Soluble human leukocyte antigen-G (SHLA-G) in Tunisian kidney transplantation.

To investigate the relationship between the soluble HLA-G (sHLA-G) and the appearance of acute renal rejection (AR) episodes we have quantify in this study the level of sHLA-G by enzyme-linked immunosotrbent assay in 42 kidney transplant patients classified in two groups: G1: 17patients with acute rejection (AR+) and G2: 25 patients without AR (AR-). To establish our normal sHLA-G ranges, serum samples from 18 healthy controls were tested. Pre-transplantation sHLA-G levels were significantly increased in patients (mean +/- standard error of the mean, 60.48 +/- 12.18 units/ml) than healthy subjects (19.11 +/- 4.9 units/ml) (p = 0.001). Although the difference was not statistically significant, G1 patients (AR+) revealed lower levels of sHLA-G (mean +/- standard error of the mean, 31.25 +/- 6.71 units/ml) compared to G2 patients (AR-) (53.43 +/- 1721 units/ml). Nevertheless, the course of total sHLA-G levels was nearly identical in patients with and without rejection. Nonparametric analysis revealed that pre-transplantation levels of sHLA-G < 18.00 units/ ml (sensitivity: 87.8% and specificity of 72.2%) were not related to rejection. Also, multivariate analysis regarding anti-HLA antibody status, recipient age and gender showed that sHLA-G could not be an independent risk factor for renal graft rejection. However, a higher sera levels of sHLA-G seemed to contribute to better kidney allograft survival rate after 10 years of follow-up (significance tendency: p = 0.091) as shown by the survival analysis. Because of the small number of subjects studied, these results must be treated with caution. A much larger cohort of kidney transplant patients according to acute rejection would seem necessary to confirm these findings.

Association of specific amino acid sequence (QRRAA) of HLA-DRB1*0405 with rheumatoid arthritis in a Tunisian population.

This study aimed to investigate HLA-DRB1 alleles in rheumatoid arthritis (RA) patients from Tunisia and to examine the effect of these alleles on disease severity. HLA-DRBI alleles and sub-typing of DRBI*04 and *01 were determined in 90 patients and 100 healthy controls, by PCR-SSP. HLA-DRB1*04 was significantly higher in patients (51.1%) than in controls (27%) [OR=2.83, p=0.00066]. DRBJ*0405 was found to be the unique DR4 allele associated with RA (28.88% vs 6%) [OR=6.36, p=0.000059]. A significant decrease in the frequency of HLA-DRB1*0701 was observed in RA patients (16.66%) compared to controls (36%) [p=0.0026]. However, the frequency of patients carrying the shared epitope (SE) QRRAA, was slightly increased compared with controls (37.8% vs 23%) [OR=2.03, p=0.039]. We found that the presence of rheumatoid factor, HLA-DR4 and HLA-DRBI*0405 were not significantly associated with bone erosions or the presence of extra-joint involvement. In our population, the SE (QRRAA) expressed in DRBI*04 alleles is related to the susceptibility to RA but it is not involved in RA severity in Tunisia, while DRBI*0701 might protect against this disease.

Mannose binding lectin (+54) exon 1 gene polymorphism in Tunisian kidney transplant patients.

Mannose-binding lectin (MBL), a collagen-like serum protein, is a key component of innate immunity. MBL binding to carbohydrates present on pathogens mediates lectin-dependent activation of the complement pathway. There is growing interest in the importance of innate immunity in host defense, particularly when adaptive immunity is compromised. Three single nucleotide polymorphisms (SNPs) of the MBL gene have been described in the first exon to be associated with low MBL serum concentrations as well as impaired MBL structure and function. Clinical studies have shown that these MBL SNPs are associated with increased susceptibility to infections, especially in immunocompromised patients. To investigate the association between acute kidney transplant rejection and polymorphism at codon 54 of the MBL gene, the DNA genomic of 133 renal transplant recipients and 117 healthy blood donors was analyzed by restriction fragment length polymorphism-polymerase chain reaction. The patients were classified into two groups: group 1 included 32 HLA-identical recipients and group 2, 101 one haplo-identical recipients. Forty-eight (36.1%) subjects had developed one or more acute rejection episodes (AREs) within the first 6 months after transplantation: 9 in group 1 (28.12%) and 39 in group 2 (38.61%). The genotype and allele frequencies of (+54) MBL gene polymorphism among patients and controls did not reveal a significant difference. However, the frequency of MBL-B mutant allele was increased among patients with AREs compared with those without AREs: group 1 (0.167 vs 0.065) versus group 2 (0.205 vs 0.105). Although the difference was not significant, perhaps because of the small number of patients, the MBL at codon (+54) polymorphism could be involved in the susceptibility of Tunisian kidney transplant recipients to acute allograft rejection episodes.

The first year renal function as a predictor of long-term graft survival after kidney transplantation.

This study examined the impact of graft function at the end of the first year after kidney transplantation on long-term graft survival. We analyzed the roles of serum creatinine (Scr) and other variables as predictors of graft survival among 235 adult kidney transplant patients. The subjects were divided into 3 groups according to their Scr at the end of the first year: group 1, Scr < 100 micromol/L; group 2, 100 micromol/L < or = Scr < or = 150 micromol/L; and group 3, Scr >150 micromol/L. The annual rate of graft loss of 0.7% (95% confidence interval [CI], 0.63-0.77) in group 1, was lower than those in group 2 (2.1%; 95% CI, 2.02-2.18; P < .0001) and group 3 (6%; 5.74-6.26; P < .0001). Regression analysis showed the role of recipient age at the time of operation, and Scr level at the end of the first year to be independent predictors of graft loss. Graft survival was not influenced by any other studied parameter, including donor age, year of procedure, warm ischemia time, history of acute tubular necrosis, and occurrence of an acute rejection episode. We conclude that the 1-year Scr value predicts long-term renal graft survival, representing a simple, practical tool to identify recipients with an high risk for late graft failure.

The PTPN22 C1858T (R620W) functional polymorphism in kidney transplantation.

To investigate the association between kidney transplant rejection and PTPN22 (protein tyrosine phosphatase non-receptor 22) polymorphism, genomic DNA of 175 renal transplant recipients and 100 healthy blood donors were genotyped by restriction fragment length polymorphism-polymerase chain reaction. The patients were classified in two groups: G1 included 33 HLA-identical recipients and G2 included 142 with one or more HLA mismatches. Forty-nine patients developed an acute rejection episode (ARE): 8 in G1 and 41 in G2. The allelic frequencies of PTPN22 R620W revealed a significant difference between patients and controls. In fact, the W-allele was significantly more frequent in graft recipients than in blood donors (0.05 vs 0.01, P < .05). Furthermore, the frequency of this allele was increased in G1 patients with an ARE (0.188) compared with those without an ARE (0.040), but the difference was not statistically significant. Thus, we concluded that the PTPN22 W-variant allele could be involved in the susceptibility to acute allograft rejection in Tunisian kidney transplant patients.

Kidney transplantation: Charles Nicolle Hospital experience.

The aim of our retrospective study was to analyze the short- and long-term follow-up of 298 renal transplantations performed between June 1986 and May 2005. All were first transplantations except 4 cases, with 54 from cadaveric and 244 from living donors. The recipients included 196 males and 102 females of overall mean age of 31.21 +/- 8.9 years (range, 16-61 years). A combination of prednisolone and azathioprine was presented for 212 patients or mycophenolate mofetil for 86 patients. Polyclonal or monoclonal antibodies were used as induction therapy in 183 cases. Cyclosporine was administered to 188 cases and tacrolimus only to 16. HLA matching was 0 mismatches (MM) in 65 cases; 1 or 2 MM in 113; 3 MM in 99; and > or =4 MM in 21. Acute tubular necrosis occurred in 45 cases. One hundred eighteen patients experienced at least 1 acute rejection episode: 102 cases (41.8%) among living and 16 (29.6%) among cadaveric kidneys donor (P = .0007). The actuarial patient and graft survival rates at 1, 5, 10, 15, and 20 years were 95.9%, 87.4%, 77.5%, 65.6%, and 60.8%, and 94.9%, 84.5%, 75.4%, 65.4%, and 53%, respectively. Sixty-three patients died and 72 patients returned to dialysis. Our results were comparable to experienced centers. However, the member of kidney transplantations does not match the increased number of patients on renal replacement therapy. It is advisable to promote obtaining organs from brain-dead donors.

[HLA-G: an immunoregulatory non classical class I HLA molecule]. / HLA-G: une molécule HLA de classe I non classique à pouvoir immunorégulateur.

HLA-G is a particular non classical HLA class I molecule. Despite its tissue-restricted expression and low polymorphism, this molecule plays an important role in innate and adaptative immunity. The tolerogenic propriety of HLA-G makes it an immunomodulatory molecule acting in the early phases of conception, protecting fetal tissues from the maternal immune system. Immunomodulatory functions of HLA-G and the associations of this molecule with some pathological states are reported in this review. So, little amounts of soluble HLA-G or particular allelic expression of this molecule are associated with some pregnancy complications. HLA-G expression on tumor cells by preventing antitumor responses via a trogocytosis mechanism and regulatory T cells induction is associated with invasiveness and clinical evolution of some tumor types. HLA-G is also involved in the protection of the transplanted tissues from rejection. Revealing of new more functional homomultimeric isoforms of this molecule offers new insight in a better understanding of clinical and biological role of HLA-G.

[Lymphoproliferative disorders in kidney transplant recipients: incidence, clinical characteristics and outcome]. / Syndromes lymphoprolifératifs après transplantation rénale: incidence et particularités cliniques et évolutives.

PURPOSE: The aim of this study was to determine the epidemiological and the clinical characteristics of post-transplant lymphoproliferative disease (PTLD) and to evaluate its impact on patients' and grafts' survival. PATIENTS AND METHODS: Three hundred and sixteen adult kidney recipients, transplanted between June 1986 and May 2006, were included. The incidence rates were calculated by dividing the number of different events (PTLD, death and graft-loss) by the total duration of follow-up. The survival rates and the cumulated frequency of PTLD were calculated according to the actuarial method. RESULTS: Seven recipients developed PTLD during a cumulated follow-up of 2202 years. The annual incidence was of 0.32% (95% CI : 0.30-0.34). It was of 0.81% (0.70-0.92) in recipients of kidneys from deceased donors, and of 0.25% (0.23-0.27) in patients transplanted from living donors (NS). The delay after transplantation for the diagnosis of PTLD ranged from 7.4 months to 7.7 years. PTLD was a B cell lymphoma in six cases and affected extra nodal sites in most of the cases. The treatment, comprising the cessation of immunosuppressive therapy in all cases, resulted in complete remission in four patients. Three patients died, representing an annual death rate of 6.1%, versus 2.8% in patients without PTLD (NS). The annual incidence of graft loss was 6.1% versus 3.2% among patients without PTLD (NS). CONCLUSION: PTLD was observed in 2.2% of our patients, with an annual incidence of 0.32%. It resulted in a decrease of both patients' and grafts' survivals. Preventive measures, including the improvement of the monitoring of immunosuppressive drugs and the prevention of viral infections, should be considered to reduce the risk of PTLD.

Impact of Interleukin-17F Gene Polymorphisms in Outcome of Kidney Transplantation in Tunisian Recipients.

BACKGROUND: Genetic polymorphisms of interleukin (IL)-17F, associated with functional and/or quantitative change in this glycoprotein, have been described as predisposing to various autoimmune diseases. The proinflammatory IL-17 has some roles in renal transplantation. In this context, the relationship between the most common IL-17F polymorphisms with acute renal allograft rejection susceptibility in Tunisian renal recipients has been investigated. METHODS: We examined 93 renal transplant recipients who were enrolled and classified as follows: GI, 48 transplant recipients who developed at least one episode of acute rejection; and GII, 45 controls, kidney recipients who also were followed for at least 1 year and had stable renal function. Single nucleotide polymorphisms (SNPs) of IL-17F gene, including -1507 C/T (rs18889570), 7384 A/G (rs2397084), 7469 C/T (rs11465553), and 7489 A/G (rs763780), were evaluated using direct sequencing. RESULTS: No statistically significant association of the IL-17F SNPs studied with the onset of acute rejection was observed. However, AA genotype on 7489A/G SNP showed anti-HLA antibodies less than other genotypes and a higher graft survival time (P = .017). CONCLUSION: The AA genotype on 7489A/G SNP of IL-17F and the A allele might be associated with a lower risk of acute rejection with better graft survival.

Human platelet antigens: HPA-1, -2, -3, -4, and -5 polymorphisms in kidney transplantation.

To investigate the association between kidney transplant rejection and polymorphisms of HPA-1, -2, -3, -4, and -5, the genomic DNA of 70 renal transplant recipients and 100 healthy blood donors was analyzed by polymerase chain reaction (PCR)-SSP. The patients were classified into two groups. Group 1 included 33 HLA-identical recipients and group 2, 37 one haplo-identical recipients. Thirty-one recipients experienced an acute rejection episode (ARE): 10 in group 1 and 21 in group 2. Ten group 2 patients developed chronic allograft dysfunction (CAD). Before transplantation, five patients in group 1 were lymphocytocytotoxic antibodies (LCT) positive, among them three developed an ARE. In group 2, seven recipients were LCT positive and four had an ARE. After transplantation, 29 patients were LCT positive: 11 in group 1 and 18 in group 2, among them: 6/11 and 11/18 had an ARE. The allelic frequencies of HPA-1, -2, and -5 among patients and controls did not reveal significant differences, whereas the HPA-3a and HPA-4b alleles were significantly more frequent among patients than controls: 91.4% and 27.8% versus 76.5% and 11.5% respectively (P < .05 and P < .001). The frequency of the HPA-3b allele was increased in patients with an ARE (11.3%) and those who developed CAD (20%) compared with those not affected by these complications (6.6% and 6.4%, respectively), but the difference was not significant. The genotype distribution of HPA-1, -3, and -4 genes of GPIIb/IIIa revealed that the most frequent genotype was HPA-1a1a/3a3a/4a4a (19%) among controls and HPA-1a1a/3a3a/4a4b (31.4%) among patients. This genotype was associated with an ARE in 25.8%, namely 50% of group 1 recipients and 14.28% of group 2. The HPA-4b polymorphism of GPIIb/IIIa receptor seem to be an independent risk factor for acute allograft rejection in kidney transplantation.

Pustular psoriasis after renal transplantation.

Cutaneous manifestations in renal transplant recipients are frequently represented by infections and cancerous lesions. However, dermatologic lesions secondary to autoimmune diseases are rare. We report a case of pustular psoriasis occurring after renal transplantation in a 31-year-old woman with a history of vitiligo. The patient was on hemodialysis for 2 years for undetermined chronic nephropathy. She received an HLA identical live related transplant from her brother. She was maintained on an immunosuppressive regimen of corticosteroids, azathioprine, and cyclosporine, which was replaced with mycophenolate mofetil because of neurotoxicity and azathioprine was stopped. Thirty-one months after renal transplantation, she developed pustular psoriasis which was treated with retinoids; she experienced a relapse and resistance to treatment despite the reintroduction of cyclosporine.

Impact of dialysis modality on posttransplantation results in kidney transplantation.

Studies looking at the type of pretransplantation renal replacement therapy on graft and patient survivals after kidney transplantation have produced conflicting results. Therefore, we studied the effect of pretransplantation dialysis modality (peritoneal dialysis [PD] or hemodialysis [HD]) on transplant outcomes. We performed a retrospective study of 78 patients (39 PD and 39 HD) who had their first renal transplantation between January 1986 and December 2004. Comparisons between groups were made using chi-square tests for qualitative parameters and nonpaired Student t tests for continuous variables. Comparisons between actuarial curves of patient and technique survivals used log-rank tests. The percentages of recipient males, cadaveric donors, transplant-induced diabetes, mean period of dialysis, mean transplantation follow-up, mean duration of first hospital stay, first infection, acute tubular necrosis, and acute rejection episodes were not significantly different among PD versus HD patients, whereas recipient and donor mean ages were significantly higher in HD and PD patients, respectively. There were no differences in graft and recipient survivals among PD versus HD patients. After kidney transplantation, there was no difference between PD and HD patients concerning percentages of infection, acute tubular necrosis, acute rejection episodes or graft and recipient survivals.

Risk factors of arterial hypertension after renal transplantation.

Arterial hypertension often present after kidney transplantation is of multifactorial origin. The aim of this study was to determine the role of donor and recipient factors in the development of hypertension after renal transplantation. We retrospectively analyzed the data of 280 patients transplanted between 1985 and 2005, who still had functioning grafts at 1 year after transplantation. We recorded donor and recipient parameters. One hundred eighty-seven patients (66.8%) were hypertensive. Upon multivariate analysis of recipient factors, pretransplant hypertension (odds ratio) [OR]: 8.5, 95% confidence interval [CI]: 4.5 to 16.1); serum creatinine level > 130 micromol/L at 6 months (OR: 2.5, 95% CI: 1.3 to 4,7), male gender (OR: 2.02, 95% CI: 1.2 to 3.4), and chronic rejection (OR: 2.4, 95% CI: 1.2 to 4.7) were independent predisposing factors. Among donor factors, age was significantly associated with arterial hypertension upon univariate analysis. In conclusion, recipient factors, especially pretransplant hypertension, contribute to the disorder in renal transplant patients.

Polymorphism of the renin-angiotensin-aldosterone system in patients with chronic allograft dysfunction.

Polymorphism of the gene encoding components of the renin-angiotensin-aldosterone synthase system (RAAS) represents an area of intense research of cardiovascular disease associations. Numerous studies have addressed the role of RAAS gene polymorphisms in the development and progression of renal disease. Also, it has been reported that patient with ACE (DD) and angiotensinogen AGT (TT) genotypes are associated with chronic allograft dysfunction (CAD). We investigated the effects of gene polymorphisms of the renin-angiotensin-aldosterone system in renal transplant patients (81 males and 50 females; mean age 29.6+/-10.2 years). Genotypes were determined using polymerase chain reaction sequence specific primers and PCR followed by RFLP analysis. Renal allograft recipients with chronic allograft dysfunction had significantly higher frequencies of the MM genotype than those without CAD (P<0.05). The other genetic polymorphisms of the RAAS were not associated with CAD. This study proves that determination of AGT M235T genotype before transplantation may help identify patients who are at risk for chronic renal transplant dysfunction.

Plasma levels of soluble CD30 in kidney graft recipients as predictors of acute allograft rejection.

In renal transplant recipients elevated soluble serum CD30 levels are associated with increased rejection and graft loss. We sought to determine the sCD30 plasma levels before and after kidney transplantation and to assess whether sCD30 was a predictive factor of immunological risk. sCD30 plasma levels were determined by an enzyme-linked immunosorbent assay assay in 52 kidney graft recipients before as well as 7, 15, and 21 days after transplantation. Eighteen patients developed acute allograft rejection (group I) and 34 patients showed uneventful courses (group II). Before transplantation sCD30 plasma levels were elevated in both groups (mean: 162.6 +/- 89.5 U/mL). After transplantation, group I recipients with acute rejection showed higher relative levels of plasma sCD30 on days 7 and 15 (120.8 +/- 74.6 U/mL and 210.6 +/- 108.7 U/mL respectively) compared with group II patients without rejection (95 +/- 45 U/mL and 59.4 +/- 31.6 U/mL), a difference that was significant for group I (P = .0003) and not significant for group II (P = .09). On day 21, sCD30 decreased in the two groups but remained higher among group I patients (120.6 +/- 92.7 U/mL). HLA antibodies were positive in 18 patients (34.6%) with 9 (50%) experiencing at last one episode of acute rejection. Among 34 patients negative for anti-HLA antibodies, nine displayed acute rejection only (26.4%), a difference that was not significant (P > .05). If we consider 100 U/mL as the minimum predictive level for allograft rejection, our results suggested that levels of sCD30 should be taken into consideration with the presence of HLA-antibodies detectable before and after transplantation, especially in patients with more than three HLA mismatches [RR = 3.20 (0.94 < RR < 10.91)]. These data suggested that measurement of plasma sCD30 is a useful procedure for the recognition of rejection in its earliest stages.

Ctla-4 exon 1 (+49) and promoter (-318) gene polymorphisms in kidney transplantation.

To investigate the association between kidney transplant rejection and the polymorphisms of CTLA-4 gene exon 1(+49) and promoter (-318), genomic DNA of 70 renal transplant recipients and 110 healthy blood donors were genotyped by PCR-RFLP and PCR-SSP, respectively. The patients were classified in two groups: G1 included 33 HLA-identical recipients and G2, 37 one haplo-identical recipients. Thirty-one recipients experienced an acute rejection episode: 10 in G1 and 21 in G2. Ten G2 patients developed chronic allograft dysfunction (CAD). Allelic frequencies and genotype distribution were similar among patients and controls. CTLA-4 exon 1 genotype A/A and CTLA-4 promoter genotype C/C were significantly higher among G2 patients with CAD than without CAD (P < .01). The distribution of CTLA-4 exon 1-promoter genes did not reach significance between graft recipients and controls. The genotype frequency of (G/G-C/C) was increased among controls (42.72%) compared with graft recipients (G1 and G2; 35.71%). CTLA-4 polymorphisms gene were associated with susceptibility to chronic allograft dysfunction.

Behçet's disease and major histocompatibility complex class II antigens in Tunisians.

Forty-two Tunisian patients suffering from Behçet's disease (23 with uveitis) were typed for HLA-DR and DQ antigens. There was a significant excess of HLA-DQw3 (p less than 0.01) but also an important deficiency of HLA-DRw6 and DQw1 (p less than 0.01). A substantial increase of HLA-DR2 (p less than 0.01) for those with uveitis, and of HLA-DR4, DR7, for the others has been recorded (p less than 0.01).

HLA-antigens in a Tunisian familial chondrocalcinosis.

Thirty members of a Tunisian family with hereditary chondrocalcinosis were typed for HLA-A, B, and DR antigens: 7 affected and 23 unaffected subjects in three consecutive generations. The haplotype A1 B12 DR3 was found in all affected subjects and in 8 unaffected members. Chondrocalcinosis in this family may be associated with the haplotype A1 B12 DR3. The mode of transmission was autosomal dominant with incomplete penetrance.

HLA A, B, and DR antigens and complotype in Tunisian patients with diabetes mellitus.

The frequency of HLA A, B, and DR antigens as well as the Bf and C4 allotypes have been investigated in insulin-dependent diabetes mellitus (IDDM) and compared to that of healthy controls in the Tunisian population. An increase of A30, DR3, DR4, BfF1, C4Ao, and C4Bo and decrease of B40, DR2, DR5, and DR6 were found in diabetics when compared to the value observed in controls. The strongest association was noticed with HLA DR3 and DR4. Heterozygotes DR3 DR4 were very frequent in diabetics: 24.2 per cent versus 3.6 per cent in controls (relative risk 7.72). The protective role of DR2 and DR5 antigens were also confirmed. No supratypes of HLA, Bf, and C4 alleles associated with IDDM have been observed among these Tunisian patients.

Extended HLA haplotypes in multiplex families with insulin dependent diabetes mellitus in Tunisian population: HLA serological typing and RFLP analysis.

Haplotypes including HLA A, B, C, DR, and DQ were compared in a study population comprising 18 Tunisian multiplex families with diabetic children. Eighty haplotypes found in IDDM patients were compared with 148 haplotypes present in healthy family members. RFLP analysis showed that two DR subtypes were significantly more common in the diabetic haplotypes (DR4-DQw8: 82 per cent in IDDM members compared to 0 per cent in healthy members, p less than 0.001 and DR-Dw25: 56 per cent in IDDM patients compared to 16.7 per cent in healthy members, p less than 0.001) and these were in most cases found in haplotype combinations with HLA A2 B44 DR4 DRw53 and HLA A 24 B18 DR3 genes, respectively.