Acute vascular rejection in renal transplantation--diagnosis and outcome.

Thirty episodes of histologically verified acute vascular rejection in kidney transplant recipients were studied. In 11 grafts the rejection was mainly vascular, whereas in 19 grafts a concomitant cellular rejection was seen. Histological features prognostic for bad outcome were glomerular necrosis and thrombi in the arteries and arterioles. Characteristic findings in transplant cytology, i.e., high number of monocytes and low number of lymphocytes and blast cells were noted prior to the onset of clinical signs of rejection, and this finding was also persisting throughout the rejection episode. The numbers of lymphocytes and blast cells were significantly lower in grafts with a pure vascular rejection than in grafts with a concomitant cellular rejection. Vascular rejection was reversible in 15 cases. As rescue therapy plasmapheresis and added immunosuppression were often successful.     

Renal tubular peptide catabolism in chronic vascular rejection

Chronic vascular rejection (CR) is the commonest cause of renal transplant loss, with few clues to etiology, but proteinuria is a common feature. In diseased native kidneys, proteinuria and progression to failure are linked. We proposed a pathogenic role for this excess protein at a tubular level in kidney diseases of dissimilar origin. We demonstrated in both nephrotic patients with normal function and in those with failing kidneys increased renal tubular catabolism and turnover rates of a peptide marker, Aprotinin (Apr), linked to increased ammonia excretion and tubular injury. These potentially injurious processes were suppressed by reducing proteinuria with Lisinopril. Do similar mechanisms of renal injury and such a linkage also occur in proteinuric transplanted patients with CR, and if so, is Lisinopril then of beneficial value? We now examine these aspects in 11 patients with moderate/severe renal impairment (51CrEDTA clearance 26.2+/-3.3 mL/min/1.73 m2), proteinuria (6.1+/-1.5 g/24 h) and biopsy proven CR. Lisinopril (10-40 mg) was given daily for 2 months in 7 patients. Four others were given oral sodium bicarbonate (Na HCO3) for 2 months before adding Lisinopril. Renal tubular catabolism of intravenous 99mTc-Apr (Apr* 0.5 mg, 80MBq), was measured before and after Lisinopril by gamma-ray renal imaging and urinary radioactivity of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Total 24 h urinary N-acetyl-beta-glucoaminidase (NAG) and ammonia excretion in fresh timed urine collections were also measured every two weeks from two months before treatment. After Lisinopril proteinuria fell significantly (from 7.8+/-2.2 to 3.4+/-1.9 g/24 h, p<0.05). This was associated with a reduction in metabolism of Apr* over 26 h (from 0.5+/-0.05 to 0.3+/-0.005% dose/h, p < 0.02), and in fractional degradation (from 0.04+/-0.009 to 0.02+/-0.005/h, p<0.01). Urinary ammonia fell, but surprisingly not significantly and this was explained by the increased clinical acidosis after Lisinopril, (plasma bicarbonate fell from 19.1+/-0.7 to 17.4+/-0.8 mmol/L, p < 0.01), an original observation. Total urinary NAG did fall significantly from a median of 2108 (range 1044-3816) to 1008 (76-2147) micromol/L, p < 0.05. There was no significant change in blood pressure or in measurements of glomerular hemodynamics. In the 4 patients who were given Na HCO3 before adding Lisinopril, both acidosis (and hyperkalemia) were reversed and neither recurred after adding Lisinopril. These observations in proteinuric transplanted patients after Lisinopril treatment have not been previously described.     

Acute vascular rejection: a clinical and morphological study

Abstract We analyzed one special type of acute vascular rejection (AVR), defined as fibrous thickening of the arterial intimal layer that leads to early renal failure. Twenty-one patients who presented this histological pattern were studied among 339 transplanted over 4 years. Patients were separated into two groups. Thirteen patients have restained their kidneys (Group A, 61.9 %) and 8 have lost their grafts (Group B, 38 %). Diagnosis was made on average 430. POD in GA and at 49° POD in GB on the 43rd postoperative day in group A and on the 49th postoperative day in group B (NS). In group A, mean serum creatinine is 2.2 mg/dl and follow-up time is 29 months. Oliguria was much more frequent in group B (75% versus 15.3%, P = 0.01). These patients were submitted to 91 renal biopsies always because of non-function. Typical vascular lesions began at arcuate arteries and progressed, as seen in sequential biopsies, to interlobular arteries and arterioles. When only arcuate arteries were affected, 22.5 % of renal losses were seen, but when arcuate plus interlobular arteries were compromised, 72.2 % of patients lost their kidneys ( P = 0.006). We did not identify any difference in immunofluorescent staining from biopsies with or without vascular rejection, or between groups A and B. We concluded that about 2.3 % of our patients lost their kidneys because of this kind of AVR, diagnosed near the 43rd postoperative day. The only clinical predictive sign of poor reversibility was oliguria. The attack on arcuate plus interlobular arteries meant a poor prognosis. Immunofluorescent staining did not have a prognostic value.     

Manipulation of cytokines as a novel approach to overcome xenotransplant rejection

The current overwhelming unmet demand for donor organs warrants the search for alternative sources. Pig-to-human xenotransplantation represents a promising approach; however, before this solution can be realized, there are many immunological hurdles to overcome. The first of those hurdles, hyperacute rejection, has been overcome only to uncover another rejection profile that is unresponsive to current immunotherapies—acute vascular rejection. We have shown that manipulation of cytokine profiles, and, accordingly, T cell polarization, is an effective method of down-regulating acute vascular rejection to cell-mediated rejection, which can then be managed with available antirejection treatments. The inherent nature of cytokines, specifically their short half-lives, multicomponent receptor systems, and nonspecific effects, presents limitations in the use of therapeutic cytokine modulation. For this reason, modulation therapies that target cells producing cytokines, instead of the cytokines themselves, represent a novel approach which would eliminate these aforementioned problems. We have found that transfer of distinct dendritic cell subsets and control of dendritic cell–mediated costimulation can effectively direct the cytokine profile and change an acute vascular xenorejection profile to cell-mediated rejection, which is responsive to immunotherapy.     

Renal vascular injuries.

Even today, most renal vascular injuries result in loss of renal function. Kidney salvage is not possible because of late diagnosis and the presence of severe associated injuries. Physical exam and basic laboratory tests are not sensitive; thus, a high index of suspicion is required. Repair should be attempted for all solitary kidneys and for patients sustaining bilateral injuries. All viable kidneys should be revascularized in order to increase the chances of obtaining adequate functional renal tissue. In the event that revascularization is not feasible, nephrectomy can be performed at a later time, if hypertension develops. In some cases, delayed return of function is possible, but in most cases the kidney will atrophy without producing hypertension. Most importantly, maintaining a high index of suspicion, prompt diagnostic evaluation, and judicious treatment can optimize outcome lowering the significant morbidity and mortality of renal vascular injuries.     

T cells are necessary and critical for xenograft rejection in new concordant cardiac xenotransplant model.

BACKGROUND: A new vascularized concordant xenotransplant model using the Chinese hamster as donor and mouse as recipient species is reported. This model takes advantage of the wealth of informative immune reagents and knockout and transgenic backgrounds available for the mouse. METHODS: Heterotopic auxillary cardiac transplantation was performed. The mean survival time was assessed by daily palpation. Xenoreactive antibody production was measured by flow cytometry, and cardiac xenografts were examined by light microscopy. RESULTS: The tempo of xenograft rejection in this model is consistent with concordant species combination. IgM and IgG3 responses were not critical for the concordant xenograft rejection. Long-term survival (>100 days) of the concordant cardiac xenografts was observed without any immunosuppression in nude mice. Reconstitution of nude mice with CD3+ T cells induced the xenograft rejection in 5.7 days (P<0.01). CONCLUSION: This new concordant cardiac xenotransplant model demonstrates that T-dependent xenogeneic immune response is necessary and critical for the xenograft rejection.     

Renal transplant rejection markers

Acute rejection is one of the key factors which determine long-term graft function and survival in renal transplant patients. Timely detection and treatment of rejection is therefore, an important goal in the post-transplant surveillance. The standard care with serum creatinine measurements and biopsy upon allograft dysfunction implies that acute rejection is detected in an advanced stage. Therefore, non-invasive monitoring for acute rejection by markers in blood and urine has been tried over the past decades. This review describes the requirements that should be met by non-invasive markers. The experience with single biomarkers and with newer approaches—mRNA expression analysis, metabolomics, and proteomics—will be discussed, including future directions of necessary research.     

Renal transplant rejection. Transient immunodominance of HLA mismatches

Many studies have shown long-term benefits of HLA matching in kidney transplantation. By examining rates of graft loss within consecutive posttransplant intervals, using data from the UK Transplant Service, we show that the long-term benefits of HLA matching are due to reduction of the graft failure rate within five months of transplantation. After 5-months, HLA-A,B,DR matching appears to have little impact on graft loss. We suggest that graft losses after 5 months may be attributable to non-HLA targets.     

Acute rejection episodes and long-term transplant function.

From 1974 to 1976, 114 kidneys transplanted to 108 patients underwent acute rejection episodes. With repeated rejections there was an increased likelihood of recovery without subsequent rejections, eg, 59% of kidneys that had three rejections regained prolonged good function. Repetitive rejections did not increase mortality. Discriminate analysis of the best serum creatinine level or creatinine clearance within 30 days of rejection and the time interval between rejection episodes correctly predicted the outcome of second rejections in 20/25 cases and correctly predicted the outcome of third rejections in 23/29 cases. Treatment of a third rejection was successful in 70% of kidneys if the best serum creatinine level was less than 2 mg/dL after the second rejection and was successful in 77% of kidneys if the time interval between second and third rejections was longer than one month.     

Acute cellular xenograft rejection

Abstract: The acute cellular rejection process after xenotransplantation of vascularized organs, i.e. heart, kidney and liver, has so far been difficult to study since the implanted organs are lost in a hyperacute rejection before cellular rejection develops. Primarily non-vascularized xenografts-e.g. pancreatic islets-escape the hyperacute rejection, but succumb to cell-mediated rejection during the first week after transplantation in either mice, rats or cynomolugus monkeys. The present view on the mechanisms orchestrating islet xenograft rejection in these animal models will be summarized and in part generalized to give insight into the process of acute cellular xenograft rejection.     

Acute and chronic rejection

The major histocompatibility complex molecules are the primary antigens responsible for causing graft rejection, and T-cell recognition of alloantigens is the cardinal event initiating cellular rejection. Current concepts suggest that direct allorecognition mediates acute rejection, whereas indirect allorecognition mediates chronic rejection. In biopsy tissue of rejecting human renal allografts, several cytotoxic T-lymphocyte molecules are upregulated. The net result of cytokine release and the acquisition of cell surface receptors is the emergence of antigen-specific and graft-destructive T cells. Acute rejection is more frequent in children than in adults. By the end of the first year posttransplantation, 45% of living donor recipients and 60% of cadaver donor recipients will have an episode of rejection. In recent years, with improved immunosuppressive therapy, the incidence of acute rejection is decreasing at a rate of about 8% each year, however, chronic rejection graft loss has increased to 41% of all graft losses in the last 2 years. The mechanisms leading to chronic rejection and attempts to reduce acute rejections should provide a better half-life to children postrenal transplantation.     

Renal allograft rejection. Possible involvement of antibody-dependent cell-mediated cytotoxicity

We have demonstrated that serum from appropriately sensitized patients can contain IgG antibodies that bind to cultured renal epithelial cells. The presence of such antibodies on the surface of renal cells enables otherwise nonlytic PBMC to lyse these renal cells by an antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. Experiments involving cell-sorting and specific complement-mediated lysis showed that the ADCC effector cells were of the CD3 -ve, C16 +ve phenotype characteristic of NK cells. In this report it is argued that an ADCC mechanism may be of importance in mediating chronic renal cell damage in the absence of acute allograft rejection.     

Renal vascular injuries

Fifteen patients with injuries to the renal arteries and/or veins have been treated in the past ten years. Nine injuries were the result of gunshot wounds, and six were from blunt trauma. Twelve patients presented to the emergency department in shock; two of these did not have a palpable blood pressure. Time from admission to time of operation averaged 6.4 hr for patients with blunt trauma and 1.25 hr for patients with penetrating trauma. Seven patients had ten associated abdominal vascular injuries, and two patients had injuries to both the right renal artery and left renal vein. Associated nonvascular abdominal injuries were found in all 15 patients. Efforts were made to repair renal vascular injuries with suture or grafting of the injured vessel in eight cases (53%). These efforts were successful in four patients, but in four the repair failed and a nephrectomy could not be avoided. Two patients died in the operating room or immediately postop in spite of successful repair of their renovascular injury. One injured left renal vein was ligated and nephrectomy was not necessary. In five patients, ligation of the injured renal artery and nephrectomy were necessary. There were five deaths (33%). Three of the deaths occurred in the operating room and two were postoperative deaths. Only one of the patients who died had a renal vessel injury without other major vessels involved. He did, however, have serious liver and kidney injuries. Multiple associated vascular, nonvascular, and head injuries were present in all four of the other deaths. We have continued to take an aggressive approach to exploration, isolation of the injury, and repair of the vessel whenever possible if a renal vessel injury is suspected.(ABSTRACT TRUNCATED AT 250 WORDS)