Tubulointerstitial Rejection Research Articles

Is patchy tubular injury a histopathological marker of acute rejection?

Abstract: Renal allograft specimens often show patchy tubular injury (PTI), or patches of injured tubular sections. PTI reflects damage to the proximal tubules, and the histologic findings consist of tubular cell necrosis and tubular regeneration without tubulitis. Unlike acute tubular necrosis (ATN) in cadaveric donors, PTI can be observed in kidneys from living donors when there is no history of acute renal failure after transplantation. In this study, we examined the clinicopathological importance of PTI in acute rejection. Between April 2000 and May 2007, 2252 biopsies of living kidney grafts were performed at least one d after the transplant operation. Acute rejection was observed in 877 biopsies. Of these cases, 78 (8.9%) biopsies from 43 patients showed PTI. The severity of the PTI was graded semiquantitatively as follows: grade 1 cases had three or four damaged tubular sections, grade 2 cases had >5 sections, and grade 3 cases had >10 sections. The incidence of PTI was significantly higher in vascular rejection (VR) and antibody‐mediated rejection (AMR) patients than in those experiencing tubulointerstitial rejection (TIR). The mean PTI score was significantly higher (2.00 ± 0.12) in VR than in TIR (1.39 ± 0.10) and AMR (1.68 ± 0.08) patients. The mean serum creatinine (sCr) at the time of biopsy was higher in VR patients than in AMR and TIR patients. Moreover, in VR patients, those with severer PTI developed higher sCr levels. These data suggest that PTI has a strong relationship with local ischemic damage delegated by VR, and the severity of PTI could be a practical histological marker in acute vascular rejection.

Persistent subclinical rejection associated with nodular B‐cell infiltrates in a renal transplant recipient

Abstract: Recently, B‐cell infiltrates in acute rejection grafts have attracted interest as an indicator of refractory rejection. Here, we report a case of deceased donor renal transplantation in a Japanese recipient operated overseas in which the recipient suffered from persistent tubulointerstitial rejection episodes associated with B‐cell infiltrates. A 59‐yr‐old man with end‐stage renal disease caused by immunoglobulin A nephropathy underwent deceased donor renal transplantation overseas in December 2005. The initial post‐operative course was uneventful. The patient was referred to our hospital one month after transplantation. He maintained stable renal function throughout the follow‐up period. The maintenance immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil and methylprednisolone. His serum creatinine concentration remained around 1.0 mg/dL, with no evidence of proteinuria. However, a discrepancy was detected between the renal function and the pathological findings. The pathology showed subclinical tubulointerstitial rejection with nodular B‐cell infiltrates refractory to aggressive antirejection therapy. A steroid pulse and 15‐deoxyspergualin were ineffective and the patient developed interstitial fibrosis and tubular atrophy by one yr after the transplantation, with persistent tubulitis and B‐cell infiltrates. We treated the refractory rejection with B‐cell infiltrates with a single 200 mg/body dose of rituximab and obtained an improvement. The pathological findings after administering rituximab consisted of mild tubulitis classified as Banff borderline, and elimination of the nodular B‐cell infiltrates. At present, 20 months after renal transplantation, the patient continues to maintain stable renal function, with a good serum creatinine concentration (0.87 mg/dL).

Light Chain Deposition Disease After Renal Transplantation

Light Chain Deposition Disease After Renal Transplantation

Poly(ADP-Ribose) Polymerase Expression in Kidney Transplantation: From Alfa (α) to Omega (Ω)

Introduction Overactivation of the enzyme poly(ADP-ribose) polymerase (PARP-1) can be induced by ischemia-reperfusion and involved in the renal injury subsequent to kidney transplant. The poly(ADP-ribosy)lation mechanism alters free radical-induced DNA damage, which is repair by PARP-1 polymer. However, PARP-1 overexpression induces cellular necrosis. Our aim was to study the immunohistochemical PARP-1 expression in kidney transplant biopsies associated with various events. Materials and Methods We studied the nuclear expression of PARP-1 in kidney tubule cells by immunohistochemistry using the monoclonal antibody PAR01 in donor biopsies without acute tubular necrosis (ATN) ( n = 60; controls), allografts that suffer ATN ( n = 90) or an episode of acute humoral rejection ( n = 12) or acute tubulointerstitial rejection ( n = 25), or chronic allograft nephropathy ( n = 25). Furthermore, we also studied protocol biopsies with subclinical rejection ( n = 60). Renal lesions in transplant biopsies were graded blindly using 1997 Banff criteria without any clinical information. Results Biopsies without morphological features of ATN, namely acute tubulointerstitial rejection, borderline or subclinical rejection, showed lesser PARP-1 expression compared with biopsies with ATN or with ischemic mechanism of acute humoral rejection or chronic allograft nephropathys. We observed an inverse relation between PARP-1 expression and renal function ( P < .001). Overall, renal biopsies showing ATN revealed greater expression of PARP-1 ( r = 0.785, Pearson test). A significant relationship with PARP-1 expression was demonstrated with renal function (effective diuresis, serum creatinine levels) and pretransplant cold ischemia time ( P < .001). Conclusion Kidney transplant events including ischemia were associated with the highest PARP-1 expression and worse allograft renal function.

A case of massive kidney graft calcification that developed early in a child recipient with hyperparathyroidism

Abstract: A boy aged six yr and six months with end‐stage renal disease because of focal segmental glomerulosclerosis underwent cadaveric renal transplantation. Ischemic injury during the operation resulted in a severely dysfunctional graft. A renal graft biopsy was performed on post‐operative day (POD) 21. The biopsy specimen showed the presence of many intratubular calcium crystals, patchy tubular injury, and focal aggressive tubulointerstitial rejection. Pelvic computed tomography performed on POD 23 also showed prominent calcification in and around up to two‐thirds of the graft. After the biopsy, the graft function recovered, and hemodialysis was stopped on POD 22. A second graft biopsy was performed on POD 52. This biopsy specimen showed recovery from rejection, although the nephrocalcinosis remained. It was suggested that secondary hyperparathyroidism and hyperphosphatemia provoked nephrocalcinosis in this patient.

Resolution of Gastrointestinal Side Effects in a Patient Converted from Mycophenolate Mofetil to Enteric-coated Mycophenolate Sodium (myfortic??)

A 25-year-old man with chronic renal failure as a result of membranoproliferative glomerulonephritis with horseshoe kidneys underwent renal transplantation inDecember2003. Initial immunosuppression comprised mycophenolate mofetil (MMF) 1000mg twice a day and sirolimus 3mg/day, adjusted to a target trough level of 8–12 ng/ml. Daclizumab induction (1mg/kg for five doses) was given. Two months posttransplant, the patient was hospitalised because of lymphocele, believed to be sirolimus related, and a urinary tract infection. The patient also experienced an increase in serum creatinine (figure 1). Ceftriaxone 2000mg/day resolved the urinary tract infection, and the patient was discharged with a serum creatinine level of 106mmol/l. Recurrence of the urinary tract infection one month later led to rehospitalisation and a diagnosis of lymphocele with vesicoureteral reflux to the transplanted kidney (grade III). After surgical repair of the lymphocele and reflux, the patient was discharged again; serum creatinine was 155mmol/l (figure 1). Renal biopsy at the time of surgery showed tubulointerstitial rejection (Banff grade Ib). Rejection was treated with ‘pulse’ methylprednisolone 1000mg/day for 3 days; as a result, sirolimus was discontinued and tacrolimus initiated at 7mg/day (target trough level 8–12 ng/ml). MMF 1000mg twice a day was continued. Seven months later, the patient presented with nausea and dyspepsia, which persisted without improvement despite a reduction in the MMF dose to 500mg three times a day for 2 weeks then to 500mg twice a day. At that time, the patient was also started on famotidine 40mg/day, but there was no improvement. The patient was switched from MMF to enteric-coated mycophenolate sodium (EC-MPS; myfortic) 360mg twice a day. The patient’s gastrointestinal symptoms resolved completely, and after 2 weeks the EC-MPS dose was increased to 720mg twice a day. The patient is currently receiving tacrolimus 6mg/day and EC-MPS 1440mg/day, with a serum creatinine level of 140mmol/l (figure 1) and no gastrointestinal complaints, and has returned to full-time employment.

Serum sCD30 in Monitoring of Alloresponse in Well HLA-Matched Cadaveric Kidney Transplantations

In kidney transplantation, pretransplant serum sCD30 testing has been proposed in immunological risk estimation together with anti-HLA antibodies. We evaluated the risks associated with high pretransplant serum sCD30 in well HLA-matched cadaveric kidney recipients recruited in a clinical study comparing different immunosuppressive regimens. Rejection rate was similar in 37 recipients with high pretransplant serum sCD30 compared to 117 recipients with low serum sCD30 (16% vs. 15%, P=NS). Compared to pretransplant levels, the posttransplant sCD30 levels generally decreased, also in patients with rejection, although on day 21 posttransplant, rejecting patients had significantly higher relative sCD30 than nonrejecting patients (P<0.01). However, steroid-resistant rejection was associated with increasing posttransplant sCD30 levels. High pretransplant sCD30 values were associated with tubulointerstitial rejection. There was no correlation of sCD30 with delayed graft function. Good HLA matching seems to be effective in neutralizing the negative effect of a high pretransplant serum sCD30.

High Pre‐Transplant Soluble CD30 Levels are Predictive of the Grade of Rejection

In renal transplantation, serum soluble CD30 (sCD30) levels in graft recipients are associated with increased rejection and graft loss. We investigated whether pre-transplant sCD30 concentrations are predictive of the grade of rejection. Pre-transplant sera of 51 patients with tubulointerstitial rejection (TIR), 16 patients with vascular rejection (VR) and an age-matched control group of 41 patients with no rejection (NR) were analyzed for sCD30. The transplant biopsies were immunostained for C4d. The median sCD30 level was significantly elevated in the group with VR (248 Units (U)/mL, range: 92-802) when compared with TIR (103 U/mL, range: 36-309, p<0.001) and NR (179 U/mL, range: 70-343, p<0.03). Moreover, patients with TIR had significantly lower sCD30 levels compared to NR. Based on C4d staining, a TH2 driven process, the median sCD30 levels were significantly raised in C4d+ patients compared with C4d- group (177 U/mL vs. 120 U/mL, p<0.05). sCD30 levels measured at time of transplantation correlate with the grade of rejection. High pre-transplant levels are associated with antibody-mediated rejection which carries a poorer prognosis. sCD30 could be another tool to assess immunological risk prior to transplantation and enable a patient centered approach to immunosuppression.

Detection of Acute Tubulointerstitial Rejection by Proteomic Analysis of Urinary Samples in Renal Transplant Recipients

This study investigates proteomic analysis of urinary samples as a non-invasive method to detect acute rejection of renal allografts. Capillary electrophoresis coupled to mass spectrometry (CE-MS) was used to analyze urinary samples in 19 patients with different grades of subclinical or clinical acute rejection (BANFF Ia to IIb), 10 patients with urinary tract infection and 29 patients without evidence of rejection or infection. A distinct urinary polypeptide pattern identified 16 out of 17 cases of acute tubolointerstitial rejection, but was absent in two cases of vascular rejection. Urinary tract infection resulted in a different polypeptide pattern that allowed to differentiate between infection and acute rejection in all cases. Potentially confounding variables such as acute tubular lesions, tubular atrophy, tubulointerstitial fibrosis, calcineurin inhibitor toxicity, proteinuria, hematuria, allograft function and different immunosuppressive regimens did not interfere with test results. Blinded analysis of samples with and without rejection showed correct diagnosis by CE-MS in the majority of cases. Detection of acute rejection by CE-MS offers a promising non-invasive tool for the surveillance of renal allograft recipients. Further investigation is needed to establish polypeptide patterns in vascular rejection and to explore whether changes in the urinary proteome occur before the onset of histologically discernible rejection.

Proteomic-Based Identification of Cleaved Urinary β2-microglobulin as a Potential Marker for Acute Tubular Injury in Renal Allografts

Our aim is to develop noninvasive tests to monitor the renal allograft posttransplant. Previously, we have reported that an unbiased proteomic-based approach can detect urine protein peaks associated with acute tubulointerstitial renal allograft rejection. Identification of these proteins peaks by mass spectrometry demonstrated that they all derive from nontryptic cleaved forms of beta2-microglobulin. In vitro experiments showed that cleavage of intact beta2-microglobulin requires a urine pH < 6 and the presence of aspartic proteases. Patients with acute tubulointerstitial rejection had lower urine pH than stable transplants and healthy individuals. In addition, they had higher amounts of aspartic proteases and intact beta2-microglobulin in urine. These factors ultimately lead to increased amounts of cleaved urinary beta2-microglobulin. Cleaved beta2-microglobulin as an indicator of acute tubular injury may become a useful tool for noninvasive monitoring of renal allografts.

CLINICO-PATHOLOGICAL CHARACTERISTICS OF RENAL TRANSPLANTS AFTER ABO-INCOMPATIBLE KIDNEY TRANSPLANTATION

O77 Aims: Both anti-HLA antibody and anti-blood group antibody are responsible for antibody-mediated humoral rejection. Clinicopathological characteristics of acute humoral rejection after ABO-compatible renal transplantation are well investigated, recently. However, those of ABO-incompatible renal transplantation are still unclear; especially in terms of correlation with concomitant ordinary (T-lymphocyte dependent) rejection and graft dysfunction. The precise pathogenesis occurred in acute rejection after ABO-incompatible renal transplantation is important. Methods: We studied the significance of C4d deposition in peritubular capillaries (PTC) as a sensitive indicator of humoral rejection and concomitant cellular rejection in renal allograft biopsies of ABO-incompatible renal transplantation. We analyzed 63 graft biopsy specimens from 27 patients with ABO-incompatible living recipients within 90 days after renal transplantation. Only diffuse and bright stain of C4d was consider as a positive finding of acute humoral rejection and severity of acute cellular rejection was classified by Banff scheme. Results: No graft was lost by acute rejection. Acute humoral rejection was noted in 14 graft biopsies; pure type in 8 and 6 combined with cellular rejection. Positive C4d was noted in all 14 graft biopsies. Ordinary cellular rejection was diagnosed in 14 biopsies. The diffuse C4d deposition in PTC was noted in 4 of 16 biopsies with acute tubulo-interstitial rejection of Grade I and no morphological findings of humoral rejection. Furthermore in the well functioning grafts with no morphologic findings of both humoral and cellular rejection, we found 3 diffuse and 2 focal and bright C4d positive biopsies. Focal and weak positive C4d is often noted in grafts without episode of graft dysfunction. No positive C4d deposition was noted in one-hour biopsy during transplant operation. Conclusions: Strong C4d deposition in PTC is valuable as a relatively specific and sensitive indicator for acute humoral rejection. However, the meaning of positive C4d is still unclear and requires further study after ABO-incompatible renal transplantation.

Histological analysis of late renal allografts of antidonor antibody positive patients with C4d deposits in peritubular capillaries.

The association of humoral immunity with late renal allograft dysfunction has recently been recognized, and many reports have revealed C4d deposits in peritubular capillaries (C4d in PTC), and the presence of serum antidonor HLA antibody in patients suffering from graft dysfunction, long time after transplantation. In this study, morphological changes in renal allograft biopsies more than 1 year after transplantation in 14 patients with C4d in PTC and serum antidonor antibody were investigated for the presence of chronic rejection (CR). In addition to the light microscope study, an electron microscope study was done to evaluate the multilayering of the peritubular capillary basement membrane (MLPTC). Histologically, only seven of 14 patients met the criteria of CR, and 71.4% (5/7) of CR patients had episodes of acute humoral rejection (AHR), coexisting with acute tubulointerstitial rejection. Peritubular capillaritis was observed in all patients, although it differed in severity. Transplant glomerulitis and interstitial inflammation were also observed in many patients: 71.4% (10/14) and 92.9% (13/14) respectively. MLPTC was observed in 12 patients (85.7%), but the severity of the MLPTC did not reflect the severity of peritubular capillaritis or any other histological features. The long-term outcomes of the patients CR, especially those with episodes of AHR, were poor, and two of them lost their graft functions. On the other hand, patients without CR had relatively favourable outcomes. In conclusion, we confirmed the diverse morphological changes of late renal allografts, which cannot be categorized as chronic humoral rejection (CHR), and such patients who do not have typical morphological changes such as CHR, should be followed-up on a long-term basis in order to clarify the significance of C4d on PTC in late renal allografts.

Cerebroside Sulfotransferase Deficiency Ameliorates L-selectin-dependent Monocyte Infiltration in the Kidney after Ureteral Obstruction

Mononuclear cells infiltrating the interstitium are involved in renal tubulointerstitial injury. The unilateral ureteral obstruction (UUO) is an established experimental model of renal interstitial inflammation. In our previous study, we postulated that L-selectin on monocytes is involved in their infiltration into the interstitium by UUO and that a sulfated glycolipid, sulfatide, is the physiological L-selectin ligand in the kidney. Here we tested the above hypothesis using sulfatide- and L-selectin-deficient mice. Sulfatide-deficient mice were generated by gene targeting of the cerebroside sulfotransferase (Cst) gene. Although the L-selectin-IgG chimera protein specifically bound to sulfatide fraction in acidic lipids from wild-type kidney, it did not show such binding in fractions of Cst(-/-) mice kidney, indicating that sulfatide is the major L-selectin-binding glycolipid in the kidney. The distribution of L-selectin ligand in wild-type mice changed after UUO; sulfatide was relocated from the distal tubules to the peritubular capillaries where monocytes infiltrate, suggesting that sulfatide relocated to the endothelium after UUO interacted with L-selectin on monocytes. In contrast, L-selectin ligand was not detected in Cst(-/-) mice irrespective of UUO treatment. Compared with wild-type mice, Cst(-/-) mice showed a considerable reduction in the number of monocytes/macrophages that infiltrated the interstitium after UUO. The number of monocytes/macrophages was also reduced to a similar extent in L-selectin(-/-) mice. Our results suggest that sulfatide is a major L-selectin-binding molecule in the kidney and that the interaction between L-selectin and sulfatide plays a critical role in monocyte infiltration into the kidney interstitium.

ELEVATED NUMBERS OF CIRCULATING ENDOTHELIAL CELLS IN RENAL TRANSPLANT RECIPIENTS

Damage of microvascular endothelial cells is a salient feature of acute vascular rejection and chronic allograft nephropathy, yet specific blood markers of ongoing endothelial injury are currently unavailable. Circulating endothelial cells have recently been established as a novel marker of endothelial damage in a variety of vascular disorders. We studied 129 renal transplant recipients who underwent percutaneous graft biopsy. Circulating endothelial cells were isolated with immunomagnetic anti-CD146-coated Dynabeads. Cells were stained with acridine and counted. To verify their endothelial origin, staining for Ulex europaeus lectin 1 (UEA-1) was performed in parallel. Twenty-one healthy controls were also studied. On biopsy, seven patients had acute vascular rejection, 15 patients had acute tubulointerstitial rejection, 14 patients had borderline rejection, and 93 patients had no rejection. Patients with acute vascular rejection had the highest cell numbers (72+/-39 cells/mL) when compared with all other patients (P<0.02). Regardless of their biopsy findings, however, all other renal transplant recipients had significantly higher numbers of circulating endothelial cells (25+/-20 cells/mL) than healthy controls (7+/-5 cells/mL, P<0.001). Finally, there was a significant correlation of cell numbers and serum cyclosporine A trough levels. By contrast, there was no correlation with serum creatinine, age, or the number of immunosuppressive drugs. The number of circulating endothelial cells is a novel marker of endothelial damage in renal transplant recipients. Further studies must now evaluate the origin of these cells, corroborate the clinical significance of our findings, and delineate the influence of calcineurin inhibitors.

The Impact of Cytomegalovirus Infection and Disease on Rejection Episodes in Renal Allograft Recipients

Cytomegalovirus (CMV) infection and disease are potential risk factors for acute allograft rejection in renal transplant recipients. The present study specifically addresses this issue. From October 1994 to July 1997, 477 consecutive renal allograft recipients (397 first transplants and 80 retransplants) were included in the study. CMV infection (cytomegalovirus pp65 antigen in leukocytes) and disease (infection and clinical symptoms or signs of disease) were examined prospectively for 3 months. No CMV prophylaxis was given, and CMV disease was treated with intravenous (i.v.) ganciclovir. The retransplantation of four patients transplanted twice during the study and 22 patients receiving kidneys from human leucocyte antigen (HLA)-identical siblings were excluded from statistical analysis. Rejections were evaluated clinically [277(61%)] and 173 (38%) also had a biopsy verified rejection. CMV infection occurred in 64% of the patients and 24% experienced CMV disease. In a multiple time-dependent Cox analysis, CMV infection and CMV disease were independent significant predictors for clinical acute rejections, RR = 1.6 (1.1-2.5, p = 0.02) and RR = 2.5 (1.2-5.1, p = 0.01), respectively. Among 173 patients with biopsy verified rejection, 72% of the patients had tubulointerstitial rejection whereas 28% had a vascular rejection. CMV disease, but not CMV infection was a predictor of tubulointerstitial rejection, RR = 3.1 (1.1-9.3, p = 0.04). CMV infection and disease are independent risk factors for clinical acute rejection in kidney allograft recipients. CMV disease is an independent risk factor for biopsy verified acute tubulointerstitial rejection in kidney allograft recipients.

Diagnosis of acute renal allograft rejection: evaluation of the Banff 97 Guidelines for Slide Preparation.

Arteritis and tubulitis, the diagnostic features of acute renal allograft rejection, are typically focal lesions. To avoid under-diagnosis, the Banff '97 schema recommends the preparation of multiple slides, of which three should be stained with hematoxylin and eosin (H&E) and three with periodic acid-Schiff (PAS) or silver. In this study, we examine the validity of the Banff '97 recommendations and determine how widely these recommendations are applied. We reviewed 52 consecutive renal transplant biopsy specimens showing both acute tubulointerstitial and vascular rejection. Arteritis was graded for each H&E slide, and tubulitis was graded for each H&E and PAS/silver. The handling of renal allograft biopsy specimens in the U.K. was determined by means of a questionnaire. When two, as opposed to three, H&E slides were examined, arteritis was missed in 11.4% of cases; when only one H&E slide was examined, arteritis was missed in 33.3% of cases. When only one, as opposed to three, PAS/silver slide was examined, tubulitis was under-graded in 33.3% of cases. In the U.K., 40% of laboratories stain at least three slides with H&E, and 42% stain at least three slides with PAS/silver. Only 30% of laboratories conform to all the Banff guidelines for slide preparation. There is likely to be significant under-diagnosis and under-grading of acute rejection if the Banff '97 guidelines for slide preparation are not implemented. Most laboratories in the U.K. do not conform to these guidelines.

Chronic allograft nephropathy--biopsy findings and outcome.

Chronic allograft nephropathy (CAN) is a composite term for various types of damage to a kidney transplant. We wanted to analyse its components in relation to baseline biopsy findings, transplant function, and outcome. Among renal transplantations performed from 1985 to 1997, 156 were identified where allograft biopsies had been obtained on clinical indication 6 months after transplantation or later, baseline biopsies were available in each case and the patient's original disease was known. Time after transplantation was median 2.2 years (range 0.5-13). The biopsies were reviewed and the Banff 1997 CAN score obtained. All but one late biopsy showed some CAN grade, 48% grade II, and 7.5% grade III. Acute tubulointerstitial rejection was seen in 9% but vascular rejection in only 3%. Arterial wall thickening was present in 66% of the late biopsies, correlated with donor age and its presence at baseline but also with time after transplantation. The Banff CAN score and serum creatinine level were both independent predictors of further graft survival, relative risk 0.35 (confidence interval 0.15-0.82, P=0.015) for CAN grade I vs III and 0.30 (0.14-0.67, P=0.003) for serum creatinine <170 vs >250 micromol/l. Presence of arterial wall thickening had no prognostic impact. The CAN grade is predictive of further graft survival independently of the serum creatinine level. Interstitial fibrosis and tubular atrophy are more prominent features of chronic graft damage than vascular rejection. Unspecific arterial wall thickening is partly dependent on baseline conditions and lacks prognostic impact in this late stage.

Interstitial Capillary in Normal and in Transplanted Kidneys: An Ultrastructural Study

Knowledge about the normal structure and pathology of interstitial capillary is limited. Splitting and multilayering of the basal membrane (BM), as a marker of chronic rejection, has been published in association with transplant glomerulopathy. The authors investigated the ultrastructural features of the interstitial capillary basal membrane in normal (15 biopsies) and in transplanted kidneys (27 biopsies from 21 patients), expressing transplant glomerulopathy (8 biopsies from 6 patients), acute tubulo-interstitial rejection (9 biopsies from 6 patients), and recurrent or de novo glomerulonephritis (10 biopsies from 8 patients). All biopsies were fixed in 1%OsO 4, embedded in Epon, and examined by electron microscope. Measurements of the interstitial capillary BM were made. The BM of interstitial capillary of intact kidney was a homogenous continuous structure, 88 nm in width on average. Thickening with diffuse multilayering of BM was most intensive in patients with transplant glomerulopathy, and much less intensive in patients with acute tubulointerstitial rejection and in patients with recurrent or de novo glomerulonephritis. These findings may provide the first information about the morphology of the normal basal lamina of interstitial capillary and support the diagnostic value of interstitial capillary changes in chronic rejection.

An evaluation of the Banff classification of early renal allograft biopsies and correlation with outcome

The Banff classification for assessment of renal allograft biopsies was introduced as a standardized international classification of renal allograft pathology and acute rejection. Subsequent debate and evaluation studies have attempted to develop and refine the classification. A recent alternative classification, known as the National Institutes of Health Collaborative Clinical Trials in Transplantation (NIH-CCTT) classification, proposed three distinct types of acute rejection. The 1997 Fourth Banff meeting appeared to move towards a consensus for describing transplant biopsies, which incorporated both approaches. Patients who received a renal allograft at the Oxford Transplant Centre were managed by a combination of protocol and clinically indicated biopsies. We have undertaken a retrospective analysis of the biopsies correlated with the clinical outcome to test the prognostic value of the original Banff (Banff 93-95) and NIH-CCTT classifications. Three hundred and eighty-two patients received renal allografts between May 1985 and December 1989, and were immunosuppressed using a standard protocol of cyclosporine, azathioprine and steroid. Adequate 5-year follow-up data were available on 351 patients, and of these, 293 had at least one satisfactory biopsy taken between days 2 and 35 after transplantation, the latter patients forming the study group. The D2-35 biopsies taken from these patients, which were not originally reported according to the Banff classification, were re-examined and classified according to the Banff 93-95 protocols. For each patient the biopsy found to be the most severely abnormal was selected, and the Banff and NIH-CCTT grading compared with the clinical outcome. Seven hundred and forty-three biopsies taken from 293 patients between days 2 and 35 after transplantation were examined and the patients categorized on the basis of the 'worst' Banff grading as follows. Normal or non-rejection, 20%; borderline, 34%; acute rejection grade I (AR I), 18%; AR IIA, 6%; AR IIB, 14%; AR III, 1%; AR IIIC, 3%; widespread necrosis 3%. The clinical outcome for the last two groups combined was very poor with 18% of grafts functioning at 3 months and 6% at 5 years. The other groups with vascular rejection (AR IIB and AR III) had an intermediate outcome, graft survival being 78% at 3 months and 61% at 5 years. The remaining four groups (normal, borderline, cellular AR I and AR IIA) had the best outcome: graft survival 95% at 3 months and 78% at 5 years with virtually no difference between the four groups. Three forms of acute rejection, namely tubulo-interstitial, vascular and transmural vascular, were identified, but only the latter two categories were associated with a poor outcome. The eight sub-categories of the Banff classification of renal allograft biopsies are associated with three different prognoses with respect to graft survival in the medium term. These three prognostic groups correspond to the three NIH-CCTT types. The data provide support for the consensus developed at Banff 97 separating tubulo-interstitial, vascular and transmural vascular rejection (types I, II and III acute rejection).

Banff criteria as predictors of outcome following acute renal allograft rejection

The Banff classification of renal allograft rejection grades acute tubulointerstitial rejection (AIR) by severity of tubulitis and acute vascular rejection (AVR) by severity of arteritis. The intensity of tubulitis has not, however, been demonstrated to be of prognostic value and other features such as glomerulitis and eosinophil infiltration are of uncertain significance. This study was performed in order to determine the clinical value of this pathological classification. Banff criteria were correlated with outcome in 134 consecutive graft recipients transplanted in our unit over a 3-year period (1994 1996) who experienced at least one biopsy-confirmed acute rejection episode. Of 197 biopsies performed for the diagnosis of rejection, 177 contained at least one artery and were suitable for Banff grading. Tissue eosinophil counts were available for 101 biopsies. Clinical severity of rejection was classified as mild (fully responsive to pulse steroid therapy), moderate (partially steroid responsive) and severe (steroid unresponsive/requiring ATG therapy). Graft failure ensued in 18 of 58 patients with AVR compared with 10 of 65 patients with AIR (P= < 0.05). Clinical severity of rejection correlated with the presence of arteritis, but not severity of tubulitis; rejections graded I, IIA and IIB according to the Banff' 93 classification were clinically severe in 3/68 (4%), 2/28 (7%) and 15/67 (22%) respectively (P= <0.05). The presence of glomerulitis showed no correlation with clinical severity or graft loss. Tissue eosinophilia (>10 eosinophils/mm2) was present in 18 of 33 patients who had at least one episode of AVR (v1/2), compared with 11 of 45 patients who suffered only AIR (P= <0.02). We conclude that: arteritis, but not severe tubulitis or glomerulitis, is an adverse prognostic factor in acute rejection and that tissue eosinophilia is associated with vascular rejection. Our findings support the 1997 revision of the Banff classification, replacing grades with types of acute rejection.