Pradeep V. Kadambi

Treatment of renal allograft polyoma BK virus infection with leflunomide.

Background. Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals. Methods. We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 &mgr;g/ml to 100 &mgr;g/ml (150 &mgr;M to 300 &mgr;M). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy. Results. In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 &mgr;g/ml did not clear the virus until these levels were attained or cidofovir was added. Conclusions. Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Treatment of Refractory BK Virus‐Associated Nephropathy With Cidofovir

BK virus‐associated nephropathy (BKVN) has become recognized as an important cause of allograft dysfunction in renal transplant recipients and despite reduction in immunosuppression, 30–40% of recipients ultimately progress to allograft loss. Cidofovir is an antiviral agent that demonstrates in vitro activity against murine polyomavirus and has been proposed for treatment of BKVN in renal allograft recipients. We describe the clinical course, renal function, serial renal histology and urine and blood viral load measurements in two consecutive patients with refractory BKVN who were treated with low‐dose cidofovir (0.25 mg/kg IV). In each case, renal dysfunction and BK viral load progressed despite reduced immunosuppression, and persistent BK virus infection was documented in serial renal allograft biopsy specimens. Administration of low‐dose cidofovir was associated with clearance of BK virus DNA from blood and allograft, and stabilization of renal function in both patients, without significant toxicity. These preliminary data suggest that low‐dose cidofovir may be tolerated, even among renal transplant recipients with significant renal dysfunction due to BKVN. Prospective, controlled trials are warranted to further define the optimal dose, toxicity and potential role of cidofovir in renal transplant recipients with BK virus nephropathy.

Implications of Immunohistochemical Detection of C4d along Peritubular Capillaries in Late Acute Renal Allograft Rejection

Background. Immunohistochemical detection of the C4d complement product along peritubular capillaries (PC) may indicate humoral rejection of renal allografts. We examined the frequency of PC C4d expression in renal-allograft biopsies with acute rejection (AR) arising more than 6 months after transplantation and the impact of this finding. Methods. C4d was detected by immunoperoxidase in 2-micron paraffin sections of consecutive biopsies obtained over a 3-year period. The extent was classified as diffuse (≥50% PC C4d+), focal (<50% C4d+), and negative (C4d−). Clinical data were obtained by retrospective chart review. Fifty-five AR episodes with Banff 97 types 1A (n=13), 1B (n=26), 2A (n=11), 2B (n=3), and 3 (n=2) met inclusion criteria. Results. PC C4d expression was diffuse in 23 (42%), focal in 9 (16%), and negative in 23 (42%) biopsies. AR episodes with focal and diffuse C4d expression had higher proportionate elevation of serum creatinine at biopsy and 4 weeks after diagnosis (P≤0.05). Biopsies with diffuse PC C4d had interstitial hemorrhage (56.5%) and plasmacytic infiltrates (52%) more frequently than C4d− biopsies (22% and 16%), P=0.02, but had no other distinctive histologic features. Graft loss was greater in diffuse (65%) compared with focal C4d+ (33%) and C4d− (33%) groups 1 year after diagnosis, P=0.03. Other clinical and pathologic parameters did not differ significantly, including treatment received for AR. Conclusion. Evidence of acute cellular with occult humoral rejection is identified in more than 40% of late AR episodes. Late acute humoral rejection may be associated with interstitial hemorrhage and plasma cells and contributes significantly to graft loss.

Thrombotic Microangiopathy and Peritubular Capillary C4d Expression in Renal Allograft Biopsies

BACKGROUND AND OBJECTIVES This study characterizes the pathologic and clinical relationships of thrombotic microangiopathy (TMA) to antibody-mediated rejection (AMR) in renal allograft biopsies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Consecutive renal allograft biopsies, routinely stained for C4d over a period of 51 months (n=1101), were reviewed. For comparative analysis of histology and clinical features, additional patients with TMA and peritubular capillary (PTC) C4d (n=5) were combined with those identified in the 51-month period of review (n=6). RESULTS One hundred eighty-two of 1073 adequate biopsies from 563 allografts had PTC C4d in the study period. Six of 37 biopsies with TMA had PTC C4d (five at ≤90 days and one at 213 days). Early (≤90 days) C4d+ biopsies (n=5) had more frequent TMA (11.9% C4d+ versus 3.4% C4d-; odds ratio, 3.84; P=0.03). Graft loss was significantly greater in an early C4d+TMA+ group (n=5 study+2 archival patients) than in C4d+ controls without TMA (n=21) (57% versus 9.5%; P=0.02). Early TMA+C4d+ biopsies had more severe glomerulopathy and less severe arteriolopathy than TMA+C4d- and had more frequent neutrophilic capillaritis than TMA-C4d+ biopsies. CONCLUSIONS TMA was infrequent in this series of unselected, consecutive, renal allograft biopsies (3.4%). PTC C4d may be a significant risk factor for early TMA, and TMA is associated with glomerular thrombi and neutrophilic capillaritis. TMA in allografts with suspected AMR may portend a higher risk of graft loss.

Changing Attitudes Toward Influenza Vaccination in U.S. Kidney Transplant Programs Over the Past Decade

BACKGROUND AND OBJECTIVES Influenza infection in transplant recipients is often associated with significant morbidity. Surveys were conducted in 1999 and 2009 to find out if the influenza vaccination practices in the U.S. transplant programs had changed over the past 10 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In 1999, a survey of the 217 United Network for Organ Sharing-certified kidney and kidney-pancreas transplant centers in the U.S. was conducted regarding their influenza vaccination practice patterns. A decade later, a second similar survey of 239 transplant programs was carried out. RESULTS The 2009 respondents, compared with 1999, were more likely to recommend vaccination for kidney (94.5% versus 84.4%, P = 0.02) and kidney-pancreas recipients (76.8% versus 48.5%, P < 0.001), family members of transplant recipients (52.5% versus 21.0%, P < 0.001), and medical staff caring for transplant patients (79.6% versus 40.7%, P < 0.001). Physicians and other members of the transplant team were more likely to have been vaccinated in 2009 compared with 1999 (84.2% versus 62.3% of physicians, P < 0.001 and 91.2% versus 50.3% of nonphysicians, P < 0.001). CONCLUSIONS Our study suggests a greater adoption of the Centers for Disease Control and Prevention influenza vaccination guidelines by U.S. transplant programs in vaccinating solid-organ transplant recipients, close family contacts, and healthcare workers.

Pauci-immune and Immune Glomerular Lesions in Kidney Transplants for Systemic Lupus Erythematosus

BACKGROUND AND OBJECTIVES Glomerular lesions in allografts in recipients with end-stage nephritis resulting from systemic lupus erythematosus (SLE) were examined to determine the spectrum of glomerular pathology in recurrent glomerulonephritis (GN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 156 biopsy samples, from 49 serial allografts in 43 recipients with end-stage lupus nephritis, were examined by light microscopy, and by immunofluorescence and electron microscopy in selected cases. These were compared with control allografts (n = 35). RESULTS Glomerular lesions best explained by recurrent lupus nephritis were observed in 19 of 49 allografts (38.8%) in lupus recipients. Three categories of glomerulopathies were identified: 1) immune complex glomerulopathies, including mesangial GN (28%) and membranous GN (4%); 2) atypical glomerulopathies, including acute proliferative GN (32%) and focal segmental glomerulosclerosis (12%), with scant immune deposits in glomerular capillaries, frequent endothelial tubuloreticular inclusions, and thrombotic microangiopathy; and 3) transplant-associated glomerulopathies (24%). CONCLUSIONS Allografts from recipients with SLE had typical immune complex-mediated GN and atypical pauci-immune, proliferative GN and segmental glomerular sclerosis. Atypical glomerulopathies like these suggest a role for nonimmune complex-mediated glomerular injury in recurrent lupus GN.

Use of Leflunomide in Renal Transplant Recipients with Ganciclovir-Resistant/Refractory Cytomegalovirus Infection: A Case Series from the University of Chicago

Introduction: Although antiviral prophylaxis for cytomegalovirus (CMV) is widely used, CMV infection remains common in renal transplant recipients with adverse consequences. Methods: We report 5 cases of renal transplant recipients with resistant CMV infection who were successfully managed with leflunomide at the University of Chicago Medical Center. Results: Five renal transplant recipients (2 simultaneous pancreas/kidney transplants, 3 deceased donor kidney transplants) were diagnosed with GCV-resistant CMV infection from 2003 to 2011. Of the 4 patients who had resistance genotype testing, 3 showed a UL97 mutation and 1 patient had a clinically resistant CMV infection. All patients received CMV prophylaxis with valganciclovir for 3 months. The number of days from the date of transplant to viremia ranged from 38 to 458 days (median 219). All 5 patients received other antiviral agents (e.g. ganciclovir, foscarnet), and in 4 patients, viremia was cleared before leflunomide was initiated as consolidation (or maintenance) therapy. Conclusion: Leflunomide was well tolerated and successful in preventing recurrence of viremia in renal transplant recipients with resistant CMV infection. The beneficial effect of leflunomide in this setting warrants further investigation.

Reuse of a previously transplanted kidney: does success come with a price?

Longer wait times for deceased donor kidney transplant have prompted newer initiatives to expedite the process. Reuse of a previously transplanted kidney might be appropriate in certain circumstances. However, one must also consider the unique issues that may arise after such transplants. We describe our experience in one such case where the donor kidney had lesions of focal and segmental glomerulosclerosis and signs of alloreactivity (positive C4d staining) prior to transplantation and the recipient developed ganciclovir-resistant cytomegalovirus (CMV) infection, which was perhaps transmitted from the donor. Despite the challenges, the allograft function remained stable 5 years after reuse.

Epidemiology of Glomerular Disease in Southern Arizona: Review of 10-Year Renal Biopsy Data

AbstractGlomerulonephritis stands third in terms of the etiologies for end-stage kidney disease in the USA. The aim of this study was to look at the patterns of biopsy-proven glomerulonephritis based on data from a single center.Kidney biopsy specimens of all patients above the age of 18 years, over a 10-year period, who had diagnosis of nondiabetic glomerular disease, were selected for the study.The most common histopathological diagnosis was focal and segmental glomerulosclerosis (FSGS) (22.25%, 158/710) followed by membranous nephropathy (20.28%, 144/710) and immunoglobulin (Ig)A nephropathy (19.71%, 140/710). There was male preponderance in all histological variants except IgA nephropathy, lupus nephritis, and pauci-immune glomerulonephritis. The race distribution was uneven, and all histological variants, except minimal change disease and lupus nephritis, were more commonly seen in whites. In a separate analysis of the histological pattern in Hispanics, lupus nephritis was the most common pathology (28.70%, 62/216) followed by FSGS (18.05%, 39/216). In American Indian population, the most common pathology was IgA nephropathy (33.33%, 8/24) followed by FSGS (16.67%, 4/24).This study highlights the histopathological patterns of glomerular disease in southern Arizona. The data suggest regional and ethnic variations in glomerular disease that may point towards genetic or environmental influence in the pathogenesis of glomerular diseases.

Intragraft vascular occlusive sickle crisis with early renal allograft loss in occult sickle cell trait

Early renal allograft failure due to sickle cell trait is rare. We present clinical and pathologic findings in 2 cases of early renal allograft failure associated with renal vein thrombosis and extensive erythrocyte sickling. Hemoglobin AS was identified in retrospect. In case 1, a 41-year-old female recipient of a deceased donor renal transplant developed abdominal pain and acute allograft failure on day 16, necessitating immediate nephrectomy. In case 2, the transplanted kidney in a 58-year-old female recipient was noted to be mottled blue within minutes of reperfusion. At 24 hours, the patient was oliguric; and the graft was removed. Transplant nephrectomies had diffuse enlargement with diffuse, nonhemorrhagic, cortical, and medullary necrosis. Extensive sickle vascular occlusion was evident in renal vein branches; interlobar, interlobular, and arcuate veins; vasa recta; and peritubular capillaries. The renal arteries had sickle vascular occlusion in case 1. Glomeruli had only focal sickle vascular occlusion. The erythrocytes in sickle vascular occlusion had abundant cytoplasmic filaments by electron microscopy. Acute rejection was not identified in either case. Protein C and S levels, factor V Leiden, and lupus anticoagulant assays were within normal limits. Hemoglobin analysis revealed hemoglobin S of 21.8% and 25.6%, respectively. Renal allograft necrosis with intragraft sickle crisis, characterized by extensive vascular occlusive erythrocyte sickling and prominent renal vein thrombosis, was observed in 2 patients with sickle cell trait. Occult sickle cell trait may be a risk factor for early renal allograft loss.