Long-term follow-up of non-HLA and anti-HLA antibodies: incidence and importance in renal transplantation.

BACKGROUND: Detection of antibody-mediated injury is becoming increasingly important in post-transplant patient care. The role of donor-specific anti-human leukocyte antigen (HLA) antibodies in kidney transplant damage is known, whereas the significance of non-HLA antibodies remains an unresolved concern. The aim of the study was to determine the presence and influence on renal function of non-HLA and anti-HLA antibodies in stable patients at 5 years after kidney transplantation. METHODS: We evaluated the antibodies in 35 consecutive patients with stable renal function at 5 years after transplantation. RESULTS: Pretransplant screening for donor-specific antibodies by CDC cross-matches was negative in all patients. Anti-endothelial cell antibodies (AECA), anti-angiotensin II type 1 receptor antibodies (anti-AT1R), and anti-endothelin receptor antibodies (anti-ETAR) were assayed as non-HLA antibodies. Non-HLA antibodies were observed in 12 (34%) patients, including AECA (n = 5; 14%), anti- AT1R (n = 6; 17%), anti-ETAR (n = 4; 11%), and both anti-AT1R and anti-ETAR (n = 3). Among 13 (37%) patients with anti-HLA antibodies, 7 also had both non-HLA antibodies: AECA (n = 1), anti-AT1R (n = 3), and anti-ETAR (n = 3). The antibody-negative group (n = 13) showed significantly better renal function than the antibody-positive group (non-HLA and/or anti-HLA; n = 22). Biopsy-proven acute rejection had occurred in 2 of 13 (15%) antibody-negative versus 8 of 22 (36%) antibody-positive patients. These preliminary data revealed an high prevalence of autoantibody and alloantibody production among stable patients at 5 years after kidney transplantation. CONCLUSION: Simultaneous production of these antibodies and their association with reduced renal function suggests that active humoral immune responses are poorly controlled by immunosuppression.

Adventitial lymphatics and atherosclerosis.

Lymphatic vessels are important in reverse cholesterol transport and play a crucial role in regression of atherosclerotic plaque in experimental animal models. Therefore, we attempted to analyze adventitial microcirculation including lymphatic vessels and adventitial macrophages in large human arteries in various stages of atherosclerosis. Eighty-one arterial segments of large arteries (iliac arteries and abdominal aortas) were obtained from deceased organ donors. Lymphatic vessels were identified using anti-LYVE-1 and anti-D2-40/podoplanin immunohistochemical staining. Adventitial blood vessels and macrophages were visualized using anti-CD-31 and anti-CD-68. Intimal thickness was measured under 100x magnification with an Olympus BX 41 light microscope using the visual mode analySIS 3.2 software. Lymphatic vessels were counted in each cross section of the examined arteries, and adventitial blood vessels (CD31+) were counted using the "hot spot" method. Statistical analysis was performed with Statistica 9.1 PL software (StatSoft, Cracow, Poland). Mann-Whitney, F-Cox, Chi-square, and Spearman's correlation tests were performed and the differences were considered significant at p < 0.05. Lymphatic and blood vessels in the adventitia of examined arteries were identified and quantified. Significant positive correlations were found between the number of adventitial lymphatics (LYVE-L +) and intimal thickness (r = 0.37; p < 0.05) as well as with age of the subjects (r = 0.3; p < 0.05). Thus, lymphatic vessels are present in the adventitia of large arteries in humans and the number of adventitial lymphatic vessels increases with progression of atherosclerosis as assessed by intimal thickness.

Duration of brain death and cold ischemia time, but not warm ischemia time, increases expression of genes associated with apoptosis in transplanted kidneys from deceased donors.

Apoptosis is one of the most important mechanisms leading to kidney graft injury during transplantation. The aim of this study was to assess the expression of genes involved in apoptosis in transplanted kidneys derived from deceased donors (DD) at various stages of the transplant procedure, seventy eight transplanted kidneys procured from 43 DD were included in this study. As a baseline control for gene expressions we used six kidney allografts obtained from living donors (LD). Three core biopsies were performed: biopsy 1--5 minutes before organ perfusion in the donor; biopsy 2--at the end of cold ischemia before kidney implantation; and biopsy 3--30 minutes after reperfusion. Tumor protein p53 (TP53), caspase-3 (CASP3), B-cell lymphoma 2 protein (Bcl2), and heme oxygenase 1 (HO-1) gene expression levels were determined using custom-designed low-density arrays (TaqMan assay). Comparison of gene expression between DD and LD kidneys revealed greater expression of all genes in kidneys from DD in all biopsies; however, only CASP3 expression in biopsy 1 and TP53 expression in biopsy 3 were statistically significant. Prolongation duration of brain death beyond 10 hours in DD resulted in a significantly decreased CASP3 expression in biopsy 1. When the cold ischemia time (CIT) was longer than 24 hours, the expressions of Bcl2, TP53, and CASP3 were significantly higher compared to kidneys with ClT<24 hours. There was no correlation between warm ischemia time and gene expression in biopsy 3. CASP3 and TP53 expression only in biopsy 1 were significantly higher among kidney allografts with delayed (DGF) compared with immediate graft function. In conclusion expression of genes involved in apoptosis was more pronounced in kidney allografts from deceased donors. A prolonged donor brain-death period beyond 10 hours resulted in decreased CASP3 expression. CIT longer than 24 hours was associated with increased expressions of Bcl2, TP53, and CASP3. CASP3 and TP53 expressions were significantly higher among kidneys allografts displaying DGF.

Kidney ischemic injury genes expressed after donor brain death are predictive for the outcome of kidney transplantation.

The results of deceased donor kidney transplantation largely depend on the extent of organ injury induced by brain death and the transplantation procedure. In this study, we analyzed the preprocurement intragraft expression of 29 genes involved in apoptosis, tissue injury, immune cell migration, and activation. We also assessed their influence on allograft function. Before flushing with cold solution we obtained 50 kidney core biopsies of deceased donor kidneys immediately after organ retrieval. The control group included 18 biopsies obtained from living donors. Gene expression was analyzed with low-density arrays (Taqman). LCN2/lipocalin-2 is considered a biomarker of kidney epithelial ischemic injury with a renoprotective function. HAVCR1/KIM-1 is associated with acute tubular injury. Comparison of deceased donor kidneys to control organs revealed a significantly higher expression of LCN2 (8.0-fold P=.0006) and HAVCR1 (4.7-fold, P<.0001). Their expressions positively correlated with serum creatinine concentrations after 6 months after transplantation: LCN2 (r=.65, P<.0001), HAVCR1 (r=.44, P=.006). Kidneys displaying delayed graft function and/or an acute rejection episode in the first 6 months after showed higher LCN2 expression compared to event-free ones (1.7-fold, P=.027). A significantly higher increase in expression of TLR2 (5.2-fold), Interleukin (IL) 18 (4.6-fold), HMGB1 (4.1-fold), GUSB (2.4-fold), CASP3 (2.0-fold) FAS (1.8-fold), and TP53 (1.6-fold) was observed among deceased donor kidneys compared with the control group. Their expression levels were not related to clinical outcomes: however, they showed significant correlations with one another (r>.6, P<.0001). We also observed a slightly reduced expression of IL10 (0.6-fold, P=.004). Our data suggested that increased LCN2 and HAVCR1 expression observed in the kidneys after donor brain death were hallmarks of the organ injury process. LCN2 expression level in retrieved kidneys can predict kidney transplantation outcomes.

1,25-dihydroxyvitamin D deficiency predicts poorer outcome after renal transplantation.

OBJECTIVE: To assess 1,25-dihydroxyvitamin D status and the effect of vitamin concentration on transplantation outcome in renal allograft recipients. PATIENTS AND METHODS: Ninety patients underwent renal transplantation between 2002 and 2005. All received alfacalcidol supplementation before surgery. 1,25-Dihydroxyvitamin D concentration was determined on day 3 posttransplantation and at 1-, 6-, 12-, 18-, and 24-month follow-up. RESULTS: Severe 1,25-dihydroxyvitamin D deficiency was noted in 83% of patients immediately posttransplantation. From 1 to 12 months thereafter, concentrations increased almost 3-fold, and remained constant to 24 months. In 50% of patients, the 1,25-dihydroxyvitamin D concentration reached a concentration of more than 30 pg/mL, similar to that in healthy volunteers; in the other 50%, the concentration reached 17.2 pg/mL. A high incidence of delayed graft function was observed in patients with 1,25-dihydroxyvitamin D deficiency (44% vs 6%). There was a negative correlation between the initial 1,25-dihydroxyvitamin D and serum creatinine concentrations at day 3 and month 6 (P < .03). Similarly, the 1,25-dihydroxyvitamin D concentration at 1 month was negatively correlated with creatinine concentration at months 1 through 24 (P < .01). Poor outcome was observed primarily in patients with 1,25-dihydroxyvitamin D deficiency; 2 patients developed cancer, 5 grafts were lost, and 4 patients died of cardiovascular events. CONCLUSIONS: 1,25-Dihydroxyvitamin D deficiency is highly prevalent in renal allograft recipients. Patients with 1,25-dihydroxyvitamin D deficiency are at greater risk of delayed graft function, and the graft is more likely to be lost. These findings suggest the necessity of adequate vitamin D supplementation both before and after transplantation.

Pretransplantation cellular alloreactivity is predictive of acute graft rejection and 1-year graft function in kidney transplant recipients.

OBJECTIVE: To study cellular alloimmunity in kidney allograft recipients using an interferon-gamma enzyme-linked immunosorbent spot assay (ELISPOT). MATERIAL AND METHODS: Donor splenocyte peripheral blood mononuclear cells were obtained during kidney recovery in 53 kidney recipients including 11 with positive panel-reactive antibodies pretransplantation. For ELISPOT data analysis, the spot number, size, and intensity were calculated, reflecting the volume of cytokine secretion at the single-cell level. Results were recalculated as the ratio of the values observed for donor-stimulated to unstimulated recipient cells corrected for residual donor activity. RESULTS: Significantly greater pretransplantation donor-stimulated activity was observed in recipients who experienced an acute rejection episode (ARE) within 1 year (P < .05). Mean change in spot number, size, and intensity in patients without or with AREs was 0.99 vs 3.33, 1.60 vs 6.05, and 1.40 vs 6.31, respectively. The assessed parameters were prognostic of high risk of ARE: 1.5-fold increase in spot number (ARE incidence, 52% vs 9%), 2.5-fold increase in spot size (ARE incidence, 53% vs 13%), and 2.7-fold increase in spot intensity (ARE incidence, 52% vs 9%). The 3 parameters correlated with 1-year serum creatinine concentration (P < .05). In 14 recipients, AREs could have been predicted in 11 using pretransplantation ELISPOT results, and in only 2 on the basis of panel-reactive antibodies. CONCLUSION: The ELISPOT-determined capacity of donor-induced reactivity observed in recipient cells obtained just before transplantation is predictive of risk of graft rejection and 1-year allograft function.

Evolution of bone disease at 2 years after transplantation: a single-center study.

Posttransplant bone disease is caused by renal osteodystrophy. We sought to examine bone mineral density (BMD) among 90 renal allograft recipients of mean age 42.7 +/- 11.4 years to identify factors preventing bone loss at 2 years posttransplant. Subjects treated with cyclosporine or tacrolimus plus azathioprine/MMF and prednisone underwent BMD estimates of the lumbar spine (LS) and of the proximal femur using dual energy x-ray absorptiometry (DEXA) at 3 months and every 6 months for 2 years. We assayed markers of bone remodeling: intact parathyroid hormone (iPTH), calcitriol, osteocalcin, and carboxyterminal telopeptide of type I collagen on day 3, as well as month 1 and every 6 months after transplantation. At the initial measurement, we observed osteopenia (OSP) among 35% in the LS and 52% in the femur: there was osteoporosis in 8.3%. The prevalence of OSP increased during the first year, thereafter decreasing to the initial value, but the rate of osteoporosis did not change significantly (8.3% vs 6.0%). BMD and Z-score decreased during the first and increased in the second year; 27% of patients regained initial values and 38% higher ones. BMD gains in the LS and femur were observed among subjects with higher calcitriol levels during the first 6 months (P < .01), higher osteocalcin (P < .05), higher estimated glomerular filtration rate during 1-24 months and in the tacrolimus group. Improvement of LS BMD occurred in younger patients (38 vs 46 years; P < .027); BMD gain in the femur correlated with higher levels of iPTH from 1-12 months (P < .01). The tacrolimus group showed higher Z-scores in the LS and femur at 24 months (P < .05). Two years after transplantation >60% of recipients showed stabilization or gain in bone mass. A sufficient calcitriol level in the early transplant period, an adequate iPTH, good renal function, and tacrolimus therapy prevented BMD disease progression.

A detailed comparison of the functional outcome after midforearm replantations versus midforearm transplantation.

OBJECTIVES: The functional outcome after midforearm transplantation (HT) is believed to be similar to the outcome after replantation. However, the few existing reports comparing functional outcomes are based on amputations at the level of the distal forearm. This report provides a comparative analysis of the functional results after midforearm replantation (HR) versus HT. MATERIALS AND METHODS: Transplantation of a dominant right forearm performed in a 32-year-old man was compared to the outcomes after five dominant (right) forearm replantations (four men and one woman) in patients ranging from 22 to 38 years of age. Cold ischemia time ranged from 6 to 12.5 hours in all cases. We used similar operative technique and rehabilitation protocol. At 26 (+/-2) months after replantation/transplantation, we recorded, bony union (x-ray), arterial flow (ultrasonography), range of motion, grip strength, sensation (2 PD Weisensten's filaments), quality of life (DASH, 30-150 points), general evaluation of function according to Chen's or the IRHCTT scoring system. RESULTS: A complication of wound infection was observed in one HR patient; Marginal skin necrosis accompanied by prolonged wound healing, in one HT patient. Unification of bones was achieved faster after forearm replantation when compared with transplantation. Grip strength was 17% greater after replantation, but ranges of motion were comparable in both groups. Sensitivity was superior after forearm transplantation (2 PD 15 mm) and overall patient satisfaction was comparable (90 points of DASH questionnaire for HR versus 108 points for HT patients). None of the patients returned to their previous occupations. CONCLUSION: The functional outcome after HT was comparable, and in some respects superior, to the outcome after replantation performed at the midforearm level.

Mild rejection episode evoked by modification of immunosuppressive protocol observed in a patient with forearm transplantation: case report.

Skin is the most immunogenic component of a composite tissue allograft (CTA). Clinicopathologic monitoring of the skin seems to be the most reliable method to detect rejection in CTA patients. The symptoms in cases demonstrating full-blown rejection are clear, contrary to those of just mild rejection. The aim of the study was to present the symptoms of mild rejection observed in a midforearm transplant patient at 20 months postoperative. The 32-year-old man underwent right dominant forearm transplantation at 12 years after a traumatic amputation. During the first 20 months, the course was uneventful, with no signs of impaired function. Immunotherapy at 20 months consisted of: Cellcept (2 g/d), prednisolone (10 mg/d), tacrolimus (7 mg/d; level C(0) of 13 ng/mL), An attempt was made to modify therapy by diminishing the tacrolimus dose to 4 mg/d (C(0)-8 ng/mL). After 10 days postimplementation of the new regimen, are hardly visible macullopapular erythematous rash appeared on the palmar and dorsal sides of the hand as well as the skin of the forearm. There was a slight red swelling of the nail bed margins. No deterioration of hand function was observed. The patient was immediately admitted to the hospital; despite unclear clinical and pathomorphological symptoms, we diagnosed a mild rejection (grade I). The therapy consisted of methylprednisolone (500 mg three times daily for 3 consecutive days) and 5 days of topical application of immunosuppressant ointments (tacrolimus and Protopic) with maintenance of the previously applied oral tacrolimus doses. After 5 days of treatment, the symptoms subsided. This approach utilized the advantage of the unique possibility to treat rejection locally, consistent with current awareness that skin is the primary target of hand rejection. However, topical application of immunosuppressants has not been extensively investigated. The manifestations of rejection in CTA patients may be heterogeneous and difficult to diagnose.

Kidney donation from a patient with cardiac myxoma: a case report.

INTRODUCTION: Renal transplantation has still become the preferred method to treat end-stage renal failure. The majority of organs are obtained from individuals with irreversible central nervous system injury. This group is nowadays unsatisfactory and small relative to the needs. A significant percentage of donors may be found among patients primarily suffering from benign neoplasms whose nature does not show malignant potential and do not metastasize. To date, there have been no reports about successful organ transplantation from an organ donor with cardiac myxoma. AIM: The aim of this report was to present a successful transplantation of cadaveric kidney grafts from a 61-year-old female donor with a left atrial cardiac myxoma, which initially appeared as an embolic cerebral infarct. The kidney graft recipients were a 51-year-old woman and a 57-year-old man with long-lasting histories of chronic renal failure under treatment by hemodialysis. The transplant function of both kidneys has been satisfactory with a 5-year follow-up. For the present, apart from single event of acute rejection in a male recipient, the patients have maintained stable renal function. Routine accessory examinations did not reveal any changes within the kidney or other organs. To date, a renal biopsy has not been taken. Both recipients are undergoing special follow-up. CONCLUSION: Patients with myxoma should be accepted as donors, since the risk of dying on the waiting list is greater than the tumor transfer risk. Exclusion of these potential donors decreases the donor pool and unnecessarily wastes valuable organs.

Blood group Lewis alloantibodies cause antibody-mediated rejection in renal transplant recipients.

Three patients with negative Lewis phenotypes who displayed anti-Lewis antibodies suffered severe kidney allograft dysfunction. One woman and two men (22-44 years) received ABO compatible kidney transplants with negative donor-recipient cross-match tests. Two patients had the phenotype Le(a-b-) with anti-Le(a) and anti-Le(b) complement binding antibodies. The third patient of phenotype Le(a+b-) developed anti-Lewis(b) antibody a few months after transplantation. One patient presented recurrence of worsened graft function from the day 6 to 4 months after transplantation; despite treatment there was not full recovery. The second patient had recurrences of acute graft dysfunction at 4 and 6 months after transplantation with nephrotic range proteinuria. The third patient showed progressive graft dysfunction at 7 months after transplantation. Biopsy specimens showed histological changes of antibody-mediated rejection. In the third patient, we observed fibrinoid necrosis and thrombosis of arterioles and glomerular capillaries. Immunofluorescence studies showed immunoglobulin IgG and IgM in glomerular capillaries and C4d and C3 on endothelial cells of peritubular capillaries. Posttransplantation cross-match tests with donor lymphocytes were negative. Anti-Lewis antibodies were observed during follow-up. All patients were treated with methylprednisolone boluses. In addition, one subject received antithymocyte globulin (ATG) and 1 received plasmapheresis. Two patients had moderate renal dysfunction (creatinine levels 1.8 and 1.9 mg/dL) after 8-17 months follow-up. The third patient lost her graft at 11 months after transplantation. Lewis antibodies may injure a renal allograft. C4d deposition and failure to show donor-specific anti-HLA antibodies suggested the participation of other antibodies.

C4D deposition and positive posttransplant crossmatch are not necessarily markers of antibody-mediated rejection in renal allograft recipients.

UNLABELLED: The aim of the study was to search for serologic, immunopathologic, and morphologic evidence of antibody-mediated rejection (AMR) among patients with acute renal allograft dysfunction. The study included 19 patients with episodes of acute rejection (ARE) within the first year after transplantation. All patients had negative crossmatch tests before transplantation. Patients underwent biopsy for histologic and C4d examinations. All patients were monitored for donor-specific HLA alloantibodies during the first posttransplant year. Complement-dependent cytotoxic crossmatches were performed with donor lymphocytes. In eight patients, the crossmatch test results changed to positive during ARE. In all biopsies except one with cortical infarction, we observed C4d staining (group 1). The biopsies of four patients showed histologic changes of AMR, and all of their grafts were lost. In one patient, cellular and vascular rejection (Banff II) were present; in two, Banff I; and in one, borderline lesions. These results were compared with 11 patients with ARE but negative posttransplant crossmatches and negative staining for C4d (group 2). The histologic findings in the biopsies of these patients were cellular interstitial and vascular rejection (Banff I and Banff II). With no features suggestive of AMR. During the first year after transplantation, the creatinine levels of group 1 patients, were significantly higher than group 2 patients. One-year graft survival was 50% in group 1 and 91% in group 2. CONCLUSIONS: C4d and a positive posttransplant crossmatch were not associated with histologic features of AMR in half of the ARE. Nevertheless, C4d deposition and positive posttransplant crossmatches correlated with allograft injury among renal transplant patients.

Anticancer effect of sirolimus in renal allograft recipients with de novo malignancies.

The inhibition of mTOR is a target for anticancer drugs in posttransplant malignancies. The influence of conversion to sirolimus after malignancy diagnosis was investigated on patient and renal allograft survivals. The 20 renal allograft recipients (4 women, 16 men) of ages 26 to 73 years (mean, 59 years) developed malignancies within 6 to 172 months (mean, 53 months) after transplantation. Three patients developed posttransplant lymphoproliferative disease (PTLD); four, Kaposi sarcoma, three, lung cancer; two, malignant melanoma; two, breast cancer; two, renal cell carcinoma; one, Merkel cell carcinoma; one, cutaneous T-cell lymphoma; one, larynx cancer; and one, gingival cancer. After tumor diagnosis, calcineurin inhibitors, azathioprine, or mycophenolate mofetil (MMF) were discontinued abruptly and sirolimus introduced (2 mg/d; target trough level, 4.0 to 8.0 ng/mL). Prednisone was maintained. The observation time of sirolimus therapy was 4 to 48 months (mean, 14 months). Two patients with PTLD (large B-cell lymphoma) and four with Kaposi sarcoma had full regressions. Eleven patients (larynx cancer, melanoma, breast cancer, T-cell lymphoma, renal cell carcinoma, Merkel cell carcinoma, and skin lymphoma) in addition to sirolimus therapy, underwent oncologic treatment, namely, surgery and/or chemotherapy. Six patients died from disseminated malignancy 4 to 9 months after conversion. One patient with T-cell lymphoma lost his graft; in the remaining patients, serum creatinine level was stable. In conclusion, Conversion to sirolimus resulted in regression of large B-cell lymphoma and Kaposi sarcoma. In patients with advanced or disseminated malignancy, the tumors progressed. Graft function was preserved after conversion to sirolimus.

Possible association of CTLA-4 gene polymorphism with cyclosporine-induced gingival overgrowth in kidney transplant recipients.

T-lymphocytes may play a role in the pathogenesis of inflammatory periodontal diseases and cyclosporine (CsA)-induced gingival overgrowth (GO). The gene encoding CTLA-4 (Cytotoxic T-lymphocyte antigen 4, a molecule influencing T-cell activation), is known to have a single nucleotide polymorphism (SNP) in promoter C>T -318; an exon 1 A>G 49, and a microsatellite dinucleotide repeat polymorphism (AT)(n) in exon 4. The purpose of this study was to analyze the possible influence of polymorphisms of CTLA-4, interleukin (IL)-2, and tumor necrosis factor (TNF)-alpha on GO incidence in eighty two renal transplant recipients. 34 CsA-treated with significant GO (CsAGO+); 22, CsA-treated with no GO (CsAGO-), and 26 tacrolimus (Tac)-treated without GO (TacGO-). The SNPs of CTLA-4 (-318 C>T and +49 A>G), IL-2 (-330T>G), and TNF-alpha (-308 G>A) were determined by SSP-PCR methods. The CTLA-4 (AT)(n) genotype was determined using polymerase chain reaction and fluorescence-based analysis with capillary electrophoresis. Allele frequencies in all patient groups were similar for CTLA-4 -318C>T, IL-2, and TNF-alpha. However, patients with CsAGO+ showed differences from CsAGO- for allele and genotype frequencies in position +49A>G of the CTLA-4 gene. The +49G allele was two times less frequent among CsAGO+ than CsAGO- (P = .0052; P corrected = .008). Slight differences between CsAGO+ and CsAGO- were noticed for the genotype distribution of CTLA-4 (AT)(n) (P = .056). The results suggested that appearance of an adenosine allele(A) in position +49 of the CTLA-4 gene may be a permissive element for CsA-induced GO.

Kidney transplantation and enzyme alpha-galactosidase A therapy in patient with Fabry disease: a case report.

Fabry disease, an X-linked recessive glycolipid storage disease, is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A), which cleaves a fatty substance called globotriaosylceramide (GL3). The abnormal storage of GL3 in blood vessel walls leads to ischemia and necrosis, particularly in blood vessels of the skin, kidneys, heart, brain, and nervous system. The aim of our study was to present the results of cadaveric kidney transplantation with enzyme alpha-Gal A therapy in a patient with Fabry disease. The patient was diagnosed with Fabry disease at the age of 33 years, based on enzymatic tests. Renal manifestations occurred a year later as proteinuria. At the age of 35 years, the glomerular filtration rate (GFR) was within the normal range. The patient received supplemental enzyme treatment with alpha-Gal (1 mg/kg every 2 weeks). At 3 months after starting supplementation, renal function worsened with serum creatinine levels at 1.7 to 1.8 mg/dL. The following months of supplementation (alpha-Gal 1 mg/kg) concurred with progressive renal dysfunction. After 27 months of supplementation at 37 years, with a creatinine value of 5.5 mg/dL, hemodialysis began and months later the patient received a cadaveric kidney graft. The patient no longer required dialysis. On postoperative day 5 the serum creatinine was 3.9 mg/dL; on day 7, 2.2 mg/dL; on day 14, 1.5 mg/dL. Enzyme supplementation began on posttransplant day 13. Renal graft function has been good during 5 months of observation with creatinine levels at 1.2 to 1.3 mg/dL. The treatment does not interfere with tacrolimus metabolism. Simultaneous chronic enzyme supplementation is the optimal treatment in the fifth stage of end-stage renal disease in Fabry disease.

Predictive value of Banff score of early kidney allograft biopsies for 1-year graft survival.

The aim of this study was to evaluate the Banff score of early kidney allograft biopsies, taken during the first month after transplantation, seeking an association between early rejection and acute tubular necrosis. We analyzed data from 71 patients transplanted between 2000 and 2004 who had renal allograft biopsies performed within the first posttransplant month (23 women, 48 men), ages 18 to 67 years. All biopsies performed in cases of delayed or deteriorated graft function were graded according to the Banff' 97 classification. Twelve months after transplantation, 19 patients exhibited excellent renal function (group 1, serum creatinine concentration [Scr] < or = 1.5 mg/dL); 25 patients demonstrated preserved renal function (group II, Scr 1.51-1.99 mg/dL); and 19 patients showed deteriorated renal function (group III, Scr > or = 2.0 mg/dL). Eight recipients lost their grafts within 1 year after transplantation (group IV). The Banff index was defined as a sum of all components (value of glomerulitis ["g"] + interstitial inflammation ["i"] + tubulitis ["t"] + arteriolar hyaline thickening ["ah"] + intimal arteritis ["v"]). The deterioration of renal function was associated with a higher Banff index; patients who lost their grafts showed the highest values of this index. Scores of "v," "ah," and Banff index were positively correlated with serum creatinine concentrations at 28, 90, 180, and 360 days (P < .05). Glomerulitis ("g") was correlated with creatinine concentrations at 90 and 360 days (P < .05). Tubulitis ("t") and interstitial inflammation ("i") displayed no association with renal function at any time.

Conversion to sirolimus from cyclosporine may induce nephrotic proteinuria and progressive deterioration of renal function in chronic allograft nephropathy patients.

Antiproliferative and non-nephrotoxic properties of sirolimus have been exploited for treatment of patients with chronic graft dysfunction. In this paper we point to the possible association of nephrotic syndrome and renal impairment with rapid conversion from cyclosporine (CsA) to sirolimus in patients with chronic nephropathy. Five male patients, ages 34 to 56 years, with chronic renal failure in the course of glomerulonephritis, were transplanted between 1997 and 1999. For the first 49 to 65 months, the immunosuppressive regimen consisted of CsA, azathioprine (AZA), and prednisone. Thereafter, due to chronic nephropathy evidenced by biopsy, conversion to sirolimus was performed with sharp withdrawal of CsA. The serum creatinine level prior to conversion was 1.9 +/- 0.3 mg/dL. Trace to 86 mg/dL proteinuria was found in 3 patients, while 2 patients had about 200 mg/dL. After 2 to 4 months of sirolimus treatment the proteinuria progressed (558 +/- 183 mg/dL); edema, hypoproteinemia, hypoalbuminemia, and hyperlipidemia developed; and the serum creatinine increased to 3.5 +/- 0.8 mg/dL. Biopsies performed in three patients revealed new pathologic changes. After 4 to 5 months, we performed reconversion to calcineurin inhibitor. Proteinuria decreased to 0 to 150 mg/dL; nevertheless the serum creatinine was continuously rising. Six to 15 months after the conversion, 3 patients returned to dialysis. The fourth patient, who was earlier reconverted, has a serum creatinine level of 2.0 mg/dL after 15 months. In conclusion, conversion from CsA to sirolimus may induce nephrotic syndrome with progressive deterioration of renal function. Converted patients require careful monitoring of proteinuria and renal function. Early reconversion to calcineurin inhibitor may prevent progressive deterioration of graft function.

Incidence and outcome of transplant renal artery stenosis: single center experience.

Since the incidence of transplant renal artery stenosis (TRAS) in renal allografts varies from 1% to 23%, we sought to examine its incidence, to analyze treatment options, and to ascertain its outcomes. Retrospective analysis of 793 kidney allograft recipients transplanted between 1996 and 2004 revealed an incidence of 0.9% (n = 7). Time from kidney transplantation to the first symptoms varied from 1 week to 3 years (median, 4 months). Three patients experiences refractory hypertension and six patients developed allograft dysfunction. Screening color Doppler ultrasonography showed hemodynamic changes in six patients with the definitive diagnosis confirmed by angiography in all patients. One patient with an anastomotic stenosis was treated with a surgical operation and six patients, percutaneous transluminal angioplasty (PTA), with stenting in three cases. Both surgical as well as PTA treatment were successful in all but one patient, who underwent PTA alone, developed chronic renal insufficiency necessitating hemodialysis and finally lost his allograft. In the other patients all symptoms resolved after treatment and the patients are doing well with functioning allografts. Although TRAS was an uncommon complication, if recognized promptly it could be treated by surgery or PTA with a high success rate.

Iatrogenic injuries of the carotid arteries.

BACKGROUND: Iatrogenic trauma of the carotid artery (CA) is a dangerous intraoperative complication, especially during oncological and endocrinological procedures. In these cases massive hemorrhage and severe neurological complications may occur. The outcome of reconstructive procedures is often fatal because of the long delay of surgery after the injuries occuring in non-vascular centers. PATIENTS AND METHODS: In this paper 22 cases of iatrogenic CA trauma will be presented, operated in the period of 1980-2003. Different methods of operation were performed according to the extent of trauma and anatomical changes. RESULTS: In spite of emergency help two patients died. In three cases cerebral stroke was observed. Additionally peripheral nervous damages were noted. CONCLUSIONS: Iatrogenic CA trauma is one of the most dangerous vascular injuries, connected with hemorrhage and neurological complications. We recommend intravenous administration of 5000 units unfractionated Heparin, anatomical artery preparation, then shunt inserting. Autogenous material should be used if possible. For reconstruction of the initial part of internal carotid artery the transposition of the external carotid artery is useful.

Intragraft mRNA expression of cytokines and growth factors in human kidney allograft biopsies by in situ RT-PCR analysis.

The aim of our study was to correlate intragraft mRNA expression of cytokines and growth factors with histopathologic features in renal allograft biopsies. Fifty-six core biopsies performed in 51 kidney transplant recipients were assessed by the Banff '97 classification. Tubular and glomerular expressions of IFN-gamma, TGF-beta1, and PDGF-B as well as IL-2, IL-6, and IL-10 mRNA were assessed using semiquantitative RT-PCR in situ. No significant differences were noted between acute cellular and vascular rejection with regard to the glomerular and tubular mRNA expression of cytokines examined. We observed a positive correlation between tubular and glomerular IL-10 and IFN-gamma mRNAs during acute rejection. In chronic rejection the mRNA expression levels of IFN-gamma and IL-2, IL-6, and IL-10 did not differ from those of acute rejection; moreover, the glomerular expression of mRNA for TGF-beta1 (P < .05) and PDGF-B (P < .1) was even lower than during acute rejection episodes. Both tubular and glomerular IL-2, TGF-beta1, and PDGF-B mRNA expression levels in biopsies with acute rejection were significantly higher than in acute tubular necrosis (ATN). Biopsy samples with borderline changes exhibited the lowest levels of cytokine gene expression and were close to the intensity of control specimens obtained from living donor kidney biopsies taken during organ harvest. Our data failed to show a dichotomy between Th1 and Th2 cytokine activation in biopsy specimens from kidney allograft recipients; both Th1- and Th2-derived cytokines were involved to similar extents in rejection processes.