Cadaveric Kidney Allograft Research Articles

Role of Octreotide and Instillation of Povidone-Iodine in the Treatment of Lymphorrhea in Renal Transplantation: A Comparative Study

Background: Lymphorrhea is a minor complication after kidney transplantation but may develop into a lymphocele and prolong hospital stay. Treatment is conservative based on percutaneous drainage until lymphatic leakage cessation. It has been reported that povidone iodine instillation and octreotide has beneficial effects to treat lymphorrhea after renal transplantation. Aims and Objectives: The aim of this study was to compare the povidone iodine instillation and octreotide treatment in lymphorrea after kidney transplantation. To evaluate the efficacy of povidone iodine and octreotide injection in comparison to control group for the treatment of lymphorrhea in renal transplant patient. Materials and Methods: It was comparative analytical study included 60 recipients of both cadaveric and live kidney allografts with posttransplant lymphorrhea including 20 treated with instillation of betadine solution, 20 with octreotide (0.1 mg three times a day subcutaneously), and 20 was control group (no betadine and octreotide was used). We reviewed the daily amount of fluid collection, duration of lymphorrhea, complications, lymphocele formation, rejection episodes, graft outcomes, and hospital stay. Results: The average duration of lymphorrhea was (8.85 ± 0.88) and (11.6 ± 0.94) and (16.15 ± 0.81) days for the betadine groups, the octreotide groups and control groups respectively. (P < 0.05). No lymphoceles occurred among the betadine group, while three lymphoceles were found among patients treated with octreotide and five lymphocele were found among control groups. No differences were observed for wound infection, graft dysfunction episodes or renal function and death between the groups. No octreotide and povidone related adverse events were noted. Conclusion: The mean length of lymphorrhea was lower with povidone iodine instillation as compared to octreotide treatment. There was a shorter hospital stay and minor patient discomfort in betadine groups. In conclusion, lymphatic leakage after kidney transplantation may be successfully managed by betadine instillation as compared to octreotide and control groups.

Short-term outcome of kidney transplantation from deceased donors with nephrolithiasis.

Shortage of kidney allografts is a major barrier to end-stage renal disease patients receiving kidney transplantation, and it is necessary to enlarge the donor pool and find better ways of using available allografts. The global incidence of nephrolithiasis is increasing, nephrolithiasis affects approximately 10% of adults worldwide, and it also affects the kidney donors. However, there is little information about the use of cadaveric kidney allografts with nephrolithiasis. This study aims to evaluate the safety and outcome of kidney transplantation with allografts from the deceased donors with nephrolithiasis. A total of 520 deceased donors who was at least 10 years old, and 945 adult recipients with single kidney transplantation at the Department of Kidney Transplantation, the Second Xiangya Hospital from 2016 to 2020 were included in this study. The donors were divided into 2 groups according to nephrolithiasis diagnoses: The donors with nephrolithiasis (D + ) and the donors without nephrolithiasis (D - ). The recipients were assigned into 3 groups according to their donors and the allografts they received: The allografts from donors without nephrolithiasis (D - K - ), the allografts without nephrolithiasis from donors with nephrolithiasis (D + K - ), and the allografts with nephrolithiasis (D + K + ). The demographic and clinical data of enrolled subjects were retrospectively analyzed. The allograft discard ratio between different donors were analyzed. The one-year survival of allografts and recipients, as well as the allograft function and the complications of kidney transplantation were compared. Fifty out of 520 donors had nephrolithiasis, and the nephrolithiasis incidence was 9.6%. We recovered 1 040 kidneys, and total discard rate was 4.4% (46/1 040). The D + group had a rate of 7% discard. The donors with kidney discard accounted for 12% in the D + group, and this was higher than that of donors in the D - group (5.1%, P <0.05). The total incidence of delayed graft function (DGF) was 7.5%, and there were no significant differences in the incidence of DGF in recipients among the D - K - , D + K - , and D + K + group (7.5% vs 6.5% vs 8.2%, P> 0.05). During the one-year follow-up, 8 allografts lost function and 19 recipients died with a functional allograft. Recipients in the D - K - , D + K - ,and D + K + groups also had no significant difference between a one-year allograft and patient survival rate ( P >0.05). However, recipients in the D + K + group had a higher level of serum creatinine [(139.2±62.46) μmol/L vs (117.19±51.22) μmol/L, P <0.05] and lower estimated glomerular filtration rate [eGFR; (56.67±23.31) mL/(min·1.73 m -2 ) vs (66.86±21.90) mL/(min·1.73 m -2 ), P <0.05] compared with recipients in the D - K - group at 12 months after transplantation. During the first year after transplantation, 4 recipients developed urolithiasis, and recipients who received allografts from the D + group donors had a higher incidence of urolithiasis than those who received allografts from the D - group donors (2.2% vs 0.2%, P <0.05). There were no significant differences in the incidence of urinary tract infections and ureteral strictures at 1 year between recipients of D + and D - donors (both P >0.05). The cadaveric kidney allografts with nephrolithiasis could be safely used for transplantation, and the short-term outcome is acceptable. However, nephrolithiasis in donors may increase the rate of kidney discard, disturb the short-term function of allografts, and increase the risk of urolithiasis in recipients. Further research with a long-term study is needed to verify the long-term outcome of kidney transplantation using cadaveric kidney allografts with nephrolithiasis.

Cadaveric kidney allograft transplantation using the Da Vinci robotic surgical system. Initial experience in the Russian Federation

Kidney transplantation is the treatment of choice for patients with end-stage renal disease. In order to reduce the number of postoperative complications following open surgeries, a number of clinics in the USA and Europe are currently developing robot-assisted surgical techniques. Studies have shown that robotic surgery facilitates kidney transplantation under optimal ergonomic position for the surgeon, with functional results and patient safety comparable to those obtained under an open approach. We herein present our initial experience (in the Russian Federation) on heterotopic cadaveric kidney transplantation by laparoscopic surgery using the Da Vinci robotic surgical system.

KIR and their HLA Class I ligands: Two more pieces towards completing the puzzle of chronic rejection and graft loss in kidney transplantation.

BackgroundKidney transplantation is a life-saving treatment for patients with end-stage renal disease. However, despite progress in surgical techniques and patient management, immunological rejection continues to have a negative impact on graft function and overall survival. Incompatibility between donors and recipients for human leukocyte antigens (HLA) of the major histocompatibility complex (MHC) generates a series of complex cellular and humoral immune response mechanisms that are largely responsible for rejection and loss of graft function. Within this context, a growing amount of evidence shows that alloreactive natural killer (NK) cells play a critical role in the immune response mechanisms elicited by the allograft. Killer immunoglobulin-like receptors (KIRs) are prominent mediators of NK cell alloreactivity.Methods and findingsA cohort of 174 first cadaveric kidney allograft recipients and their donors were selected from a total cohort of 657 transplanted patients for retrospective immunogenetic analyses. Patients with HLA Class II mismatches were excluded. HLA Class I allele frequencies were compared among patients with chronic rejection, patients with stable graft function and a group of 2388 healthy controls. Activating and inhibitory KIR gene frequencies, KIR haplotypes, KIR-HLA ligand matches/mismatches and combinations of recipient KIRs and donor HLA Class I ligands were compared among patients with and without chronic rejection and a group of 221 healthy controls.Patients transplanted from donors homozygous for HLA-C1 antigens had a significantly higher risk for chronic rejection than patients transplanted from donors homozygous or heterozygous for HLA-C2 antigens or with epitopes belonging to the HLA-Bw4 ligand group.The Kaplan-Meier curves obtained by dividing the patients into 3 groups according to the presence or absence of one or both of the combinations of recipient KIRs and donor HLA ligands (rKIR2DL1/dHLA-C2 and rKIR3DL1/dHLA-Bw4) showed a significantly higher cumulative incidence of chronic rejection in the group of patients completely lacking these functional units. These patients showed a progressively stronger decline in modification of diet in renal disease-estimated glomerular filtration rate.ConclusionsKIR genotyping should be performed at the time of enrolment of patients on the waiting list for organ transplantation. In our study, a significantly higher risk of chronic rejection after kidney transplantation was observed when recipient (r) and donor (d) pairs completely lacked the two functional rKIR-dHLA ligand combinations rKIR2DL1/dHLA-C2 and rKIR3DL1/dHLA-Bw4. This immunogenetic profile corresponds to low levels of NK cell inhibition. Therefore, patients with this high risk profile could benefit from immunosuppressive therapy aimed at reducing NK-cell cytotoxicity.

Expanded Criteria Donors, Histological Scoring, and Prolonged Cold Ischemia: Impact on Renal Graft Survival

The use of expanded donors or kidneys with preexistent chronic damage remains controversial, but they offer the opportunity to expand the donor pool. We investigated the impact of these conditions as predictors of graft survival among a cohort of recipients with prolonged cold ischemia times and a high incidence of delayed graft function. We included 70 consecutive cadaveric kidney allografts implanted between 2001 and 2005, which had undergone an early graft biopsy. Delayed graft function was present in 84% of cases with moderate or severe preexistent chronic damage in 63% and 27% of biopsies, respectively, and acute rejection was diagnosed in 14.3% of overall cases. The graft survival was 73.3% at 48 months. Primary nonfunctioning kidneys were more frequent using kidneys from expanded compared with standard donors (20.0% vs 0.0%, P < .002). Multivariate analysis showed that only the donor condition (standard vs expanded) was independently associated with graft survival (hazard ratio: 0.12; 95% confidence interval: 0.01–0.87; P < .03). Our results suggested that the donor characteristics prevail over other variables to predict graft outcomes.

Octreotide in the Treatment of Lymphorrhea After Renal Transplantation: A Preliminary Experience

Background Lymphorrhea is a minor complication after kidney transplantation but may develop into a lymphocele and prolong hospital stay. Treatment is conservative based on percutaneous drainage until lymphatic leakage cessation. It has been reported that octreotide has beneficial effects to treat lymphorrhea after axillary node dissection and excision of lymphatic malformations. The aim of this study was to report preliminary experience about octreotide treatment in lymphorrea after kidney transplantation. Materials and Methods This retrospective study included 20 recipients of cadaveric kidney allografts with posttransplant lymphorrhea including 10 treated with instillation of povidone iodate solution, and the other 10 with octreotide (0.1 mg three times a day subcutaneously). We reviewed the daily amount of fluid collection, duration of lymphorrhea, complications, lymphocele formation, rejection episodes, graft outcomes, and hospital stay. Results The average duration of lymphorrhea was 8.5 (±4.5) and 16.3 (±7.3) days for the octreotide versus the povidone groups, respectively ( P = .001). No complications occurred among the octreotide group, while three lymphoceles grew among patients treated with povidone solution. No differences were observed for acute rejection episodes or renal function between the groups. No octreotide-related adverse events were noted. Conclusion The mean length of lymphorrhea was lower with octreotide versus iodate povidone solution treatment. There was a shorter hospital stay and minor patient discomfort. In conclusion, lymphatic leakage after kidney transplantation may be successfully managed by octreotide administration.

Renal Function and Tubular Phosphate Handling in Long-Term Cyclosporine- and Tacrolimus-Based Immunosuppression in Kidney Transplantation

The aim of the study was to assess impaired tubular phosphate reabsorption and renal function among patients on cyclosporine- or tacrolimus-based immunosuppression for 2 years after kidney transplantation. Among 60 cadaveric kidney allograft recipients observed for 48 months, 40 received cyclosporine, azathioprine, and prednisone (group A and B). Group C consisted of 20 patients receiving tacrolimus with steroid withdrawal at 3 months after transplantation. Renal function and calcium-phosphate metabolism—iPTH, 25-OHD, 1,25(OH) 2D concentration, phosphate reabsorption (TRP; mmol/L), and tubular maximum phosphate reabsorption per glomerular filtration rate (TmPO 4/GFR; mmol/L)—were assessed at 1, 6, 12, 18, and 24 months (groups A and C) or 24, 30, 36, 42, and 48 months (group B). Renal function after 24 months of observation was significantly better among tacrolimus-treated patients (serum creatinine concentration μmol/L; C: 94.6 ± 16.8 vs A: 110.5 ± 22.1 vs B: 121.1 ± 30.9; P < .05). Among tacrolimus-treated recipients, TRP and TmPO 4/GFR remained within normal values during the whole observation period. In groups A and B, TRP improved during the first year of observation; after 2 years it reached values observed in group C (TRP: A: 0.67 ± 0.1; B: 0.72 ± 0.13; C: 0.76 ± 0.07; P = NS), whereas TmPO 4/GFR remained low in group A after 2 years (A: 0.78 ± 0.19; B: 0.91 ± 0.25; C: 0.94 ± 0.15; P < .05). Tacrolimus-treated patients exhibit significantly faster recovery from tubular phosphate reabsorption impairment compared with cyclosporine-treated recipients. Tacrolimus-based immunosuppression led to better kidney allograft function during 2-year observation.

Peritransplant Immunoadsorption: A Strategy Enabling Transplantation in Highly Sensitized Crossmatch-Positive Cadaveric Kidney Allograft Recipients

Kidney transplant recipients with a current positive complement-dependent cytotoxicity crossmatch (CDCXM) are at high risk for hyperacute rejection and graft loss. Immunoadsorption (IA) represents an efficient strategy to remove donor-specific alloantibodies. In this analysis, we evaluated effectiveness of peritransplant IA as an anti-humoral strategy to overcome a current positive CDCXM in presensitized renal allograft recipients. Between 1999 and 2003, 40 high risk cadaveric kidney allograft recipients (median CDC panel reactive antibody [PRA] level, 77%; number of retransplants, n = 38) were subjected to peritransplant IA with protein A (one pretransplant IA session followed by a course of repeat posttransplant IA sessions) in addition to preemptive antilymphocyte antibody therapy. In nine of these patients, a current positive CDCXM was rendered negative by a single pretransplant IA session. Thirty-one recipients had a negative CDCXM already before pretransplant IA. No difference in graft survival was found between CDCXM-positive and CDCXM-negative recipients (3-year graft survival, 78% vs. 71%, P = 0.6). Comparable rates of immunological graft loss at 3 years were observed (11% vs. 13%, P = 0.8). Patient groups did not significantly differ with respect to median serum creatinine at 1 year (1.23 mg/dL [CDCXM-positive] vs. 1.57 mg/dl [CDCXM-negative], P = 0.07) and at the end of follow-up (median 32 months; 1.19 mg/dL vs. 1.63 mg/dL, P = 0.06). Moreover, patient groups showed similar rates of biopsy-proven cellular rejection (11% vs. 20%) or C4d-positive graft dysfunction (33% vs. 32%). Our results demonstrate that peritransplant IA enables successful cadaveric kidney transplantation in the context of a positive CDCXM.

Serum TGF-β1 Correlates With Chronic Histopathological Lesions in Protocol Biopsies of Kidney Allograft Recipients

Introduction Transforming growth factor-β (TGF-β) is a well-known profibrotic factor playing a role in chronic kidney allograft nephropathy. Cyclosporine (CsA)-sparing immunosuppressive regimens may improve long-term graft function. Our aim was to study the influence of immunosuppressive treatment with versus without calcineurin inhibitors on serum TGF-β levels and histological changes in protocol biopsies of kidney allograft recipients. Patients and Methods In this prospective, randomized study of 42 low-rejection risk patients we randomized two groups: group A: mycophenolate mofetil (MMF), prednisone, daclizumab, and reduced CsA dose for 7 months (5 mg per kg per day) followed by complete withdrawal ( n = 21); and group B: normal CsA dose (10 mg per kg per day adjusted according to C 2 levels), MMF, prednisone, and no daclizumab ( n = 21). Methods In both groups we performed histological assessments (Banff 97) and measured serum TFG-β levels before as well as, at 3 and 12 months after transplantation. Results We found a relationship between immunosuppressive regimen and the TGF-β concentration over 1 year of observation. Before transplant the TGF-β1 levels did not differ between the groups ( P = .29); at 3 months they were 33 ± 9 vs 49 ± 15 pg per mL, respectively, in groups A and B ( P = .08), and at 12 months they were 39.5 ± 4 versus 55.5 ± 11 pg per mL, respectively, in groups A and B ( P = .03). Protocol biopsies at 12 months in group B showed chronic tubular lesions more pronounced than in group A. TGF-β1 concentrations were significantly higher among group B than A. We conclude that TGF-β1 concentration may predict the development of kidney graft fibrosis; early CsA withdrawal may achieve a reduction in chronic tubular and interstitial injury of cadaveric kidney allografts.

Kidney transplantation in older adults: does age affect graft survival?

There is a paucity of data on long-term patient and graft survival in the older kidney recipients. Our aim was to evaluate the long-term outcomes of kidney transplantation in patients aged 50 years and older and compare them with outcomes in younger recipients. Forty-seven recipients aged 50 years and older and 47 recipients aged younger than 50 years were randomly assigned to two groups (groups 1 and 2, respectively). Patients who had received a cadaveric kidney allograft were excluded from the study. Data including demographic and clinical characteristics, early complications, early mortality, and actuarial patient and graft survival rates were collected, and the two groups were compared, accordingly. The rates of early complications and mortality were not different between the two groups. Patient survival rates at 1, 3, 5, and 7 years were 72%, 58%, 41%, and 41% for patients in group 1 and 95%, 86%, 86%, and 86% for patients in group 2, respectively (P = 0.007). Graft survival rates were 72%, 58%, 41%, and 41% for patients in group 1 and 95%, 85%, 85%, and 85% for patients in group 2, respectively (P = 0.006). Graft loss due to patient death was 33.33% in group 1 compared with 4.25% in group 2 (P < 0.001). Kidney transplantation should be considered in patients older than 50 years, since the graft survival rate is acceptable in this population, and early mortality and complications in this group are not different than those of younger recipients. Although older patients have a shorter life expectancy, they benefit from renal transplantation in ways similar to younger kidney transplant recipients.

ANTI-DONOR DR103 IMMUNIZATION IN A DRB1*0101 KIDNEY ALLOGRAFT RECIPIENT.

P11 Aims: Molecular biology techniques have improved our knowledge on HLA genomic polymorphism, especially on class II polymorphism. We provide evidence that a DRB1*0101 kidney allograft recipient can immunize against a DR103 antigen carried by the graft. Methods and results: A 47-year-old woman received a cadaveric kidney allograft on February 1991. HLA recipient phenotype, determined by serological method, was A2 B44 B62 DR1 DR4 and HLA donor phenotype was A2 B15 B35 DR1 DR2. Chronic allograft nephropathy lead to allograft failure on December 1997. A retrospective study of circulating HLA antibodies using flow cytometry identified anti-HLA DR103 three weeks after allograft nephrectomy. Anti-DR103 antibodies were also identified with flow cytometric assay in eluates of the removed kidney. These data and the availability of HLA molecular typing lead us to control donor and recipient tissue typing performed by serological methods. Using molecular biology (PCR-SSP primer), class II donor HLA genotype was DRB1*0101, 0103 and recipient genotype was DRB1*0101, 04. Furthermore the husband and one daughter of the propositus also carry the class II allele DRB1*0103. Conclusions: HLA class II genomic polymorphism has been precised by molecular biology techniques. At least eight DRB1*01 alleles are currently recognized. DRB1*0101 is the most common allele in Caucasians. DRB1*0103 is an uncommon allele associated with inflammatory bowel diseases. DRB1*0103 differs from DRB1*0101 by six base pairs clustered in the third variable region of the second exon, leading to three amino acids changes in the β chain of the HLA DR molecule. Despite these only three amino acids replacement we observed an alloimmunization against DR 103 antigen in a DRB1*0101 recipient. DRB1*0103 was identified in the patient’s husband and one out of their children, thus suggesting a presensitization to this antigen during pregnancy and a second set reaction induced by the transplant carrying this antigen. The deleterious role of the anti DR 103 antibody found in both serum samples and eluates of the removed kidney is retrospectively probable in the graft loss.

Donor heme oxygenase-1 genotype is associated with renal allograft function.

The heme oxygenase (HO) isoenzyme HO-1 has recently been suggested to protect transplants from ischemia/reperfusion and immunologic injury. Inducibility of this enzyme is modulated by a (GT)n dinucleotide length polymorphism in the HO-1 gene promoter. Short (class S) repeats are associated with greater up-regulation of HO-1 than are long repeats. In the present study we investigated the impact of the promoter polymorphism of kidney allograft donors on clinical outcomes after transplantation. We enrolled 101 recipients of cadaveric donor kidney allografts (who underwent transplantation between June 1998 and September 1999) in this retrospective study. The HO-1 genotype was assessed using genomic DNA isolated from cryopreserved donor splenocytes. Fifty patients (49.5%) had received a kidney from a donor with at least one class S allele. Recipients of allografts from a class S allele carrier had significantly lower 1-year serum creatinine levels (median 1.46 mg/dL, interquartile range 1.17-1.68 mg/dL) compared with recipients of a non-class S allele donor kidney (median 1.61 mg/dL, interquartile range 1.38-2.22 mg/dL, P =0.01). After adjustment for cold ischemia time, retransplantation, donor age, delayed graft function, and HLA mismatch, recipients of a class S allele transplant had serum creatinine levels 0.81 times (95% confidence interval: 0.70-0.95, P =0.01) those of recipients of a non-class S allele transplant. The two patient groups did not differ significantly with respect to the incidence of delayed graft function, allograft rejection, or immunologic graft loss. Our data suggest an influence of the HO-1 gene promoter polymorphism on kidney allograft function and thus support previous studies indicating a protective effect of HO-1 induction in organ transplantation.

Ten-year survival of second kidney transplants: Impact of immunologic factors and renal function at 12 months

The aim of the present study was to assess long-term survival of cadaveric second kidney allografts performed in our center and to determine risk factors predictive of long-term graft outcome. Of 1704 kidney transplantations performed between January 1985 and March 1998, 233 were second grafts. The majority of the recipients were sensitized. All patients were treated with the same quadruple immunosuppressive regimen. Kaplan-Meier analysis documented graft survival of 89% at 1 year, 76% at 5 years, and 53% at 10 years. Graft survival was similar for second and primary kidney transplants performed during the same period of time. When long-term second graft survival was examined, only two risk factors were found to be significant: (1) the degree of human leukocyte antigen (HLA) DR mismatch (MM) and (2) the number of acute rejection episodes. Multivariate analysis of several pre- and posttransplant variables also confirmed the importance of HLA MM (DR> A), but also, identified serum creatinine at 12 months as the most significant predictor of graft survival. In addition, the Cox proportional hazards model revealed that only the year of transplantation had an independent significant effect on acute rejection occurrence (RR = 0.591, 95%CI 0.437 to 0.801, P < 0.0007). Indeed, the incidence of acute rejection was found to decrease over time (44% of patients experienced at least one episode of acute rejection before 1990 vs. 17% after 1990). Finally, second graft long-term outcome shows an improved evolution according to the time period resulting from a strong decrease in acute rejection incidence and the impact of creatinine at 12 months.

The impact of cytomegalovirus infections and acute rejection episodes on the development of vascular changes in 6-month protocol biopsy specimens of cadaveric kidney allograft recipients.

The role of cytomegalovirus (CMV) in chronic kidney allograft rejection remains controversial. The purpose of this study was to examine the impact of CMV infection on histopathologic changes in 6-month protocol biopsy specimens of kidney allografts. Altogether, 52 renal allograft recipients were studied. CMV infection was diagnosed by CMV antigenemia test, viral cultures from blood and urine, or both. CMV was demonstrated in the biopsy specimens by antigen detection and hybridization in situ. Acute rejections were diagnosed by biopsy histology, and biopsy specimens were graded according to the Banff '97 classification. CMV infection was diagnosed in 41 patients. The 11 patients in whom CMV infection was not detected were used as controls. Acute rejection was diagnosed in 22 of 41 CMV patients and in 6 of 11 control patients. CMV was demonstrated in the biopsy specimens of 19 of 41 CMV patients. CMV was not associated with increased glomerular, tubular, or interstitial changes. However, the arteriosclerotic changes in small arterioles were significantly increased in the subgroup of patients where CMV was demonstrated in the graft as compared with controls (P<0.01). Analysis of the impact of acute rejection on arteriolar thickening showed that only a positive history of both acute rejection and CMV found in the graft was associated with significantly increased vascular changes compared with CMV-free recipients (P<0.05). Neither CMV nor acute rejection alone was associated with increased vascular or other histopathologic changes in 6-month protocol biopsy specimens of kidney allografts, but a previous history of both acute rejection and the presence of CMV in the graft was associated with increased vascular changes.

Superiority of pronase flow CXM for living and cadaveric donor kidney allografts

Superiority of pronase flow CXM for living and cadaveric donor kidney allografts

Histological alterations in implant and one-year protocol biopsy specimens of renal allografts.

The natural course of histological changes and their correlations with clinical parameters have not been studied in large numbers in renal allograft specimens. The aim of this study was to determine whether any histological alterations developed during the first posttransplantation year. Immunological and nonimmunological factors possibly associated with subsequent histopathological changes and development of chronic rejection were also assessed. We studied 102 cadaveric kidney allografts for which both implant and 1-year protocol biopsy specimens were available. The chronic allograft damage index (CADI) was used to quantify the extent of histological changes that developed during the first year. Overall, an increase in histological alterations were seen during the first posttransplantation year, and the CADI increased significantly. The mean CADI was 0.7 in relation to implant biopsy samples and 2.9 in relation to 1-year biopsy samples (P<0.05). Although the degree of changes increased during the first posttransplantation year, they were seldom severe. Significant increases in incidences of interstitial inflammation and fibrosis, tubular atrophy, and basement-membrane thickening were seen. Vascular intimal proliferation and glomerular mesangial matrix increase and glomerular sclerosis were also noted. In contrast, anisometric vacuolization in the tubular epithelium decreased significantly in incidence during the first year. CADI values 1 year after transplantation were significantly affected by donor age, occurrence of acute rejection episodes, and prevalence of HLA-DR mismatches. CADIs were also significantly higher in grafts with decreased function. Histopathological alterations increased in almost every graft, even well-functioning grafts, during the first year. The CADIs relating to alterations seen in cases of chronic rejection increased significantly and were strongly affected by both immunological and nonimmunological factors.

Tolerance, mixed chimerism and protection against graft-versus-host disease after total lymphoid irradiation.

Total lymphoid irradiation (TLI), originally developed as a non-myeloablative treatment for Hodgkin's disease, has been adapted for the induction of immune tolerance to organ allografts in rodents, dogs and non-human primates. Moreover, pretransplantation TLI has been used in prospective studies to demonstrate the feasibility of the induction of tolerance to cadaveric kidney allografts in humans. Two types of tolerance, chimeric and non-chimeric, develop after TLI treatment of hosts depending on whether donor bone marrow cells are transplanted along with the organ allograft. An advantageous feature of TLI for combined marrow and organ transplantation is the protection against graft-versus-host disease (GVHD) and facilitation of chimerism afforded by the predominance of CD4+ NK1.1(+) -like T cells in the irradiated host lymphoid tissues. Recently, a completely post-transplantation TLI regimen has been developed resulting in stable mixed chimerism and tolerance that is enhanced by a brief course of cyclosporine. The post-transplantation protocol is suitable for clinical cadaveric kidney transplantation. This review summarizes the evolution of TLI protocols for eventual application to human clinical transplantation and discusses the mechanisms involved in the induction of mixed chimerism and protection from GVHD.

Renal transplantation and evolution of hemochromatosis: a clinical case report

A 66-year-old white woman received a cadaveric kidney allograft on 4 April 1999. Her past clinical history included lung tuberculosis in infancy, one episode of acute glomerulonephritis when she was 17, hypertension since she was 23, and preeclampsia on both her two term pregnancies. She began a regular hemodialysis program 7 years ago, when she was 59, due to end-stage renal disease, probably related to an ongoing chronic glomerulonephritis. No biopsy was performed. While on dialysis, she had chronic anaemia compensated with recombinant human erythropoetin (rHuEPO) and occasionally intravenous iron. In addition, there was a fluctuating rise of hepatic transaminases, although the AgHBs and both anti-HCV antibody and HCV-PCR were all negative, and there was no history of ethanol abuse. Serum transferrin saturation and ferritin were also elevated in the last 2 years before transplantation, but she had no symptoms associated with parenchymal iron overload (see Table 1). In April 1998 she was diagnosed with a reactivation of lung tuberculosis, with Koch bacilli being isolated in her sputum, and she was medicated with antituberculous agents until December 1998. On 4 April 1999, she was transplanted with a cadaveric kidney with two HLA matches on DR and a cold ischemia time of 12 hours. A triple immunosuppressive therapy was begun with cyclosporine, prednisone, and azathioprine. There was an immediate diuresis with a rapid decline of serum creatinine (Scr). She was medicated with isoniazid for tuberculosis prophylaxis. There was a slight rise of hepatic transaminases (two to three times the reference value) while she was in the hospital, which persisted in spite of the reduction on isoniazid dosage (300 to 150 mg/day). She was discharged on the ninth day with an Scr of 1.5 mg/dL. On her first outpatient visit, she complained of tiredness, and we noticed a hyperpigmented skin. In addition, the evolution of several hematological and biochemical parameters was surprising: there was not just a rise of hemoglobin, but also of serum fast glycemia and of serum transaminases, as well as of both serum fast transferrin saturation and ferritin (Table 1). In the face of this clinical and laboratorial data, we considered hemochromatosis as the most likely diagnosis and ordered several exams to confirm it. The abdominal CT scan showed evidence of a slightly enlarged but hyperdense liver. Its biopsy showed abundant iron deposits within the hepatocytes, compatible with the diagnosis of hemochromatosis. The hepatic iron concentration was found to be 384 mmol/g of dry weight (normally less than 36 mmol/g). The calculated hepatic iron index (hepatic iron concentration/patient’s age) was 5.8, the norm being 1 or less and values equal to or greater than 1.9 were found in hereditary hemochromatosis. The echocardiogram showed moderate concentric ventricular hypertrophy, good systolic function, and fibrosed nodule on the aortic valve. We were not able to investigate her past family history, and her only living daughter has no signs of the disease. Her genetic study showed the presence of HLA A3, but was negative for the mutations in the HFE gene, namely C282Y and H63D. On 1 June 1999, she was started on a weekly phlebotomy program, removing 350 mL of blood at each session, and she was started on subcutaneous rHuEPO (2000 U/week, about 30 U/kg/ week), aiming to mobilize and remove parenchymal iron stores. To control diabetes, she began oral gliclazide. Since then, transferrin saturation and ferritin have been decreasing. Also, diabetes has been easier to control and transaminases have reached normal values. This evolution is shown in Table 2. Fatigue complaints have disappeared, and her skin hyperpigmentation is less marked.

Calcineurin-inhibitors in renal transplantation. Too precious to be abandoned.

Drugs which inhibit the calcineurin enzymatic complex 30% in randomized studies [9–12]. Finally, the associmay be responsible for renal toxicity, which is occasion- ation CsA–rapamycin reduced the incidence of acute ally progressive and irreversible. Thus, in spite of rejection to 7.5% in a series of 40 living mismatched improving results obtained with the use of calcineurin kidney transplants [13]. We reviewed our own data of inhibitors in the field of renal transplantation, many cadaveric renal transplants performed between January physicians are concerned about the long-term use of 1995 and December 1998. Only five of 248 cadaveric these agents and try to replace them sooner or later renal transplant recipients lost their allograft because with non-nephrotoxic immunosuppressive agents such of acute rejection. Three deaths and two non-viable as azathioprine, mycophenolate mofetil, and/or rapa- kidneys accounted for other failures in the first year. mycin. Before this policy is generally adopted, however, This yielded an actual cadaveric kidney allograft surone should consider the results that can be achieved vival of 96% at one year. All patients were treated today with the correct use of calcineurin inhibitors. with Neoral or Tacrolimus as basic immunosuppressive The main aims of modern immunosuppression are: agent, often associated with MMF, anti-CD25 mono(i) to minimize risk and outcome of acute rejection; clonal antibodies or rapamycin. (ii) to reduce the risk of comorbidity caused by It is our impression, therefore, that the frequency of immunosuppressive agents, particularly cortico- acute rejection is decreasing progressively. Today it steroids; and (iii) to reduce late graft failure caused by has become exceptional that it is the direct cause of chronic rejection. All these goals may be achieved graft failure. This success can be attributed in large through administration of the calcineurin inhibitors, part to the use of calcineurin inhibitors, although the cyclosporin (CsA) or tacrolimus (FK ) respectively, combination with newer immunosuppressive drugs has especially when these drugs are given in combination certainly also played an important role. with newer immunosuppressive agents.

Cytokine gene polymorphisms predict acute graft rejection following renal transplantation

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of acute rejection, while animal models suggest a role for interleukin-10 (IL-10) in promoting graft survival. It has also been shown that polymorphisms in the TNFA gene promoter (position -308) and in the IL-10 gene promoter (position -1082) correlate with differential production of these cytokines in vitro. The aim of this study was to determine whether TNF-alpha and IL-10 gene polymorphisms influence the incidence and severity of acute rejection in the first six months following renal transplantation. The cytokine genotypes of 115 consecutive first cadaveric kidney allograft recipients and their donors were screened. The rejection episodes (REs) were defined clinically and confirmed histologically where possible and further classified according to severity (RS), namely steroid-resistant or responsive REs. The genotypes were then correlated with the REs and RS. The recipient TNF-alpha high producer genotype and IL-10 high producer genotype were significantly associated with multiple REs (>/=2) in human leukocyte antigen (HLA)-DR mismatched transplants (P = 0.0047 and P = 0.045, respectively), whereas only the TNF-alpha high producer genotype was associated with steroid-resistant REs (P = 0.025). When recipient cytokines were analyzed together, the TNF-alpha high/IL-10 high producer genotype had the worst prognosis, whereas TNF-alpha low/IL-10 low producer genotype was protective. We conclude that recipient TNF-alpha and IL-10 gene polymorphisms are determinants of REs and RS following kidney transplantation. Routine screening of these gene polymorphisms may have a clinical role in identifying patients at risk of multiple REs and severe rejections.