was positively associated with these CVD risk factors.ConclusionThis study indicates that although the prevalence of dynapenic obesity and sarcopenic obesity are relatively low in PD patients, these disorders may be associated with CVD risk factors.

Helicobacter Pylori Prevalence in Hemodialysis Patients

Aim: The aim of this study is to investigate the prevalence of Helicobacter pylori in hemodialysis patients and its relationship with gastric juice urea, ammonia, urea/ammonia ratio, and urea fraction. Materials and Methods: 20 hemodialysis patients on whom gastroscopy, antrum and corpus biopsy, and histopathologic evaluation were performed due to various reasons, and 30 non-uremic patients were included in the study. Helicobacter pylori prevalence, gastric juice urea nitrogen, ammonia, and urea nitrogen/ammonia ratio were determined. Furthermore, gastric juice urea fraction was also calculated in hemodialysis patients. Results: Eight hemodialysis patients (40%), and twenty non-uremic patients (66%) were positive for Helicobacter pylori. The relationship between gastric juice ammonia value, urea nitrogen/ammonia ratio, gastric juice urea fraction and Helicobacter pylori presence was significant in hemodialysis cases. Conclusions: The prevalence of Helicobacter pylori in hemodialysis patients is significantly lower than in non-uremic patients. Although there is no relationship between gastric juice urea nitrogen and low prevalence of Helicobacter pylori, there is a relationship between gastric juice ammonia value, urea nitrogen/ammonia ratio, and gastric juice urea fraction. In addition, factors other than Helicobacter pylori are thought to have a role in the pathogenesis of gastroduodenal mucosal lesions

Update on pancreatic transplantation on the management of diabetes.

Pancreas transplantation is the only therapy that can restore insulin independence in beta-cell penic diabetic recipients. Because of the need for life-long immunosuppression and the intial surgical risk associated with the transplant procedure, Pancreas transplantation is a therapeutic option only in selected diabetic patients. Based on renal function, three main populations of diabetic recipients of a pancreas transplant can be identified: uremic patients, posturemic patients (following successful kidney transplantation), and non-uremic patients. Uremic patients are best treated by simultaneous kidney-pancreas transplantation with grafts obtained from the same deceased donor. Posturemic patients can receive a pancreas after kidney transplantation, if the previous renal graft has a good functional reserve. Non-uremic patients can receive a pancreas alone transplant if their diabetes is poorly controlled, despite optimal insulin therapy, suffer from unawareness hypoglycemia events and/or develop progressive chronic complications of diabetes. The results of pancreas transplantation have improved over the years and are currently not inferior to those of renal transplantation in non-diabetic recipients. A functioning pancreatic graft can prolong the life of diabetic recipients, improves their quality of life, and can halt, or reverse, the progression of chronic complications of diabetes. Unfortunately, because of ageing of donor population and lack of timely referral of potential recipients, the annual volume of pancreas transplants is declining. Considering that the results of pancreas transplantation depend on center volume, and that adequate center volume is required also for training of newer generations of transplant physcians and surgeons, centralization of pancreas transplantation activity should be considered.

Inflammatory Biomarkers and Liver Histopathology in Non-Uremic and Uremic Chronic Hepatitis C Patients

The aim of this study is to investigate the association between hepatic activity index (HAI) and fibrosis score (FS) with inflammation biomarkers in non-uremic and uremic hepatitis C positive patients. Fifty chronic hepatitis C (cHepC) positive patients, having a liver biopsy were included in this study. Liver biopsies were scored according to modified ISHAC scoring system. 25 healthy controls of similar age and gender were also enrolled as control group. Serum YKL-40, neutrophil/lymphocyte ratio (NLR), thrombocyte/lymphocyte ratio (PLR), CRP and Immunoglobulin (IgG, A and M) levels were used to determine inflammation. AST to Platelet Ratio Index (APRI) score was also evaluated. According to biopsy findings patients were divided into 2 groups: low (0-2) and severe (3-6) FS. Patients with cHepC had increased inflammation compared to the healthy controls. End-stage renal disease (ESRD) patients had higher levels of inflammation markers (NLR, IgG, CRP and YKL-40) and lower HCV RNA levels, HAI and FS compared to non-uremic patients. When patients were grouped into 2 according to FS as mild and severe, IgG (p < 0.001), YKL-40 (p = 0.02) levels and APRI score (p = 0.002) were significantly higher compared to mild FS (p = 0.002). YKL-40 levels (t value: 3.48; p = 0.001) and APRI score (t value: 4.57, p < 0.001) were found as independent associated with FS in non-uremic patients. However, in adjusted models, only APRI score (t value: 3.98, p = 0.002) was an independent associated with FS in ESRD patients. In non-uremic cHepC patients, YKL-40 levels and APRI score may be valuable markers of FS. In ESRD patients, there is not sufficient data for prediction of HAI and FS. In these patients, APRI score may provide better information.

Hypothermia in Uremic Dogs and Cats.

BackgroundThe prevalence of uremic hypothermia (UH) and the effects of improving uremia on body temperature have not been determined in veterinary patients.ObjectivesTo determine the prevalence of UH and correlations between uremia and body temperature in patients undergoing intermittent hemodialysis (IHD).AnimalsUremic dogs (n = 122) and cats (n = 79) treated by IHD at the Bobst Hospital of the Animal Medical Center from 1997 to 2013.MethodsRetrospective review of medical records.ResultsThe prevalence of hypothermia was 38% in azotemic cats and 20.5% in azotemic dogs. Statistically significant temperature differences were observed between uremic and nonuremic dogs (nonuremic: mean, 100.8°F; range, 91.2–109.5°F; uremic: mean, 99.9°F; range, 95.6–103.8°F; P < .0001) and cats (nonuremic: mean, 100.6°F; range, 94.0–103.8°F; uremic: mean, 99.3°F; range, 92.3–103.4°F; P < .0001). In dog dialysis patients, significant models included (1) timing (pre‐dialysis versus post‐dialysis) with weight class (small [P < .0001], medium [P = .016], and large breed [P = .033] dogs), (2) timing with serum creatinine concentration (P = .021), and (3) timing with BUN concentration (P < .0001). In cat dialysis patients, there was a significant interaction between timing and weight as a categorical variable (<5 kg and ≥5 kg).Conclusions and Clinical ImportanceUremic hypothermia appears to be a clinical phenomenon that occurs in cats and dogs. Uremic patients are hypothermic compared to ill nonuremic patients and body temperatures increase when uremia is corrected with IHD in dogs and in cats >5 kg. In cats, UH seems to be a more prevalent phenomenon driven by uremia. Uremic hypothermia does occur in dogs, but body weight is a more important predictor of body temperature.

Current outcomes in islet versus solid organ pancreas transplant for β-cell replacement in type 1 diabetes.

With continued optimization of islet isolation and immunosuppression protocols, the medium-term rates of insulin independence following islet transplantation have improved significantly. This review evaluates the most up-to-date outcomes data for both solid organ pancreas and islet transplantation to develop an algorithm for selection of β-cell replacement in type 1 diabetes patients. Solid organ pancreas and islet transplantation have both displayed improved rates of 5-year insulin independence, largely attributable to improvements in immunosuppressive regimens. The medium-term rates of insulin independence following islet transplantation in highly selected type 1 nonuremic diabetic recipients is beginning to approach the success rates observed following solitary pancreas transplantation. Although pancreas transplantation has historically been favored for β-cell replacement, current outcomes following islet transplantation justify the use of this minimally invasive therapy in carefully selected patients. Pancreas transplant remains the procedure of choice for β-cell replacement in uremic patients. Islet transplantation should be considered in nonuremic patients with low BMI and low insulin requirements, patients lacking the cardiovascular reserve to undergo open abdominal surgery, or patients who elect to forego the risks of a major operation in exchange for an increased risk of islet graft failure.

A Comparative Analysis of the Safety, Efficacy, and Cost of Islet Versus Pancreas Transplantation in Nonuremic Patients With Type 1 Diabetes

Few current studies compare the outcomes of islet transplantation alone (ITA) and pancreas transplantation alone (PTA) for type 1 diabetes (T1D). We examined these two beta cell replacement therapies in nonuremic patients with T1D with respect to safety, graft function and cost. Sequential patients received PTA (n = 15) or ITA (n = 10) at our institution. Assessments of graft function included duration of insulin independence; glycemic control, as measured by hemoglobin A1c; and elimination of severe hypoglycemia. Cost analysis included all normalized costs associated with transplantation and inpatient management. ITA patients received one (n = 6) or two (n = 4) islet transplants. Mean duration of insulin independence in this group was 35 mo; 90% were independent at 1 year, and 70% were independent at 3 years. Mean duration of insulin independence in PTA was 55 mo; 93% were insulin independent at 1 year, and 64% were independent at 3 years. Glycemic control was comparable in all patients with functioning grafts, as were overall costs ($138 872 for ITA, $134 748 for PTA). We conclude that with advances in islet isolation and posttransplant management, ITA can produce outcomes similar to PTA and represents a clinically viable option to achieve long-term insulin independence in selected patients with T1D.

The efficacy of udenafil in end-stage renal disease patients undergoing hemodialysis

Introduction Erectile dysfunction (ED) is frequently observed in end-stage renal disease (ESRD) patients on hemodialysis (HD) compared to non-uremic patients. This situation causes severe psychogenic problems in patients and disrupts the quality of life. Different phosphodiesterase type 5 (PDE-5) inhibitors have been used, and efficacies revealed, for the treatment of ED in HD patients; however, there are no studies related to udenafil use or results for HD patients. This study retrospectively evaluated the efficacy and reliability of udenafil for HD patients. Materials and methods The laboratory findings, side effects after treatment, and International Index of Erectile Function (IIEF) scores before and after treatment were compared and evaluated for HD patients who applied to our urology clinic with ED complaints and were treated with udenafil. Results The results showed that in the HD patient group with ED, apart from ED, there were severe rates of other sexual dysfunction. In our patient group, there was a statistically significant improvement in all scores for erectile function (p = 0.033), orgasmic function (p < 0.001), sexual desire (p < 0.001), relationship satisfaction (p < 0.001), and general satisfaction (p < 0.001) after treatment. The reported side effects were headache in one patient and dyspepsia in one patient. Conclusion We concluded that udenafil is an effective and reliable treatment approach for HD patients; however, our results require support from prospective randomized crossover studies with sildenafil.

Beta-Cell Replacement: Pancreas and Islet Cell Transplantation.

Pancreas and islet transplantation are 2 types of beta-cell replacement therapies for type 1 diabetes mellitus. Since 1966, when pancreas transplantation was first performed, it has evolved to become a highly efficient procedure with high success rates, thanks to advances in surgical technique and immunosuppression. Pancreas transplantation is mostly performed as simultaneous pancreas-kidney transplantation in patients with end-stage nephropathy secondary to diabetes. In spite of its efficiency, pancreas transplantation is still a major surgical procedure burdened by high morbidity, which called for the development of less invasive and hazardous ways of replacing beta-cell function in the past. Islet transplantation was developed in the 1970s as a minimally invasive procedure with initially poor outcomes. However, since the report of the 'Edmonton protocol' in 2000, the functional results of islet transplantation have substantially and constantly improved and are about to match those of whole pancreas transplantation. Islet transplantation is primarily performed alone in nonuremic patients with severe hypoglycemia. Both pancreas transplantation and islet transplantation are able to abolish hypoglycemia and to prevent or slow down the development of secondary complications of diabetes. Pancreas transplantation and islet transplantation should be seen as two complementary, rather than competing, therapeutic approaches for beta-cell replacement that are able to optimize organ donor use and patient care.

影响慢性肾脏病患者血清甲状旁腺素的相关因素分析

目的：甲状旁腺激素(parathyroid hormone, PTH)，是甲状旁腺主细胞分泌的碱性单链多肽类激素，在慢性肾病的并发症发病中日益显示其重要性。通过检测本肾病中心599例慢性肾病患者的PTH值，探讨不同阶段的慢性肾病PTH异常率的差异，并分析性别和年龄是否影响慢性肾病患者的PTH值。方法：利用化学发光免疫夹心法检测PTH浓度。结果：统计结果显示尿毒症患者组的PTH异常率显著高于非尿毒症患者组(P = 0.02)；男性尿毒症患者的PTH异常率明显高于女性尿毒症患者(P = 0.007)；尤其值得注意的是，无论是尿毒症组还是非尿毒症组，年龄 ≥ 50的慢性肾病患者PTH异常率比年龄 < 50的患者低，且在非尿毒症组具有显著性差异(P = 0.006)。结论：PTH异常与慢性肾脏病的恶化明显相关，年龄因素参与慢性肾病患者PTH调控的机理有待进一步阐明。 Objective: Parathyroid hormone (PTH), is a basic single chain polypeptide hormone secreted by parathyroid cells, has become increasingly important in the pathogenesis of chronic kidney disease. By testing the PTH value of 599 patients with chronic kidney disease (CKD), we investigate the dif-ference of PTH abnormal rate in different stages of chronic kidney disease, and analyze whether the gender and age affect the PTH value of patients with chronic kidney disease. Methods: The concen-tration of PTH was detected by chemiluminescence immunoassay. Results: Statistical results showed that the abnormal rate of PTH in uremic patients was significantly higher than that in non-uremic patients (P = 0.02). The abnormal rate of PTH in male uremic patients was significantly higher than that in female patients with uremia (P = 0.007). In particular, it was worth noting that, in both uremic group and non-uremic group, the PTH abnormal rate of the CKD patients aged ≥50 was lower than that of age < 50, and there was a significant difference in the non-uremic group (P = 0.006). Conclusion: PTH abnormalities were significantly correlated with the progression of chronic kidney disease, and the mechanism of PTH influenced by the age in CKD patients needed to be further clarified.

Increased storage and secretion of phosphatidylcholines by senescent human peritoneal mesothelial cells.

Human peritoneal mesothelial cells (HPMC) secrete phosphatidylcholines (PC) which form a lipid bilayer lining the peritoneum. They prevent frictions and adhesions and act as a barrier to the transport of water-soluble solutes while permitting water flux. PC may play an essential role in peritoneal integrity and function, the role of PD induced HPMC senescence on PC homeostasis, however, is unknown. HPMC cell lines were isolated from four non-uremic patients. Expression of the three PC synthesis genes (rt-PCR), and cellular storage and secretion of PC (ESI-mass-spectrometry) were analyzed in young and senescent HPMC (>Hayflick-limit). Senescent cells displayed significantly altered morphology; flow cytometry demonstrated extensive staining for senescence-associated beta galactosidase. Nine different PC were detected in HPMC with palmitoyl-myristoyl phosphatidylcholine (PMPC) being most abundant. In senescent HPMC mRNA expression of the three key PC synthesis genes was 1.5-, 2.4- and 6-fold increased as compared to young HPMC, with the latter, phosphatidylcholine cytidylyltransferase, being rate limiting. Intracellular storage of the nine PC was 75-450% higher in senescent vs. young HPMC, PC secretion rates were 100-300% higher. Intracellular PC concentrations were not correlated with the PC secretion rates. Electron microscopy demonstrated lamellar bodies, the primary storage site of PC, in senescent but not in young cells. Senescent HPMC store and secrete substantially more PC than young cells. Our findings indicate a novel protective mechanism, which should counteract peritoneal damage induced by chronic exposure to PD fluids.

Different Risk of Common Gastrointestinal Disease Between Groups Undergoing Hemodialysis or Peritoneal Dialysis or With Non-End Stage Renal Disease: A Nationwide Population-Based Cohort Study.

Peritoneal dialysis (PD) is one type of renal replacement therapy, but potential peritoneal damage and gastrointestinal (GI) tract adverse effects during long-term exposure to bio-incompatible dialysate remain a concern. Although GI disease frequently occurs in dialysis patients, whether the risk of GI diseases differs among PD and hemodialysis (HD) or non-uremic groups is still uncertain.In this retrospective cohort study, data were obtained from the National Health Insurance Research Database, which includes almost all dialysis patients in Taiwan. Between 2000 and 2009, a total of 1791 PD and 8955 HD incident patients were enrolled and matched for age and sex or for propensity score. In addition, a comparison cohort of 8955 non-uremic patients was also selected. Individuals were monitored for the occurrence of common GI diseases until 2010, and data were analyzed using several different models.Generally speaking, the results showed that the risk of gastroesophageal reflux, intestinal obstruction or adhesions, and abdominal hernia was significantly higher in the PD group, whereas the risk of peptic ulcer disease and lower GI diverticula and bleeding was significantly greater in the HD group. Meanwhile, the risk of mesenteric ischemia, liver cirrhosis, and acute pancreatitis was higher in dialysis patients, but was not significantly different between the PD and HD groups; moreover, the risk of appendicitis in the PD group appeared to be lower than that in the HD group.In conclusion, dialysis patients have a higher risk of most common GI diseases, and PD and HD modalities are associated with different GI diseases.

Interference of peritoneal dialysis fluids with cell cycle mechanisms.

Peritoneal dialysis fluids (PDF) differ with respect to osmotic and buffer compound, and pH and glucose degradation products (GDP) content. The impact on peritoneal membrane integrity is still insufficiently described. We assessed global genomic effects of PDF in primary human peritoneal mesothelial cells (PMC) by whole genome analyses, quantitative real-time polymerase chain reaction (RT-PCR) and functional measurements. PMC isolated from omentum of non-uremic patients were incubated with conventional single chamber PDF (CPDF), lactate- (LPDF), bicarbonate- (BPDF) and bicarbonate/lactate-buffered double-chamber PDF (BLPDF), icodextrin (IPDF) and amino acid PDF (APDF), diluted 1:1 with medium. Affymetrix GeneChip U133Plus2.0 (Affymetrix, CA, USA) and quantitative RT-PCR were applied; cell viability was assessed by proliferation assays. The number of differentially expressed genes compared to medium was 464 with APDF, 208 with CPDF, 169 with IPDF, 71 with LPDF, 45 with BPDF and 42 with BLPDF. Out of these genes 74%, 73%, 79%, 72%, 47% and 57% were downregulated. Gene Ontology (GO) term annotations mainly revealed associations with cell cycle (p = 10(-35)), cell division, mitosis, and DNA replication. One hundred and eighteen out of 249 probe sets detecting genes involved in cell cycle/division were suppressed, with APDF-treated PMC being affected the most regarding absolute number and degree, followed by CPDF and IPDF. Bicarbonate-containing PDF and BLPDF-treated PMC were affected the least. Quantitative RT-PCR measurements confirmed microarray findings for key cell cycle genes (CDK1/CCNB1/CCNE2/AURKA/KIF11/KIF14). Suppression was lowest for BPDF and BLPDF, they upregulated CCNE2 and SMC4. All PDF upregulated 3 out of 4 assessed cell cycle repressors (p53/BAX/p21). Cell viability scores confirmed gene expression results, being 79% of medium for LPDF, 101% for BLPDF, 51% for CPDF and 23% for IPDF. Amino acid-containing PDF (84%) incubated cells were as viable as BPDF (86%). In conclusion, PD solutions substantially differ with regard to their gene regulating profile and impact on vital functions of PMC, i.e. on cells known to be essential for peritoneal membrane homeostasis.

Activation of nuclear factor of activated T cells 5 in the peritoneal membrane of uremic patients.

Peritoneal inflammation and fibrosis are responses to the uremic milieu and exposure to hyperosmolar dialysis fluids in patients on peritoneal dialysis. Cells respond to high osmolarity via the transcription factor nuclear factor of activated T cells (NFAT5). In the present study, the response of human peritoneal fibroblasts to glucose was analyzed in vitro. Expression levels of NFAT5 and chemokine (C-C motif) ligand (CCL2) mRNA were quantified in peritoneal biopsies of five nonuremic control patients, five uremic patients before PD (pPD), and eight patients on PD (oPD) using real-time PCR. Biopsies from 5 control patients, 25 pPD patients, and 25 oPD patients were investigated using immunohistochemistry to detect the expression of NFAT5, CCL2, NF-κB p50, NF-κB p65, and CD68. High glucose concentrations led to an early, dose-dependent induction of NFAT5 mRNA in human peritoneal fibroblasts. CCL2 mRNA expression was upregulated by high concentrations of glucose after 6 h, but, most notably, a concentration-dependent induction of CCL2 was present after 96 h. In human peritoneal biopsies, NFAT5 mRNA levels were increased in uremic patients compared with nonuremic control patients. No significant difference was found between the pPD group and oPD group. CCL2 mRNA expression was higher in the oPD group. Immunohistochemistry analysis was consistent with the results of mRNA analysis. CD68-positive cells were significantly increased in the oPD group. In conclusion, uremia results in NFAT5 induction, which might promote early changes of the peritoneum. Upregulation of NFAT5 in PD patients is associated with NFκB induction, potentially resulting in the recruitment of macrophages.