Variability in assessing for BK viremia: whole blood is not reliable and plasma is not above reproach - a retrospective analysis.

Polyomavirus nephropathy (PVN) is a major complication of kidney transplantation. Most reports describe polyomavirus viremia either precedes or is detectable at the time of diagnosis of PVN. This association is the basis of current screening recommendations. We retrospectively reviewed the PCR results of blood and urine samples from 29 kidney transplant recipients with biopsy-proven PVN. Biopsies were performed for a rise in serum creatinine or persistent high-level BK viruria. All biopsies showed polyoma virus large T-antigen expression in tubular epithelium using immunohistochemistry. All had viruria preceding or at the time of biopsy (range, 5.2 × 104 to >25 × 106 BKV DNA copies/ml). Twenty (69%) had viremia ranging from 2.5 × 103 to 4.3 × 106 copies/ml at the time of the biopsy. Via blood BK PCR assay, nine (31%) had no BK viremia detected either preceding or at the time of the biopsy. In five recipients where sufficient specimen permitted, additional plasma BK assessment revealed positive detection of viremia. A comparative analysis of assays from two centres was performed with spiked samples. BK DNA may not be detected in the blood of some kidney transplant recipients with histologically confirmed PVN. This may reflect limitation of whole blood as opposed to plasma-based BK DNA assessment.

A New Reality for Multiple Myeloma Renal Failure: US Data Report on Kidney Transplant Outcomes.

INTRODUCTION: Describe graft and overall survival outcomes in multiple myeloma (MM) patients who underwent kidney transplant (KT) compared to the general KT population. PATIENTS AND METHODS: The Organ Procurement and Transplantation Network/National United Network for Organ Sharing (OPTON/UNOS) database was analyzed from 1988 to 2019 with R 4.00 and the 2013-2017 United States Renal Data System (USRDS) was surveyed for incidence and mortality of MM ESRD. RESULTS: USRDS analysis revealed 961 patients diagnosed with ESRD due to MM on average annually, accounting for 0.8% of the ESRD population. Without KT, 44.4% of MM patients died in the first year of renal replacement initiation. OPTON/UNOS analysis identified 218 MM KT patients, compared to 490,089 patients without MM. There was no difference in graft survival between MM KT and the general population (P-value = .13, HR = 1.19 [0.95, 1.49], 95% CI). Median graft survival in MM KT was 2683 days (7.4 years). KT patients with MM had a higher risk for death (P-value = <.0001, HR = 1.83 [1.41, 2.37], 95% CI), and median overall survival was 3076 days (8.4 years). Survival difference was lost when comparing patients ≥50 years (P-value = .42, HR = 1.14 [0.83, 1.56], 95% CI). CONCLUSION: Patients with MM renal failure who underwent KT had equivalent graft and age-matched overall survival compared to the general KT population. Therefore select patients with MM renal failure have potential for excellent KT outcomes, should be considered for transplantation when feasible, and should not be excluded from KT based on a history of MM.

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 microg/ml to 100 microg/ml (150 microM to 300 microM). 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 microg/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.

Pre-empting Antibody-Mediated Rejection: A Program of DSA Monitoring and Treatment Can Effectively Prevent Antibody Mediated Rejection.

Antibody-mediated rejection (AMR) remains a problem without a reliable treatment in the care of kidney transplant patients. We proposed and tested a program of screening for donor specific antibodies (DSA) to initiate treatment of patients before AMR was detected and to prevent its occurrence. Starting in April 2012, we stratified patients into high-, medium-, and low-risk groups for the development of DSA and instituted a program of screening for and treatment of these antibodies. We used a historic control group of patients transplanted at our center as a comparator and looked at rates of DSA testing and development as well as rates of development of AMR, cell-mediated rejection, and graft loss. 614 patients were transplanted under the protocol compared with 266 patients in the control group. Length of follow-up was similar in both groups. The group undergoing DSA screening had lower rates of DSA development (17.6% versus 24.8%, p=0.016) and that DSA was found at a significantly earlier time post-transplant (147 versus 248 days, p=0.02). Incidence of AMR was dramatically lower in the screened group (1.3% versus 8.6%, p<0.0001) with no grafts lost due to AMR. AMR was found to occur at an average of 181 days post-transplant. Rates of acute cellular rejection did not decrease in a manner similar to AMR rates. In conclusion, a program of universal risk-stratified DSA testing in kidney transplant patients can dramatically reduce rates of AMR and virtually eliminate graft loss due to AMR.

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 (> or =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< or =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.

Polyoma virus infection of renal allografts: relationships of the distribution of viral infection, tubulointerstitial inflammation, and fibrosis suggesting viral interstitial nephritis in untreated disease.

Whether polyoma virus (PV) infection of renal allografts induces an antiviral or antigraft immune reaction is unclear. By examination of the relationships of tubular PV to graft inflammation and scarring, this study sought histological evidence of viral interstitial nephritis in allograft biopsies with untreated PV infection and compared the inflammatory indices to controls with acute rejection (AR). Morphological features including viral cytopathic changes (VCCs) and modified Banff 97 histological indices were evaluated in sections of 28 diagnostic biopsies from a group of patients receiving prednisone, tacrolimus, and mycophenolate mofetil at constant dosage before biopsy. Two-micrometer paraffin sections were stained for PV large T antigen (TAg) and for C4d, by immunohistochemistry. Tubular profiles with 1 or more nuclei expressing TAg per x200 field were scored using an interval scale (0-10; none to 91-100%) by 2 observers. Controls with AR (n = 38, TAg negative) were matched for time after transplantation and severity of Banff 97 interstitial inflammation (i) and tubulitis (t) scores. Median t scores for tubules with VCC or TAg or both exceeded scores for tubules without VCC or TAg (3 versus 0, P = .001). Tubular TAg score correlated with i score (r = 0.58, P < .01) and sum ct + ci score (r = 0.61, P < .001). Atrophic tubules in scars had persistent VCC and/or TAg. Interstitial plasma cells (75% versus 21%) and neutrophils (32% versus 0%) were more frequent, and interstitial fibrosis was more severe (ci >1 in 54% versus 21%) in polyoma virus nephropathy (PVN) than in the group with AR (P < .01). Intimal arteritis (0% versus 35.7%), peritubular capillary C4d (0% versus 47.4%), and interstitial hemorrhage (4% versus 37%) were almost exclusively found in AR (P < .01). Tubular inflammation in untreated PVN involves infected tubular profiles with greater severity than those without evidence of infection. The extent of tubular PV infection is proportional to interstitial inflammation and scarring. Tubulointerstitial inflammation in PV infection has significant qualitative differences from AR. Observations in these examples of untreated PVN suggest that the allograft inflammatory reaction may exhibit features of viral tubulointerstitial nephritis distinct from AR.

Treatment of de novo and recurrent membranous nephropathy in renal transplant patients.

Membranous nephropathy (MN) is one of the common glomerular diseases diagnosed in transplanted kidneys. The exact impact of posttransplantation MN on the risk for graft loss and long-term graft outcome is not defined clearly. In recent reports, it has emerged as the third most frequent glomerulonephritis (de novo or recurrent) associated with renal allograft loss. Most cases of posttransplantation MN are thought to be idiopathic but cases associated with established secondary causes also have been reported. Patients can present with varying degrees of proteinuria and graft dysfunction. Risk factors that predict a poor outcome are not well established and unlike MN in the native kidneys, spontaneous remission is rare. Patients should be evaluated carefully for complications associated with nephrotic syndrome or graft dysfunction and managed accordingly. The beneficial effects of steroids, cyclosporine, mycophenolate mofetil, cyclophosphamide, chlorambucil, or other agents have not been validated. The role of specific treatments in cases of secondary MN is uncertain. Retransplantation is a reasonable option for patients who develop graft failure secondary to MN.

Cardiovascular diseases in kidney transplant recipients: the role of anemia.

Cardiovascular diseases are among the leading causes of mortality and death associated graft loss in kidney transplant recipients. Recently, there has been an increased awareness of the potential role of nontraditional risk factors such as anemia in contributing to the increased burden of cardiovascular diseases in kidney transplant recipients. Studies that are primarily based on retrospective data analyses have shown an association between anemia and cardiovascular outcomes. These findings underscore the need for prospective studies to better understand these risks and to implement management strategies that would have a positive impact on patient and graft outcomes. On the basis of the available data, this article reviews the magnitude of cardiovascular diseases and anemia in kidney transplant recipients with a focus on the role of anemia on cardiovascular outcomes in these patients.

BK polyomavirus infection in the renal transplant recipient.

Renal transplant recipients continue to have progressive kidney dysfunction and renal graft loss has been attributed to emerging opportunistic infections, specifically BK virus (BKV). BKV is postulated to be selected by the new potent immunosuppressive medications and to be an important factor in graft failure. The prevalence of BKV nephropathy (BKVN) is estimated to be 1% to 10% and renal allograft loss from BKVN has been estimated to occur in up to 50% of affected recipients. With the increasing recognition of BKV infection using PCR assays coupled with the immediate reduction in immunosuppression for BKVN, the incidence of graft failure secondary to BKVN may be decreasing.

Kidney transplant chains amplify benefit of nondirected donors.

IMPORTANCE: Despite the potential for altruistic nondirected donors (NDDs) to trigger multiple transplants through nonsimultaneous transplant chains, concerns exist that these chains siphon NDDs from the deceased donor wait list and that donors within chains might not donate after their partner receives a transplant. OBJECTIVE: To determine the number of transplantations NDDs trigger through chains. DESIGN: Retrospective review of large, multicenter living donor-recipient database. SETTING: Fifty-seven US transplant centers contributing donor-recipient pairs to the database. PARTICIPANTS: The NDDs initiating chain transplantation. MAIN OUTCOMES MEASURE: Number of transplants per NDD. RESULTS: Seventy-seven NDDs enabled 373 transplantations during 46 months starting February 2008. Mean chain length initiated by NDDs was 4.8 transplants (median, 3; range, 1-30). The 40 blood type O NDDs triggered a mean chain length of 6.0 (median, 4; range, 2-30). During the interval, 66 of 77 chains were closed to the wait list, 4 of 77 were ongoing, and 7 of 77 were broken because bridge donors became unavailable. No chains were broken in the last 15 months, and every recipient whose incompatible donor donated received a kidney. One hundred thirty-three blood type O recipients were transplanted. CONCLUSION AND RELEVANCE: This large series demonstrates that NDDs trigger almost 5 transplants on average, more if the NDD is blood type O. There were more blood type O recipients than blood type O NDDs participating. The benefits of transplanting 373 patients and enabling others without living donors to advance outweigh the risk of broken chains that is decreasing with experience. Even 66 patients on the wait list without living donors underwent transplantation with living-donor grafts at the end of these chains.

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.

The outcome of renal transplantation among systemic lupus erythematosus patients.

BACKGROUND: Clinical outcome of renal transplantation among systemic lupus erythematosus (SLE) patients remains a topic of controversy. Most of the previous reports were based upon small single-centre studies that were not always well-designed. METHODS: We conducted the retrospective analysis using data from USRDS and UNOS databases. Patients were divided into five groups based on the cause of end-stage renal disease (ESRD): diabetes mellitus (DM), SLE, glomerulonephritis, hypertension and other causes. Between 1990 and 1999, 2886 renal transplantation recipients with ESRD due to SLE were identified from a total of 92 844 patients. RESULTS: The mean follow-up period of this study was 4.7 +/- 2.4 years. While unadjusted analysis using Kaplan-Meier curves demonstrated an association between SLE and improved allograft survival compared with DM, in multivariate analysis the SLE group had worse allograft [hazard ratio (HR) 1.09, P < 0.05] and recipient (HR 1.19, P < 0.05) survival compared with the DM group. Subgroup analysis based on the type of donor showed that SLE patients who received deceased donor allograft had worse allograft and recipient survival (HR 1.14, P = 0.002 and HR 1.30, P = 0.001, respectively) compared with non-SLE deceased donor allograft recipients. Among living allograft recipients, there were no significant differences in either allograft or recipient survival compared with non-SLE recipients. CONCLUSIONS: SLE as a cause of ESRD in renal transplant recipients is associated with worse allograft and recipient survival compared with DM; this association is true for the entire population and for the recipients of deceased donor (but not living donor) transplant. Deceased donor allograft recipients have worse outcomes compared with living allograft recipients.

Treatment of glomerulonephritis: will we ever have options other than steroids and cytotoxics?

Glomerulonephritis refers to a collection of primary renal disorders and those secondary to a systemic disease, all characterized by inflammation within the glomerulus. Given the underlying immunologic nature of these disorders, they are routinely treated with corticosteriods and various cytotoxic agents. Although in many instances such therapies are successful, they are associated with significant morbidity; as such, alternatives are clearly necessary. Our understanding of the pathogenesis of immunologic glomerular diseases has grown remarkably, in large part from the study of rodent disease models. Fundamental to each disorder is the development of an antigen-specific immune response followed by the effector stage of inflammation. To block the immune response, antigen-specific therapy can be used to induce tolerance, such as through the use of double-stranded DNA molecules in lupus nephritis. Since other antigen systems are less well characterized, inducing a more generalized impairment in the immune response by blocking costimulatory molecules CD40-CD154 and CD28-CD80/86 is a growing approach to treat various immunologic disorders and transplantation. To reduce glomerular inflammation, a variety of effector systems have been targeted, including complement, cytokines/chemokines, adhesion molecules, and mediators of cellular proliferation. Of these, antibodies targeting C5 in the complement system, and antibody and receptor antagonists of tumor necrosis factor-alpha (TNF-alpha) have already been used in glomerular disorders with some promise. Less specific blockade of receptor-mediated events stimulated by platelet-derived growth factors and cell cycle proteins may soon be applied to glomerulonephritis. Finally, interruption of fibrosing pathways, which lead to glomerulosclerosis and interstitial fibrosis common to the end-stage of all glomerulonephritis, is the subject of intense effort which may yield effective biologic therapies. In spite of all these advances, we still are dependent on steroids and cytotoxics to treat glomerulonephritis. To get past this, we must devote significant resources to take observations made in basic research laboratories to develop therapeutics and prove their utility in human disease.

Glomerular injury and tubular loss in adriamycin nephrosis.

Glomerular injury manifested by sustained proteinuria usually leads to tubule injury and reduction of the GFR. The current study explored the link between these processes in rats with adriamycin nephrosis. One group of nephrotic rats received a vasopressin V2 receptor blocker (V2X) from 4 to 16 wk after injection of adriamycin, whereas a second group received no treatment (NoRx). V2 receptor blockade increased urine volume without affecting protein excretion. At 16 wk, both groups of nephrotic rats exhibited a marked reduction in GFR in comparison with normal controls (V2X, 0.22 +/- 0.19 ml/min; NoRx, 0.20 +/- 0.11 ml/min; control, 1.23 +/- 0.11 ml/min). Morphologic studies revealed that the majority of glomeruli in nephrotic rats were no longer connected to normal tubule segments (V2X, 81 +/- 21%; NoRx, 85 +/- 18%; control, 1 +/- 2%). Glomeruli without tubules were not, however, globally sclerosed. Disruption of the glomerular tubular junction was associated with the presence of amorphous material separating damaged tubule cells from the basement membrane. Serial sections revealed that this material spread from extensive areas of adhesion between the glomerular tuft and capsule to invest the tubular neck. Reduction of the GFR was strongly correlated with the fraction of glomeruli not connected to normal tubules (r(2) = 0.82; P < 0.0001). V2 receptor blockade did not preserve renal function or structure. These findings suggest that local extension of glomerular injury to destroy the tubule neck is an important cause of loss of renal function in adriamycin nephrosis.