The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials.

The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i-IFTA) and its relationship to T cell-mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody-mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i-IFTA is associated with reduced graft survival. Furthermore, these groups presented that i-IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i-IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor-specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next-generation clinical trials.

BK Virus Nephropathy: Histological Evolution by Sequential Pathology.

Reactivation of BK virus in renal allografts causes a destructive chronic infection. This single-center retrospective cohort study describes the evolution of BK virus allograft nephropathy (BKVAN) from 63 kidneys (from 61 patients) using sequential histopathology (454 biopsies, averaging 7.8 ± 2.6 per kidney) followed for 60.1 mo. Uninfected protocol biopsies formulated time-matched control Banff scores (n = 975). Interstitial inflammation occurred in 73% at diagnosis, correlating with viral histopathology (r = 0.413, p = 0.008) and amplifying early injury with accelerated interstitial fibrosis and tubular atrophy (IF/TA, p = 0.017) by 3 mo. Prodromal simian virus 40 large T antigen (SV40T)-negative inflammation with viremia preceded the histological diagnosis in 23.8%. Persistent subacute injury from viral cytopathic effect was associated with acute tubular necrosis and ongoing interstitial inflammation, culminating in IF/TA in 86.9%. Overall, cellular interstitial infiltration mitigated the intensity of subsequent tubular injury, SV40T, and tissue viral load, assessed by sequential paired histology (p < 0.001). Graft loss was predicted by high-level viremia (hazard ratio [HR] 4.996, 95% CI 2.19-11.396, p < 0.001), deceased donor (HR 3.201, 95% CI 1.149-8.915, p = 0.026), and late acute rejection (HR 3.124, 95% CI 1.037-9.413, p = 0.043). Transplant failure occurred in 38.1%, with uncontrolled infection (58.3%) and SV40T-negative chronic rejection (41.7%) causing losses. BKVAN is characterized by subacute virus-induced tubular injury, inflammation, and progressive nephron destruction. Effective antiviral therapy remains an unmet clinical need.

The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology.

The XIII Banff meeting, held in conjunction the Canadian Society of Transplantation in Vancouver, Canada, reviewed the clinical impact of updates of C4d-negative antibody-mediated rejection (ABMR) from the 2013 meeting, reports from active Banff Working Groups, the relationships of donor-specific antibody tests (anti-HLA and non-HLA) with transplant histopathology, and questions of molecular transplant diagnostics. The use of transcriptome gene sets, their resultant diagnostic classifiers, or common key genes to supplement the diagnosis and classification of rejection requires further consensus agreement and validation in biopsies. Newly introduced concepts include the i-IFTA score, comprising inflammation within areas of fibrosis and atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active T cell-mediated rejection (TCMR) or chronic ABMR. The pattern of mixed TCMR and ABMR was increasingly recognized. This report also includes improved definitions of TCMR and ABMR in pancreas transplants with specification of vascular lesions and prospects for defining a vascularized composite allograft rejection classification. The goal of the Banff process is ongoing integration of advances in histologic, serologic, and molecular diagnostic techniques to produce a consensus-based reporting system that offers precise composite scores, accurate routine diagnostics, and applicability to next-generation clinical trials.

Recent advances in autosomal-dominant polycystic kidney disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease in adults, affecting one in every 1000 Australians. It is caused by loss-of-function heterozygous mutations in either PKD1 or PKD2 , which encode the proteins, polycystin-1 and polycystin-2 respectively. The disease hallmark is the development of hundreds of microscopic fluid-filled cysts in the kidney during early childhood, which grow exponentially and continuously through life at varying rates (between 2% and 10% per year), causing loss of normal renal tissue and up to a 50% lifetime risk of dialysis-dependent kidney failure. Other systemic complications include hypertensive cardiac disease, hepatic cysts, intracranial aneurysms, diverticular disease and hernias. Over the last two decades, advances in the genetics and pathogenesis of this disease have led to novel treatments that reduce the rate of renal cyst growth and may potentially delay the onset of kidney failure. New evidence indicates that conventional therapies (such as angiotensin inhibitors and statins) have mild attenuating effects on renal cyst growth and that systemic levels of vasopressin are critical for promoting renal cyst growth in the postnatal period. Identifying and integrating patient-centred perspectives in clinical trials is also being advocated. This review will provide an update on recent advances in the clinical management of ADPKD.

The role of macrophages in the development of human renal allograft fibrosis in the first year after transplantation.

The aim of this study was to investigate the role of infiltrating macrophages in renal allograft fibrosis. Forty-six protocol renal allograft biopsies obtained 1 year after transplantation were stained with Sirius red to quantify fibrosis and double stained with CD68 and CD206 to identify the proportion of alternatively activated (M2) macrophages. Biopsies were analyzed for gene expression by microarray, which was correlated with macrophage infiltration and the severity of fibrosis. The number of infiltrating CD68+ cells strongly correlated with the percentage of interstitial fibrosis (r = 0.73, p < 0.0001). Macrophage infiltration at 1 year correlated with renal dysfunction at 1, 12 and 36 months posttransplant (estimated GFR low vs. high: 1 month 78 ± 26 vs. 54 ± 19 mL/min, p < 0.01; 12 months 87 ± 29 vs. 64 ± 19 mL/min, p < 0.05; 36 months 88 ± 33 vs. 60 ± 24 mL/min, p < 0.05). Ninety-two percent of infiltrating macrophages exhibited an M2 phenotype with CD68+ CD206+ dual staining. Gene microarrays demonstrated an alloimmune response with up-regulation of interferon-γ-response genes despite the lack of rejection or inflammatory infiltrate. Consistent with this was the presence of CXCL10 in proximal tubular cells at 3 months. This suggests that M2 macrophage proliferation, or infiltration, was associated with subclinical alloimmune inflammation, tubular injury and progression of fibrosis.

Test performance characteristics of quantitative nucleic acid testing for polyomaviruses in kidney and kidney-pancreas transplant recipients.

Screening for polyoma BK virus (BK) using nucleic testing (NAT) is recommended for kidney and kidney-pancreas transplant recipients, but the performance characteristics of quantitative BK NAT at different thresholds of plasma BK viral loads are unclear. We aim to evaluate the diagnostic accuracy of quantitative BK NAT as an add-on test to qualitative polyoma NAT for the diagnosis of BK virus-associated nephropathy (BKVAN) in kidney and kidney transplant recipients. We calculated the test sensitivity, specificity, and predictive values at the different thresholds of plasma BK viral load for BKVAN. At the recommended threshold of >1 × 10(3) serum BK copies/mL serum for test positivity, the sensitivity for BKVAN was 92.9% (95% confidence intervals [CI]: 66.1-99.8) and specificity 79.1% (95%: CI 67.4-88.1), with corresponding positive and negative predictive values of 42.0% (95% CI: 24.8-57.7%) and 98.6% (95% CI: 98.3-99.9%), respectively. The overall area under curve for the quantitative BK NAT was 0.92 (95% CI: 0.85-0.97). Quantitative BK NAT displays properties of high sensitivity and specificity that are fit for purpose as an add-on test to qualitative polyomavirus NAT for kidney and kidney-pancreas transplant recipients at risk of BKVAN.

Surveillance protocol kidney transplant biopsies: their evolving role in clinical practice.

Protocol renal allograft biopsies at fixed time points from transplantation have aided research and provided insights into the pathogenesis of early and late allograft injury. Their role is evolving from research to a clinical management tool needed to detect subclinical pathology requiring treatment adjustment. They frequently reveal unexpected findings and influence therapy in the majority of patients. Detection of subclinical rejection (SCR) remains important despite declining prevalence with triple therapy, the evidence favors treatment, if found. Surveillance biopsies in steroid avoidance and calcineurin inhibitor (CNI) withdrawal programs provide an important safety net against the increased rates of late acute and SCR. Individualization of therapy in high-risk patients and safe reduction of immunosuppression in standard risk individuals becomes possible. Other potentially reversible chronic pathologies that may be detected, include chronic T-cell or antibody-mediated rejection, recurrent disease, BK virus-associated nephropathy, interstitial fibrosis and tubular atrophy and CNI nephrotoxicity, allowing modifications of therapy to limit ongoing graft injury. Biopsy is safe and inexpensive compared with costs of earlier graft failure and return to dialysis. This review summarizes current evidence on use of surveillance histology for the clinical practice of renal transplantation.

Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema.

The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.

Banff '09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups.

The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v-lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics-technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future.

Banff 07 classification of renal allograft pathology: updates and future directions.

The 9th Banff Conference on Allograft Pathology was held in La Coruna, Spain on June 23-29, 2007. A total of 235 pathologists, clinicians and scientists met to address unsolved issues in transplantation and adapt the Banff schema for renal allograft rejection in response to emerging data and technologies. The outcome of the consensus discussions on renal pathology is provided in this article. Major updates from the 2007 Banff Conference were: inclusion of peritubular capillaritis grading, C4d scoring, interpretation of C4d deposition without morphological evidence of active rejection, application of the Banff criteria to zero-time and protocol biopsies and introduction of a new scoring for total interstitial inflammation (ti-score). In addition, emerging research data led to the establishment of collaborative working groups addressing issues like isolated 'v' lesion and incorporation of omics-technologies, paving the way for future combination of graft biopsy and molecular parameters within the Banff process.

Diagnostic utility of whole blood cyclosporine measurements in renal transplantation using triple therapy.

Whole blood CsA concentrations measured by specific monoclonal RIA (CYCLO-Trac SP whole blood RIA, IncSTAR) were compared with episodes of renal dysfunction (n = 138) and protocol biopsies (n = 52) that occurred within the first 100 days in consecutive renal allograft recipients receiving triple therapy (n = 92). Histological confirmation of events was available in 98% episodes of acute rejection (n = 60/61), 59% of episodes of CsA nephrotoxicity (22/38), and 100% of the diagnoses of acute tubular necrosis (35/35). Mean, minimum, and maximum CsA levels were elevated in CsA nephrotoxicity compared with all other groups (P < 0.001). Interestingly, CsA levels achieved relative to administered dose also increased at the time of CsA nephrotoxicity compared with other groups (P < 0.01). In the context of acute dysfunction, the sensitivity and specificity of mean CsA levels above 400 ng/ml to predict CsA nephrotoxicity were 32% and 89%, respectively. The negative predictive value of a high CsA level to exclude acute rejection was 88% (at 400 ng/ml), 92% (450 ng/ml), and 95% (500 ng/ml). As a marker of effective immunosuppression, CsA levels were not correlated with in vitro proliferation of PHA-stimulated PBL and did not reduce the severity and degree of cellular infiltration in needle core biopsies during rejection. The sensitivity and specificity of a low CsA level (150 ng/ml) in the diagnosis of acute rejection were 31% and 91%, respectively. The majority of episodes of acute dysfunction, including 63% of CsA nephrotoxicity and 59% of acute rejections, occurred with CsA levels between 150 and 400 ng/ml. In summary, when using low dose triple therapy regimens, CsA levels within the range of 150-400 ng/ml were of little diagnostic value in acute allograft dysfunction. In contrast, levels outside this range were useful in the clinical diagnosis of CsA nephrotoxicity and acute allograft rejection.

Renal graft thrombosis. A survey of 134 consecutive cases.

Despite overall improved graft survival, renal graft thrombosis (RGT) remains an important cause of graft loss. Of 6153 consecutive renal transplants (RTx), 134 index cases of graft loss from RGT were reported to the Australian and New Zealand Dialysis and Transplant Registry between 1980 and 1992. Two groups were selected for comparison: (1) institutional controls (n = 127), the previous RTx at the same institution as each index case; and (2) graft controls (n = 107), the contralateral cadaveric donor kidney of each index case. RGT cases that coincidentally occurred in control groups were deleted from those groups (6 of institutional controls, 2 of graft controls). RGT within the first 30 days after RTx occurred in 1.9% of all RTx and was constant from 1980 to 1992. In contrast, RGT caused an increasing proportion of early (within 30 days of RTx) graft losses (P = 0.01). The cumulative occurrence of RGT in those who thrombose was 62.6%, 83.7%, 90.2%, and 93.5% at 2, 7, 14, and 30 days after RTx, respectively. By comparison, with the control groups, no association with RGT was demonstrated for recipient age or sex, primary renal disease, type of dialysis, treatment with CsA, degree of HLA mismatch, panel reactive antibody levels, perfusion solution and perfusion technique, or immunosuppressive therapy. There was a significantly increased incidence of RGT with both extremes of donor age, female donors, and prolonged total ischemic time.

Predicting glomerular filtration rate after kidney transplantation.

Serum creatinine is an important clinical measure of impairment of glomerular filtration rate (GFR) after kidney transplantation. The use of formulas that predict GFR (such as the Cockcroft-Gault) derived from patients with chronic renal failure and standardized against measured creatinine clearance may not be accurate when applied to kidney transplant recipients. The purpose of this study, was to investigate the level of inaccuracy and its causes and then to derive predictive GFR formulas that are appropriate to renal transplantation. Determinants of isotopic GFR, serum creatinine, and muscle mass were evaluated in consecutive kidney recipients (n = 146) using 99mTc DTPA GFR (n = 751) as a reference method. Factors that predicted GFR apart from serum creatinine included sex, height, body weight, serum urea, years on dialysis, numbers of rejections and infective episodes, and prednisolone dose. The relationship between serum creatinine and GFR was highly variable and dependent on factors that alter muscle mass and muscle catabolic rate. The relationship was further altered by ATN and chronic rejection when tubular secretion of creatinine was reduced. Three alternative GFR formulas (which can be applied to renal transplant patients according to the availability of clinical parameters) were derived and tested against six published methods of GFR estimation. Our derived formulas had the highest correlation, no overall bias, least scatter of sum of squares, and least error at low levels of GFR. They represent a better estimation of GFR in kidney transplantation than published formulas, and would allow a standardized approach to the study of long-term renal dysfunction.

Renal dysfunction in acute rejection. Effect of HLA typing, therapy, and histology.

Acute rejection is a frequent cause of early graft dysfunction in renal transplantation, and serum creatinine is the most important measure of clinical response. However, there is little information on serum creatinine during rejection episodes. In this study, the determinants that might influence the clinical response of serum creatinine during acute rejection were evaluated in 96 renal transplant recipients with 100 episodes of biopsy-proven rejection, by univariate and multivariate analysis. The factors assessed for their influence on serum creatinine in acute rejection included: presence and severity of vascular or cellular rejection on biopsy, time taken to institute therapy, HLA mismatch, and the use of OKT3. The presence of vascular rejection on biopsy (n = 28) was a major determinant of impaired reciprocal area under the curve (AUC) of serum creatinine (P < 0.01), and was correlated with HLA-A and -B mismatch (r = 0.21, P < 0.05). Acute rejection associated with HLA-DR mismatch resulted in a more rapid increase of serum creatinine, a higher maximal creatinine, and a greater AUC creatinine (all P < 0.05). Treatment of acute rejection with OKT3 had a beneficial effect on AUC creatinine (P < 0.05) when compared with intravenous corticosteroids, by multivariate analysis. However, vascular rejection and HLA-DR mismatch had no effect on serum creatinine 1 year after transplantation. The biopsy cellular rejection score had no effect on AUC creatinine, although there was a modest effect on gradient of creatinine prior to biopsy. A minor adverse effect of delay in therapy of acute rejection could be demonstrated in the methylprednisolone-treated subgroup. In summary, HLA-DR mismatch and the presence of vascular rejection were the most important predictors of the severity of rejection assessed by the response of serum creatinine to treatment. Appropriate antirejection therapy should be instituted promptly to optimize clinical response during acute rejection.

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.

Clinical determinants of glucose homeostasis after pancreas transplantation.

Although successful simultaneous pancreas and kidney transplantation (SPK) achieves normoglycemia in the majority of diabetic recipients with end-stage renal disease, little is known about the factors that influence long-term endocrine function. In this prospective study of 48 bladder-drained SPK patients, 209 oral glucose tolerance tests were performed between 3 months and 6 years after transplantation. Normal fasting glucose levels and systemic hyperinsulinemia were stable for up to 6 years after SPK. Multivariate analysis revealed that increased area-under-curve (AUC) levels of C-peptide 3 months after transplantation were predicted by short surgical pancreas anastomosis time, greater recipient body weight, and total HLA mismatch score. Episodes of acute pancreas rejection were not associated with reduced allograft insulin output in the long term. Insulin output, stimulated by oral glucose tolerance tests and assessed by the ratio of AUC insulin to AUC glucose, fell gradually after transplantation and was decreased by an elevated serum calcium level and high cyclosporine dose. The ratio of fasting insulin to glucose, which acts as a marker of peripheral insulin resistance, fell with time after transplantation and was increased by greater body weight, higher prednisolone dose, and lower cyclosporine dose. The inhibitory effect of cyclosporine on both fasting and postprandial insulin output was, however, minor when quantified by multivariate analysis. Endocrine function of the transplanted pancreas was not correlated with its exocrine function measured by urinary amylase excretion, nor was there a correlation with change in renal function measured by isotopic glomerular filtration rate. In summary, simultaneous pancreas and kidney transplantation leads to excellent long-term glucose homeostasis maintained at the expense of systemic hyperinsulinemia. The key factors adversely affecting peripheral resistance in SPK were corticosteroid therapy, body weight, and time after transplantation. The susceptibility of islets to ischemia-reperfusion injury, as quantitated by surgical anastomosis time, may have implications for islet transplantation programs, as may the relative resistance of islets to allograft rejection. Glucose homeostasis after SPK, while remaining abnormal, may be used as the standard against which islet transplantation must be measured.

Posttransplant cataract: lessons from kidney-pancreas transplantation.

INTRODUCTION: Cataract is a major cause of visual disturbance after transplantation. Although corticosteroid therapy has been linked with posterior subcapsular cataract, its natural history in the cyclosporine era is not well understood. METHODS: Baseline and regular postoperative slit-lamp biomicroscopy and ophthalmic examinations (n=432) were performed in 108 eyes of simultaneous kidney/pancreas (SPK) recipients (n=54) for up to 10 years after transplantation. Triple therapy immunosuppression of cyclosporine, azathioprine, and prednisolone was used. RESULTS: Cataract was present in 40% of eyes at simultaneous kidney/pancreas associated with duration of diabetes, lower insulin dose, and the use of pretransplant hemodialysis (P<0.05-0.01). Cataract became increasing more common 2 years after simultaneous kidney/pancreas, and lens abnormalities were virtually universal at 6-10 years by slit lamp biomicrosopy. The instantaneous hazard rate for new cataract formation was highest within the first 2 years and remained abnormal for the study duration. Nuclear and posterior subcapsular cataract increased significantly after transplantation (P<0.05) and were the predominant types of cataract presenting late. Risk factors for posttransplant cataract formation included older age and high-dose pulse methylprednisolone dose. Visual acuity was reduced by severity of cataract grade, presence of combined nuclear and subcapsular cataract, retinal hemorrhage and underlying diabetic retinopathy (P<0.05-0.001). Cataract formation imposed significant additional impairment of visual acuity above that of diabetic retinopathy. Cataract surgery was undertaken in 14% of eyes, improving visual acuity from mean decimalized score of 0.28 to 0.43, P<0.01 but did not normalize it to the noncataract level of 0.72. CONCLUSION: Transplantation substantially increases all types of cataract, and is highly prevalent by slit lamp examination. High-risk patients are older and diabetic, and received hemodialysis and pulse corticosteroid therapy. In contrast to older studies using high-dose corticosteroid and azathioprine, the pattern of cataract in the cyclosporine era is different with broader cataract types, a weaker association with corticosteroids and a progressive course. Regular screening of visual acuity and appropriate surgery for posterior subcapsular or severe cataract are recommended.

Progression of macrovascular disease after transplantation.

INTRODUCTION: Cardiovascular and cerebrovascular disease are major causes of morbidity and mortality after kidney transplantation. The aim of this longitudinal study was to examine the natural history of carotid plaque and to determine risk factors for the progression of vascular disease in uremic, type 1 diabetic patients who received a combined kidney and pancreas transplant. METHODS: Carotid artery (n=765) and lower limb vascular duplex scanning (n=656) were prospectively undertaken in 82 recipients before transplantation, at 6 months, and then at annual intervals for up to 10 years. Plaque in the internal carotid artery (ICA), external carotid artery, and common carotid artery was classified by type, location, extent, and degree of functional obstruction, and evaluated using multivariate analysis. RESULTS: Carotid plaque was present in 22.5% of patients at initial scanning, but increased to 56.6% by 7-10 years after transplantation, especially in the ICA and common carotid artery. Both the severity and extent of plaque increased, and plaque became more complex and heterogeneous with time after transplantation (P<0.001). Carotid plaque was associated with older age, current cigarette smoking, hyperphosphatemia, hypoalbuminemia, duration of pretransplantation dialysis, and presence of lower limb plaque (P<0.05-0.001). The severity of carotid plaque increased in older, hypertensive recipients and was associated with metabolic acidosis and hyperphosphatemia (all P<0.05). Severity of ICA disease correlated with disease in the contralateral ICA (r=0.57, P<0.001) and femoral arteries (r=0.42, P<0.001). Paradoxically, each carotid artery progressed independently of the other. ICA disease severity progressed when heterogenous, calcified, or new plaque was present on scanning, and with reduced renal transplant function (P<0.01-0.001). The mean ICA blood flow remained stable with time but was progressively impaired by hypertension, fasting hyperglycemia, and a lower prednisolone dose (P<0.05). Cerebrovascular events occurred in only four patients and were unrelated to carotid disease, implying relative plaque stability. CONCLUSION: Extensive carotid vascular wall abnormalities increased significantly despite kidney and pancreas transplantation. Initiation of plaque was associated with systemic factors, whereas progression of established plaque was largely influenced by local factors within the arterial wall.

Percutaneous biopsy of bladder-drained pancreas transplants.

Percutaneous biopsy is a valuable investigation in the management of allograft rejection for all solid organs. Pancreas transplants have not been biopsed percutaneously, though open and percystoscopic biopsies have proved useful. We have compared percutaneous needle core biopsy with fine-needle aspiration cytology for the diagnosis of rejection in 18 patients receiving combined kidney and pancreas transplants and in one who was transplanted with the pancreas alone. Percutaneous needle core biopsy was successful in 37 of 40 attempts (93%), while fine-needle aspiration yielded diagnostic material on 33 of 47 attempts (70%). Transient hyperamylasemia occurred in 29%, returning to baseline in three days. One patient twice developed transient macroscopic hematuria. There was agreement between needle core biopsy and fine-needle aspiration on the diagnosis of rejection on six occasions and for the absence of rejection on 16. There was an 8% false-positive rate for fine-needle aspiration. In 13 instances of histologically proved renal rejection, concurrent pancreas biopsy revealed rejection in 69%. Pancreas rejection was not, however, seen in the absence of renal rejection. In this pilot study, percutaneous biopsy of the bladder-drained pancreas allograft was shown to be a practicable and valuable investigation without major complications.