Antibody-mediated rejection and treatment in pediatric patients: one center's experience.

OBJECTIVES: Antibody-mediated rejection is a rare complication that often results in the loss of the kidney graft. Treatment options include plasmapheresis, intravenous immunoglobulin, and use of rituximab. MATERIALS AND METHODS: We retrospectively evaluated the data files from 86 pediatric renal transplant patients over the last 5 years. A biopsy was taken for each rejection episode. RESULTS: Seven patients (7.7%) developed antibody-mediated rejection. All patients with antibody-mediated rejection had histologic evidence of severe acute humoral rejection and extensive C4d staining in peritubular capillaries. Staining was diffuse (involving > 50% of peritubular capillaries) for 4 biopsies, and it was focal (involving < 50% of peritubular capillaries) for 3 biopsies. Twelve biopsies demonstrated at least 1 histologic feature associated with acute humoral rejection. Donor-specific antibodies were evaluated in recipients. The mean peak panel reactive antibody class 1 was 7.16% (range, 0%-86%). The mean time between rejection episodes and the transplant was 16.9 ± 13.5 months. All patients were treated with high-dose intravenous methylprednisolone and intravenous immunoglobulin. Three patients recovered renal function rapidly after this treatment. Donor-specific antibodies were negative in these patients. Five sessions of plasmapheresis were used simultaneously in these 4 patients. In 3 resistant patients, rituximab was prescribed after plasmapheresis and intravenous immunoglobulin. The presence of donor-specific antibodies was demonstrated in 4 patients. Two patients were refractory to antibody-mediated rejection treatment and lost their transplants. One patient had interstitial fibrosis and tubular atrophy during the 16th month after her antibody-mediated rejection. Graft survival in patients with antibody-mediated rejection at the end of 1 year was 71.4%. CONCLUSIONS: Early diagnosis and treatment with plasmapheresis, intravenous immunoglobulin, and rituximab may resolve antibody-mediated rejection. Although effective therapy is available for acute antibody-mediated rejection, the allograft remains at risk for chronic antibody-mediated rejection and shortened survival.

Acute humoral rejection after kidney transplantation: a report of two cases.

Acute humoral rejection (AHR) should be considered in patients with renal allograft dysfunction that develops at any stage of the post-transplant course. AHR has become increasingly recognized and is now more accurately diagnosed by the use of flow cytometry cross-matching, the identification of C4d deposits shown on renal allograft biopsy, and the assessment of allograft function. Although plasma exchange has been a popular treatment for AHR, other treatment modalities have also been used by transplant centers. We present case reports of two patients whose AHR was diagnosed and treated at our medical center.

Prevalence of zinc deficiency and immune response in short-term hemodialysis.

Zinc is an essential trace element for many biological functions, including immune functions. The mechanism by which zinc may affect the immune system is certainly multifaceted, due to zinc's widespread action on different enzymes, peptides, transcriptional factors and cytokines involved in the various physiological steps of immune development and reactivity. In this study, prevalence of zinc deficiency and alteration in complement system, immunoglobulins and T cell subsets depending on zinc levels were analyzed in short-term hemodialysis patients and compared with healthy controls. Plasma zinc levels were measured by flame atomic absorption spectrometry. Serum levels of complement C3 and C4, immunoglobulins G (IgG), M (IgM), and A (IgA), and prealbumin were measured by nephelometry depending on antigen-antibody reactions. Percentages of CD4 and CD8+ were calculated using a flow cytometer. Statistically significant decreased zinc levels, especially in the age group > or = 40 years, and increased C4, IgA, IgM, IgG and CD4+ levels were observed in hemodialysis patients. The prevalence of hypozincemia in hemodialysis patients was found to be 40%. A higher CD4+/CD8 ratio was also obtained in patients. We conclude that patients on maintenance hemodialysis for a short time exhibit zinc deficiency and disturbed immune response.

Effect of obesity on inflammatory markers and renal functions.

AIM: To examine the relationship between inflammation criteria and body mass index in otherwise-healthy obese schoolchildren and to evaluate the effect of obesity on renal functions. METHODS: Sixty-five otherwise-healthy obese children (median age 10.8 y, range 7.1-16.5 y; median body mass index 26.8 kg/m(2), range 19.9-38.7 kg/m(2)) and 20 healthy controls (median age 12.4 y, range 10.1-17.1 y; median body mass index 18.8 kg/m(2), range 17.3-23.1 kg/m(2)) were included. Blood and urine samples were taken from every child. RESULTS: Children in the obese and control groups had similar age and sex distributions (p>0.05). Inflammatory mediators were higher in obese children (p<0.05). A significant positive correlation was found between glomerular filtration rate and body mass index in the whole study group (r=0.39, p=0.001). A positive correlation was found between body mass index standard deviation and inflammatory mediators and glomerular filtration rate. No significant difference existed regarding protein and microalbumin excretion in the urine. CONCLUSION: Inflammatory mediators increased significantly in obese children, and the glomerular filtration rate increased as the body mass index increased. To prevent obesity-related complications in adulthood, it is important to take measures to prevent development of obesity during childhood.

Relationships between HLA-A, -B, -DQ and -DR antigens and interstitial fibrosis in renal allografts.

Although renal transplant recipients tend to exhibit similar clinical and immunological changes over time, some allograft biopsies show early IF. To evaluate the relationship between HLA antigens and IF in renal allografts, we reviewed for HLA-A, -B, -DQ, and -DR antigens in 88 renal transplant recipients. For each antigen type, we determined the numbers of patients who did and did not possess the antigen. We then determined the mean time to onset of IF for each of these two groups, and statistically compared the means. In the second part of the analysis, we divided the 88 patients into those who did and did not show IF at 6 months posttransplantation, and then calculated the prevalence of each antigen type in the IF (+) and IF (-) groups. This same procedure was repeated with the patients grouped according to presence of IF at 12 months posttransplantation. The patient groups with HLA-B8, -B27, -DQ2, -DQ5, -DQ6, -DQ7, -DR4, -DR13, and -DR15, respectively, had significantly shorter times to IF onset after transplantation than the corresponding groups without these antigens (p<0.05). The groups that were IF (+) at 6 and 12 months posttransplantation had significantly higher frequencies of HLA-B8, -B27, -DQ2, and -DR4 than the corresponding IF (-) groups at these two time points (p<0.05). The results indicated that any kidney recipient with these antigens is predisposed to developing diffuse IF in their graft relatively soon after transplantation. We conclude that although there are multiple etiological agents in the pathogenesis of interstitial fibrosis, one cannot exclude an HLA association in these cases.

Renal transplantation in amyloidosis: effects of HLA matching and donor type on recurrence of primary disease.

The aim of this study is to evaluate the effect of HLA-matching and donor type on recurrence of amyloidosis after renal transplantation. The study includes 30 patients with systemic amyloidosis who received kidney transplants between 1985 and 2001. Donor source and HLA tissue typing of the donor and recipient were evaluated in each case. Of the 30 patients, 20 developed a recurrence of amyloidosis in their allografts, as confirmed by biopsy. The time from transplantation to diagnosis of amyloidosis in the graft ranged from 18 months to 10 years. Of the 20 patients with recurrence, 18 had received their grafts from living related donors (LRDs), and 2 had received their grafts from cadaveric donors (P < 0.01). There was a strong correlation between amyloidosis recurrence and degree of HLA-DR matching (P < 0.05). Furthermore, in the recipients of LRD grafts, the risk of amyloidosis recurrence was much higher if the donor-recipient pair were HLA-identical than if they were not perfectly matched (P < 0.01). The incidence of amyloidosis recurrence in our patients was significantly higher than the rates reported for other series. Most of the cases in previous reports involved cadaveric grafts. The higher rate of amyloidosis recurrence in our patients may be explained by the high proportion of LRD grafts and by genetic susceptibility.

Effect of simvastatin in the treatment of highly sensitized dialysis patients: the pre and post-renal transplantation follow-up outcomes.

The graft survival rates of sensitized kidney recipients have been shown to be lower than non-sensitized patients. Therefore, panel reactive antibody (PRA) and cross-match determination is accepted as mandatory screening for renal transplantation candidates. Our recent previous study has shown that simvastatin had a significant immunosuppressive effect in PRA-positive and/or crossmatch-positive patients. We present the pre and post-transplantation follow-up outcomes of simvastatin treatment in the highly sensitized dialysis patients. Thirty patients were followed for a mean period of 26 months. The PRA and flow cytometric measurements were performed at monthly intervals. Ten patients underwent successful kidney transplantation (eight living-related and two cadaveric). None of the patients developed hyperacute or acute rejection, and there was no graft loss during 19.8+/-6.2 months of post-transplantation follow-up. Of the 18 patients who stayed on dialysis throughout the study with PRA positivity, six were lost to follow-up and three spontaneously stopped taking the simvastatin. In the latter three cases, the PRA levels rose significantly after the drug was discontinued. Eight of the remaining nine PRA-positive patients showed significant drops in mean PRA level over the study period, and entered the range considered acceptable for transplantation. Only one patient showed persistently high PRA levels throughout the study. In one patient, the drug had to be discontinued due to acute toxic hepatitis. In conclusion, the results indicate that continuous simvastatin therapy effective in immunized and highly sensitized dialysis patients. Meanwhile, it has beneficial effect on 1-year graft survival in sensitized renal transplantation group.

Transplant coordination activities in the Baskent University Hospital Network.

Our transplantation center adopted a new model of operation, with 3 affiliated centers of the Baskent University. The aim of this system is to standardize procedures related to organ procurement and transplantation, to increase organ donation, and to improve the quality of services. The transplant team is composed of a transplant coordinator, and transplant clinicians and surgeons. The transplant coordinator works independently, and promotes organ donation and procurement, organizes interviews with donor families, and is in contact with national and international organ-sharing organizations. The organs and tissues are transplanted in the Ankara hospital of the network if the cadaver organ source is one of the Baskent University hospitals. If no appropriate recipient is available, the organs and tissues are offered to the National Coordination Center for other transplantation centers. To implement this system most efficiently and effectively, periodic situation analyses were made.

Panel reactive antibody positivity and associated HLA antibodies in Turkish renal transplant candidates.

Pre- and post-renal transplantation panel reactive antibody (PRA) screening is associated with increased incidence of hyperacute or acute graft rejection and graft loss. This study was designed to find any relationship PRA sensitization and associated human leukocyte antigen (HLA)-specific antibodies in Turkish renal transplant candidates. We included 340 patients who were in the renal transplantation waiting list in the study. We determined PRA sensitization ratio and the associated anti-HLA IgG antibody distribution of the patient group. The PRA testing was currently performed and levels above 30% were accepted to be positive. The PRA class I positivity was determined in 24 (7%) and class II in 34 (10%) of the patients. The most frequent HLA antibodies for class I were B56, A2, A34, A1, A23, A24 and B61; and for class II were DR11, DR14, DQ7, DR10, DQ5, DR1 and DR7, respectively. From these, the increase of the numbers of anti-HLA class II antibodies was significantly correlated with the increase of PRA sensitization ratio. In conclusion, the identification of the associated HLA-specific antibodies and correlation with the Turkish population HLA antigen distribution will identify the high-risk patients who are candidates for transplantation.

The impact of transient elevation of intra-abdominal pressure on liver regeneration in the rat.

Transient increased intra-abdominal pressure (IIAP) due to carbon dioxide insufflation is suspected to cause a form of ischemia-reperfusion injury. Considering this, a study was designed to assess the effect of transient IIAP on liver regeneration in a rat model. Six groups of animals (each n = 6) were studied. While experiments in Group 1 (IIAP+PHR) were subjected to IIAP, following partial hepatic resection (PHR), those in Group 2 (IIAP) experiments were subjected to IIAP. Animals in Group 3 (IR+PHR) were subjected to liver ischemia-reperfusion (IR) following PHR, and those in Group 4 (IR) underwent only IR. Group 5 (PHR) and Group 6 (healthy) served as controls. Blood was taken for assessment of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 with enzyme-linked immunosorbent assay (ELISA) at day 5 postoperatively. Each rat was then given a lethal injection of pentobarbital. Gravimetric analysis and immunohistochemistry staining for proliferating cell nuclear antigen (PCNA) were used for assessments of liver regeneration. Apoptosis was assessed by immunohistochemical TUNEL index, expressed as the number of positive cells/per total number of cells at the same time. Although mean liver regeneration rates of Group 1 and Group 3 were the same, that of Group 5 was the highest (p = .04). Serum TNF-alpha levels of Group 1 versus Group 3 were 340 pg/ml versus 352 pg/ml. Serum IL-l levels of Group 1 versus Group 3 were 124 pg/ml versus 135 pg/ml. Serum TNl-alpha and IL-6 levels of Group 1 and Group 3 were the same at the first day of surgical procedure (p > .05). Mean serum TNF-alpha levels of Group 5 (387 pg/ml) were significantly higher than those of both Group 1 and Group 3 at 24 h of operation. Serum IL-6 levels of Group 5 (174 pg/ml) at the same time was higher than those of Group 1 and Group 3 at the same time (p = .01). Proliferating cell nuclear antigen indices of Group 1, Group 2, Group 3, Group 4, and Group 6 were the same; however, the mean PCNA-labeling index of Group 5 was higher than those of the others. There were no significant differences between the groups (p > .05). Liver regeneration is suppressed by transient IIAP. However, the effect of IIAP on liver apoptosis needs to be clarified.

Carbon coating of stents has no effect on inflammatory response to primary stent deployment.

The aim of this study was to investigate the effects of stent carbon coating on inflammatory response. The authors serially measured plasma concentrations of C-reactive protein (CRP), fibrinogen, and several cytokines (tumor necrosis factor, interleukin [IL]-1-beta, IL-6, and IL-8) in patients with single-vessel coronary stenosis who underwent primary stent implantation. None of the subjects had inflammatory or infectious disease at the time of the procedure. Forty-six patients (38 males; mean age 55 +/-9 years) were studied. Blood samples were collected before and at 2, 4, 6, 24, and 48 hours after stent implantation. Patients were randomly assigned 1 of 2 different stent types, an uncoated MAC (AMG Raesfeld-Erle, Germany) (UC-MAC) or a carbon-coated MAC (CC-MAC) stent. Implantations were performed without predilatation, and stents were deployed at a maximum pressure of 6 atmospheres for 90 seconds. Of the 46 patients, 14 had stable, 27 had unstable, and 5 had atypical angina. According to ACC/AHA classification, 35 lesions (76.1%) were type A, 10 (21.7%) were type B, and 1 (2.2%) was type C. Single stenosis of 28 left anterior descending, 12 circumflex, and 6 right coronary arteries were treated. Serum IL-6 increased in both the UC-MAC and CC-MAC groups, with concentrations significantly elevated above baseline at 6 hours, and then decreasing after 24 hours (baseline, 6-hour, and 24-hour values = 3.1 +/-2.3, 5.7 +/-3.8, and 6.3 +/-4.6 pg/mL, respectively, in UC-MAC; 3.7 +/-2.6, 6.2 +/-6.0, and 4.6 +/-3.7 pg/mL, respectively, in CC-MAC [p=0.002]). Plasma fibrinogen, CRP, and leukocyte concentrations also increased in both groups over the 24 hours (p < 0.05). The elevations of IL-6, CRP, and fibrinogen were similar in the 2 groups. The percent increases in IL-6, fibrinogen, and CRP were not associated with stent length, size, or clinical presentation (all p > 0.05). The results showed that stent implantation increases plasma IL-6, fibrinogen, and CRP concentrations, but carbon coating of the stent does not seem to affect this inflammatory response.

Possible association between cockroach allergy and HLA class II antigens.

BACKGROUND: Susceptibility to the development of allergic diseases is known to be associated with genetic components, as well as environmental factors. Although the genetics of immunoglobulin E, atopy, and asthma are complex, genetic markers are needed to identify populations at risk and to plan intervention studies. OBJECTIVE: Human leukocyte antigen (HLA) class II genes play a major role in the control of immune response. We investigated the association between HLA class II alleles of DRB1 and DQB1 and the expression of atopy in cockroach-sensitive patients. METHODS: Levels of total and specific immunoglobulin E were determined. Skin prick tests were performed. HLA class II typing was performed by the Polymerase chain reaction with sequence-specific primers. Distribution of the HLA genotypes of 32 cockroach-positive atopic patients from the inner city were compared with those of 32 healthy, nonatopic controls of Turkish Caucasian origin. RESULTS: HLA class II gene analysis showed an increase of the HLA-DRB1*0701 and HLA-DQB1*02 alleles in atopic patients compared with nonatopic controls (31.3% vs 3.1% and 50% vs 15.6%, Pc < 0.036 and Pc < 0.021, respectively). Conversely, HLA-DRB1*15 allele was encountered more frequently in the control subjects. An association between cockroach sensitivity and cutaneous reactivity to other aeroallergens was observed (P < 0.001). CONCLUSIONS: It is suggested that the higher frequencies of HLA-DRB1*0701 and HLA-DQB1*02 alleles are probably related to atopy rather than an association between class II antigens and cockroach allergy in this group of polysensitized, atopic individuals. Further studies may lead to a better understanding of the genetically determined susceptibility, and evaluate the individual effects of each locus (or allele) on sensitivity to specific allergens in the Turkish population.

Triad of malnutrition, inflammation, and atherosclerosis in hemodialysis patients.

BACKGROUND/AIM: As chronic inflammation underlies both atherosclerosis and malnutrition, a possible link between these factors has been suggested in hemodialysis (HD) patients. We designed this study to compare nutritional indices and inflammatory parameters of HD patients with demonstrated atherosclerosis (group I) and HD patients without (group II). METHODS: We included 59 and 57 patients in groups I and II, respectively. The patient groups were matched for the risk factors for atherosclerosis such as age, gender, smoking habits, hypertension, and HD duration. The nutritional status of the patients was evaluated according to laboratory parameters, normalized protein catabolic rate, anthropometric measurements, and subjective global assessment. RESULTS: Laboratory parameters (albumin, prealbumin, total cholesterol, phosphorus, creatinine), normalized protein catabolic rate, and triceps skinfold thickness revealed a significant decline in the nutritional status of the patients with atherosclerosis. We found that the patients with atherosclerosis had significantly higher C-reactive protein, ferritin, and fibrinogen levels when we compared the patient groups for acute-phase reactants. When we assessed malnutrition as being in category B/C (B = mild to moderately malnourished, C = severely malnourished) according to subjective global assessment and inflammation on the basis of a C-reactive protein level > or =10 mg/l, among patients with atherosclerosis, there was a significantly higher proportion of them having malnutrition and inflammation. Additionally, the proportion of patients without any evidence of malnutrition and inflammation was significantly lower in group I than in group II. CONCLUSION: Our study gives evidence for the possible triad of malnutrition, inflammation, and atherosclerosis in HD patients.

The association of interdialytic weight gain with nutritional parameters and mortality risk in hemodialysis patients.

High interdialytic weight gain (IDWG) is considered as an indicator of noncompliance but could also be interpreted as an index of appetite. This study was designed to investigate the relationship IDWG with malnutrition and mortality risk in hemodialysis (HD) patients through a follow-up of 24 months. We divided HD patients into two groups according to their IDWG as Group I (IDWG < 3% of dry weight/day) (27 patients; age 46.8 +/- 21.1 years; HD duration: 28.3 +/- 39.5 months) and Group II (IDWG > or = 3% of dry weight/day) (41 patients; age 40.9 +/- 11.3 years; HD duration: 54.7 +/- 38.7 months). We investigated malnutrition through biochemical analysis (albumin, prealbumin, total cholesterol, creatinine, predialysis potassium and phosphorus levels), normalized protein catabolic rate (nPCR), anthropometric measurements. On initial assessment, group I had significantly lower predialysis creatinine, prealbumin and potassium levels than Group II (p < 0.0001, p < 0.01 and p < 0.001, respectively). At the 24th month, there were significantly lower creatinine, prealbumin, potassium and phosphorus levels in the low-IDWG group. Group I had significantly lower nPCR, body weight, body mass index and triceps skinfold thickness during the follow-up. Over the 24 months, 13 (48.1%) Group I patients and nine (21.9%) Group II patients exhibited loss of dry weight (p < 0.02). According to the survival curves prognosis was significantly poorer for Group I than Group II (2-year survival 74.0% and 92.6%, p < 0.03). Group I individuals with low albumin levels had the worst survival rate (57.1%). In conclusion there is a strong association of IDWG with nutritional parameters in HD patients. Our study draws attention for a possible risk of developing malnutrition in a HD patient with low IDWG.