David K. Klassen

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.

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.

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.

Renal Effects of Ibuprofen, Piroxicam, and Sulindac in Patients with Asymptomatic Renal Failure: A Prospective, Randomized, Crossover Comparison

STUDY OBJECTIVE To evaluate the effects of three chemically distinct nonsteroidal anti-inflammatory drugs (NSAIDs) on renal function in patients with asymptomatic, mild but stable chronic renal failure. DESIGN Prospectively randomized, triple-crossover study with at least 1-month washout between each of three treatment periods. SETTING Inpatient and outpatient clinical research center of a university teaching hospital. PATIENTS Convenience sample of 12 women with serum creatinine levels between 130 and 270 mumols/L (1.5 and 3.0 mg/dL). Mean glomerular filtration rate +/- standard error was 0.36 +/- 0.03 mL/s.m2 (37 +/- 3 mL/min.1.73 m2); mean effective renal plasma flow was 1.6 +/- 0.18 mL/s.m2 (166 +/- 19 mL/min.1.73 m2). INTERVENTIONS Patients received ibuprofen, 800 mg three times daily; piroxicam, 20 mg daily; and sulindac, 200 mg twice daily for 11 days. Treatment was discontinued if serum creatinine rose by 130 mumols/L (1.5 mg/dL) or serum potassium exceeded 6 mmol/L (6 mEq/L). MEASUREMENTS AND MAIN RESULTS Three patients met our criteria for stopping ibuprofen by day 8; however, all patients completed piroxicam and sulindac therapy. When the three patients in whom ibuprofen was withdrawn were rechallenged with ibuprofen, 400 mg three times daily, two again developed evidence of acute renal deterioration. All three regimens suppressed renal prostaglandin production. CONCLUSIONS These findings indicate that a brief course of ibuprofen, a compound widely used on a nonprescription basis, may result in acute renal failure in patients with asymptomatic, mild chronic renal failure. Additional studies are needed to assess the risk of piroxicam and sulindac in patients with more pronounced renal impairment and in patients receiving longer courses of therapy, which, according to our data, may result in drug accumulation.

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.

Mic Expression In Renal And Pancreatic Allografts

BACKGROUND MHC class I chain-related antigen A (MICA) and MHC class I chain-related antigen B (MICB) are HLA class I related products of polymorphic MHC genes. Constitutive expression in normal tissue is limited to gut epithelium but can be induced in other epithelial cells by stress. Specific antibodies against MICA have been reported in the serum of patients who had rejected kidney allografts, suggesting a potential role for these molecules in transplant immunopathology. However, expression of MICA and MICB in transplanted organs has not been demonstrated. In this study, we report the expression of MICA and MICB in renal and pancreatic allograft biopsies, which were obtained due to clinical signs of rejection. METHODS A monoclonal antibody directed against MICA and MICB was used to perform indirect immunohistochemistry on formalin fixed, paraffin embedded needle biopsies of kidney and pancreas allografts. The results of staining were then compared to the standard light microscopic evaluation of the biopsies for rejection. RESULTS A total of 53 individual renal transplant biopsies and 19 pancreas transplant biopsies were assayed for expression of MIC. Histologically, renal biopsies were diagnosed as no rejection, acute tubular necrosis (ATN), acute rejection (AR), chronic rejection (CR), and acute and chronic rejection (ACR). No staining was observed in 7 of 10 kidneys showing no rejection. All 11 of the kidney biopsies with AR were positive, as were the 11 ATN cases, 9 of the 11 kidney biopsies with CR, and 7 of the 10 with ACR. The acini of normal, nontransplanted, pancreas, control specimen were consistently negative; however, islets were positive in all specimens. The acini and islets of five histologically normal pancreas biopsies were positive, as were the four biopsies with AR, seven biopsies with CR, and two with ACR. CONCLUSIONS MICA and MICB are expressed in epithelial cells in allografted kidney and pancreas that show histologic evidence of rejection and/or cellular injury. In addition to previous findings of alloantibodies against MICA, expression of these gene products may play a role in allograft rejection.

Banff Schema for Grading Pancreas Allograft Rejection: Working Proposal by a Multi-Disciplinary International Consensus Panel

Accurate diagnosis and grading of rejection and other pathological processes are of paramount importance to guide therapeutic interventions in patients with pancreas allograft dysfunction. A multi‐disciplinary panel of pathologists, surgeons and nephrologists was convened for the purpose of developing a consensus document delineating the histopathological features for diagnosis and grading of rejection in pancreas transplant biopsies. Based on the available published data and the collective experience, criteria for the diagnosis of acute cell‐mediated allograft rejection (ACMR) were established. Three severity grades (I/mild, II/moderate and III/severe) were defined based on lesions known to be more or less responsive to treatment and associated with better‐ or worse‐graft outcomes, respectively. The features of chronic rejection/graft sclerosis were reassessed, and three histological stages were established. Tentative criteria for the diagnosis of antibody‐mediated rejection were also characterized, in anticipation of future studies that ought to provide more information on this process. Criteria for needle core biopsy adequacy and guidelines for pathology reporting were also defined.

Equivalent success of simultaneous pancreas kidney and solitary pancreas transplantation. A prospective trial of tacrolimus immunosuppression with percutaneous biopsy.

OBJECTIVE This study was designed to evaluate the results of solitary pancreas transplantation in a protocol that uses the new immunosuppressant tacrolimus (FK) and liberally applies ultrasound-guided percutaneous pancreas biopsy to diagnose rejection. SUMMARY BACKGROUND DATA Pancreas graft survival in patients who simultaneously receive a kidney transplant (SPK) historically has been 75% to 90% at 1 year, approaching that of cadaveric kidney transplantations. In sharp contrast, graft survival rates in patients who receive a pancreas atone (PA) have remained static over the past decade, with approximately 50% functional at 1 year. It was hypothesized that the results of PA transplantations would improve with newer maintenance immunosuppressants and biopsy techniques. METHODS Twenty-seven PA recipients prospectively were treated with FK-based immunosuppression (PA-FK). Percutaneous biopsy was performed for hyperamylasemia, hyperlipasemia, hypoamylasuria, or unexplained fever. One year pancreas graft survival in these patients was compared to 15 cyclosporine treated PA cases (PA-CsA) and 113 SPK recipients. RESULTS The 1-year pancreas graft survival rate of 90.1% in technically successful PA-FK patients was significantly better than the 53.4% rate in PA-CsA recipients (p = 0.002) and no different than the 87.4% rate in SPK recipients. The only graft lost to acute rejection in the PA-FK group was because of acknowledged patient noncompliance. Percutaneous biopsy substantially improved the diagnostic certainty in cases of suspected rejection and was associated with a low complication rate (3/178 = 1.5%). CONCLUSIONS Modern immunosuppression and biopsy techniques have improved the success of solitary pancreas transplantations to the point where outcome is now equivalent to that of SPKs.

Increased living donor volunteer rates with a formal recipient family education program

We have generally encouraged living donation among our kidney recipients. However, an examination of our clinical practice revealed inconsistencies in the depth and content of information transmitted to kidney recipient families regarding living donation. We therefore initiated a structured education program, including an educational video, to ensure that all recipient families would receive a similar exposure to a standard block of information. After the program had been functioning for over a year, we compared the living donor (LD) volunteer rates between the 3-year period before (BEFORE) and the 18 months after (AFTER) initiation of the formal education program. There were 1,363 patients registered on our kidney transplantation waiting list during the 54-month study period (757 white [56%] and 580 black [43%]). We found that 33.4% of the kidney transplant candidates in the period BEFORE the LD education program had at least one potential LD tissue typed, compared with 39.4% in the period AFTER starting the program (P = 0.03). The increase in the proportion of patients with potential donors was greatest among the black (P < 0.05) and elderly (P < 0.01) registrants, which were the groups with the lowest volunteer rates before the program began. Among the registrants with at least one potential donor, the percentage of registrants who ultimately received an LD transplant was highly correlated with the number of donors (R = 0.98). The rate of LD kidney transplantation was significantly higher (P = 0.02) for the patients referred in the period AFTER initiation of the LD education program compared with the period BEFORE the program. The 1- and 3-year graft survival rates for the 170 LD transplants performed in these patients were 96.9% and 93.2%, respectively. These were significantly better than the corresponding 83.9% and 71.4% rates for the 341 kidney transplants from cadaver donors in these registrants (P < 0.001). Black recipients of LD transplants had graft survival rates comparable to whites; the 3-year graft survival rate for LD transplants was 93.9% in whites and 90.6% in blacks (P = NS). We conclude that living kidney donor volunteer rates can be improved by a formal family education program, especially for subgroups of patients with low volunteer rates. A substantial benefit is derived by black patients, who generally experience low graft survival rates with cadaver-donor kidneys. A local formal LD education program is a useful adjunct to national organ donation campaigns.