Cause Of Renal Allograft Dysfunction Research Articles

Acute diffuse proliferative post‐infectious glomerulonephritis in renal allograft – A case report and literature review

PVN is a well-known cause of renal allograft dysfunction and failure. The diagnosis is established by examination of tissue from the renal graft, and confirmed by immunohistochemical or in situ hybridization techniques. Electron microscopy can be utilized as an ancillary modality to identify the viral particles ultrastructurally. The tubular epithelial cells are the primary target of PV cytopathic effect; however, PV-associated glomerular changes have also been described. Immune-type electron-dense deposits in the TBMs have been described in the setting of PVN, and rarely, likewise have glomerular subepithelial hump-like deposits. Diffuse immune-mediated proliferative glomerulonephritis in the setting of PVN has not been reported before. In this report, we describe an 11-yr-old kidney transplant recipient boy who developed immune-mediated glomerulonephritis with light microscopic, immunofluorescence, and ultrastructural features compatible with acute PIGN superimposing chronic PVN, discuss this unusual association and the possible mechanisms of antigen clearance in PVN and present a literature review.

BK polyoma virus nephropathy in the native kidney

While BK polyoma virus nephropathy (PVN) is a well-recognized cause of renal allograft dysfunction, PVN of native kidneys is likely under-recognized. We present the pathologic features, risk factors and outcomes of eight cases of PVN in native kidneys. The cohort included eight males aged 16-73 years (mean 47.4) with an immunocompromised state (mean duration 3.15 years) attributable to: hematologic malignancies (n = 6), for which three had undergone bone marrow transplant; lung transplant (n = 1) and combined tuberculosis and diabetes (n = 1). Seven patients were receiving specific immunosuppressive therapies. Patients were biopsied for acute kidney injury (AKI) with rise in mean creatinine levels from baseline 1.6 to 2.8 mg/dL. Pathology showed BK PVN with characteristic intranuclear inclusions staining positive for SV40 T antigen and negative for JC virus (JCV), with positive serum and/or urine PCR for BK virus. One patient had focal medullary JCV co-infection. Two patients also had renal infiltration by chronic lymphocytic leukemia (CLL). Six patients received specific therapy directed to PVN (cidofovir or leflunomide). Follow-up ranged from 2 to 20 (mean 10) months. Despite marked decrease in serum BK viral copy numbers, creatinine continued to rise in six cases (mean 3.7 mg/dL in four, requiring dialysis in two) and three patients died of malignancy, opportunistic infection or renal failure. Advanced histologic stage of PVN, ineffective antiviral therapy, co-morbidities and persistent immunocompromised state likely contributed to the poor outcomes. A high level of suspicion in immunocompromised patients is needed to diagnose PVN in an early stage that may respond more favorably to antiviral therapy.

Polyomavirus nephropathy – recent pathological diagnostic problems and the report from the 2011 Banff meeting

Polyomavirus nephropathy (PVN) is a cause of renal allograft dysfunction. Early detection of pathological abnormalities is not easy even in cases with urine decoy cells or polyomavirus viremia. A pathological classification for PVN was proposed by the Banff PVN working group, although the availability of the proposed schema has not been extensively evaluated in the clinical field. At the Banff meeting in 2011, the PVN working group reported the results of the evaluation on interobserver reproducibility and a clinicopathological study of PVN stages and renal outcome. Fair or good reproducibility was noted, although the PVN classification required further modification.

Polyomavirus-Associated Nephropathy

Polyomavirus-associated nephropathy (PVAN) is an increasing cause of renal allograft dysfunction, but the optimal management of immunosuppression for these patients is unclear. We examined the clinical course of 58 patients with biopsy-proven PVAN diagnosed from 1997 to 2008 at Johns Hopkins Medical Institutions. Immunosuppression management was analyzed as 2 different immunosuppression reduction strategies, the first centered on eliminating a single immunosuppressive drug and reducing the doses of all other immunosuppressive drugs (Strategy A, n = 40), compared with the second, centered on reducing the doses of all immunosuppressive drugs and eliminating none (Strategy B, n = 18). Primary outcome was graft failure, defined as a 50% reduction in estimated glomerular filtration rate, or the need for dialysis within 2 years of PVAN diagnosis. Graft failure developed in 17 (29%) patients during follow-up. In unadjusted and adjusted Cox models, both strategies of immunosuppression reduction had similar efficacy in preventing graft failure (hazard ratio [HR], 0.61; 95% confidence interval, 0.18-2.06; p = 0.43). Rejection after PVAN occurred in 24 of 58 patients and was associated with a 3-fold higher risk of graft failure (HR, 2.99; p = 0.005). Ancillary therapies (cidofovir or leflunomide) were associated with a trend toward faster clearance of viremia (p = 0.65) but were not predictive of outcome.In conclusion, the 2 strategies of immunosuppression reduction had similar efficacy in preventing graft failure. Post-PVAN rejection leads to graft failure. Early repeat allograft biopsy should be considered in the management of PVAN with persistent graft dysfunction.

Transcriptional Profiles in Urine During Acute Rejection, Bacteriuria, CMV Infection and Stable Graft Function After Renal Transplantation

Acute rejection remains an important cause of renal allograft dysfunction and the need for accurate diagnosis is essential to treat transplant recipients successfully. Molecular markers in urine may serve as a diagnostic tool in acute rejection, but controversy still exists regarding the uniqueness of these biomarkers. We measured mRNA of perforin (PRF), granzyme B (GZMB) and granulysin (GNLY) normalized to cyclophilin B in urine specimens from 24 renal allograft recipients with acute rejection, 12 with bacteriuria, 11 with cytomegalovirus (CMV) infections and 17 controls with stable graft function. Measurements were performed using a real-time polymerase chain reaction assay. mRNA levels (means [95% CI]) for all three markers were significantly higher in recipients with acute rejection compared with controls: PRF (0.23 [0.12-0.42] versus 0.04 [0.02-0.07] P<0.001), GZMB (0.14 [0.09-0.23] versus 0.05 [0.03-0.08] P=0.003), GNLY (0.24 [0.14-0.41] versus 0.06 [0.03-0.11] P=0.001). GZMB and GNLY levels during acute rejection were significantly higher when compared with bacteriuria (P=0.011 and P=0.005 respectively), and PRF level during acute rejection was significantly elevated compared with CMV infection (P=0.015). No significant difference was found when comparing marker levels during bacteriuria and CMV infection to controls. Urinary mRNA levels of PRF, GZMB and GNLY are significantly elevated during acute rejection but not during bacteriuria or CMV infections when compared with recipients with stable graft function. The ability to differentiate acute rejection from bacteriuria and CMV infections was only present for some of the markers, that is why careful consideration should be given before applying this technique to clinical practice.

BK virus nephropathy in the native kidneys of a pediatric heart transplant recipient

BK virus is a human polyoma virus that may cause nephropathy in immunosuppressed patients. It is a well-recognized cause of renal allograft dysfunction and allograft loss in renal transplant recipients, but it is an infrequent cause of nephropathy outside this setting. There are a few case reports of BK virus nephropathy in the native kidneys of immunosuppressed adult patients with non-renal transplants, but so far it has not been reported in pediatric non-renal solid organ transplant recipients. We report a case of a seven-yr-old heart transplant patient who was diagnosed with BK virus nephropathy, eight months after his second heart transplant. Despite intervention, his renal dysfunction progressed to renal failure. He is currently receiving maintenance hemodialysis and awaiting renal transplantation. It is important to recognize BK virus infection as a possible cause of renal dysfunction in immunosuppressed children who are non-renal transplant recipients.

Diagnostic efficacy of C4d immunostaining in the detection of the humoral component of renal allograft rejection and therapeutic implications

In the current scenario of renal transplantation, the role of immunological methods in the detection of C4d has emerged as a useful adjunct in the recognition of acute humoral rejection (AHR). Few reports of this nature are available from the Indian context although there are several from the Western literature. To study the humoral component of renal allograft rejection in patients presenting clinically with graft dysfunction by histopathological detection of polymorphs in the peritubular capillaries and the expression of C4d using immunological techniques, as well as the response of patients to appropriate antirejection therapy. This study from a tertiary care center reemphasizes the importance of recognition of AHR as a cause of renal allograft dysfunction. Percutaneous renal biopsies were obtained from 40 postrenal transplant patients and evaluated for C4d using immunofluorescence and immunohistochemical methods. SPSS software. Positive expression of C4d was seen in a total of 19/40 cases (44.4%) indicating immunological evidence of AHR. Diffusely positive cases were treated with IV immunoglobulin therapy, plasmapheresis and Rituximab following which graft function was restored. Patients with minimal to focal positive expression of C4d responded well to pulse steroids and change in immunosuppressive therapy. C4d staining is a useful adjunct to routine histopathological methods in evaluating the humoral component of acute renal allograft dysfunction and helps in planning appropriate antirejection therapy with the goal of achieving long-term graft survival.

An Experimental Model of Acute Humoral Rejection of Renal Allografts Associated with Concomitant Cellular Rejection

Acute humoral rejection (AHR), which occurs in up to 8% of kidney transplant recipients, is a significant cause of renal allograft dysfunction and loss. More efficacious treatment modalities are needed to eliminate or curtail alloantibody production and its deleterious effects on the kidney. The availability of animal models mimicking human AHR is essential to understand its pathophysiology and develop new treatment strategies. Using a mouse kidney transplant model, we demonstrate that presensitization of recipients with donor skin grafts results in rejection of subsequent renal allografts. All presensitized mice developed renal failure 8.6 +/- 4.3 days after engraftment, with serum creatinine values near 100 micromol/dl. Graft histology revealed mild, diffuse, interstitial, mononuclear cell infiltrates; prominent peritubular capillary inflammatory cell margination; patchy interstitial hemorrhage; interstitial edema; and focal glomerular fibrin deposition. Complement (C3d) deposition was diffuse and prominent in peritubular capillaries. Serum analysis demonstrated high levels of circulating alloantibodies with broad cross-reactivity to many MHC haplotypes. The clinical setting and histological findings of our model strongly resemble AHR, which is frequently associated with cellular rejection, a situation commonly encountered in human renal allograft recipients. This animal model provides a valuable tool to study the pathogenesis of AHR, its relationship to cellular alloimmunity, its contribution to graft injury, and the effects of various potential therapeutic interventions.

The role of C4d immunostaining in the evaluation of the causes of renal allograft dysfunction

Renal biopsy is the gold standard for diagnosis of acute rejection in renal transplant recipients. The Banff (1997) classification was revised in 2003 incorporating morphological criteria and C4d immunostaining for the diagnosis of acute antibody-mediated rejection. The aim of this study was to evaluate the role of histomorphology and C4d immunostaining in indicated renal allograft biopsies with a clinical follow-up for a minimum duration of 1 year. Histological analysis and C4d immunostaining were performed on 132 needle core biopsies and 2 nephrectomy specimens from 107 patients from July 2004 to June 2005. Histological analysis revealed 59 cases of acute rejection, 10 biopsies of acute tubular necrosis, 41 cases of chronic allograft nephropathy (CAN), either alone or in combination with other diseases, and 18 biopsies of normal morphology. There were four cases of BK nephropathy (BK N) and eight cases had miscellaneous diagnoses. C4d immunostaining was performed on 126 biopsies. Overall, the prevalence of C4d positivity was 45% (57 of 126). Fifty-five percent (28 of 51) of the cases of acute rejection showed C4d positivity including 81% of presumptive antibody-mediated rejection (P-AbAR), 20% acute cellular rejection and 58% acute cellular rejection + P-AbAR. Overall C4d positivity was 37% in chronic allograft nephropathy. Acute tubular necrosis and borderline rejection showed 25 and 50% C4d positivity, respectively. Amongst various histological features, capillary margination of polymorphs and dilatation of peritubular capillaries (PTC-D) showed significant association with C4d positivity (P < 0.005). In cases of CAN, transplant glomerulopathy had significant association with C4d positivity. C4d-positive cases had a higher mean value of serum creatinine at the time of biopsies. It is concluded that C4d staining is a useful adjunct marker of the humoral limb of rejection, both in early and late post-transplant periods.

Ureteral Stents: A Novel Risk Factor for Polyomavirus Nephropathy

Polyomavirus virus nephropathy (PVN) is an important cause of renal allograft dysfunction. The risk factors for the development of PVN have not been completely elucidated. We investigated the hypothesis that ureteral trauma caused by placement of indwelling stents is an independent risk factor for PVN. Twenty cases of PVN were compared with 46 controls. Logistic regression was used to calculate odds ratios and to construct multivariate models. A total of 75% of cases and 35% of controls had stents placed during renal transplantation. In both univariate and multivariate logistic regression analyses adjusting for age, gender, deceased donor transplant, delayed graft function, tacrolimus and exposure to antibodies, the placement of a ureteral stent at the time of kidney transplantation was found to have a statistically significant association with developing PVN. Our findings reveal that the presence of a ureteral stent is associated with an increase in the risk of PVN.

Utility of Biopsy in Kidney Transplants With Delayed Graft Function and Acute Dysfunction

Renal biopsy is currently the gold standard to assess the causes of renal allograft dysfunction. In the present study, we prospectively assessed the role of the renal allograft biopsy in the diagnosis and treatment of renal allograft dysfunction. Seven hundred and fifteen biopsies were performed in 399 patients. The anatomopathological results in group 1 (delayed graft function) were: 60.4% acute tubular necrosis, 17.6% acute rejection, 4.3% calcineurin inhibitor toxicity, and 17.7% other diagnoses; in group 2 (acute graft dysfunction): 42.3% acute rejection, 22% acute tubular necrosis, 8.4% calcineurin inhibitor toxicity, and 27.3% other diagnoses. Among patients with delayed graft function, 42.2% of biopsies led to a change in the treatment. In 60.5%, the biopsy of patients with acute dysfunction led to a change in the patient management. In our series, the result of the biopsy disagreed with the clinical diagnosis in 39.6% and 57.7% of cases, respectively. These results demonstrated that renal graft biopsy remains an indispensable tool for the accurate management of kidney transplant patients.

Detection of Human Polyomavirus BK (BKV) in Bulgarian Adult Kidney Transplant Recipients by Polymerase Chain Reaction

ABSTRACTReactivation of the Polyomavirus BK (BKV) is increasingly recognized as a cause of renal-allograft dysfunction. Currently, patients at risk of nephropathy due to active BKV infection are identified by the presence of cells containing viral inclusion bodies (“decoy cells”) in the urine or by biopsy of the allograft tissue. Demonstrating viral DNA by molecular methods in urine and/or blood is emerging as a non-invasive tool for virology diagnosis and patient management. We report here the development of an in-house polymerase chain reaction (PCR) assay for BKV and its application for detection of BKV DNA in 43/50 (86%) of the urine samples, and in 4/50 (8%) of the peripheral blood leukocytes (PBLs) samples collected from adult kidney transplant recipients between 30 and 70 years of age. Testing for BKV in urine and PBLs from renal-allograft recipients by the use of the PCR is sensitive and specific method for identifying the patients at risk of viral nephropathy.

Cholesterol atheroembolic disease in kidney allografts – case report and review of the literature

Cholesterol atheroembolic renal disease is a rare cause of renal allograft dysfunction. Two recipients of cadaveric kidney transplantats from the same donor are discussed with presumed graft failure due to cholesterol emboli of donor origin. A review of the literature summarizes the reported cases in renal transplant recipients. While cholesterol embolization of presumed donor origin seems to have a poor renal outcome, cholesterol emboli originating in the recipient have a more favorable prognosis. As donors and recipients of increasing age or prominent atherosclerosis are accepted for transplantation, cholesterol atheroembolic renal disease may become more prevalent and should be considered in patients with renal allograft dysfunction.

Renal transplant patient with polyoma virus bladder infection and subsequent polyoma virus nephropathy

Polyoma virus nephropathy (PVN) is a significant cause of renal allograft dysfunction in transplant patients. A 58-year-old male received a cadaveric renal transplant and 12 weeks later presented with fever, diarrhea, and dysuria. He was diagnosed with a polyoma virus infection of the bladder by a transurethral bladder biopsy. One year post-transplant, he presented with renal allograft dysfunction and was diagnosed by biopsy with PVN of the non-native kidney. The diagnosis of a polyoma virus infection was confirmed by immunoreactivity to the polyoma T-antigen. We suggest that polyoma virus infection of the bladder be included in the differential diagnosis of urinary dysfunction in post-transplant patients, as such infections might be an under-recognized comorbidity in individuals with PVN.

Intravenous Immunoglobulin as a Treatment for BK Virus Associated Nephropathy: One-Year Follow-Up of Renal Allograft Recipients

BK virus associated nephropathy (BKVAN) has emerged as an important cause of renal allograft dysfunction and graft loss. Although several treatment strategies have been proposed, the rate of graft loss remains high. We studied the outcome of renal transplant patients with BKVAN treated with IVIG. After 11.4 +/- 3.9 months (mean +/- SEM) from the time of transplantation, 8 renal allograft recipients were diagnosed with BKVAN. In addition to a reduction of immunosuppressive therapy, patients received 2 g/kg IVIG. After a mean follow-up of 15 months, all except one patient are currently off dialysis. In summary, after IVIG therapy, 88% of patients still have functioning grafts, although renal function continues to be impaired. The benefit of concomitant IVIG and reduction of immunosuppressive therapy in BKVAN needs to be further addressed in randomized, multicentered trials.

Renal Allograft Accumulation of Technetium-99m Sulfur Colloid as a Predictor of Graft Rejection

Differentiation between rejection (the most common cause) and many other possibilities for detrimental effects on graft function represents a difficult issue to diagnose the cause of renal allograft dysfunction. This study was designed to determine whether technetium-99m sulfur colloid (TSC) accumulation predicted graft rejection. We prospectively studied 54 episodes of allograft dysfunction in 53 kidney transplant recipients who underwent TSC scintiscanning and graft biopsy. Visual analysis of TSC uptake compared uptake, in the allograft with that in the marrow of the fifth lumbar vertebra (L5). A 3+ result meant that allograft uptake was greater than L5 marrow uptake; 2+, the same; 1+, less and finally 0, no allograft uptake. Transplant accumulation of 2+ or more was considered consistent with rejection ( P = .01). Allograft biopsies interpreted based on the Banff Working Classification showed rejection in 45 of 54 renal biopsies with 42 the biopsy-proven rejection episodes showing atleast 2+ graft uptake. Furthermore, this nuclear medicine technique had a sensitivity of 93.3%, a specificity of 44.4%, a positive predictive value of 89.3%, a negative value of 57.1% and an efficiency of 83.3% for the diagnosis of renal allograft rejection.

BK Nephropathy in Kidney Transplant Recipients Treated with a Calcineurin Inhibitor-Free Immunosuppression Regimen

Recently, polyomavirus-associated nephropathy (PVAN) has been reported more frequently and is emerging as an important cause of renal allograft dysfunction and graft loss. Susceptibility appears to be related to the type and intensity of pharmacologic immunosuppression but some reports have suggested a link among the development of PVAN, the treatment of rejection or maintenance with a tacrolimus-based immunosuppressive regimen. We report three cases of PVAN in patients who never received immunosuppression with calcineurin inhibitors (CNIs). Two patients received induction immunosuppression consisting of an IL-2 receptor antagonist while 1 received thymoglobulin. These 3 patients were maintained on prednisone, sirolimus and mycophenolate mofetil (MMF) and none was treated for rejection. All three patients presented with an elevated serum creatinine and demonstrated polyomavirus infection on biopsy and by blood PCR. These cases demonstrate that, unlike reports linking tacrolimus and PVAN, polyomavirus infection may develop in patients maintained on CNI-free immunosuppressive regimens and have not had episodes of rejection.

BK virus colonic ulcerations

The papovavirus is categorized into 2 subgroups, the papilloma and the polyoma. Members of the papilloma subgroup include the human papilloma virus, whereas those of the polyoma subgroup include the BK virus (BKV), JC virus (JCV), and Simian virus 40 (SV 40). The BKV is approximately 40 nm in diameter with a nonenveloped, icosahedral virus containing doublestranded DNA. BKV is being increasingly recognized as a cause of renal allograft dysfunction and failure. Although BKV has been reported in association with cystitis, 1,2 nephritis, ureteral stenosis, 3–5 encephalitis, 6 interstitial pneumonia, 7 hepatic dysfunction, 8 central nervous system neoplasm, 9,10 and pancreatic islet tumors, 9 to date, BKV has not been reported as a cause of gastrointestinal disease. We report a patient with cadaveric renal transplant who presented with abdominal pain and diarrhea. Colonoscopic examination showed colonic ulcers caused by BKV. To our knowledge, this is the first case reported of BKV-induced colonic ulcers in an immunocompromised host.

A rare infectious cause of renal allograft dysfunction

Frequent causes of renal allograft dysfunction include acute rejection, calcineurin inhibitor toxicity, and chronic allograft nephropathy. Less common etiologies include acute tubular necrosis, recurrent and de novo glomerular disease, the full spectrum of renal diseases seen in the native kidney, and infectious diseases related to immunosuppressive therapy. The list of infectious agents commonly implicated in renal allograft dysfunction includes BK polyoma virus, cytomegalovirus, adenovirus, and Epstein-Barr virus with associated posttransplant lymphoproliferative disorder.

Noninvasive diagnosis of BK virus nephritis by measurement of messenger RNA for BK virus VP1 in urine.

Polyoma virus type BK (BKV) nephritis has emerged as an important cause of renal allograft dysfunction and graft failure. Its diagnosis is contingent on the invasive procedure of allograft biopsy. A noninvasive diagnostic test for BKV nephritis could improve clinical outcome. We obtained 25 urine specimens from 8 renal allograft recipients with biopsy-confirmed BKV nephritis, 31 samples from 28 recipients in whom BKV nephritis was excluded by allograft biopsy, and 74 specimens from 34 patients with stable allograft function. RNA was isolated from the urinary cells and reverse transcribed to complementary DNA. We designed gene-specific oligonucleotide primers and probes for the measurement of messenger RNA (mRNA) encoding BKV VP1 protein and a constitutively expressed 18S ribosomal RNA (rRNA) by real-time quantitative polymerase chain reaction. We explored the hypothesis that BKV VP1 mRNA levels predict BKV nephritis. The levels of BKV VP1 mRNA but not the levels of 18S rRNA predicted BKV nephritis. Analysis involving the receiver operating characteristic curve demonstrated that BKV nephritis can be predicted with a sensitivity of 93.8% and a specificity of 93.9% with the use of a cutoff value of 6.5 x 10 BKV VP1 mRNA copy number per nanogram of total RNA ( <0.00001). In the receiver operating characteristic curve analysis, the calculated area under the curve was 0.949 (95% confidence interval, 0.912 to 0.987, <0.00001) for BKV VP1 mRNA levels and 0.562 (95% confidence interval, 0.417 to 0.708, >0.2) for 18S rRNA. Measurement of BKV VP1 mRNA in urinary cells offers a noninvasive and accurate means of diagnosing BKV nephritis.