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Cinthia B Drachenberg,
Hans H Hirsch,
John C Papadimitriou,
Rainer Gosert,
Ravinder K Wali,
Raghava Munivenkatappa,
Joseph Nogueira, Charles B Cangro,
Abdolreza Haririan,
Susan Mendley,
Emilio Ramos
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ABSTRACT: 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.
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%.
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 > or =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%.
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.
Transplantation 08/2007; 84(3):323-30. · 4.00 Impact Factor
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ABSTRACT: 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 x 10(8) and 2.32 x 10(7) 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.
American Journal of Transplantation 01/2005; 4(12):2082-92. · 6.39 Impact Factor
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ABSTRACT: Mycophenolate mofetil (MMF) is widely used for maintenance immunosuppression in solid organ transplantation. Gastrointestinal toxicity, usually manifested as diarrhea, is the most common side effect of MMF. We evaluated colonic biopsies from 20 renal transplant patients with MMF-related diarrhea. The latter was defined by the absence of any other demonstrable etiology and improvement or resolution of symptoms by the discontinuation or reduction of the dose of MMF alone. These biopsies were compared with colon biopsies from patients with the following: acute graft-versus-host disease (GVHD, n=10), inflammatory bowel disease (IBD) or infectious colitis (n=10), and colon biopsies from renal transplant patients not receiving MMF (n=8). Normal colonic segments from surgical specimens served as normal controls (n=5). Colonic biopsies from patients with MMF-related diarrhea showed prominent crypt cell apoptosis and reactive/reparative changes including enterocyte cytologic atypia, increased neuroendocrine cells, and glandular architectural distortion. The changes were similar, although of milder degree to the ones seen in patients with acute intestinal GVHD. This pattern of injury was not seen in controls or in biopsies from transplant patients not receiving MMF, and it was markedly different from the one seen in idiopathic inflammatory or infectious colitis. The severity of histologic changes correlated significantly with the endoscopic degree of "colitis." There was no statistically significant correlation between histologic damage and the dose of MMF (corrected for body weight and renal function). MMF-related colitis is a distinct entity that displays histologic features remarkably similar to the ones associated with intestinal GVHD. This form of injury could be related to either direct toxicity or an "innocent by-stander" phenomenon secondary to the alteration of the immunologic microenvironment of the colon caused by the MMF.
International Journal of Surgical Pathology 11/2003; 11(4):295-302. · 1.00 Impact Factor
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John C Papadimitriou,
Cinthia B Drachenberg,
David K Klassen,
Lillian Gaber,
Lorraine C Racusen,
Ludek Voska, Charles B Cangro,
Emilio Ramos,
Ravinder Wali,
Matthew R Weir,
Stephen T Bartlett
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ABSTRACT: Chronic rejection (CR) of pancreas allografts needs to be accurately defined and diagnosed. We propose a grading scheme designed for percutaneous needle biopsies (C0-CIII). Grading is based on the semi-quantitative determination of fibrosis and corresponding proportional loss of exocrine parenchyma. Pancreas biopsies (n = 141) from 46 patients were studied. Twenty-six patients lost graft function after a mean time of 25.5 months, whereas 20 patients retained good graft function during a mean follow-up of 67.7 months. Sequential biopsies showed gradual progression of CR over time (p = 0.0001), and good correlation was found between the CR grade and the time elapsed from transplantation (p = 0.0001). The CR grade was predictive of the remaining time of graft function (54.3 months for C0, 24.6 months for CI, 9.7 months for CII and 1.6 months for CIII p = 0.00001). Preceding episodes of acute rejection (AR) were more frequent and more severe, and often occurred late in patients with graft loss due to CR (p = 0.04). Reproducibility among pathologists from different institutions was excellent for grades C0 (Kappa 0.9) and CIII (0.87), substantial for Grade CII (0.61) and moderate for Grade CI (0.59). The proposed grading scheme provides a reliable and reproducible tool for the assessment of CR in percutaneous needle biopsies, with definite prognostic significance.
American Journal of Transplantation 06/2003; 3(5):599-605. · 6.39 Impact Factor
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Emilio Ramos,
Cinthia B Drachenberg,
John C Papadimitriou,
Omar Hamze,
Jeffrey C Fink,
David K Klassen,
Rene C Drachenberg,
Anne Wiland,
Ravinder Wali, Charles B Cangro,
Eugene Schweitzer,
Stephen T Bartlett,
Matthew R Weir
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ABSTRACT: 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.
Journal of the American Society of Nephrology 09/2002; 13(8):2145-51. · 9.66 Impact Factor
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ABSTRACT: 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.
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.
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.
Percutaneous pancreas allograft biopsy has a low rate of complication and a high success rate.
Transplantation 03/2002; 73(4):553-5. · 4.00 Impact Factor
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Emilio Ramos,
Cinthia B Drachenberg,
Miguel Portocarrero,
Ravinder Wali,
David K Klassen,
Jeffrey C Fink,
Alan Farney,
Hans Hirsch,
John C Papadimitriou, Charles B Cangro,
Matthew R Weir,
Stephen T Bartlett
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ABSTRACT: The first case of BK virus allograft nephropathy at the University of Maryland Renal Transplant Program was diagnosed in 1997. Since then more than 100 cases have been identified. The incidence of BKAN has increased from 1% for patients transplanted in 1997 to 5.8% for patients transplanted in 2001. BKAN is an important cause of premature kidney graft loss at the University of Maryland Transplant Program. One-third of the patients diagnosed with BKAN since 1997 have already lost graft function, and a third of the remaining patients have creatinine levels over 3 mg/dl. We could not determine that a specific immunosuppressive drug increased the incidence of BKAN. Older patients had an increased risk of developing the disease. The histological diagnosis of BKAN was made at a mean time of 14.4 months after transplantation (range 1.2-53 months). BKAN occurred in 4.3% of all patients biopsied during the period described. The diagnosis of BK allograft nephropathy was based on a combination of renal biopsy to demonstrate viral cytopathic chages, urine cytology and quantitative viral load in plasma. A threshold of >10,000 copies of BK virus per ml of plasma is proposed as an indication of BKAN. Following diagnosis of BKAN, patients on a single immunosuppressve drug (FK506, CsA, sirolimus or MMF) in addition to prednisone had less graft loss and higher viral clearance in comparison to patients on prednisone and 2 immunosuppressant drugs (FK506, CsA or sirolimus and MMF). There was no difference in the rate of acute allograft rejection among different immunosuppression reduction protocols. Three patients who lost their grafts to BKAN were retransplanted. For these patients there has not yet been evidence of recurrence of BKAN. After reduction of immunosuppression, the course of BKAN in most patients followed one of 2 pathways: 1) Clearance of the infection and disappearance of the viral cytopathic changes in biopsies and urine (20%); 2)Persistence of viral replication with continuous associated tubular damage (70%). Renal transplant patients should be routinely screened with urine cytology. The presence of decoy cells in the urine is an indication for quantitative measurement of viral load in plasma. Patients with any evidence of BK viral reactivation should be followed closely. In patients biopsied early due to persistence of BK virus-infected cells in urine, there is a higher rate of conversion from positive to negative urine cytology after reduction of immunosuppression.
Clinical transplants 02/2002;
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Rene C. Drachenberg,
Cinthia B. Drachenberg,
John C. Papadimitriou,
Emilio Ramos,
Jeffrey C. Fink,
Rawinder Wali,
Matthew R. Weir, Charles B. Cangro,
David K. Klassen,
Amr Khaled,
Rochelle Cunningham,
Stephen T. Bartlett
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ABSTRACT: 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.
American Journal of Transplantation 10/2001; 1(4):373 - 381. · 6.39 Impact Factor
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American Journal of Transplantation 02/2001; 1 Suppl 2:3-95. · 6.39 Impact Factor
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ABSTRACT: 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.
American Journal of Nephrology 24(4):379-86. · 2.54 Impact Factor
