Renal Transplant Biopsies Research Articles

Renal transplant biopsy: what does it tell?

The value of the renal allograft biopsy has been significantly enhanced by several developments in 1997 including the following: the first convincing demonstration that molecular biology techniques can be applied to renal allograft tissue to obtain a diagnosis of acute rejection with high sensitivity and specificity; the development of an improved, internationally agreed classification of kidney transplantation pathology ('Banff 1997'); and significant new insights into the specific pathology of chronic rejection, involving splitting and lamination of peritubular capillary basement membranes and the presence of increased apoptotic cell death. Although it is predictable that long-term technology might eliminate the need for renal allograft biopsies altogether, in the short term these new breakthroughs will greatly increase the value of this procedure in the management of renal transplant patients.

Renal transplant fibrosis: Histomorphometric assessment of early renal transplant biopsies for markers of chronic rejection

Renal transplant fibrosis: Histomorphometric assessment of early renal transplant biopsies for markers of chronic rejection

Manipulation of cytokine networks in transplantation: false hope or realistic opportunity for tolerance?

Manipulation of cytokine networks in transplantation: false hope or realistic opportunity for tolerance?

Alpha-smooth muscle actin and collagen deposition in dysfunctional renal transplants.

In normal kidneys, alpha-smooth muscle actin and collagen type III expression is restricted to vascular smooth muscle cells and perivascular fibrous tissues, respectively, but in pathological conditions their expression or deposition is more extensive. Using immunohistochemistry, we examined the expression of alpha-smooth muscle actin and type III collagen in 31 human renal transplant biopsy specimens obtained from patients with graft dysfunction. We found that dysfunctional renal transplants have increased alpha-smooth muscle actin and collagen III expression in the glomerulus and interstitium, but only glomerular alpha-smooth muscle actin expression correlates with graft function and prognosis.

Validation of the Banff criteria for acute rejection in renal transplant biopsies.

The histological criteria for the diagnosis of mild acute rejection in renal transplant biopsies have not been well defined. To ascertain the value of the Banff criteria for transplant biopsy reporting, particularly for the diagnosis of acute rejection, and the 'borderline' category. We compared two systems of histological assessment in 23 transplant biopsy specimens and compared histological diagnoses to separately defined clinical diagnoses. The histological criteria applied were those of the recently described Banff criteria which were compared with our traditional diagnostic method for each specimen. We found the Banff diagnoses more closely related to the clinical outcome than the system of histological diagnosis that we had previously been using. We conclude that the Banff criteria more accurately reflect the clinical situation.

Thromboelastography for the prediction of bleeding after transplant renal biopsy.

The ability of prebiopsy coagulation assays to predict mild postbiopsy bleeding was evaluated in renal transplant patients undergoing renal allograft biopsy (N = 120). The coagulation assays studied included the bleeding time, prothrombin time, partial thromboplastin time, platelet count, and thromboelastograph (TEG). Coagulation results were defined as abnormal if they fell outside the established normal reference range. Bleeding was defined as a drop in the hematocrit equal to or more than 4 points 6 h after the procedure or ultrasound evidence of a new perirenal hematoma. Overall, 21% of patients showed evidence of mild bleeding. Of those who bled, 78% had normal results on all coagulation tests, indicating that most mild bleeding was not associated with coagulation abnormalities. Of the assays tested, only abnormal TEG:angle (P < 0.01) and TEG:k (P < 0.04) values were associated with an increased risk of bleeding. Bleeding times were not predictive of an increased risk of postbiopsy bleeding; five patients had abnormal bleeding times ranging from 10 to 20 min of whom only one bled. All prothrombin time, partial thromboplastin time, and platelet count abnormalities were mild (e.g., no prothrombin times longer than 15 s, no platelet counts below 129,000/microL); none of these assays predicted postbiopsy bleeding. Other clinical characteristics, including patient age, sex, serum creatinine, blood pressure (if less than 160/90 mm Hg), number of biopsy passes, or renal pathology, did not appear to influence bleeding after biopsy. It was concluded that most bleeding after transplant renal biopsy was not associated with coagulation abnormalities and that the TEG was the best assay for detecting mild coagulation abnormalities associated with an increased risk of bleeding.

SONOGRAPHY OF RENAL TRANSPLANTATION

Marked improvements in graft survival have made renal transplantation the treatment of choice for end-stage renal disease. Ultrasound, because it is an accurate and noninvasive screening examination for graft dysfunction, clearly has had an impact upon graft survival rates. Gray scale sonography easily detects hydronephrosis and perinephric fluid collections. Vascular complications of transplantation--AVFs, pseudoaneurysms, arterial/venous thrombosis and stenosis--are readily identified by color and duplex Doppler sonography. Initial enthusiasm for the gray scale and Doppler identification of acute rejection largely has been proved to be unfounded. Ultrasound guidance, however, clearly minimizes the risk and discomfort of definitive percutaneous renal transplant biopsy.

Combined liver and kidney transplantation in patients with chronic nephritis associated with end-stage liver disease

A variety of renal diseases can be associated with end-stage liver diseases requiring orthotopic liver transplantation (OLT), including cirrhosis-associated glomerulonephritis (GN), and nephropathy unrelated to the liver disease. A retrospective survey showed that nine patients undergoing liver transplantation in our centre had histologically proven GN or interstitial nephritis with renal failure and/or nephrotic-range proteinuria, and experienced severe complications post-OLT since nephrotoxic immunosuppressive drugs (CsA and FK506) could not be adequately given. Four of the nine patients died. Therefore, combined liver-kidney transplantation has been suggested as first choice treatment in such patients. From January 1990 to February 1994, in patients with end-stage liver disease referred for OLT, and who presented with unexplained renal function impairment and/or significant proteinuria, severe nephropathy was confirmed by renal biopsy in nine: four mesangiocapillary GN with immune deposits, one membranous nephropathy, two diabetic glomerulosclerosis and two interstitial nephritis. All underwent liver transplantation immediately followed by kidney transplantation. The postoperative period was uneventful, and neither death nor renal failure were recorded. Combined transplantation resulted in all patients in the normalization of renal function, and in the disappearance of proteinuria within the first postoperative month. From 6 months to 4 years post-transplant, the renal function remained within normal ranges in all patients. Routine renal transplant biopsy was performed in two patients with pre-transplant cirrhosis-associated GN, and showed no evidence of recurrence of the original nephropathy. We conclude that combined liver-kidney transplantation is an adequate therapeutic option in patients with end-stage liver disease associated with advanced kidney disease.(ABSTRACT TRUNCATED AT 250 WORDS)

The importance of E-selectin as a marker for renal transplant rejection

Vascular endothelial cells express membrane bound adhesion molecules which play a direct role in the localization and subsequent movement of leucocytes from the blood into sites of inflammation. E-Selectin is a cytokine induced adhesion molecule, known to be expressed by endothelial cells in inflammatory conditions, which binds to various leucocyte subpopulations. In a prospective study we have investigated the expression and distribution of E-selectin on renal allograft needle biopsies taken from 16 pretransplant kidneys and 119 post-transplant kidneys. Post-transplant biopsies were taken at times of graft dysfunction and at times of normal graft function. Formal histology was also performed and assessed independently. E-Selectin was found predominantly on the intertubular endothelium and on the endothelium of larger vessels. E-Selectin was present, at low intensity, in some pretransplant biopsies and also some post-transplant biopsies which were reported histologically as normal. In post-transplant biopsies taken for dysfunction E-selectin was present in the majority of cases. Expression was strong in biopsies showing acute cellular rejection and this was associated with a CD4 positive cellular infiltrate. Biopsies showing other causes of dysfunction, in particular acute tubular necrosis, also were E-selectin and CD4 positive with lower intensity than those with acute cellular rejection. These results suggest that E-selectin is a good marker for endothelial activation in renal transplant biopsies. Its presence in histologically apparently normal biopsies suggests that its in vivo kinetics may differ from previously reported in vitro kinetics. E-Selectin may be a potential target for therapeutic intervention.

Influence of nifedipine on interstitial fibrosis in renal transplant allografts treated with cyclosporin A.

To compare the degree of interstitial fibrosis in renal transplant biopsy specimens from immunosuppressed patients using conventional doses of cyclosporin with and without calcium channel blockade with a combination of low dose cyclosporin and azathioprine; to correlate the degree of interstitial fibrosis with the glomerular filtration rate. A single blind histomorphometric assessment was done of cortical interstitial volume fraction from biopsy specimens taken intraoperatively and at one, six, and 12 months after transplantation from three prospectively randomised groups of patients: (A) conventional dose cyclosporin; (B) conventional dose cyclosporin plus nifedipine; (C) low dose cyclosporin plus azathioprine. Interstitial volume increased with time in all groups. No differences in interstitial volume were present at operation or at one month, but at six months interstitial volume was significantly less in group B than group A (p < 0.001) or group C (p < 0.05). More grafts failed in group A than group B leaving only small numbers for comparison at 12 months. At 12 months the differences persisted but did not reach significance. These results strongly reflected the clinical findings, where glomerular filtration rate was significantly lower in group A than groups B or C at six and 12 months; no differences in glomerular filtration rate were found at one month. In a direct comparison glomerular filtration rate showed a significant negative correlation with interstitial volume fraction. These findings suggest that calcium channel blockade with nifedipine slows the development of interstitial fibrosis in renal transplant recipients treated with cyclosporin. When clinical data are considered, it is suggested that calcium channel blockade may have a mitigating effect on the long term nephrotoxic effects of cyclosporin and should be considered as adjunctive treatment in patients requiring this immunosuppressant following renal transplantation.

Evaluation of Doppler ultrasound in primary non‐function of renal transplants

Doppler ultrasound investigation was performed in the renal grafts of 86 patients with primary non‐function following cadaveric renal transplantation. Pulsatility Index, defined as: urn:x-wiley:09020063:ctrbf01006:equation:ctrbf01006-math-0001 was assessed to examine its predictive use in the diagnosis of rejection episodes as judged by a retrospective analysis of histological data. Altogether 415 Doppler examinations and 228 renal biopsies were performed. In our population the incidence of rejection was 57%. Using a pulsatility index (PI) &gt; 1.8 to be indicative of rejection, the sensitivity of our lest was 68% for vascular rejection and 65% for all rejection episodes. The specificity was 25%. We conclude that Doppler ultrasound cannot replace the need for transplant renal biopsy in patients with primary non‐function.

Presence of Cytomegalovirus Genome and Leucocyte Subsets in Renal Transplant Biopsies: Relationship with Prognosis

The influence of immunosuppressant therapy and of the presence of CMV genome on the distribution of lymphoid subpopulations of the inflammatory infiltrate in renal graft rejection was analyzed, as was the role of both factors in the evolution and survival of the graft. The study included 22 patients treated with Cyclosporin A (CsA) and 22 patients treated with Azathioprine (AZA). Inflammatory infiltrate was studied by immunostaining with a panel of monoclonal antibodies, and CMV DNA was detected by in situ hybridization on tissue sections. In patients treated with CsA, increased cellularity was found at both glomerular and interstitial levels, consisting mainly of macrophages and T-cells, which was consistent with the higher rate of glomerulointerstitial rejection found in this group. In contrast, the vascular type of rejection predominated in AZA treated patients. However, the presence of CMV DNA did not influence the phenotype of the inflammatory infiltrate, and was not associated with any specific lesion. Furthermore, the final outcome of the renal graft was independent of the detection of CMV. Therefore, this study provides no evidence of any active role of the CMV genome in renal graft rejection, and suggests that therapy should be adapted to the type of rejection as defined on morphologic and immunophenotypic grounds.

Analysis of factors associated with complications following renal transplant needle core biopsy

To determine factors associated with complications in patients undergoing renal transplant biopsy. A total of 210 consecutive renal transplant patients biopsied for acute graft dysfunction or as part of a long term surveillance programme. Biopsies were performed under ultrasound control at two centres (Nottingham City and Leicester General Hospitals). Seventeen patients developed macroscopic haematuria following biopsy (8%). There were no graft losses. In cases where at least one biopsy core contained only renal medullary tissue, there was a significantly higher risk of a post-biopsy bleed (P < 0.001). This study demonstrates that even with careful ultrasound guidance, renal transplant biopsy has an important complication rate. Every effort must be made to obtain very superficial biopsies which consist largely or exclusively of renal cortex.

Glomerular perfusion in renal allograft biopsies

In the commonest causes of impaired renal transplant function there is reduced renal and glomerular perfusion. We investigated the possibility of identifying this phenomenon in renal transplant biopsies, by the crude but simple method of counting the mean numbers of glomerular capillary loops which contained erythrocytes. In cyclosporin toxicity, acute tubular necrosis and in acute cellular rejection there was a considerable reduction in the numbers of erythrocyte-containing glomerular capillaries. The separation of the acute tubular necrosis group from normal was almost complete. This feature is therefore not specific but appears to correlate well with states of impaired glomerular perfusion. We suggest that a simple assessment of glomerular erythrocyte 'load' forms a useful part of the histological examination of renal transplant biopsies.

Recurrence of SLE in transplanted kidneys: a follow-up transplant biopsy study

Renal transplant biopsies were obtained from 16 patients with systemic lupus erythematosus 6 months to 11 years post-transplant. Eight biopsies were taken on clinical grounds while eight were elective. Histopathological findings suggesting recurrent lupus nephritis were found in seven biopsies, five of which were taken on clinical indication. By light-microscopy, five graft biopsies showed proliferative glomerulopathy and two glomerulosclerosis. Immunofluorescence was positive for IgM and C3 in a finely granular pattern in all biopsies, for C1q in three, but for IgG in only two. Electron-dense deposits were found in all seven biopsies with predominantly subendothelial location. All but one patient had clinical signs of renal involvement, but only three had extrarenal symptoms and three had serological signs of active SLE. Upon increased immunosuppressive therapy, renal and serological signs improved but one graft was later lost due to recurrent SLE nephritis.

Peritubular Capillary Congestion in Renal Allograft Biopsies May be an Unreliable Marker for Cyclosporine Nephrotoxicity

E XTENSIVE AGGREGATION of inflammatory cells in peritubular capillaries (peritubular capillary congestion, PCC), as the principal abnormality encountered in a renal transplant biopsy, is an uncommon finding. l To our knowledge, only one transplantation center has reported extensively on their experience with this entity2; that group has strongly suggested that this lesion may be a specific manifestation of cyclosporine nephrotoxicity. Our experience has instead suggested that this pattern of injury can be the principal histologic manifestation of underlying or developing vascular rejection and is not necessarily related to cyclosporine therapy. We report a pertinent example, because we believe that it may be misleading to use this histopathologic finding as a criterion for reduction of cyclosporine dosage in a patient with acute allograft dysfunction.

1990 ARRS Executive Council Award. Renal transplant rejection: diagnosis with 31P MR spectroscopy.

We evaluated the role of 31P MR spectroscopy in the diagnosis of renal transplant allograft dysfunction. Thirty-six 31P MR spectroscopy examinations were prospectively performed in 35 patients with renal allografts. The study was performed in two phases. In the first phase, 12 transplant recipients with normal graft function were studied as normal controls. During phase two, 24 31P MR spectroscopy studies were performed in patients at the time of renal transplant biopsy for allograft dysfunction. Twenty-one of these studies were technically adequate. Pathologic analysis of the biopsy specimens showed evidence of allograft rejection in 14 and no rejection in seven. Various phosphorus metabolite ratios were calculated for each patient, including phosphodiesters/phosphomonoesters (PDE/PME), phosphomonoesters/inorganic phosphate (PME/Pi), and inorganic phosphate/adenosine triphosphate (Pi/ATP). The PDE/PME and Pi/ATP ratios in the allografts with rejection differed significantly from the corresponding metabolite ratios in patients without rejection (p = .017 and p = .024, respectively). A PDE/PME ratio exceeding 0.8 had a sensitivity of 100% and specificity of 86% for predicting rejection. A Pi/ATP ratio greater than 0.6 had a sensitivity of 72% and a specificity of 86% for predicting rejection. We conclude that 31P MR spectroscopy may be useful as a noninvasive method for evaluating renal metabolism during episodes of transplant allograft dysfunction.

Renal Transplant Biopsy using Real Time Ultrasound Guidance

We describe a safe method of percutaneous renal transplant biopsy using real time ultrasound guidance. The method provides a good histological sample, is straightforward and has a low complication rate.

MR diagnosis of pancreatic transplant rejection.

To determine the role of MR imaging in the assessment of pancreatic transplant rejection, we prospectively obtained 13 MR scans in nine transplant patients. The presence of rejection was verified pathologically by pancreatic transplant biopsies in five patients. In two additional patients, rejection was proved by concordant renal transplant biopsy as well as by compatible clinical and laboratory data. In the remaining two patients, in whom no biopsy was done, clinical and laboratory data showed no evidence of rejection. The mean T2 of the seven pancreata undergoing rejection was significantly elevated (86 msec) compared with the mean T2 of the two transplants not undergoing rejection (59 msec) (p less than .002). These preliminary results suggest that MR may be useful in the noninvasive diagnosis of pancreatic rejection.

Summary: Diagnostic Uses

ONOCLONAL ANTIBODIES have ad­ vanced the clinical utility of various forms of renal transplant biopsies. With respect to core needle biopsies of the renal transplant, immuno­ peroxidase studies using monoclonal antibodies to specific cell markers have to date been adjunctive. Standard histochemical and pathologic analysis of the core biopsy permits an accurate clinical diagnosis to be made based on the architecture of the tissue and the presence, position, and nature of immunocompetent cell infiltrates. The role of monoclonal antibodies has been able to delineate the pedigree of the infiltrating lymphocyte respon­ sible for rejection that may be discerned. Because rejection is a heterogenous entity, cells from a wide range of different pedigrees participate in the phenomenon. Little additional diagnostic informa­ tion has so far been gained by analysis of these markers by monoclonal antibodies. In contrast, the presence of activation markers, such as the in­ terleukin 2 (IL-2) receptor, the transferrin recep­ tor, or the appearance of class II antigens on tubu­ lar cells has been instructive as it may confirm the presence of rejection diagnosed by standard technique. Dual markers will in the future improve the role that the surface structures playas diagnos­ tic elements. The most important role for the panel of described monoclonal antibodies at present may be prognosis. In terms of the fine needle aspiration biopsy, monoclonal antibodies may play a greater diagnostic role. The goal of this form of biopsy is to aspirate out of the allograft an array of cells including immunocompetent cells and isolated tubular structures. Morphologic analysis by stand­ ard histochemical techniques permits one to appre­ ciate the stage of maturation of the