Charles B. Cangro

Clinical Course of Polyoma Virus Nephropathy in 67 Renal Transplant Patients

Polyoma virus (PV) can cause interstitial nephritis and lead to graft failure in renal transplant recipients. The clinical course of patients with polyoma virus nephritis (PVN) is not well understood, partially due to its relatively low incidence. This study is a retrospective analysis of our experience over 4 yr. The specific purpose is to outline the clinical course and outcome of patients with PVN and to study the relationship between immunosuppression and the disease process. Between June 1997 and March 2001, 67 patients with graft dysfunction were found to have biopsy-proven PVN. The diagnosis was made at a mean of 12.8 +/- 9.9 mo posttransplantation. The majority of patients were men (79%) with a mean age of 54 +/- 14 yr (range, 28 to 75). All patients received immunosuppression with a calcineurin inhibitor (tacrolimus in 89% of patients). All patients except two received mycophenolate mofetil and prednisone. After the diagnosis of PVN, maintenance immunosuppression was reduced in 52 patients and remained unchanged in 15 patients. After reduction of immunosuppression, eight patients (15.3%) developed acute rejection and six (11.5%) became negative for PV in biopsy and urine. After a mean observation period of 12.6 mo (mean of 26 mo posttransplantation), 16.4% of patients had lost their grafts (8 of 52 in the reduction group and 3 of 15 in the no change group). In comparison to a case-matched polyoma virus-negative control group, the PVN patients were older (P =.0004) and there was a predominance of men (P = 0.02). Kaplan-Meier analysis demonstrated that patients with PVN had reduced graft survival compared with negative controls (P =.0004). It is concluded that PVN is a serious hazard for renal transplant recipients and contributes directly to graft loss. Antiviral drugs are needed, as the reduction of immunosuppression alone may not significantly improve graft function in patients with already established PVN. Although multiple factors probably play a role in the development of PVN, judicious use of immunosuppressive agents is indicated to minimize the occurrence of this infection.

Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load.

Polyomavirus‐associated nephropathy (PVAN) is a significant cause of allograft loss. The diagnosis requires allograft biopsy, but the impact of the histological features on diagnosis and outcome has not been described. We studied the distribution and extent of PVAN in 90 patients. Viral cytopathic changes, tubular atrophy/fibrosis and inflammation were semi‐quantitatively scored and classified into histological patterns. The histological findings were correlated with viruria, viremia and graft survival. PVAN lesions were random, (multi‐)focal and affected both cortex and medulla. Areas with PVAN coexisted with areas of unaffected parenchyma. In 36.5% (15/41) of biopsies with multiple tissue cores, discordant findings with PVAN‐positive and ‐negative cores were observed. However, all patients with PVAN had decoy cells in urine as well as significant viruria and viremia (mean of 2.5 × 108 and 2.32 × 107 viral copies, respectively). Biopsies showing lesser degrees of renal scarring at the time of diagnosis were associated with, more likely, resolution of the infection, in response to decrease of immunosuppression (p = 0.001). More advanced tubulointerstitial atrophy, active inflammation and higher creatinine level at diagnosis correlated with worse graft outcome (p = 0.0002, 0.0001 and 0.0006). Due to the focal nature of PVAN, correlation of biopsy results with viruria and viremia are required for diagnosis.

A comparison of recipient renal outcomes with laparoscopic versus open live donor nephrectomy.

Background. Laparoscopic donor nephrectomy (laparoNx) has the potential to increase living kidney donation rates by reducing the pain and suffering of the donor. However, renal function outcomes of a large series of recipients of laparoNx have not been studied. Methods. We retrospectively reviewed the records of 132 recipients of laparoNx done at our center between 3/96 and 11/97 and compared them to 99 recipients of kidneys procured by the open technique (openNx) done between 10/93 and 3/96. Results. Significantly more patients in the laparoNx group (25.2%) were taking tacrolimus within the first month than those in the openNx group (2.1%). Mean serum creatinine was higher in laparoNx compared with openNx at 1 week (2.860.3 and 1.860.2 mg/dl, respectively; P50.005) and at 1 month (2.060.1 and 1.660.1 mg/dl, P50.05) after transplant. However, by 3 and 6 months, the mean serum creatinine was similar in the two groups (1.760.1 versus 1.560.05 mg/dl, and 1.760.1 versus 1.760.1, respectively). By 1 year posttransplant, the mean serum creatinine for laparoNx was actually less than that for openNx (1.460.1 and 1.760.1 mg/dl, P50.03). Although patients in the laparoNx compared to the openNx group were more likely to have delayed graft function (7.6 versus 2.0%) and ureteral complications (4.5 versus 1.0%), the rate of other complications, as well as hospital length of stay, patient and graft survival rates were similar in the two groups. Conclusion. Although laparoNx allografts have slower initial function compared with openNx, there was no significant difference in longer term renal function. Kidney transplantation is considered to be the treatment of choice for end-stage renal failure. Insufficient supply of organs for donation has produced long waiting times for many patients who may benefit from transplantation (1). During this period patients accumulate the morbidity of renal failure, they must endure the lifestyle limitations of dialysis, and they often die while waiting for the organ sharing system to grant them this resource. Live donor renal transplantation represents a large potential supply of organs that may relieve much of this shortage. Additionally, recipients of live renal transplants may reap benefits of improved patient and allograft survival that have been clearly demonstrated in this population (2,3). Although unilateral nephrectomy has proven to be safe and the solitary kidney state has been found to be well tolerated in a carefully chosen candidate for donation (4,5), substantial disincentives to donation exist. These include a significant hospitalization, prolonged convalescence period with time away from jobs, intractable perioperative pain, and, for some, cosmetic concerns of the resulting

Human polyoma virus in renal allograft biopsies: Morphological findings and correlation with urine cytology

Human polyoma virus (PV) interstitial nephritis occurs in immunosuppressed patients after reactivation of latent virus in renal epithelium. Currently, there is neither general consensus about the incidence of clinically significant PV infection in renal transplants nor conclusive evidence determining its significance in the long-term graft outcome. We evaluated 601 renal transplant biopsy specimens (from 365 patients) by routine light microscopy and immunoperoxidase stains with antibody against SV40 (which cross reacts with PV). We also examined urine samples from 200 patients (100 obtained concurrently with a renal biopsy in patients presenting with acute graft dysfunction and 100 from patients with stable graft function). Electron microscopic evaluation was performed in 50 renal biopsy specimens and in 23% of all urine samples. PV was identified in 1.8% biopsy specimens (1.9% of patients). PV interstitial nephritis showed the typical viral cytopathic changes in tubular epithelial cells associated with marked tubular damage and a disproportionately mild degree of tubulitis. There was no difference in the incidence of PV in the urine of patients with acutely deteriorating versus stable renal function (18% and 19%, respectively); however, urines with large numbers of infected cells (> 10/cytospin) and inflammatory changes in the sediments corresponded invariably to patients with acute allograft dysfunction (8 of 8), and in most cases to biopsy specimens showing PV interstitial nephritis (7 of 8). Based on these findings, urine samples seem to be the most sensitive and cost-effective screening method for PV infection; only urine samples with inflamed sediments and abundant infected cells correlate with clinically significant disease. In these cases, examination of a renal biopsy is indicated. Immunohistochemical stains are useful to confirm the presence of PV but do not increase the sensitivity of diagnosis of PV if this is not already suspected on routine light microscopy. In our material, immunostains were helpful ruling out the presence of PV in a small number of biopsy specimens (2%) that showed markedly reactive tubular cells resembling PV infection. Most patients with PV interstitial nephritis responded to decreased immunosuppression; however, the decay in graft function (based on creatinine slopes) was significantly more rapid in these patients than in matched controls. Evidence of PV infection should be systematically sought in renal biopsy specimens and urine samples from renal allograft recipients.

Polyomavirus BK versus JC replication and nephropathy in renal transplant recipients: a prospective evaluation.

Background. JC virus (JCV) viruria is more common than BK virus (BKV) viruria in healthy individuals but in kidney transplants (KT), polyomavirus nephropathy (PVAN) is primarily caused by BKV. Few cases of PVAN have been attributed to JCV. Systematic studies on JCV replication in KT are lacking. Methods. Out of a cohort of KT patients screened with urine cytology, patients shedding decoy cells were studied (n=103). Molecular studies demonstrated BKV, JCV, or BKV+JCV shedding in 58 (56.3%), 28 (27.2%), and 17 (16.5%), respectively. Biopsy was performed when decoy cells persisted 2 months or serum creatinine increased >20%. Results. BKV viruria was strongly associated with BKV viremia (93%), PVAN (48%, P=0.01) and graft loss (P=0.03). Higher BKV viremia correlated with graft dysfunction (P=0.01), more advanced histological pattern of PVAN (P<0.0001), and more infected cells in biopsy (P=0.0001). BKV viremia of ≥10,000 copies/mL was significantly associated with histologically confirmed PVAN (P=0.0001). Reduction of immunosuppression lead to disappearance of decoy cells in patients shedding BK (>93%). JCV viruria, was more often asymptomatic (P=0.002) and affected older patients (P=0.02). JCV PVAN was less common (21.4%) and was characterized by sparse cytopathic changes but significant inflammation and fibrosis. JCV viremia was rare (14.2%), transient, and low (mean 2.0E+03/mL). After reduction of immunosuppression decoy cells persisted in >50% of patients with JCV (P=0.0001), but no graft loss occurred. During the period of the current study, the incidence of BKV-PVAN was 5.5% and the incidence of JCV-PVAN was 0.9%. Conclusions. The data point to significant differences of BKV and JCV biology regarding replication and disease in KT patients, with important implications for screening and management.

A novel approach to the treatment of chronic allograft nephropathy

BACKGROUND Progressive deterioration of renal function in kidney transplant recipients is the leading cause of graft failure. Both nonimmunologic and immunologic mechanisms contribute to this deterioration. METHODS Twenty-eight cyclosporine (CsA)-treated renal transplant recipients (21 cadaveric, 5 living, 2 simultaneous kidney-pancreas) with progressive deterioration of renal function were prospectively enrolled in a clinical trial and had their immunosuppressive regimen changed 24.3+/-7.7 months after transplant. All patients had their CsA dose reduced by 50%, azathioprine was discontinued, and mycophenolate mofetil was added to the medical regimen. The mean creatinine of the patients at the initiation of the change in immunosuppression was 3.5+/-1.2 mg/dl (range 1.9 to 6.2 mg/dl). RESULTS Before the change in immunosuppression, the mean loss in renal function as indicated by the least-squares slope of the reciprocal of creatinine versus time was -0.006+/-0.002 (mg/dl)-1 per month. The change in immunosuppression significantly decreased the rate of loss in renal function for most patients when compared with their pretreatment values with a mean slope of 0.007+/-0.003 (mg/dl)-1 per month (P=0.003). Renal function improved in 21 of 28 patients. Only one patient had continued deterioration of renal function. In a multivariate analysis adjusting for CsA dose, mean arterial blood pressure, and baseline creatinine, the change in immunosuppression was significantly associated with improved renal function (P=0.02). There were no acute rejections after the immunosuppression change. CONCLUSIONS We conclude that adding mycophenolate mofetil and reducing CsA in patients with chronic deterioration of graft function is well tolerated and results in a short-term improvement in renal function.

Morphological spectrum of polyoma virus disease in renal allografts: diagnostic accuracy of urine cytology.

The morphological features of polyoma virus disease (PVDz) in 571 concurrent urine and biopsy samples from 413 patients are described. In 54 patients PV was found in both biopsy and urine samples. Histologically, PV presented as: (a) mild, viral cytopathic/cytolytic changes, with absent or minimal inflammation involving isolated tubules; (b) moderate and severe, cytopathic/cytolytic changes associated with patchy or diffuse tubulo‐interstitial inflammation and atrophy; (c) advanced, graft sclerosis with rare or absent viral cytopathic changes, indistinguishable from chronic allograft nephropathy. Histological progression from mild to moderate or severe disease was seen in 28 patients. The mean post‐transplantation time at diagnosis was similar in patients with mild or moderate‐severe renal involvement (1.05 and 1.3 years, respectively). All patients presented with similarly increased values of serum creatinine (mean 1.35 mg/dL). There was strong correlation between the number of PV infected cells in urine and the concurrent biopsies (p = 0.0001). In 13 patients PV was found only in urine; of these, two developed PVDz later. The positive predictive value of a positive urine was 90%, the negative predictive value of a negative urine was 99% and the accuracy of the test was 97%. We conclude that urine cytology is useful to evaluate renal transplant patients with PV reactivation because sloughed tubular cells are found in urine and positive urine samples are a consistent manifestation of PV renal involvement.

Histologic grading of acute allograft rejection in pancreas needle biopsy: correlation to serum enzymes, glycemia, and response to immunosuppressive treatment

BACKGROUND Allograft rejection continues to be the most common cause of graft failure in technically successful pancreas transplants. Early diagnosis and treatment of rejection is essential for long-term graft survival. Pancreas graft biopsies are now used routinely for the diagnosis of acute allograft rejection. The correlation between clinical evidence of graft dysfunction (increased serum enzymes and glucose), severity of acute rejection on biopsy (rejection grade), and response to treatment has not been previously studied. METHODS A total of 151 pancreas transplant needle biopsy specimens from 57 patients were evaluated. Statistical correlation was done between the histologic rejection grade (O-V) and the peak level of enzymes in serum, glycemia, type of antirejection treatment instituted, and response to treatment. Differentiation between grades was also evaluated statistically. RESULTS Response to antirejection treatment was 25%, 40%, 88%, 78%, 50%, and 17% for grades O-V, respectively. The response for grades II and III was better than for grades 0-I and IV-V (P=0.0003 and 0.0008, respectively). The response to corticosteroids alone was 36%, 86%, 68%, and 0% for grades I, II, III, and IV, respectively. The response to antilymphocyte regimen was 50%, 89%, 85%, 71%, and 17% for grades I, II, III, IV, and V, respectively. Overall correlation between the mean levels of enzymes and rejection grade was seen; the increase of lipase was statistically significant (r=0.24, P=0.012). Amylase and lipase correlated very well with each other (r=0.84, P=0.0001). No correlation was found in the mean values of blood glucose with the serum enzyme increase and with severity of rejection. Hyperglycemia was present in 12 patients; this abnormality in patients with grades II-IV responded promptly to treatment, whereas in patients with grade V, hyperglycemia persisted despite antirejection treatment. Other causes of increased enzymes were found in patients with biopsy specimens showing no rejection (grades 0 and I, 43% and 31%, respectively). CONCLUSIONS Increased serum enzymes, particularly lipase, correlate with the grade of acute rejection, but their lack of specificity precludes their use as sole markers of acute rejection. Glucose levels are not a sensitive marker for acute rejection. Rejection grades II and III are the most responsive to treatment, and a significant proportion of these cases respond to treatment with corticosteroids only. The higher rejection grades (IV and V) require treatment with antilymphocytic regimens, and their overall response to treatment is moderate to poor, respectively.

Late Calcineurin Inhibitor Withdrawal as a Strategy to Prevent Graft Loss in Patients with Suboptimal Kidney Transplant Function

Chronic allograft nephropathy is a major cause of progressive renal failure in renal transplant recipients. Its etiology is multifactorial and may include both immunologic and nonimmunologic causes. In this observational cohort study we set out to see if calcineurin inhibitor withdrawal would reduce the likelihood of graft loss. Methods: One hundred and five renal transplant recipients with impaired kidney function (mean serum creatinine 3.0 ± 0.1 mg/dl) and biopsy-proven chronic allograft nephropathy had the dose of their calcineurin inhibitors, cyclosporine (CSA), or tacrolimus (FK), reduced or discontinued with either the addition of, or continuation of mycophenolate mofetil and low-dose corticosteroids. This intervention occurred at a mean of 29.0 ± 2.7 months after transplantation. Follow-up after intervention was 54.3 ± 4.1 months in the reduced CSA group (n = 64), 41.6 ± 3.2 months in the reduced FK group (n = 28), and 75.5 ± 6.7 months in the calcineurin inhibitor withdrawal group (n = 13). Results: There were 24 graft failures in the reduced CSA group, 9 graft failures in the reduced FK group, and 1 graft lost in the calcineurin inhibitor withdrawal group. The unadjusted relative risk for graft failure in the CSA and FK groups combined (confidence interval 1.05–31.6), was 4.07 using the calcineurin inhibitor withdrawal group as the reference, p = 0.05. A Cox proportional hazards model adjusting for baseline covariates including age, gender, race, type of transplant, delayed graft function, baseline blood pressure and random serum glucose and cholesterol demonstrated that only calcineurin inhibitor dose reduction but not withdrawal, older age, delayed graft function, higher serum creatinine at the time of intervention , and higher diastolic blood pressure and serum glucose, correlated with graft loss. Only 6 of the 105 patients developed Banff grade acute rejection. All responded to steroid therapy. We conclude that although this observational cohort study may have a selection bias, late calcineurin inhibitor withdrawal in patients with chronic allograft nephropathy and impaired kidney function appears safe and durable as a treatment strategy to reduce the likelihood of graft failure.

Pancreas allograft biopsy: safety of percutaneous biopsy-results of a large experience.

BACKGROUND Percutaneous pancreas allograft biopsy is the technique of choice for evaluation of pancreatic allograft rejection or dysfunction. The safety and success rate of the procedure with current surgical techniques is unclear. We report the complications and success rate in 426 consecutive percutaneous pancreas allograft biopsies performed at a single center. METHODS One hundred eighty-three patients (50% simultaneous pancreas-kidney transplant, 42% pancreas after kidney transplant, 8% pancreas transplant alone) were biopsied. Biopsies were performed using an 18-gauge automated needle with ultrasound guidance. RESULTS Thirty-seven patients had four or more biopsies (maximum, 11). Two hundred fifteen (50%) biopsies were in patients with bladder exocrine drainage, 211 (50%) in patients with enteric exocrine drainage. Of the latter, 33 (16%) were in patients with portal venous drainage. Eighty-eight percent of biopsy specimens were adequate for histologic diagnosis. There were 12 biopsy-related complications (2.8%), including eight episodes of bleeding (1.9%), five of which (1.2%) required surgical intervention and one possible extra-graft exocrine leak. Other complications included inadvertent liver (1), kidney (1), and small bowel (1) biopsy. CONCLUSIONS Percutaneous pancreas allograft biopsy has a low rate of complication and a high success rate.