Fine-needle aspiration biopsy sampling in renal transplantation: interstitial cellular infiltrates and major histocompatibility complex class-II antigen expression in renal tubular cells

The dynamics of major histocompatibility complex (MHC) class-II (DR) antigen products in renal tubular cells and cellular infiltrations in the interstitium of the kidney following renal transplantation without immunosuppressive therapy are presented. DR antigen in 27 normal kidneys and in 18 of 19 kidneys transplanted as autograft showed no DR-antigen expression on their tubular cells. These DR-antigen-negative tubular cells could be induced to express the antigen during courses of untreated rejection both in primary (n = 6) and repeat (n = 4) allografts. Parallel to the increasing DR-antigen expression in the allograft, the autologous kidney expressed this antigen with the same time dependency and with the same intensity. Graft infiltrating cells were evaluated by daily fine-needle aspiration biopsy and core biopsy. Induction of DR antigen was associated with a significant infiltration of blastogenic cells and monocytes/macrophages in the allograft. During rejection of the allograft no cellular infiltrate was noted in the autograft, but during an initial time period after allograft removal cellular infiltrates were seen. Following both courses of rejection DR antigen returns to negative by 6-8 days as did blastogenic cells and monocytes/macrophages in the autograft interstitium. Inducible antigen expression in normally DR-antigen-negative allograft parenchymal cells during rejection is shown to depend on inflammatory cells in the graft. The antigen expression is not restricted to the tissue transplanted, but also affects autologous tissue of the host organism.     

Monoclonal analysis of fine-needle aspiration biopsy in kidney allografts

To evaluate changes in T-lymphocyte subsets and DR expression on tubular cells, 74 fine-needle allograft aspirates (FNAB) were evaluated in 31 patients with cadaver kidney transplants. Monoclonal antibodies against T helper CD4+, cytotoxic/suppressor CD8+, and HLA-DR were used with an indirect alkaline-phosphatase-staining technique. Cases with acute rejection (n = 11) showed a significant increase of CD8+: CD4+ ratio versus those with stable function (n = 21), acute tubular necrosis (n = 10) or CsA toxicity (n = 7) (ANOVA F = 10; P less than 0.01). Cases with chronic rejection or CMV infection showed no differences in the CD8+: CD4+ ratio with the other groups. DR expression on tubular cells was frequently found in cases of acute rejection, chronic rejection and CMV (73%, 66%, and 43% respectively), occasionally found in CsA toxicity (14%), but never seen in controls or ATN. Both tests, the CD8+: CD4+ ratio and the DR expression on tubular cells, had a high sensitivity and specificity in differentiating acute rejection versus controls, acute tubular necrosis, and CsA toxicity. When both tests are taken together no case without rejection showed a CD8+:CD4+ ratio greater than 1.6 and DR expression on tubular cells. Cases with acute rejection who lost the graft (n = 6) had a CD8+:CD4+ ratio significantly greater than those who responded to antirejection therapy (n = 5) (t = 2.9; P less than 0.05).     

Renal allograft rupture caused by acute tubular necrosis

Renal allograft rupture is a rare but potentially lethal complication of kidney transplantation. A renal allograft recipient receiving quadruple immunosuppressive therapy developed a spontaneous allograft rupture 13 days after kidney transplantation. Warm ischaemia time during the transplant was 80 minutes. The ruptured kidney graft could not be salvaged because of the patient's haemodynamic instability. The histopathological examination showed interstitial oedema with severe acute tubular necrosis with no signs of acute rejection. The most common causes of renal graft rupture are acute rejection and vein thrombosis, while acute tubular necrosis may only rarely be responsible for this complication. Renal graft rupture may be the result of interstitial damage attributed both to the prolonged warm ischaemia time during the transplant and to post-transplant acute tubular necrosis in the absence of graft rejection. In those patients whose haemodynamic status cannot be stabilized by appropriate aggressive haemodynamic support therapy, graft nephrectomy should be considered the only definitive treatment.     

Expression of multidrug resistance P-glycoprotein in kidney allografts from cyclosporine A-treated patients.

BACKGROUND: The multidrug resistance (MDR) gene product P-glycoprotein (P-gp) is a transmembrane efflux pump for hydrophobic, potentially toxic compounds, including the immunosuppressant cyclosporine A (CsA). We have previously shown that CsA increases P-gp expression in proximal tubule and endothelial cells in vitro. The aim of the present study was to investigate the in vivo relevance of these observations in renal allograft biopsies from CsA-treated patients. METHODS: P-gp expression was determined by immunohistochemistry of paraffin sections using two different monoclonal antibodies (UIC2 and MRK16). Biopsies were taken from CsA-treated renal transplant patients with different histopathological diagnoses (N = 79) and were compared with biopsies from normal human kidneys (N = 13) or with allograft biopsies from patients under a CsA-free immunosuppression (N = 15). Moreover, biopsies from 10 donor kidneys before implantation and during rejection episodes ("zero biopsies") were investigated. RESULTS: P-gp expression in biopsies with acute tubular necrosis (ATN; N = 10) after CsA treatment was significantly higher in arterial endothelia, proximal tubules, and epithelial cells of Bowman's capsule (BC), whereas P-gp was sparsely induced in CsA nephrotoxicity (N = 19) compared with controls. Acute cellular (N = 30) and vascular rejection (N = 10) or chronic allograft nephropathy (N = 10) after CsA was associated with strong P-gp expression in infiltrating leukocytes and increased P-gp expression in arterial endothelia, proximal tubules, and BC. In contrast, biopsies of patients treated with a CsA-free immunosuppression regimen did not show increases in P-gp expression compared with controls. Zero biopsies showed a weak, homogeneous, nonpolarized expression of P-gp in tubules and an increased expression of P-gp after CsA therapy in the brush border, arterial endothelia, and BC. CONCLUSIONS: CsA treatment was associated with increased P-gp expression in parenchymal cells of kidney transplants with ATN, acute or chronic transplant rejection, but P-gp was not increased in patients with CsA nephrotoxicity. This indicates that CsA induces its own detoxification by P-gp and that inadequate up-regulation of P-gp in renal parenchymal cells contributes to CsA nephrotoxicity. Increased expression of P-gp in infiltrating leukocytes correlated with the severity of allograft rejection, suggesting that P-gp may decrease the immunosuppressive efficacy of CsA. Thus, individual differences in the P-gp induction response of CsA-exposed renal parenchymal cells and/or infiltrating leukocytes may predispose to either CsA nephrotoxicity or rejection, respectively.     

CMV infection, class II antigen expression, and human kidney allograft rejection

After successful transplantation, the major histocompatibility complex (MHC) antigens of kidney parenchymal cells are lost and no longer detectable in the graft, presumably due to administration of glucocorticosteroids. During rejection, the MHC antigens reappear in the graft parenchymal cells. The upregulation is possibly due to gamma-interferon released in situ by the allograft activated T (blast) cells. In this communication we demonstrate that cytomegalovirus (CMV) infection is invariably associated with an upregulation of the antigen display in the graft. In 12 of 14 (86%) cases with proved CMV disease, the display of class II antigens was associated with a cytological and/or clinical episode of rejection. In 223 transplant recipients without proved CMV disease transplanted during the same period, the frequency of late rejections was 17% (P less than 0.001). The results suggest that the display of class II antigens on the graft, mediated presumably by gamma-interferon as a consequence of CMV infection, is the reason for graft rejection in context of CMV disease.     

A new alloantigen-independent control for chronic allograft nephropathy rat models

BACKGROUND: Isografts are used as controls in many transplant experiments. Our laboratory and others have noticed histological changes in control isograft groups of rats similar to allograft groups, suggesting alloantigen-independent factors contributing to chronic allograft nephropathy. However, the isograft model as a nonalloantigen control is flawed because of the potential of unrecognized minor antigen differences between rats. We designed a study using autografts to isolate alloantigen-independent factors in the rat renal transplant allograft model. MATERIALS AND METHODS: Male Lewis rats weighing 150-250 g underwent a procedure designed to mimic the injury of renal transplant, in which the left kidney was perfused with cold University of Wisconsin solution and subjected to similar cold and warm ischemic times as Lewis isograft rats undergoing renal transplanation. RESULTS: Six autograft rats were compared to five isograft and three single nephrectomy rats. Autograft rats showed normal kidney function according to serum BUN, Cr, and urinary protein. At 360 days, four of six autografts displayed normal renal parenchymal histology, whereas the remaining two autografts displayed histological changes scored as Banff acute rejection 1a and 1b. At sacrifice time, four of five isografts showed histological changes scored as Banff chronic rejection 1 and the single nephrectomy group showed normal histology in the remaining native kidney. CONCLUSIONS: Our data demonstrate that the chronic nephropathy observed in the isograft cannot be completely freed from suspicion of immunological origin. We propose that the autograft model for rat renal transplant research is a better nonimmunologic control than the isograft model for chronic allograft nephropathy.     

Canine Lung Allograft Lymphatic Alterations

Lymphatic obstruction has not been emphasized as a feature of lung allograft rejection. However, accumulation of fluid and cellular infiltrate, aggravated by lymph stasis, results in impaired lung function. In this study, lung specimens were recovered at varying times up to 133 days after either reimplantation (7 dogs) or allografting (29 dogs). Azathioprine and prednisone were administered to 17 allograft recipients. The presence of abnormally dilated perivascular, peribronchiolar, and subpleural lymphatic channels was a consistent histological finding, most striking in specimens recovered from untreated allograft recipient dogs. Attenuated lymphatic alterations were noted in immunosuppressed allograft recipients. In these animals the pulmonary lymphatics seemed to be ineffectual in clearing the allograft of the accumulating cellular infiltrates and fluid during rejection.     

Acute Renal Allograft Rejection Following Pegylated IFN-α Treatment for Chronic HCV in a Repeat Allograft Recipient on Hemodialysis: A Case Report

Interferon alpha (IFN-alpha) can be effective therapy for patients with chronic kidney disease who have chronic hepatitis C (HCV). However, acute allograft rejection has been reported in association with IFN-alpha following kidney transplantation, and therefore IFN therapy is recommended prior to, rather than after, kidney transplantation whenever feasible. The special case of repeat allograft recipients who contract HCV after the first transplantation presents special difficulties. This report features the case of a repeat allograft recipient who presented with neutropenic fevers after 5 months of pegylated IFN-alpha therapy, initiated 6 months following the functional loss of his third graft and the reinitiation of hemodialysis (HD). Physical exam, radiographic and laboratory findings led to allograft nephrectomy. The pathologic findings supported a diagnosis of acute-on-chronic rejection. This represents a rare case of IFN-alpha induced rejection following allograft failure and return to HD in a repeat allograft recipient. It also calls attention to the need for a high index of suspicion for the development of allograft rejection, which may require allograft nephrectomy even after allograft 'failure'.     

Lymphokine-activated killer (LAK) activity to cultured rat kidney parenchymal components in vitro

Abstract. The susceptibility of cultured rat kidney parenchymal components to natural killer (NK) cell and lymphokine-activated killer (LAK) cell-mediated lysis in a 4-h in vitro ⁵¹chromium assay was investigated. Large granular lymphocytes (LGL) in the spleen and in the kidney allograft were able to lyse YAC cells during rejection, but they did not damage target endothelial, glomerular mesangial, glomerular epithelial, or tubular cells in resting state. Stimulation of the target cells with gamma-interferon - known to induce MHC (class II) antigens on the target cell surface - did not make the target cells susceptible to NK-mediated lysis. LAK cells generated by a 3-day incubation with interleukin-2 (IL-2) effectively lysed both YAC and P815 target cell lines. LAK cells were also slightly cytotoxic to all tested parenchymal target components in resting state. Gamma-interferon treatment of the cultured parenchymal cells prior to the chromium release assay, however, reduced LAK-mediated parenchymal cell cytotoxicity to nearly nondetectable levels. Obviously, many lymphokines, including IL-2 and gamma-interferon, are produced during rejection at the site of inflammation. This might induce the generation of LAK cells in situ as the lymphokines induce the production of MHC antigens in the graft. We interpret these findings as indicating that regardless of the generation of LAK, the protective effect of gamma-interferon neutralizes the LAK effect, and we suggest that neither LGL nor LAK cells play any essential role in rat kidney allograft rejection.     

Allograft rejection and tubulointerstitial fibrosis in human kidney allografts: Interrogation by urinary cell mRNA profiling

Because the kidney allograft has the potential to function as an in-vivo flow cytometer and facilitate the access of immune cells and kidney parenchymal cells in to the urinary space, we hypothesized that mRNA profiling of urinary cells offers a noninvasive means of assessing the kidney allograft status. We overcame the inherent challenges of urinary cell mRNA profiling by developing pre-amplification protocols to compensate for low RNA yield from urinary cells and by developing robust protocols for absolute quantification mRNAs using RT-PCR assays. Armed with these tools, we undertook first single-center studies urinary cell mRNA profiling and then embarked on the multicenter Clinical Trials in Organ Transplantation-04 study of kidney transplant recipients. We report here our discovery and validation of diagnostic and prognostic biomarkers of acute cellular rejection and of interstitial fibrosis and tubular atrophy (IF/TA). Our urinary cell mRNA profiling studies, in addition to demonstrating the feasibility of accurate diagnosis of acute cellular rejection and IF/TA in the kidney allograft, advance mechanistic and potentially targetable biomarkers. Interventional trials, guided by urinary cell mRNA profiles, may lead to personalized immunosuppression in recipients of kidney allografts.     

Complement 5a receptor inhibition improves renal allograft survival

Complement activation plays a key role in mediating apoptosis, inflammation, and transplant rejection. In this study, the role of the complement 5a receptor (C5aR) was examined in human renal allografts and in an allogenic mouse model of renal transplant rejection. In human kidney transplants with acute rejection, C5aR expression was increased in renal tissue and in cells infiltrating the tubulointerstitium. Similar findings were observed in mice. When recipient mice were treated once daily with a C5aR antagonist before transplantation, long-term renal allograft survival was markedly improved compared with vehicle-treatment (75 versus 0%), and apoptosis was reduced. Furthermore, treatment with a C5aR antagonist significantly attenuated monocyte/macrophage infiltration, perhaps a result of reduced levels of monocyte chemoattractant protein 1 and the intercellular adhesion molecule 1. In vitro, C5aR antagonism inhibited intercellular adhesion molecule 1 upregulation in primary mouse aortic endothelial cells and reduced adhesion of peripheral blood mononuclear cells. Furthermore, C5aR blockade markedly reduced alloreactive T cell priming. These results demonstrate that C5aR plays an important role in mediating acute kidney allograft rejection, suggesting that pharmaceutical targeting of C5aR may have potential in transplantation medicine.     

Lymphokine-activated killer (LAK) activity to cultured rat kidney parenchymal components in vitro

The susceptibility of cultured rat kidney parenchymal components to natural killer (NK) cell and lymphokine-activated killer (LAK) cell-mediated lysis in a 4-h in vitro⁵¹chromium assay was investigated. Large granular lymphocytes (LGL) in the spleen and in the kidney allograft were able to lyse YAC cells during rejection, but they did not damage target endothelial, glomerular mesangial, glomerular epithelial, or tubular cells in resting state. Stimulation of the target cells with gamma-interferon —known to induce MHC (class II) antigens on the target cell surface — did not make the target cells susceptible to NK-mediated lysis. LAK cells generated by a 3-day incubation with interleukin-2 (IL-2) effectively lysed both YAC and P815 target cell lines. LAK cells were also slightly cytotoxic to all tested parenchymal target components in resting state. Gamma-interferon treatment of the cultured parenchymal cells prior to the chromium release assay, however, reduced LAK-mediated parenchymal cell cytotoxicity to nearly nondetectable levels. Obviously, many lymphokines, including IL-2 and gamma-interferon, are produced during rejection at the site of inflammation. This might induce the generation of LAK cells in situ as the lymphokines induce the production of MHC antigens in the graft. We interpret these findings as indicating that regardless of the generation of LAK, the protective effect of gamma-interferon neutralizes the LAK effect, and we suggest that neither LGL nor LAK cells play any essential role in rat kidney allograft rejection.     

Early biological and immune response to semi-identical liver or kidney allograft in miniature swine

In inbred miniature swine, semi-identical liver allograft recipients survive up to 3 months without immunosuppression, whereas similarly mismatched kidney allografts are uniformly rejected within 2 weeks. The early biological and immunological events were assessed in this unique model. SLA(d/d) pigs (MGH, Harvard Medical School, Boston, MA, USA) received liver or kidney allograft from heterozygous SLA(c/d) miniature swine. Survival, graft function, histology, intragraft cytokines, peripheral lymphocyte and platelet count, plasma cortisol level and cellular/humoral anti-donor immune response were assessed. Kidney allografts were uniformly rejected within 2 weeks, whereas liver allografts survived for up to 87 days. After both liver and kidney transplantation, the peripheral lymphocyte count decreased during the first week concomitantly to a significant elevation of plasma cortisol level. Early decrease of peripheral platelet count was observed after liver but not renal transplantation. Up-regulation of transforming growth factor beta1 (TGF-beta1) and interferon-gamma (IFN-gamma) was observed during the first postoperative week in semi-identical liver allografts and IFN-gamma as well as IL-10 in kidney allografts. In liver recipients, labelled autologous lymphocytes accumulated in the liver graft and native spleen, whereas after renal allograft, lymphocytes accumulated in the native spleen and liver but never in the kidney allograft. Specific cellular anti-donor unresponsiveness was observed from the first post-transplant day in both liver and kidney recipients, while the humoral anti-donor response remained intact. In semi-identical liver allograft, recipient rejection is milder and slower than in similarly matched kidney allograft. The intragraft up-regulation of TGF-beta1 in semi-identical liver allograft might be one mediator to explain the modulation of rejection after liver transplant. The rapid, nonspecific accumulation of recipient lymphocytes in the liver allograft but not in kidney allograft might also play a role in the different survival time in this model.     

Osteopontin expression in acute renal allograft rejection

BACKGROUND: Osteopontin (OPN) is a potent chemoattractant for mononuclear cells that is up-regulated in various inflammatory states of the kidney. The role of OPN and its expression in human renal allograft rejection are unknown. METHODS: We examined by immunohistochemistry and in situ hybridization, renal biopsies from patients with acute rejection (N= 22), protocol biopsies without rejection (N= 9), and perioperative donor biopsies (N= 35) for intrarenal expression of OPN, and its correlation with clinical, laboratory, and histopathologic parameters. In the rejection biopsies, interstitial monocyte/macrophage infiltration, tubulointerstitial cell proliferation/regeneration and apoptosis were investigated. RESULTS: In the majority of rejection biopsies, OPN expression by proximal tubular epithelium was widespread, and tended to be enhanced in the tubules surrounded by numerous inflammatory cells. Conversely, in patients that did not experience episodes of rejection and in donor biopsies, OPN expression by proximal tubules was nil or weak. OPN mRNA was colocalized with its translated protein in the renal tubular epithelium. OPN expression positively correlated with the degree of interstitial inflammation (P < 0.05), CD68+ monocyte infiltration (P < 0.01), Ki-67+ regenerating tubular and interstitial cells (P < 0.05 and P < 0.005, respectively), but not with terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL)-positive apoptotic tubular cells. CONCLUSION: These data suggest that inducible expression of OPN in the tubular epithelium may have a pathogenic role in acute renal allograft rejection by mediating interstitial monocyte infiltration and possibly tubular regeneration.     

Nerve allograft transplantation: a review

Peripheral nerves that are interrupted by trauma or surgical resection require reapproximation of their ends. When primary repair cannot be performed without undue tension, nerve grafting is required. Nerve repair with autograft is limited when there is insufficient amount of autologous nerves available for large nerve defects. This encouraged the search for alternative means of reconstruction in extensive nerve injuries. The cadaveric nerve allograft provides an unlimited graft source without the morbidities associated with autograft reconstruction; but these grafts are rapidly rejected unless appropriate recipient immunosuppression is achieved. An optimal treatment method for nerve allograft transplantation must minimize or prevent rejection while permitting nerve regeneration at the same time. In this report, the literature of nerve allograft transplantation experimental studies, strategies to prevent nerve allograft rejection, and reported clinical experiences are reviewed.     

Tacrolimus in induction immunosuppressive treatment in renal transplantation: comparison with cyclosporine

The aim of the study was to compare the efficacy and safety of induction immunosuppression therapies based on tacrolimus or cyclosporine (CsA) in kidney transplantation. The 240 kidney allograft recipients were divided into two groups: group 1 (n=94) received tacrolimus (.01 mg/kg per day), mycophenolate mofetil (MMF, 2 g/d), and steroids (30 mg/d); and group 2 (n=146) CsA (6 mg/kg per day), MMF (2 g/d), and steroids (30 mg/d). Antilymphocyte serum was administered in cases of acute tubular necrosis. The acute rejection rate was higher among group 2 (30.6%) compared with group 1 patients (12.2%) (P=.001). There were no significant differences between the groups in terms of age, gender, body surface area, serologic virus markers (in donor and recipient), baseline creatinine levels, cause of death, HLA incompatibilities, response to acute tubular necrosis, and number of dialysis sessions. We conclude that both immunosuppressive regimens are effective and safe in kidney transplantation. The survival rates of patients and grafts were similar, but the incidence and degree of acute rejection events were reduced in group 1; this finding may forecast a decreased incidence of chronic renal allograft nephropathy.     

Expression of HLA-DR antigens on peripheral blood T lymphocytes and renal graft tubular epithelial cells in association with rejection

Since the expression of HLA-DR antigens on peripheral blood T lymphocytes and renal graft tubular epithelial cells may be associated with immunological stimulation, we investigated the expression of these antigens on blood T lymphocytes and graft tubular epithelium in 84 renal transplant patients. Peripheral blood T lymphocytes were monitored by flow cytometry during the first 3 months after transplantation. Since the DR+ lymphocytes were selected by a double-labeling technique used for the Leu2a phenotype, the majority of the DR+ lymphocytes were also Leu2a+ with a small percentage of unidentified Leu2a- lymphocytes. Forty-one patients were treated with cyclosporine (CsA) and 43 with azathioprine (Aza), while both groups received low-dose steroids. Frozen sections of 57 renal biopsies from 43 patients (21 on CsA and 22 on Aza) were stained for HLA-DR antigens. In the Aza group, clinical rejection episodes correlated with an increased percentage of DR+ peripheral lymphocytes (P = 0.0005), and the expression of DR antigens on graft epithelial cells (P less than 0.001). In the CsA group, no relation between the expression of DR antigens on blood lymphocytes and clinical rejection episodes was evident, and the correlation between tubular DR staining and clinical rejection episodes was weaker than in the Aza group (P = 0.03). In both the Aza and CsA group, an increase in DR+ peripheral lymphocytes correlated with positive staining of the renal tubular cells for HLA-DR antigens (P less than 0.001).     

DR antigen expression on vascular endothelium and duct epithelium in fresh or cultured human fetal pancreata in the presence of gamma-interferon

The cells expressing MHC class II antigens play an important role in allograft rejection. We examined the expression of HLA DR antigens in human fetal pancreata ranging in gestational ages from 8 to 24 weeks. DR antigens were detected by immunohistochemical techniques using H4 and 40D MoAbs with immunoperoxidase staining and the ABC procedure. Vascular endothelium was identified by goat antibodies directed to human factor VIII-related antigens. DR expression on endothelium was further confirmed by double staining of tissue sections with H4 and anti-FVIII antibodies. In pancreata younger than 18 weeks of gestation, DR antigens were found on single cells that were randomly distributed throughout the pancreatic parenchyma. These cells resembled dendritic cells in morphology, as reported previously. Some vascular endothelial cells located in the intralobular connective tissues expressed DR antigens, but those in the pancreatic parenchyma were DR-negative. In 18-22 weeks, some endothelia of small vessels in the parenchyma became DR-positive. By 24 weeks, DR antigens were also expressed on medium-sized blood vessels, whereas intraislet capillaries and duct epithelia were DR-negative. The number of DR-positive cells increased rapidly from 11.2 cells/field (x400) in 12-14 week pancreata to 42.8 cells/field in 18-22 week pancreata. Most DR-positive cells in pancreata earlier than 18 weeks were dendritic-like cells, while those in older pancreata were endothelial cells. When pancreatic tissue fragments were cultured for two days in the presence of rIFN-gamma, vascular endothelium and duct epithelium, both of which were otherwise DR-negative, had become DR-positive. Even with this increase, DR-positive cell numbers were fewer in pancreata younger than 18 weeks of gestation as compared with those in older pancreata. We also detected clusters of epithelial-like cells that were clearly stained for DR antigens. These cells were located in the parenchyma where insulin positive cells were generally found. Their DR-antigens had not changed during the 3-day rIFN-gamma culture.     

Localization of major histocompatibility complex (HLA-ABC and DR) antigens in 46 kidneys. Differences in HLA-DR staining of tubules among kidneys

Biopsies from 46 kidneys that were subsequently transplanted were examined with monoclonal antibodies and the peroxidase-antiperoxidase technique to localize HLA-ABC and DR antigens. There was no variation in the expression of HLA-ABC which was present on all cells of the renal parenchyma. HLA-DR was found consistently on the endothelium of glomeruli and of intertubular capillaries but was only weakly expressed, or not expressed at all, on the endothelium of large vessels. The mesangium of glomeruli also stained for HLA-DR. But there was a striking variation in the expression of HLA-DR by proximal renal tubular cells in the 46 kidneys. HLA-DR was absent from tubules in 11 of 46 kidneys (23%) and probably absent or very weakly expressed in a further 8 kidneys (17%). The expression of HLA-DR in tubular epithelium was not related to the donor's age, sex, blood group, or ischemia times. However, the frequency of HLA-DR3 increased (55%) in donors of kidneys with tubular DR-negative kidneys, as compared with a frequency of 15% in donors of tubular DR-positive kidneys. Although this difference was not significant after a correction for the number of comparisons made, it suggests a genetic influence on the expression of tubular DR. The survival of tubular DR-negative kidneys was better at 1 year than that of tubular DR-positive kidneys (70% vs. 57%--not significant), and tubular DR-positive grafts may have had a higher rate of delayed function when transplanted in cases with a donor-specific positive B cell crossmatch. There was no obvious variation in the number of dendritic cells stained with antibodies to HLA-DR and the leukocyte common antigen despite prior administration of high doses of steroids to some donors before nephrectomy.