HLA class II locus and susceptibility to podoconiosis.

BACKGROUND: Podoconiosis is a tropical lymphedema resulting from long-term barefoot exposure to red-clay soil derived from volcanic rock. The World Health Organization recently designated it as a neglected tropical disease. Podoconiosis develops in only a subgroup of exposed people, and studies have shown familial clustering with high heritability (63%). METHODS: We conducted a genomewide association study of 194 case patients and 203 controls from southern Ethiopia. Findings were validated by means of family-based association testing in 202 family trios and HLA typing in 94 case patients and 94 controls. RESULTS: We found a genomewide significant association of podoconiosis with the single-nucleotide polymorphism (SNP) rs17612858, located 5.8 kb from the HLA-DQA1 locus (in the allelic model: odds ratio, 2.44; 95% confidence interval [CI], 1.82 to 3.26; P=1.42×10(-9); and in the additive model: odds ratio, 2.19; 95% CI, 1.66 to 2.90; P=3.44×10(-8)), and suggestive associations (P<1.0×10(-5)) with seven other SNPs in or near HLA-DQB1, HLA-DQA1, and HLA-DRB1. We confirmed these associations using family-based association testing. HLA typing showed the alleles HLA-DRB1*0701 (odds ratio, 2.00), DQA1*0201 (odds ratio, 1.91), and DQB1*0202 (odds ratio, 1.79) and the HLA-DRB1*0701-DQB1*0202 haplotype (odds ratio, 1.92) were risk variants for podoconiosis. CONCLUSIONS: Association between variants in HLA class II loci with podoconiosis (a noncommunicable disease) suggests that the condition may be a T-cell-mediated inflammatory disease and is a model for gene-environment interactions that may be relevant to other complex genetic disorders. (Funded by the Wellcome Trust and others.).

Clinical relevance of pretransplant human leukocyte antigen donor-specific antibodies in renal patients waiting for a transplant: a risk factor.

The use of highly sensitive solid-phase antibody detection assays, including x-MAP multiple bead-based technology (Luminex), has greatly enhanced our ability to accurately detect and define very low levels of HLA antibodies. These developments have led to patients having increasing lists of antibody specificities (which may not be clinically relevant), resulting in a new "technological barrier" to transplantation in sensitized patients. Alloantibodies play a major role in all types of solid organ rejection; the presence of low-titer donor-specific antigen (DSA) identified pretransplant is associated with an increased risk of antibody-mediated rejection (AMR). However, these low-titer antibodies do not represent an absolute contraindication to transplant. Improvement in the diagnosis and treatment of AMR will allow sensitized patients with DSA to be successfully transplanted in the short term, but extended follow-up is required to ensure acceptable long-term graft survival in this group. These factors must be integrated into the decision algorithms for immunosuppressive treatment in patients at immunologic risk.

Pretransplant donor-specific antibodies in cytotoxic negative crossmatch kidney transplants: are they relevant?

BACKGROUND: The corresponding antigens of alloantibodies identified in patients awaiting kidney transplantation are often listed as unacceptable for transplantation. The use of solid phase testing, being more sensitive and accurate than conventional complement-dependent cytotoxicity (CDC) assays, has resulted in increased identification of alloantibodies. We aimed to study the clinical importance of alloantibodies defined solely by solid phase techniques. METHODS: All patients transplanted between 1999 and 2001 at our center with available day-of-transplant sera (D0) were included (121 patients). All had negative CDC crossmatches. RESULTS: Thirty-eight patients (31%) had detectable alloantibodies using high-definition assays with 16 having donor-specific antibodies (DSA) and 22 non-DSA. There were no cases of hyperacute rejection in any of the groups. Biopsy-proven acute rejection rates in the DSA and non-DSA were similar to the unsensitized group. Delayed graft function and 1-year graft survival rates were also similar for the three groups as were median 1-year serum creatinine levels. Multivariate analysis, however, showed that DSA were associated with an increased relative risk of longer-term graft failure (relative risk, 6.5; P<0.05). CONCLUSIONS: These data show that in the context of a CDC-negative crossmatch, the presence of D0 DSA has little impact on any early graft parameters. DSA, however, are associated with poorer longer-term graft outcomes in kidney transplantation.

The effect of proinflammatory cytokine gene and angiotensin-converting enzyme polymorphisms on erythropoietin requirements in patients on continuous ambulatory peritoneal dialysis.

BACKGROUND: The correction of anemia by recombinant human erythropoietin (rHuEPO) improves quality of life and prolongs life in end-stage renal failure. rHuEPO requirements for an individual are determined by a range of factors, including iron deficiency and inflammation. Single nucleotide polymorphisms in the promoter sequence of several proinflammatory cytokines have been shown, in different fields of medicine, to influence the cytokine response to different stimuli, with effects on clinical outcome. METHODS: The angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and polymorphisms in the promoter regions of the genes for tumor necrosis factor alpha (-308 A/G), interleukin-6 (-174 G/C), and interferon gamma were examined for their association with rHuEPO requirements in 112 patients on continuous ambulatory peritoneal dialysis (CAPD). Genomic DNA was extracted from peripheral blood leukocytes and genotyping performed with ARMS-PCR methodology, with sequence-specific primers. We examined rHuEPO requirements and C-reactive protein at baseline and during a 6-month study period. RESULTS: We found no significant effect of proinflammatory cytokine polymorphisms on rHuEPO responsiveness. However, throughout the study, we observed that there was a significantly higher rHuEPO requirement in the II and ID ACE genotypes compared with the DD group, which remained an independent association following multivariate analysis. CONCLUSIONS: ACE insertion/deletion polymorphism may determine rHuEPO responsiveness in CAPD patients and should be considered in relative rHuEPO resistance.

High pre-transplant soluble CD30 levels are predictive of the grade of rejection.

In renal transplantation, serum soluble CD30 (sCD30) levels in graft recipients are associated with increased rejection and graft loss. We investigated whether pre-transplant sCD30 concentrations are predictive of the grade of rejection. Pre-transplant sera of 51 patients with tubulointerstitial rejection (TIR), 16 patients with vascular rejection (VR) and an age-matched control group of 41 patients with no rejection (NR) were analyzed for sCD30. The transplant biopsies were immunostained for C4d. The median sCD30 level was significantly elevated in the group with VR (248 Units (U)/mL, range: 92-802) when compared with TIR (103 U/mL, range: 36-309, p<0.001) and NR (179 U/mL, range: 70-343, p<0.03). Moreover, patients with TIR had significantly lower sCD30 levels compared to NR. Based on C4d staining, a TH2 driven process, the median sCD30 levels were significantly raised in C4d+ patients compared with C4d- group (177 U/mL vs. 120 U/mL, p<0.05). sCD30 levels measured at time of transplantation correlate with the grade of rejection. High pre-transplant levels are associated with antibody-mediated rejection which carries a poorer prognosis. sCD30 could be another tool to assess immunological risk prior to transplantation and enable a patient centered approach to immunosuppression.

Pretransplantation levels of C-reactive protein predict all-cause and cardiovascular mortality, but not graft outcome, in kidney transplant recipients.

BACKGROUND: Chronic inflammation, the common pathway that leads to cardiovascular disease and chronic allograft nephropathy after transplantation, is prevalent in patients with end-stage renal failure. We set out to investigate the hypothesis that enhanced pretransplantation C-reactive protein (CRP) levels and Chlamydia seropositivity, both markers of an altered immune response, would predict graft failure and mortality in patients receiving renal replacement therapy. METHODS: A retrospective study of 115 patients, based on CRP levels in pretransplantation serum (group 1, 0 to 5 mg/L; group 2, 5 to 10 mg/L; group 3, >10 mg/L), were investigated for the following end points: transplant rejection, graft failure, and all-cause and cardiovascular mortality. RESULTS: There were no correlations between CRP levels or Chlamydia seropositivity with respect to rejection rates or graft failure. Furthermore, there was no relationship between Chlamydia seropositivity and survival. All-cause and cardiovascular mortality were significantly greater in patients with CRP levels greater than 10 mg/L and 5 to 10 mg/L compared with those with CRP levels less than 5 mg/L. All-cause mortality rates were 5% in the 0-to-5-mg/L group, 20% in the 5-to-10-mg/L group, and 44% in the greater-than-10-mg/L group. With regard to cardiovascular mortality, death rates were 0% in the 0-to-5-mg/L group, 10% in the 5-to-10-mg/L group, and 22% in the greater-than-10-mg/L group. Univariate analysis of cardiovascular mortality and covariates showed a significant relationship with age (relative risk [RR], 1.07; P < 0.05), diabetes (RR, 5.6; P < 0.05), aspirin intake (RR, 0.2; P < 0.05), antihypertensive therapy (RR, 0.02; P < 0.05), and CRP level (RR, 11; P < 0.05), but CRP level remained the only significant predictor (RR, 1.19; P < 0.05) on multivariate analysis. CONCLUSION: Pretransplantation CRP level is independently associated with all-cause and cardiovascular mortality in our cohort of transplant recipients and may be a useful predictive marker in the follow-up of posttransplantation patients.

Angiotensin-converting enzyme gene polymorphism and erythropoietin requirement.

OBJECTIVES: To study the effect of angiotensin-converting enzyme (ACE) polymorphisms II, ID, and DD on erythropoietin (EPO) requirement in patients on continuous ambulatory peritoneal dialysis (CAPD) therapy. DESIGN: Retrospective observational study. SETTING: CAPD Unit, Royal London/St. Bartholomews Hospital, London, UK. PATIENTS: 46 patients on the transplant waiting list (age 20-70 years), on CAPD therapy for an average of 28 months, seen consecutively over a period of 3 months in the outpatients department. MAIN OUTCOME MEASURES: Primary end point: EPO dose requirement in different ACE genotypes. Secondary end points: C-reactive protein, ferritin, parathyroid hormone, Kt/V, duration of dialysis, folate, cause of renal failure, and whether or not patients were on ACE inhibitor therapy. RESULTS: There was a statistically significant difference (p < 0.05) in EPO requirement in the II/ID group compared to the DD group. The mean +/- standard error of EPO for the II/ID group was 144 +/- 15 U/kg/week, and for the DD group, 87 +/- 9 U/kg/week. The difference in EPO requirement could not be explained by age, C-reactive protein, ferritin, parathyroid hormone, Kt/V, duration of dialysis, folate, cause of renal failure, or whether or not patients were on ACE inhibitor therapy. CONCLUSION: In CAPD patients, ACE genotype has predictive value when determining the EPO dosage, as the III/ID genotype may be associated with a suboptimal response.