Immunephenotype of Glomerular and Interstitial Infiltrating Cells in Protocol Renal Allograft Biopsies and Histological Diagnosis

Patients with a protocol renal allograft biopsy simultaneously displaying interstitial fibrosis/tubular atrophy (IF/TA) and subclinical rejection (SCR) have a shortened graft survival than patients with a normal biopsy, or with a biopsy only displaying IF/TA or SCR. The poor outcome of these patients could be related with a more severe inflammation. We evaluate the immunophenotype of infiltrating cells in these diagnostic categories. Nonexhausted paraffin blocks from protocol biopsies done during the first year were stained with anti-CD45, CD3, CD20, CD68 and CD15 monoclonal antibodies. Glomerular and interstitial positive cells were counted. C4d deposition in peritubular capillaries was evaluated. Histological diagnoses were: normal (n = 80), SCR (n = 17), IF/TA (n = 42) and IF/TA + SCR (n = 17). Only interstitial CD20 positive cells were significantly increased in patients displaying IF/TA + SCR; normal (137 +/- 117), SCR (202 +/- 145), IF/TA (208 +/- 151) and IF/TA + SCR (307 +/- 180 cells/mm(2)), p < 0.01. The proportion of biopsies displaying C4d deposition was not different among groups. The upper tertile of CD20 positive interstitial cells was associated with a decreased death-censored graft survival (relative risk: 3.01, 95% confidence interval: 1.23-7.35; p = 0.015). These data suggest that B-cell interstitial infiltrates are associated with histological damage and outcome, but do not distinguish whether these infiltrates were the cause or the consequence of chronic tubulo-interstitial damage.     

Natural history, risk factors, and impact of subclinical rejection in kidney transplantation

BACKGROUND: Subclinical rejection (SCR) is defined as histologically proven acute rejection in the absence of immediate functional deterioration. METHODS: We evaluated the impact of SCR in 961 prospective protocol kidney biopsies from diabetic recipients of a kidney-pancreas transplant (n=119) and one kidney transplant alone taken regularly up to 10 years after transplantation. RESULTS: SCR was present in 60.8%, 45.7%, 25.8%, and 17.7% of biopsies at 1, 3, 12, and greater than 12 months after transplantation. Banff scores for acute interstitial inflammation and tubulitis declined exponentially with time. SCR was predicted by prior acute cellular rejection and type of immunosuppressive therapy (P<0.05-0.001). Tacrolimus reduced interstitial infiltration (P<0.001), whereas mycophenolate reduced tubulitis (P<0.05), and the combination effectively eliminated SCR (P<0.001). Persistent SCR of less than 2 years duration on sequential biopsies occurred in 29.2% of patients and was associated with prior acute interstitial rejection (P<0.001) and requirement for antilymphocyte therapy (P<0.05). It resolved by 0.49 +/- 0.33 years and resulted in higher grades of chronic allograft nephropathy (CAN, P<0.05). True chronic rejection, defined as persistent SCR of 2 years or more duration and implying continuous immunologic activation was found in only 5.8% of patients. The presence of SCR increased chronic interstitial fibrosis, tubular atrophy, and CAN scores on subsequent biopsies (P<0.05-0.001). SCR preceded and was correlated with CAN (P<0.001) on sequential analysis. CONCLUSIONS: Histologic evidence of acute rejection in the absence of clinical suspicion resulted in significant tubulointerstitial damage to transplanted kidneys and contributed to CAN.     

Histopathologic evaluation of pretransplant biopsy as a factor influencing graft function after kidney transplantation: a 1-year observation

INTRODUCTION: Many factors affect long-term results in kidney transplantation including histologic damage as a independent predictor, such as chronic allograft/nephropathy in protocol biopsies and age-dependent lesions. Histopathologic findings correlate with the incidence of delayed graft function, renal function, and allograft survival, allowing a rather precise prediction of graft outcome. MATERIALS AND METHODS: We analyzed 92 renal thick needle preimplantation and 29 postexplantation biopsies. Biopsies were preserved in 4% formalin and immersed in paraffin. Optimal biopsies contained at least 10 glomeruli and at least 2 cross-sections of arteries. We analyzed tubulitis, intensity of acute tubular necrosis, inflammatory infiltration, glomerulonephritis, arterial hyalinization, arteritis, fibrosis, tubular atrophy, arterial intimal fibrosis, increase of mesangial matrix, and percentage of glomerulosclerosis. During the postoperative course we analyzed patients condition, exigency of postoperative dialysis, urine output, as well as serum concentrations of creatinine, urea, uric acid, and ions. During a 1-year observation period, we analyzed living recipients, graft loss, death with a functioning graft, incidence of nephropathy (CAN), and acute rejection episodes (ARE). RESULTS: We observed a significant correlation between immediate graft function (IGF) and lack of ATN in the pre-0 biopsy. We observed no correlation between renal function and arterial hyalinization and fibrosis, inflammatory infiltration, tubular atrophy. In the postoperative period, we observed a significant correlation between IGF and lack of interstitial fibrosis with significantly lower levels of creatinine, urea, and potassium and higher urine output early after transplantation. IGF and better function of the right kidney was correlated with shorter time to reach a creatinine level of 2 mg%. In the postoperative periods, we also observed a difference between renal function depending on gender. The presence of acute tubular necrosis, arterial fibrosis, lack of inflammatory infiltration in the pre-0 biopsy correlated with worse late renal function. Among explantation biopsies 65.5% showed signs of CAN, and 37.93%, histologic marks of ARE.     

Protocol biopsies in renal transplantation: prognostic value of structural monitoring

The natural history of renal allograft damage has been characterized in serial protocol biopsies. The prevalence of subclinical rejection (SCR) is maximal during the first months and it is associated with the progression of interstitial fibrosis/tubular atrophy (IF/TA) and a decreased graft survival. IF/TA rapidly progress during the first months and constitutes an independent predictor of graft survival. IF/TA associated with transplant vasculopathy, SCR, or transplant glomerulopathy implies a poorer prognosis than IF/TA without additional lesions. These observations suggest that protocol biopsies could be considered a surrogate of graft survival. Preliminary data suggest that the predictive value of protocol biopsies is not inferior to acute rejection or renal function. Additionally, protocol biopsies have been employed as a secondary efficacy variable in clinical trials. This strategy has been useful to demonstrate a decrease in the progression of IF/TA in some calcineurin-free regimens. Quantification of renal damage is associated with graft survival suggesting that quantitative parameters might improve the predictive value of protocol biopsies. Validation of protocol biopsies as a surrogate of graft survival is actively pursued, as the utility of classical surrogates of graft outcome such as acute rejection has become less useful because of its decreased prevalence with actual immunosuppression.     

Chronic allograft nephropathy--biopsy findings and outcome.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Predictors of renal transplant histology at three months.

BACKGROUND: The quality of a damaged kidney, the complexity of the surgery, and the events in the first weeks after transplantation, such as delayed graft function (DGF) and acute rejection, may influence its histological appearance and long-term survival. The aim of this study was to evaluate the importance of these factors in predicting renal allograft histology at 3 months. METHODS: Prospective, protocol kidney biopsy specimens (n=112), obtained 3 months after transplantation, were scored for chronic damage by the Banff schema and evaluated by multivariate analysis against donor factors, implantation histology, prior recipient sensitization, ischemia, perioperative factors, and subsequent clinical events, such as DGF and acute rejection. RESULTS: Adequate samples were obtained in 102 of 112 biopsies and classified as chronic Banff grade 0 (n=22), grade I (n=56), grade II (n=23), or grade III (n=1). Acute Banff scores were minimal. DGF occurred in 49% and was the strongest predictor of tubulointerstitial damage at 3 months. DGF correlated with acute tubular necrosis on the implantation biopsy specimen and with the number of acute rejection episodes; DGF also correlated with the Banff grades of chronic glomerulitis, chronic interstitial fibrosis, and tubular atrophy scores (P<0.05-0.001) in the 3-month biopsy specimen. By multivariate analysis, chronic tubular atrophy was independently predicted by the presence of vascular disease in the donor biopsy specimen, DGF, and vascular rejection occurring within the first 3 months (P<0.05-0.001). Chronic interstitial fibrosis was unrelated to fibrosis in the donor biopsy specimen but was independently predicted by DGF, donor age, and vascular rejection (P<0.05-0.001). Vascular disease in the donor biopsy specimen correlated with chronic intimal thickening (r=0.36, P<0.01) and arteriolar hyalinosis score (r=0.54, P<0.001) on the 3-month biopsy specimen. Banff chronic intimal vascular thickening was independently predicted by donor biopsy specimen vascular grade, prior vascular rejection episodes, and renal cold ischemia time (P<0.05-0.01). There were no correlates with the mean cyclosporine (CsA) dose, blood levels, diagnosis of CsA toxicity, or cellular rejection within the first 3 months. CONCLUSIONS: This study has demonstrated that the quality of the donor organ at implantation was strongly predictive of subsequent renal histology in grafts functioning at 3 months. Vascular rejection and DGF had a significant long-term effect on graft damage, but cellular rejection and simple measures of CsA exposure did not.     

Risk factors for chronic allograft nephropathy after renal transplantation: a protocol biopsy study

BACKGROUND: Chronic allograft nephropathy (CAN) leads to chronic allograft dysfunction and loss. Regular renal transplant biopsies may be useful to find risk factors for CAN. METHODS: We carried out 688 protocol biopsies in 258 patients at 6, 12, and 26 weeks after renal transplantation. Patients with signs of CAN in the biopsy 3 (N= 70, CAN group), and those without (N= 120, non-CAN group), were compared. RESULTS: Chronic tubulointerstitial changes increased from biopsy 1 to 3 (5% vs. 37%, P < 0.0001). Fifty-six of 190 patients had acute rejection within 6 months (30%), 33 of which were found in protocol biopsies (17%). On univariate analysis, the CAN group had CAN more often at biopsy 2 than the non-CAN group (23% vs. 4%, P < 0.0001), had a lower calculated creatinine clearance at biopsy 1 and 2 (49.4 +/- 25.8 vs. 57 +/- 20.2 mL/min, P= 0.01; 47.3 +/- 21.2 vs. 57.9 +/- 19.5 mL/min, P= 0.001, respectively), had a living donor less often than a brain dead donor (7% vs. 18%, P= 0.045), had a longer cold ischemia time (17.4 +/- 7 vs. 14.9 +/- 8.1 hours, P= 0.04), and had arterionephrosclerosis more often (24% vs. 12%, P= 0.02). On multivariate analysis, the differences in CAN at biopsy 2 (P= 0.001) and lower GFR at biopsy 2 (P= 0.002) were confirmed; in addition, nephrocalcinosis (P= 0.006) and acute rejection (P= 0.046) were found to occur more often. CONCLUSION: Chronic tubulointerstitial changes develop early after renal transplantation and are associated with reduced kidney function. Risk factors for CAN are arterionephrosclerosis (donor-related), nephrocalcinosis (related to preexisting hyperparathyroidism), a long cold-ischemia time (ischemia-perfusion-related), and acute rejection. Renal functional decline precedes morphologic changes of CAN, expressed as tubular atrophy and interstitial fibrosis.     

Clinicopathological evaluation of renal allografts of four patients by 20-year protocol biopsies

Abstract:  Twenty-year protocol biopsies were performed in four cases of renal transplant recipients with grafts that had survived 20 years or more . All four recipients received transplants from their parents, and never had episodes of acute rejection. They were maintained with the conventional immunosuppressive protocol including azathioprine, mizoribine, and prednisolone. Three of them had past history of malignant diseases such as breast cancer and tongue cancer. In spite of fair graft function, the microscopic findings of 20-year protocol biopsy showed various degrees of histological damage; e.g. obsolescence of the glomeruli, glomerulosclerosis, arteriole wall thickening, interstitial fibrosis and tubular atrophy. Although two of the four grafts were functioning with low serum creatinine levels (1.3–1.4 mg dL⁻¹) at 24 years and 26 years following transplantation, respectively, the function of the other two grafts had decreased more than 20 years after transplantation. In the two grafts with decreased function, glomerulosclerosis and arteriole wall thickening tended to be more severe (Banff classification of chronic allograft nephropathy [CAN] grade II and III) at the 20-year protocol biopsy compared with the two well-functioning grafts (CAN grade I and II). We conclude that the protocol biopsies even at 20 years can contribute to predict the fate of renal allografts.     

Effect of histological damage on long-term kidney transplant outcome

BACKGROUND: Chronic renal allograft failure remains a major challenge to overcome. Factors such as donor quality, delayed graft function (DGF), acute rejection, and immunosuppression are known to affect long-term outcome, but their relationship to histological damage to graft outcome is unclear. METHODS: Protocol kidney biopsies (n=112) obtained at 3 months after transplantation yielded 102 with adequate tissue. Histology was scored by the Banff schema, and compared with implantation biopsies (n=91), repeat 12-month histology (n=39), decline in serum creatinine and serial isotopic glomerular filtration rate, onset of chronic allograft nephropathy (CAN), and actuarial graft survival censored for death with a functioning graft. RESULTS: At a median follow-up of 9.3 years, 20 patients had graft failure and 26 died with a functioning graft. Banff chronic nephropathy was present in 24% of 3-month biopsies, and was predicted by microvascular disease in the donor, cold ischemia, DGF, and acute vascular rejection (P<0.001). Acute glomerulitis at 3 months correlated with segmental glomerulosclerosis at 12 months, subsequent recurrent glomerulonephritis, and graft failure (P<0.01). Subclinical rejection at 3 months occurred in 29% of biopsies, correlated with prior acute rejection and HLA mismatch, and led to chronic histological damage by 12 months (r=0.25-0.67, P<0.05-0.001). Subclinical rejection, arteriolar hyalinosis, and tubulitis present at 3 months had resolved by 12 months. The 10-year survival rates for Banff chronic nephropathy were 90.4% for grade 0, 81.0% grade 1, and 57.9% for grades 2 or greater (P<0.01). Early tubulointerstitial damage at 3 months profoundly influenced graft survival beyond 10 years. CAN was predicted by kidney ischemia, 3-month chronic intimal vascular thickening, tubular injury, proteinuria, and late rejection. Chronic fibrointimal thickening of the small arteries and chronic interstitial fibrosis at 3 months independently predicted graft loss and decline in renal function (P<0.05-0.001). CONCLUSIONS: Early transplant damage occurs in the tubulointerstitial compartment from preexisting donor kidney injury and discrete events such as vascular rejection and DGF. Subsequent chronic damage and graft failure reflect accumulated previous injury and chronic interstitial fibrosis, vascular impairment, subclinical rejection, and injury from late rejection. CAN may be conceptualized as the sequelae of incremental and cumulative damage to the transplanted kidney. The duration of graft survival is dependent and predicted by the quality of the transplanted donor kidney combined with the intensity, frequency, and irreversibility of these damaging insults.     

Loss of peritubular capillaries in the development of chronic allograft nephropathy

BACKGROUND: Chronic allograft nephropathy (CAN) remains the most important cause of late renal graft loss. In this study, we examined the role of peritubular capillary (PTC) injury in the development of CAN. METHODS: We studied renal biopsies (n = 79) obtained from grafts with CAN. PTC injury was examined morphologically by immunohistochemistry for CD34. These findings were correlated with interstitial fibrosis and graft dysfunction. Humoral immunity involved in CAN was studied by C4d staining. RESULTS: The CAN cases in the present study included chronic rejection (CR) (n = 14, 17.8%) and C4d-positive chronic humoral rejection (CHR; n = 6, 42.9% in CR cases). Irrespective of CR, CHR, or other CAN, the development of CAN was characterized by injury to and loss of identifiable PTCs, accompanied with the development of interstitial fibrosis. In CR and CHR cases, the loss of PTCs was prominent and seemed to progress within a relatively short period after transplantation. A decrease in the number of PTCs significantly correlated with the development of interstitial fibrosis (r = -0.75, P < .001) and impairment of graft function (r = -0.69, P < .001). CONCLUSIONS: Irrespective of whether CR, CHR, or other factors contribute to CAN, the processes involved in its development appear similar and are characterized by progressive injury and loss of PTCs, with the development of renal scarring. Immunohistochemistry for CD34 in human renal biopsies is a useful method for the detection of microvascular injury.     

Oxidative modification of low-density lipoproteins and the outcome of renal allografts at 1 1/2 years

BACKGROUND: Previous studies reported a significant association between hyperlipidemia of the recipient and chronic allograft nephropathy (CAN). However, the nature and the pathogenic mechanism of circulating lipid abnormalities in CAN remain unclear. METHODS: In a prospective study of 50 consecutive adult recipients of a cadaveric renal allograft, we investigated the impact of lipid abnormalities on the outcome of the graft at 1 1/2 years. Besides morphometric analysis of implantation and protocol biopsies, clinical and biochemical variables were studied at three-month intervals. Plasma concentrations of oxidized low-density lipoprotein (OxLDL) were determined by means of enzyme-linked immunosorbent assay. Immunohistochemical staining for OxLDL and macrophages was performed on paired renal biopsies. Study end points were the fractional interstitial volume and the 24-hour creatinine clearance at 11/2 years. RESULTS: High-density lipoprotein (HDL) cholesterol of the recipient < or =47 mg/dL was a risk factor for the functional (RR = 1.56; 95% CI, 0.978 to 2.497) and the morphological (RR = 2.75; 95% CI, 1.075 to 7.037) outcome of the graft, mainly in patients without acute rejection (RR = 2.03; 95% CI, 1.13 to 3.65, and RR = 4.67; 95% CI, 1.172 to 18.582, respectively). Interstitial accumulation of OxLDL was inversely associated with HDL cholesterol (R = -0.476, P = 0.019), and was associated with a higher density of tubulointerstitial macrophages (R = 0.656, P = 0.001) and a higher fractional interstitial volume at 11/2 years (P = 0.049). CONCLUSION: Decreased HDL cholesterol levels of the recipient adversely affect the outcome of renal allografts through the accumulation of OxLDL in the renal interstitium of the graft. Interstitial accumulation of OxLDL was associated with the presence of macrophages and the development of interstitial fibrosis.     

Glomerular adaptation after kidney transplantation

In renal transplantation, surrogate variables of low nephron endowment are associated with a decreased allograft survival. However, total glomerular number can only be precisely estimated in experimental models or autopsy studies because the whole kidney is necessary for this purpose. The combination of magnetic resonance imaging of the kidney and a renal biopsy allows estimating total glomerular number in vivo, and the application of this approach to stable renal allografts has shown that total glomerular number is a major determinant of graft function.Protocol biopsies performed in stable grafts have allowed the characterization of subclinical rejection (SCR) and chronic allograft nephropathy as well as their predictive value on graft outcome. However, glomerular adaptation after transplantation has not captured the interest of the transplant community despite only one kidney is transplanted and a large proportion of transplant recipients will receive an insufficient nephron number for their metabolic demand.Using protocol biopsies, it has been shown that glomeruli enlarge after transplantation to provide an adequate filtration surface area to the recipient metabolic demand. Glomerular size increases during the first year and this adaptation process is necessary to achieve an adequate renal function. This adaptation is impaired in patients with SCR and/or chronic allograft nephropathy. Furthermore, glomerulosclerosis is also increased in patients with impaired glomerular adaptation. Taken together, these data suggest that the primary target of SCR is the tubulointerstitial compartment leading to interstitial fibrosis/tubular atrophy and to impaired glomerular adaptation/glomerulosclerosis thereafter.     

The morphological compensatory change of peritubular capillary network in chronic allograft rejection

Abstract:  To clarify the compensatory hemodynamic alterations in the interstitium of renal allograft biopsies with chronic rejection, we evaluated the morphological changes in the peritubular capillary (PTC) network. Seven renal biopsy specimens from recipients with chronic rejection presenting with elevation of serum creatinine of 1.9 ± 0.5 mg/dL were examined. Renal biopsy specimens from their counterpart donors were used as normal controls. In each specimen, non-pathological interstitial areas without fibrosis, tubular atrophy or cell infiltration were compared with pathological areas (PA) showing fibrosis and/or tubular atrophy using a computer image analysis. Morphological measurements revealed that the mean cut surface area of the PTC in the non-pathological and pathological interstitial areas in the recipient biopsies were significantly larger than that of the normal controls (p < 0.001 and 0.001, respectively). In the recipient biopsies, both of the mean cut surface areas of the tubules and PTC in the non-pathological areas were significantly higher than those in the PA (p < 0.001). The mean glomerular diameter in the recipient biopsies was also significantly higher than that of the donors (p < 0.01). In this study, we provided pathological evidence for the compensatory interstitial and glomerular hemodynamic alterations in kidney graft with chronic rejection and the condition as single kidney.     

Chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is the leading cause of renal allograft loss in paediatric renal transplant recipients. CAN is the result of immunological and nonimmunological injury, including acute rejection episodes, hypoperfusion, ischaemia reperfusion, calcineurin toxicity, infection and recurrent disease. The development of CAN is often insidious and may be preceded by subclinical rejection in a well-functioning allograft. Classification of CAN is histological using the Banff classification of renal allograft pathology with classic findings of interstitial fibrosis, tubular atrophy, glomerulosclerosis, fibrointimal hyperplasia and arteriolar hyalinosis. Although improvement in immunosuppression has led to greater 1-year graft survival rates, chronic graft loss remains relatively unchanged and opportunistic infectious complications remain a problem. Protocol biopsy monitoring is not current practice in paediatric transplantation for CAN monitoring but may have a place if new treatment options become available. Newer immunosuppression regimens, closer monitoring of the renal allograft and management of subclinical rejection may lead to reduced immune injury leading to CAN in the paediatric population but must be weighed against the risk of increased immunosuppression and calcineurin inhibitor nephrotoxicity.     

Clinical significance of protocol biopsy at one month posttransplantation in deceased-donor renal transplantation

BACKGROUND: Protocol biopsy was used to detect pathologic changes in recipients with stable allograft function. With our 5-year practice, we reviewed protocol biopsies performed at 1 month posttransplantation in Chinese renal transplantation to analyze the impact of pathologic changes on allograft survival and to evaluate the clinical significance of protocol biopsy. METHODS: 227 patients who received biopsy at 1 month posttransplantation during Aug 2000 to Feb 2005 with stable graft function were enrolled. Patients were divided into normal group (NM), borderline change group (BL) and subclinical rejection group (SCR) based on pathology in protocol biopsy. Their clinical data were all reviewed. RESULTS: In the 227 patients with stable graft function, there were 173 patients (76.2%), 37 patients (16.3%) and 17 patients (7.5%) in the NM, BL, SCR group respectively. The incidence of acute rejection in the following period was significantly higher in the BL and SCR groups than that in the NM group (21.6%, 29.4% vs 7.5%, P<0.01). There was a significant difference of graft survival between the BL, SCR group and NM group (P<0.01). CONCLUSIONS: Borderline changes and subclinical rejection detected in protocol biopsy were associated with poor allograft survival. Protocol biopsy performed at 1 month posttransplantation is of great significance and can predict graft survival.     

The macrophage infiltration index and matrix metalloproteinase-II expression as a predictor of chronic allograft rejection

The presence of macrophages on renal biopsy specimens is considered an important cofactor in the development of chronic allograft nephropathy (CAN). Macrophages can activate the expression of matrix metalloproteinases (MMP), which induce glomerulosclerosis, arteriosclerosis, and interstitial fibrosis. The aim of our study was to demonstrate if they were related to the development of CAN. We analyzed matrix metalloproteinase (MMP) expression with specific monoclonal antibodies on 53 kidney biopsies performed due to the suspicion of a first acute rejection (AR) episode: 24 of the grafts have been lost due to CAN and the rest are still functioning. The group with CAN showed worse graft function and greater proteinuria from the beginning. The macrophage infiltration index (MI) expression was significantly higher in that group also (18.8 +/- 12 vs 12.5 +/- 9.15; P < .05), with a more important presence of macrophages in the interstitium and tubules. We observed a positive correlation between MI and tubular infiltration (r(2) = 0.52; P < .001) and between MMP-II and MI in the interstitium (r(2) = 0.3; P < .05) and with the global MI (r(2) = 0.3; P < 0.05). The last correlation was more powerful in the group with CAN (r(2) = 0.4; P < .05). According to our experience, global MI and tubular infiltration during an AR episode are good markers of long-term graft survival. The correlation between MI and MMP-II supports the role of macrophages in the development of CAN, although further studies are needed to clarify the nature of this relationship.     

Acute rejection in non-compliant renal allograft recipients: a distinct morphology

Non-compliance for immunosuppressive medication is frequent in renal transplant recipients, and associated with late acute rejection and graft loss. Although numerous studies were published on risk factors and outcome, no data are available on the histopathology of the 'non-compliant' allograft. As non-compliant patients swing between subtherapeutic and toxic doses of immunosuppression, trough levels show large variation. We questioned whether the histology of acute rejection in non-compliers (i) differs from the 'classical' acute rejection; (ii) shows more concomitant calcineurin-inhibitor toxicity; (iii) is associated with C4d and plasma cell (PC)-rich infiltrates. Based on validated interview methods/self reporting, 145 adult renal allograft recipients, transplanted for greater than one yr, on cyclosporine A and corticosteroids, were categorized as either compliant or non-compliant. Non-compliance was defined in 32 patients (22.1%). All late (greater than one yr) allograft biopsies were reviewed (Banff) and immuno-stained for C4d. Computerized morphometry was performed on late biopsies with features of acute cellular rejection. Sixty-two patients had > or =1 late biopsy [41 (36.2%) compliant/21 (65.6%) non-compliant; p = 0.0043], comprising a pool of 90 biopsies (61 compliant/29 non-compliant; p = 0.0303). 'Non-compliant' biopsies had higher scores of C4d (p = 0.0092), acute tubular damage (p = 0.0058), and peritubular capillaritis (p = 0.0070). 'Non-compliant' biopsies with acute cellular rejection showed less interstitial edema (p = 0.0165), more interstitial infiltrate (p = 0.0100), more interstitial fibrosis (p = 0.0277), and more tubular atrophy (p = 0.0197). PC-rich infiltrates correlated with C4d (p = 0.0080). Detection of non-compliance is mandatory as it represents an important cause of graft loss. This study describes histologic features of renal allograft biopsies in non-compliant patients that could help identifying this patient profile.     

Utility of the Doppler ultrasound parameter, resistive index, in renal transplant histopathology

BACKGROUND: Doppler ultrasonography is routinely used by many clinicians during long-term follow-up to identify high-risk patients without diagnosing the exact cause of graft dysfunction. Despite a number of studies showing a correlation between intrarenal resistive index (RI) and renal function in patients with kidney diseases, correlations between RI and renal histopathologic characteristics have not been sufficiently evaluated in renal transplant recipients. The aim of this study was to examine this relationship in grafted kidneys. PATIENTS AND METHODS: The intrarenal RI was retrospectively compared with biopsy findings in 28 kidney recipients. All renal biopsy specimens were reviewed by light microscopy and immunofluorescence staining. For glomerulosclerosis, we considered the percentage of glomeruli showing this change; for interstitial fibrosis/tubular atrophy and interstitial infiltration, we graded abnormalities according to the methods of Kliem et al (Kidney Int 49:666, 1996). RESULTS: The percentage of globally sclerosed glomeruli was significantly greater among patients with RI values higher than 0.75 than below this level (23% vs 47%; P = .022). Patients with grade 1 interstitial fibrosis and tubular atrophy (n = 14) showed lower RI values (0.68 +/- 0.03 vs 0.74 +/- 0.06; P = .047) than those with grade 3 fibrosis (n = 12). Similarly, lower RI values (0.66 +/- 0.02 vs 0.73 +/- 0.05; P = .014) were observed among patients with grade 1 (n = 13) compared with grade 3 interstitial infiltration (n = 13). CONCLUSION: RI seemed to provide a prognostic marker for the graft rather than yielding an exact diagnosis of renal graft dysfunction.     

移植肾活组织检查191例的病理学研究

目的：研究供肾可能携带的病变及移植肾在术后出现合并症时间相应的病理组织学变化。方法对191例移植肾进行了活组织检查（以下简称“活检”,其中术中活检52例,术后活检139例,并进行病理学诊断与分类。结果（1）52例术中活检,40例（76．92％）正常,余12例（23．07％）供肾携带病变,其中细小动脉硬化3例（5．77％）、间质炎症4例（7．69％）、局部肾小管轻度萎缩3例（5．77％）、肾小管上皮细胞变性2例（3．84％）。（2）139例术后活检中明确诊断的134例（96．40％）,其中正常19例（13．66％）,超急性排斥反应（SAR）1例（0．71％）疑为急性排斥反应／临界性变化（S／B）15例（10．795）,急性排斥反应（AR）23例（16．54％、慢性移植肾肾病（CNA）37例（26．61％）、环孢素肾毒性损伤（CsA-NT)29例（20．80％）、急性肾小管坏死（ATN）8例（5．75％）、复发性肾炎（RN）2例（1．43％）、难以明确诊断的5例（3．59％）。（3）免疫细胞化学色显示AR时,侵入肾小管上皮内的Leu-7阳性细胞数增加,间质内CD68阳性细胞数明显增加。结论活检是诊断术后多种合并症的有效手段;CAN可在术后3个月发生;侵入肾小管上皮的Leu－7阳性细胞是协助诊断AR的有效指标。     

Risk Factors for Banff Borderline Acute Rejection in Protocol Biopsies and Effect on Renal Graft Function

Introduction

The interpretation and handling of Banff borderline acute rejection observed in protocol biopsies from patients with stable renal function continues to be controversial. Our objective was to identify the risk factors for borderline acute rejection on 1-year protocol biopsies and to evaluate their effect on renal graft function after 2 years' follow-up.

Methods

We included 82 kidney transplant recipients (KTR), who underwent 1-year protocol biopsies with normal or stable graft function. All KTR had follow-up of at least 2 years posttransplantation. We formed three groups: (1) KTR with a normal biopsy, (2) KTR with borderline changes, and (3) KTR with interstitial fibrosis/tubular atrophy (IF/TA). We searched for risk factors related to borderline injury. The main outcome to evaluate was renal function at 1 month, at protocol biopsy, and 2 years posttransplant.

Results

The 82 patients included in this study showed no differences in immunosuppression, gender, etiology of renal failure, or percentage of panel-reactive antibodies. The risk factors associated with borderline lesions were: at least one biopsy due to allograft dysfunction and acute rejection events during the first year posttransplant (P = .011 and P = .021, respectively). Increased serum creatinine and estimated glomerular filtration rate decline were greater among the borderline lesion than the normal group, but similar to patients with IF/TA.

Conclusion

Renal function decline was greater among borderline and IF/TA groups. However, the sum of insults, and not only the borderline injury itself, produces greater declines in renal function with greater risk for graft loss.