Factors Associated With Vaccine-Induced T-Cell Immune Responses Against Severe Acute Respiratory Syndrome Coronavirus 2 in Kidney Transplant Recipients.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important prophylactic measure in kidney transplant recipients (KTRs), but the immune response is often impaired. Here, we examined the T-cell immune response against SARS-CoV-2 in 148 KTRs after 3 or 4 vaccine doses, including 35 KTRs with subsequent SARS-CoV-2 infection. The frequency of spike-specific T cells was lower in KTRs than in immunocompetent controls and was correlated with the level of spike-specific antibodies. Positive predictors for detection of vaccine-induced T cells were detection of spike-specific antibodies, heterologous immunization with messenger RNA and a vector vaccine, and longer time after transplantation. In vaccinated KTRs with subsequent SARS-CoV-2 infection, the T-cell response was greatly enhanced and was significantly higher than in vaccinated KTRs without SARS-CoV-2 infection. Overall, the data show a correlation between impaired humoral and T-cell immunity to SARS-CoV-2 vaccination and provide evidence for greater robustness of hybrid immunity in KTRs.

Immune response to third SARS-CoV-2 vaccination in seronegative kidney transplant recipients: Possible improvement by mycophenolate mofetil reduction.

Modification of vaccination strategies is necessary to improve the immune response to SARS-CoV-2 vaccination in kidney transplant recipients (KTRs). This multicenter observational study analyzed the effects of the third SARS-CoV-2 vaccination in previously seronegative KTRs with the focus on temporary mycophenolate mofetil (MMF) dose reduction within propensity matched KTRs. 56 out of 174 (32%) previously seronegative KTRs became seropositive after the third vaccination with only three KTRs developing neutralizing antibodies against the omicron variant. Multivariate logistic regression revealed that initial antibody levels, graft function, time after transplantation and MMF trough levels had an influence on seroconversion (P < .05). After controlling for confounders, the effect of MMF dose reduction before the third vaccination was calculated using propensity score matching. KTRs with a dose reduction of ≥33% showed a significant decrease in MMF trough levels to 1.8 (1.2-2.5) µg/ml and were more likely to seroconvert than matched controls (P = .02). Therefore, a MMF dose reduction of 33% or more before vaccination is a promising approach to improve success of SARS-CoV-2 vaccination in KTRs.

Intensity of mycophenolate mofetil treatment is associated with an impaired immune response to SARS-CoV-2 vaccination in kidney transplant recipients.

Kidney transplant recipients (KTRs) are extremely vulnerable to SARS-CoV-2 infection and show an impaired immune response to SARS-CoV-2 vaccination. We analyzed factors related to vaccination efficiency in KTRs. In a multicenter prospective observational study (NCT04743947), IgG antibodies levels against SARS-CoV-2 spike S1 subunit and their neutralization capacity after SARS-CoV-2 vaccination were analyzed in 225 KTRs and compared to 176 controls. After the vaccination, 56 (24.9%) KTRs became seropositive of whom 68% had neutralizing antibodies. This immune response was significantly lower compared to controls (239 [78-519] BAU/ml versus 1826 [560-3180] BAU/ml for KTRs and controls, p < .0001). The strongest predictor for an impaired response was mycophenolate mofetil (MMF) treatment. Multivariate regression analysis revealed that MMF-free regimen was highly associated with seroconversion (OR 13.25, 95% CI 3.22-54.6; p < .001). In contrast, other immunosuppressive drugs had no significant influence. 187 out of 225 KTRs were treated with MMF of whom 26 (13.9%) developed antibodies. 23 of these seropositive KTRs had a daily MMF dose ≤1 g. Furthermore, higher trough MMF concentrations correlated with lower antibody titers (R -0.354, p < .001) supporting a dose-dependent unfavorable effect of MMF. Our data indicate that MMF dose modification could lead to an improved immune response.

Impaired Immune Response to SARS-CoV-2 Vaccination in Dialysis Patients and in Kidney Transplant Recipients.

Background: Patients with kidney failure on dialysis or after renal transplantation have a high risk for severe COVID-19 infection, and vaccination against SARS-CoV-2 is the only expedient prophylaxis. Generally, immune responses are attenuated in patients with kidney failure, however, systematic analyses of immune responses to SARS-CoV-2 vaccination in patients on dialysis and in kidney transplant recipients (KTRs) are still needed. Methods: In this prospective, multicentric cohort study, antibody responses to COVID-19 mRNA vaccines (BNT162b2 [BioNTech/Pfizer] or mRNA-1273 [Moderna]) were measured in 32 patients on dialysis and in 28 KTRs. SARS-CoV-2-specific antibodies and neutralization capacity were evaluated and compared with controls (n=78) of a similar age range. Results: After the first vaccination, SARS-CoV-2-specific antibodies were nearly undetectable in patients with kidney failure. After the second vaccination, 93% of the controls and 88% of patients on dialysis but only 37% of KTRs developed SARS-CoV-2-specific IgG above cutoff. Moreover, mean IgG levels were significantly lower in KTRs (54±93 BAU/ml) compared with patients on dialysis (503±481 BAU/ml; P<0.01). Both KTRs and patients on dialysis had significantly lower IgG levels compared with controls (1992±2485 BAU/ml; P<0.001 and P<0.01, respectively). Importantly, compared with controls, neutralizing antibody titers were significantly lower in KTRs and patients on dialysis. After the second vaccination, 76% of KTRs did not show any neutralization capacity against SARS-CoV-2, suggesting impaired seroprotection. Conclusions: Patients with kidney failure show a significantly weaker antibody response compared with controls. Most strikingly, only one out of four KTRs developed neutralizing antibodies against SARS-CoV-2 after two doses of vaccine. These data suggest that vaccination strategies need modification in KTRs and patients on dialysis.Clinical Trial registry name and registration number: Vaccination Against COVID-19 in Chronic Kidney Disease, NCT04743947.

Unacceptable human leucocyte antigens for organ offers in the era of organ shortage: influence on waiting time before kidney transplantation.

BACKGROUND: The assignment of human leucocyte antigens (HLAs) against which antibodies are detected as unacceptable antigens (UAGs) avoids allocation of HLA- incompatible allografts. There is uncertainty as to what extent UAGs decrease the probability of receiving a kidney offer. METHODS: Kidney transplantations in 3264 patients on the waiting lists of six German transplant centres were evaluated for a period of at least 2 years. The proportion of excluded offers due to UAGs was calculated as virtual panel-reactive antibodies (vPRAs). RESULTS: In the common Eurotransplant Kidney Allocation Scheme, the transplant probability was unaffected by vPRAs in exploratory univariate analyses. In the multivariable model, a 1% increase in vPRA values was outweighed by an additional waiting time of 2.5 weeks. The model was confirmed using an external validation cohort of 1521 patients from seven centres. If only patients with standard risk were considered (e.g. no simultaneous transplantation of other organs), only 1.3 weeks additional waiting time was needed. In the Eurotransplant Senior Program, patients with vPRA values >50% had a strongly reduced transplant probability in the unadjusted analyses. In the multivariable model, a 1% increase in vPRA values was outweighed by an additional waiting time of 5 weeks. CONCLUSIONS: This study demonstrates that the assignment of UAGs decreases the transplant probability in both main Eurotransplant allocation programs because of insufficient compensatory mechanisms. At present, for immunized patients, a prolonged waiting time has to be weighed against the increased immunologic risk due to donor-specific antibodies not assigned as UAGs.

Delayed seroconversion and rapid onset of lymphoproliferative disease after transmission of human T-cell lymphotropic virus type 1 from a multiorgan donor.

BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1) screening of blood and organ donors is not mandatory in Germany because of its low prevalence (about 7/100 000). An HTLV-1 transmission event caused by a multiple organ donor was investigated. Validity of diagnostic procedures and HTLV-1 disease association in immunosuppressed organ recipients were analyzed. METHODS: Two screening immunoassays and an immunoblot (confirmatory assay) were used for detection of HLTV-1/2 antibodies. Proviral DNA was quantified in blood and biopsies of organ recipients by HTLV-1 real-time polymerase chain reaction (PCR). RESULTS: Proviral HTLV-1-DNA was detected in all blood samples of 3 organ recipients (1-100 copies/10(2) cells), but seroconversion was delayed for up to 2 years in screening assays and >6 years in the confirmatory assay. In 2 of 3 organ recipients, a cutaneous T-cell lymphoma was diagnosed 2 and 3 years after infection, respectively. Proviral HTLV-1 DNA concentration was almost 100 copies/10(2) cells in cutaneous lymphoma biopsies whereas in biopsies of other tissues ≤3.0 copies/10(2) cells were found. The third organ recipient did not suffer from lymphoma, but detailed clinical data on this patient were not available to us. CONCLUSIONS: Biopsy results support an etiological role for HTLV-1 in these cases of primary cutaneous T-cell lymphoma after solid organ transplant. HTLV-1-associated lymphoma can arise quickly in immunocompromised transplant recipients. The diagnosis of potentially HTLV-1-associated disease in organ recipients may require PCR because of delayed seroconversion.

Influence of aldosterone synthase gene C-344T polymorphism on focal segmental glomerulosclerosis.

AIM: We evaluated the influence of C-344T polymorphism of the aldosterone synthase gene, associated with aldosterone levels and the development of arterial hypertension, on focal segmental glomerulosclerosis (FSGS). METHODS: We studied 81 patients with primary FSGS followed up for 8.0 ± 12 years. Patients were classified according to their slope of reciprocal serum creatinine into group A (slow progressors, n = 57) and B (fast progressors, n = 24). One hundred healthy volunteers were analysed as controls. The biopsies of n = 50 patients were reviewed and analysed by the same pathologist. C-344T polymorphism was determined by polymerase chain reaction. RESULTS: The allele frequencies differed significantly between patients (C-allele: 0.55, T-allele: 0.45) and controls (C-allele: 0.45, T-allele: 0.55; P < 0.05). Patients carrying the C-allele tended to have a higher percentage of sclerosed glomeruli (41.8 ± 30% vs 31. 2 ± 19% in TT genotype, ns) and tubulointerstitial fibrosis (22.8 ± 18% vs 16.0 ± 5%, ns). The rate of deterioration of renal function was higher in the CC/CT genotypes (-0.216 ± 0.449 dL/mg per year) compared to the TT genotype (-0.030 ± 0.041 dL/mg per year, P = 0.002). Furthermore, 36.4% of the C-allele carriers and none of the patients with the TT genotype belonged to group B (P = 0.005). C-allele carriers also had a worse kidney survival in the Kaplan-Meier analysis (P = 0.027). CONCLUSION: Our results indicate that aldosterone synthase gene C-344T polymorphism not only acts as a risk factor for the development of FSGS, but also may influence its pathologic appearance and could serve as a marker of disease progression.

Impact of aldosterone synthase gene C-344T polymorphism on IgA nephropathy.

AIM: In the past years, aldosterone has been identified as an important mediator of renal injury. In this study, we evaluated the influence of C-344T polymorphism of aldosterone synthase gene, associated with serum aldosterone levels and the development of arterial hypertension, on IgA nephropathy (IgAN). METHODS: We studied n = 143 patients with biopsy-proven IgAN followed up for 7.1 ± 6.2 years. Patients were classified according to the slope of reciprocal serum creatinine into group A (slow progressors, n = 93) and group B (fast progressors, n = 50). One hundred healthy volunteers were analyzed as controls. The biopsies of n = 79 patients were reviewed and analyzed by the same pathologist. Aldosterone synthase gene C-344T polymorphism was determined by polymerase chain reaction amplification. RESULTS: The genotype distribution was similar in patients and control subjects [not significant (ns)]. Age, initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes (ns). The percentage of sclerosed glomeruli tended to be higher among patients carrying the CC/CT genotypes (29.4 ± 26.5% vs. 21.7 ± 25.2% in TT genotype; ns). C-344T polymorphism was associated with the progression of IgAN as shown by the different genotype frequencies in group Α (slow progressors, CC/CT: 60.2%, TT: 39.8%) and group B (fast progressors, CC/CT: 78.0%, TT: 22:0%; p = 0.032). CONCLUSION: Our results indicate that aldosterone synthase gene C-344T polymorphism is a risk factor for accelerated progression in Caucasian patients with IgAN.

Potential genetic risk factors in angiotensin-converting enzyme-inhibitor-induced angio-oedema.

AIMS: The pathophysiology of angiotensin-converting enzyme inhibitor (ACEi)-induced angio-oedema remains unclear. We have investigated the impact of ACE insertion/deletion (I/D) polymorphism in combination with serum ACE activity as well as the bradykinin B2 receptor 2/3 and c.C181T polymorphisms. METHODS: We analysed the ACE I/D as well as bradykinin B2 (2/3 and C181T) receptor polymorphisms in 65 patients with documented episodes of ACEi-induced angio-oedema and 65 patients matched for age and sex being under ACEi treatment without history of angio-oedema. Furthermore, we determined serum ACE activity in 47 of the 65 angio-oedema patients 3 months after the angio-oedema attack and compared these values with 51 healthy individuals (control II). RESULTS: No risk association was identified between ACE I/D (I-allele: 0.42 vs. 0.41, D-allele: 0.58 vs. 0.59; P= 0.095) or bradykinin B2 receptor polymorphisms and the development of angio-oedema during ACEi treatment. We found a trend of lower serum ACE activity in ACE I/I genotypes in comparison with control II (I/I: 28 +/- 4.5 vs. 33 +/- 1.8 U l(-1); ID: 39 +/- 3.3 vs. 41 +/- 1 U l(-1); DD: 56 +/- 6.7 vs. 52 +/- 1.8 U l(-1); P= 0.9). CONCLUSIONS: Our data suggest that polymorphism of ACE I/D and the bradykinin B2 receptor polymorphisms are not involved in the development of ACEi-induced angio-oedema when considered individually. Further studies should be carried out to clarify whether a combination of these polymorphisms might be a risk factor for ACEi-induced angio-oedema.

Is presence of ANCA in crescentic IgA nephropathy a coincidence or novel clinical entity? A case series.

BACKGROUND: There are few anecdotal reports of circulating antineutrophil cytoplasmic autoantibodies (ANCAs) in patients with immunoglobulin A (IgA) nephropathy. STUDY DESIGN: Retrospective case series. SETTING & PARTICIPANTS: We studied 8 patients with crescentic IgA nephropathy associated with ANCAs against myeloperoxidase (n = 5) and proteinase 3 (n = 3) followed up for 2.4 +/- 1.7 years. They were compared with 26 patients with IgA nephropathy with > 10% crescentic glomeruli, but negative for ANCAs. OUTCOMES: We analyzed clinical and histologic features of patients and their response to treatment. MEASUREMENTS: Screening for ANCAs was performed using indirect immunofluorescence, and positive results were verified using enzyme-linked immunosorbent assay. RESULTS: All patients with crescentic IgA nephropathy and positive for ANCAs, compared with only one-third of ANCA-negative patients, presented with the clinical syndrome of rapid progressive glomerulonephritis. ANCA-positive patients reached a higher peak serum creatinine level within the first 3 months (4.2 +/- 2.2 vs 2.5 +/- 1.9 mg/dL; estimated glomerular filtration rate, 19.3 +/- 10.2 vs 45.9 +/- 30.1 mL/min/1.73 m(2)). ANCA-positive patients with IgA nephropathy had a higher percentage of crescentic glomeruli (54.3% +/- 18%) compared with ANCA-negative patients with crescentic IgA nephropathy (34.5% +/- 26%). ANCA-positive patients were treated using cyclophosphamide and corticosteroids. Kidney function improved in all these patients: serum creatinine level decreased from the peak of 4.2 +/- 2.2 to 1.7 +/- 0.7 mg/dL at the end of follow up (estimated glomerular filtration rate, 19.3 +/- 10.2 to 44.6 +/- 11.1 mL/min/1.73 m(2)). In contrast, no significant improvement was achieved in ANCA-negative patients. CONCLUSION: Patients with IgA nephropathy, crescents, and positive for ANCAs represent a clinical entity with a diverse more exaggerated clinical and histologic picture. However, disease in these patients responded well to aggressive immunosuppressive therapy.

New influenza A (H1N1/09) in three renal transplant patients.

The pandemic new influenza A (H1N1/09) virus may be especially threatening for immunosuppressed renal transplant patients as they are at increased risk for complications, prolonged infection and mortality. This is the first case report of renal transplant patients with PCR-confirmed H1N1 respiratory tract infection. They showed a surprisingly mild clinical course despite respiratory fungal or viral co-infections in two cases. Treatment with oseltamivir in standard dosage was immediately started after diagnosis and proved to be rapidly beneficial with respect to clinical outcome and virus shedding without deteriorating renal transplant function.

Impact of genetic polymorphisms of the renin-angiotensin system and of non-genetic factors on kidney transplant function--a single-center experience.

Renin-angiotensin-aldosterone system (RAAS) polymorphisms such as the angiotensinogen-gene-M235T-, the angiotensin-conversion enzyme (ACE)-gene I/D- and the angiotensin-II-type 1-receptor-(AT1R)-A1166C-polymorphism have been implicated in renal insufficiency and hypertension. We studied the association of these RAAS genotypes and non-genetic factors with transplant function and hypertension after renal graft transplantation (NTX). A total of 229 renal graft recipients, transplanted at a single center, were monitored up to 54 months and genotyped using polymerase chain reaction. The prevalence of the genotypes was comparable to a control group of healthy volunteers. Genotype and clinical outcome was analyzed using ANOVA, while the k-nearest neighbor method was used for a pattern recognition analysis of the complete database. Hypertension after NTX was not influenced by the RAAS polymorphisms. The DD-genotype of the ACE-I/D-polymorphism was associated with significantly deteriorated renal transplant function during the months 18 to 30 after transplantation according to ANOVA at p < 0.05, as were non-genetic factors like long hospitalization, poor primary transplant function, and frequent rejections. Pattern recognition identified, the use of cyclosporine (odds ratio of 4.25) and the use of Ang II-receptor-blockers at discharge indicating the need of effective antihypertensive treatment (odds ratio of 3.26) as risk factors for transplant function loss. Altogether, the significant impact of the DD-genotype on the outcome after renal transplantation emphasizes the early identification of RAAS genotypes.

Influence of interleukin-6 G-174C gene polymorphism on coronary artery disease, cardiovascular complications and mortality in dialysis patients.

BACKGROUND: Inflammation is a well recognized central component of atherosclerotic processes in chronic kidney disease. Interleukin-6 (IL-6) levels are a strong determinant of cardiovascular mortality in dialysis patients. We evaluated the impact of IL-6 gene G-174C polymorphism associated with modified IL-6 production on the development of coronary artery disease (CAD), cardiovascular events and mortality in chronic dialysis patients. METHODS: We studied n = 463 patients on chronic dialysis with angiographically confirmed (n = 218) or excluded (n = 245) CAD followed up for 65 months after initiation of dialysis. Monitored were arterial hypertension, diabetes mellitus, hyperlipidemia, smoking, CRP and fibrinogen. IL-6 gene G-174C polymorphism was determined by PCR amplification. RESULTS: The CC genotype was associated with an impaired patient survival (p < 0.05) remaining an independent risk factor for death in multivariate analysis (HR for CC genotype: 3.58, CI: 1.41-9.07, p < 0.01). CC genotype carrying CAD patients suffered significant frequently cardiovascular events (revascularization, myocardial infarction, death) compared to GG/GC genotype carriers (85.2% vs. 66.5, p < 0.05). However, the IL-6 gene G-174C polymorphism was not related to the onset and development of CAD itself (ns) and the inflammation parameters CRP and fibrinogen did not differ between the genotypes under investigation (ns). CONCLUSIONS: Our results suggest that IL-6 gene G-174C polymorphism is associated with the incidence of cardiovascular events and mortality in chronic dialysis patients.

Influence of interleukin-10 gene G-1082A polymorphism on recurrent IgA nephropathy.

BACKGROUND: The G-1082A polymorphism of the interleukin-10 (IL-10) gene has been associated with modified gene expression and the progression of primary IgA nephropathy (IgAN). In the present study, we evaluated its influence on recurrent IgAN after renal transplantation. METHODS: We studied 103 patients who suffered from IgAN and underwent renal transplantation, followed up for 5.8 -/+ 3.4 years. A cohort of 206 matched renal allograft recipients with other primary diseases was analyzed as a control group. IL-10 gene G-1082A polymorphism was determined by PCR amplification. RESULTS: Microscopic hematuria and/or proteinuria of more than 500 mg/24 hours occurred in 22 patients (21%). Histological confirmation of IgAN recurrence was obtained in 16 patients. Young recipient age was associated with biopsy-proven IgAN recurrence in the Kaplan-Meier analysis of recurrence-free survival (p=0.05). The presence of IgAN recurrence had no impact on graft survival (not significant [NS]). Furthermore, graft survival was similar in patients with IgAN and patients with other primary diseases (NS). The IL-10 GG genotype was associated with a higher recurrence rate in the Kaplan-Meier analysis of recurrence-free survival (p<0.05). CONCLUSIONS: IgAN recurrence is a common complication, especially in younger renal transplant recipients. IL-10 gene G-1082A polymorphism was associated with an increased recurrence rate.

Early conversion from cyclosporine to tacrolimus increases renal graft function in chronic allograft nephropathy at BANFF stages I and II.

Switching from cyclosporine to tacrolimus without steroid pulse was suggested as a therapeutic option in chronic allograft nephropathy (CAN). Thirty-one renal transplant recipients with CAN were prospectively converted from cyclosporine to tacrolimus (group A), in parallel 31 matched cyclosporin A (CsA) patients (group B) without CAN were followed up for 30 months. In six matching patients of groups A and B inulin and para-aminohippurate (PAH)-clearances and mycophenolate were measured over a span of 3 months. Transplant biopsies of group A were scored according to BANFF. While group A presented with transplant dysfunction compared with group B before switching (2.7 +/- 0.16 mg/dl vs. 1.7 +/- 0.09 mg/dl; P < 0.001), transplant function was equal 30 months later: it ameliorated in group A (2.0 +/- 0.18 mg/dl vs. 2.7 +/- 0.16 mg/dl; P < 0.001) and decreased in group B (1.9 +/- 0.13 mg/dl vs. 1.7 +/- 0.09 mg/dl, P < 0.05). Especially, patients with biopsy scores I and II according to BANFF benefited from tacrolimus. Within 3 months, mycophenolate acid (MPA) levels increased under tacrolimus (P < 0.05) whereas inulin and PAH-clearances remained unchanged. At switching, antihypertensive treatment was more intense in group B, but this difference evened out. Adverse side effects were more frequent under tacrolimus. Patients with mild to moderate CAN significantly benefited from switching to tacrolimus. Increased MPA-levels under tacrolimus might have contributed to this effect.

A cell-based approach to the minimization of immunosuppression in renal transplantation.

Five renal transplant recipients were preoperatively treated with transplant acceptance-inducing cells (TAICs) in a Phase-I safety study of TAICs as an adjunct immune-conditioning therapy in living-donor kidney transplantation. Initially, patients received anti-thymocyte globulin induction therapy in combination with tacrolimus and steroid immunosuppression. Over the course of 12 weeks, steroids were withdrawn and tacrolimus therapy was minimized. Three of the five patients were able to tolerate low-dose tacrolimus monotherapy and one patient was withdrawn from all immunosuppression for over 8 months. No acute or delayed adverse events were associated with the infusion of TAICs. Monitoring of the recipient anti-donor reactivity of TAIC-treated patients in mixed lymphocyte cultures demonstrated that, during periods of clinically stable graft function, recipient T-cell proliferation and cytokine secretion in response to stimulation with donor alloantigen was relatively suppressed. Therefore, although the TAIC-II trial did not provide conclusive evidence of a beneficial effect of preoperative TAIC treatment, the results were encouraging because they suggest that TAICs promote a state of alloantigen-specific unresponsiveness, which might allow safe minimization of pharmacological immunosuppression.

Influence of cytokine gene polymorphisms on IgA nephropathy.

Aims. Recently, polymorphisms of cytokine genes have been associated with altered gene expression and modified cytokine production. We evaluated the impact of TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms on the clinical manifestations of IgA nephropathy. Patients and methods. The clinical course of 127 patients with biopsy-proven IgA nephropathy followed up for 6.6 +/- 6.0 years was studied. Patients were classified according to the slope of reciprocal serum creatinine into group A (slow progressors, n = 78) and group B (fast progressors, n = 49). TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms were determined by PCR amplification followed by restriction digestion with the endonucleases Sau96 I, Nco I, and Lwe I respectively. Results. The genotype distribution of the investigated polymorphisms was similar in patients and control subjects (ns). Age, initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes. The investigated polymorphisms were not associated with the progression of the IgA nephropathy, as shown by the similar genotype distribution in group A and group B (slow progressors: TGF-beta1, 92.3%; TNFalpha, 25.6%; IL-6, 74.4%; fast progressors: TGF-beta1, 85.7%; TNFalpha, 22.4%; IL-6: 81.6%, ns). Furthermore, these polymorphisms had no impact on renal survival in the Kaplan Meier analysis (ns). Conclusion. Our results suggest that TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A, and IL-6 gene G-174C polymorphisms are not risk factors or markers of progression in Caucasian patients with IgA nephropathy.

Influence of cytokine genes polymorphisms on long-term outcome in renal transplantation.

BACKGROUND: Recently, polymorphisms of cytokine genes have been associated with modified gene expression and increased cytokine production. We evaluated the influence of interleukin-10 (IL-10) gene G-1082A, tumour necrosis factor alpha (TNFalpha) gene G-308A and IL-6 gene G-174C polymorphisms on the rejection rate, renal function and long-term outcome in renal transplantation. PATIENTS AND METHODS: We studied n = 224 consecutive patients, who underwent renal transplantation at our centre from 1998 to 2001 (cadaveric: n = 175, living related: n = 49) followed up for 4.9 +/- 2.0 yr and n = 100 healthy volunteers. IL-10 gene G-1082A, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms were determined by polymerase chain reaction (PCR) amplification. RESULTS: The genotype distribution of the investigated polymorphisms was similar in patients and controls (ns). The age of donor and the recipient, the number of HLA mismatches and cold and warm ischemic time did not differ among patients with different genotypes (ns). No association between cytokine polymorphisms and the incidence of acute rejection episodes was detected (ns). The cytokine genotypes did not correlate with serum creatinine or creatinine clearance at any time during follow up (ns). Furthermore, there was no significant difference in the genotype frequencies among patients experiencing graft failure (ns). Patients with different cytokine gene polymorphisms showed similar outcomes in the Kaplan-Meier analysis of graft survival (ns). Finally, cytokine polymorphisms had no influence on the acute rejection rate or graft outcome also in the subgroup of HLA-DR mismatched grafts (ns). CONCLUSION: Our results suggest that IL-10 gene G-1082A, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms are no major risk factors in renal transplantation.

Hodgkin disease-like posttransplantation lymphoproliferative disorder of donor origin in a renal allograft recipient.

Posttransplantation lymphoproliferative disorder (PTLD) develops in 1.6% of renal allograft recipients. More than 90% are of recipient origin. There are only a few reports of Hodgkin disease-like PTLD in allograft patients. We report the case of a Hodgkin disease-like PTLD of donor origin in a 16-year-old renal allograft recipient. Fourteen months after transplantation, an increasing inhomogeneous structure in the hilar region of the transplanted kidney became apparent and was excised. Histological examination showed Hodgkin- and Sternberg-Reed-like cells. Immunostaining showed CD20-positive and CD15-negative cells and Epstein-Barr virus (EBV) involvement (EBV-encoded small nonpolyadenylated RNA and EBV-determined nuclear antigen 2). DNA fingerprinting analysis proved the lymphoma to be of donor origin. Treatment consisted of nephrectomy, discontinuation of immunosuppression therapy, and local radiation. Three years after lymphoma removal, the patient was still without relapse and underwent retransplantation with stable function of the second allograft for more than 2 years now.