Virus Nephropathy Research Articles

The Effects of COVID-19 in Kidney Transplantation: Evidence From Tissue Pathology.

The biological effects of SARS-CoV-2 infection in transplanted kidneys are uncertain with little pathological information. This single-center, prospective observational study evaluated kidney transplant biopsies from recipients of deceased donors with COVID-19, current recipients contracting SARS-CoV-2 Omicron variant in 2022, against prior BK virus (BKV) infection and uninfected (without SARS-CoV-2 or BKV) samples, as respective positive and negative comparators (n = 503 samples). We demonstrated nonvirus tubular injury in implanted tissue from infected donors and prevalent recipients with mild acute COVID-19 and acute kidney injury, excluding direct viral infection as a cause of kidney damage. COVID particles were absent in 4116 ultrastructural images of 295 renal tubules from 4 patients with acute COVID-19. No viral cytopathic effect, viral allograft nephropathy, or SARS-CoV-2 RNA was detected in acute tissues, nor in 128 sequential samples from infected donors or recipients with COVID-19. Following recipient COVID-19 (mean 16.8 ± 12.0 wk post-infection), the biopsy-prevalence of rejection was 33.0% (n = 100 biopsies) versus 13.4% for contemporaneous uninfected controls (n = 337; P < 0.001). Prior COVID-19 was an independent risk factor for incident rejection using multivariable generalized estimating equation adjusted for competing risks (odds ratio, 2.195; 95% confidence interval, 1.189-4.052; P = 0.012). Landmark and matched-pair analyses confirmed an association of SARS-CoV-2 with subsequent transplant rejection, with a similar pattern following BKV infection. Transplantation from COVID-19+ deceased donors yielded good recipient outcomes without evidence of viral tissue transmission. Acute kidney injury during COVID-19 was mediated by archetypical tubular injury and infection correlated with an increased risk of subsequent rejection.

#2082 Effectiveness of a surveillance protocol and early mTORi conversion according to Urine BK viral load in Thai kidney transplant recipients

Abstract Background and Aims BK viral nephropathy (BKVN) is a crucial cause of early kidney allograft failure. Early detection and prompt treatment in the case of a high urine viral load might be more advantageous than waiting until BK viremia occurs. Data regarding outcome of BK infection based on adjustments of immunosuppression according to urine viral load is limited. Method A prospective cohort study of kidney transplant (KT) recipients at Siriraj Hospital, conducted between January 2015 and June 2020, involved monitoring urine BK viral load (RT-PCR) at 1, 2, 3, 6, 12, 18, and 24 months after KT. Determination of BK viremia and adjustments to immunosuppression were performed in patients with urine BK viral loads exceeding 1,000,000 copies/ml or demonstrating progressive increments in BK viruria. Initially, mycophenolate (MPA) dosage was reduced, and subsequently, conversion to mTOR inhibitors was considered for non-responsive cases. Data on the overall incidence and risk factors of BK viremia and/or BKVN were collected. Results Out of a total of 339 enrolled patients, 234 (69%) underwent deceased KT, and 49 (14.5%) received induction therapy with anti-thymocyte globulin. The incidence of BK viruria, viremia, and BKVN were 38.6% (131 patients), 9.7% (33 patients), and 4.1% (14 patients), respectively. The median time of occurrence for BK viruria and BKVN was 3 (IQR 1-12) and 4.5 (IQR 3–18) months after KT, respectively. Most BKVN cases (71.4%) developed within the first six months post KT. We did not find any significant risk factors associated with the occurrence of BK viremia or BKVN. Regarding the adjustment of immunosuppression, the initial reduction of MPA dosage was effective in 48 out of 92 patients (52.17%). In cases with an extremely high urine BK viral load or no response to MPA reduction, 46 patients received a change from MPA to everolimus, which was successful in 38 patients (82.6%). No graft loss due to BKVN was observed throughout the study. Conclusion The incidence of BK infection after KT in Thai recipients is high, comparable to western population. A surveillance protocol with urine BK viral load and early mTORi conversion is effective for prevention of allograft loss from BKVN.

Polyomavirus nephropathy: diagnosis, histologic features, and differentiation from acute rejection.

Polyomaviruses, particularly BK virus, are ubiquitous latent infections that may reactivate with immunosuppression during kidney transplantation, resulting in polyomavirus nephropathy (PVN). The levels of viruria and viremia serve as tools for screening and making a presumptive diagnosis of PVN, respectively, while a definitive diagnosis requires a kidney biopsy. There are histologic classifications of PVN based on the extent of tubular cell viral infection, interstitial fibrosis, and interstitial inflammation. These classifications correlate to some degree with graft function and loss, aiding in determining treatment efficacy and prognostication. PVN has histologic overlap with acute cell-mediated rejection, making the differential diagnosis challenging, although there are suggestive features for these different causes of graft dysfunction. This article reviews the diagnosis, histologic findings, and classifications of PVN, and discusses how to differentiate viral nephropathy from acute rejection.

Renal Injury During Viral Infections

Renal pathologies following viral infections have become an emerging public health problem in both developed and developing countries. Diagnostic criteria are complex. In most cases, they involve correlation between clinical, biological and histological data, with occasional recourse to molecular biology techniques. Several mechanisms are involved in the pathogenesis of virus-related nephropathy, including virus tropism in the kidney, formation of immune complexes in situ or in the bloodstream, direct cytopathogenic effects, and multiple organ failure. The hepatitis C virus is responsible for three main types of kidney disease: membranoproliferative glomerulnephritis, cryoglobulinemia and membranous nephropathy. Hepatitis B virus is associated with membranous nephropathy, membranoproliferative glomerulnethritis, and IgA nephropathy. HIV (human immunodeficiency virus) infection is associated with several glomerular and tubular kidney damage. HIVAN (HIV-associated nephropathy), a specific entity mainly affecting Africans and African-Americans, presents as a rapidly progressive glomerulonephritis rapidly progressing to the terminal stage. Infections secondary to adenovirus, cytomegalovirus, epstein-barr virus, poliomavirus and coronavirus are often responsible for acute or chronic tubulointerstitial nephritis. Treatment is mainly symptomatic, based on nephroprotection measures, rarely combined with antiviral therapy. Prophylaxis with vacci-nation, when available, remains the best means of preventing viral nephropathy.

Hypoxia-inducible Factor-1α Suppresses the Innate Immune Response in Cultured Human Proximal Tubular Cells.

Retinoic acid-inducible gene (RIG)-I like receptors (RLRs) are expressed on renal proximal tubular epithelial cells (RPTECs) in viral nephropathy, indicating the presence of RLR-mediated innate immune responses in RPTECs. Hypoxia is also known to affect innate immunity. This study investigated the effects of hypoxia, and hypoxia-inducible factor (HIF) on innate immunity in RPTECs. Primary human RPTECs were cultured under normoxic or hypoxic conditions and treated with a synthetic analog of double-stranded RNA (polyIC). The expression levels of RIG-I and MDA5, as RLRs, and IFNβ, IL6, and TNFα, as inflammatory mediators were evaluated using quantitative reverse transcription-polymerase chain reaction, western blotting, and lactate dehydrogenase activity (LDH) assays. To further investigate the role of hypoxia, a small interfering RNA was used to knockdown HIF1α. Under normoxic conditions, polyIC increased RIG-I, MDA5, and IFNβ mRNA expression in RPTECs by, 9.4±0.4-, 10.8±0.5-, and 4.0±0.1-fold, respectively, compared to control, and by 5.4±0.1-, 7.4±0.1-, and 2.4±0.3-fold, respectively, under hypoxic conditions, the rate of increase was lower than that under normoxic conditions (p<0.01). Protein expression showed a similar trend. Under hypoxic conditions, polyIC treatment with HIF1α knockdown in RPTECs increased RIG-I, MDA5, and IFNβ mRNA expression by 3.1±0.5-, 2.9±0.4-, and 6.1±0.4-fold, respectively, and cytotoxicity, demonstrated by LDH assay, was increased compared to that without knockdown (all p<0.01). Hypoxia suppresses polyIC-induced RLRs mediated innate immune responses in RPTECs via HIF1α.

Intravenous drug use and kidney disease

Intravenous drug use (IVDU) is a major public health issue, associated with high mortality rates. The risk of overdose, cardiovascular and infectious complications are well known, but IVDU can also lead to different types of kidney disease. Patients can develop acute or chronic kidney injury due to direct nephrotoxicity of the drugs, or present with different types of glomerulonephritis, interstitial nephritis, and bacterial or viral infection-related nephropathy. Diagnosis can be difficult but is essential to prevent irreversible kidney damage. The number of persons with IVDU that develop end-stage kidney disease is increasing and poses challenges for dialysis and transplantation centers. This article summarizes the renal manifestations that clinicians may encounter in persons with IVDU, especially of heroin and cocaine.

Virus-Associated Nephropathies: A Narrative Review.

While most viral infections cause mild symptoms and a spontaneous favorable resolution, some can lead to severe or protracted manifestations, specifically in immunocompromised hosts. Kidney injuries related to viral infections may have multiple causes related to the infection severity, drug toxicity or direct or indirect viral-associated nephropathy. We review here the described virus-associated nephropathies in order to guide diagnosis strategies and treatments in cases of acute kidney injury (AKI) occurring concomitantly with a viral infection. The occurrence of virus-associated nephropathy depends on multiple factors: the local epidemiology of the virus, its ability to infect renal cells and the patient’s underlying immune response, which varies with the state of immunosuppression. Clear comprehension of pathophysiological mechanisms associated with a summary of described direct and indirect injuries should help physicians to diagnose and treat viral associated nephropathies.

P8.122: Tacrolimus Dose Reduction as an Effective Therapeutic Approach to the Patients With Active BK Virus Replication And Nephrotoxicity

Background: BK viral nephropathy (BKVN) affects a significant proportion of kidney grafts in the early post-transplant period and often leads to functional failure of these grafts. The intensity of immunosuppressive therapy plays a significant role in the activation of BK viral (BKV) replication. Methods: 457 per-protocol biopsies of kidney grafts were performed in a group of 161 newly transplanted patients. The incidence of histological signs of tacrolimus nephrotoxicity as a manifestation of excessive immunosuppression was calculated using the Calcineurin Inhibitor Nephrotoxicity Score (CINS). In case of detection of simultaneous toxicity and substantial BKV replication, the dose of tacrolimus and/or mycophenolate was reduced and the effect on the inhibition of BKV activation and regression of toxic changes were compared. In parallel, we studied the effect of pre-emptive reduction of tacrolimus dose on the development of BKV replication in isolated detections of toxicity during the subsequent period. Results: The reduction of tacrolimus and mycophenolate dose in patients with histological evidence of toxicity and significant BKV replication was associated with an early and significant decrease in the BKV plasma load compared to isolated mycophenolate reduction (P = 0.023), significant decrease in CINS (P = 0.001) and better functional parameters at the end of this one-year follow-up (P = 0.024). A pre-emptive dose reduction of tacrolimus in case of toxicity evidence led to a marked reduction in the incidence of substantial BKV viremia during the subsequent period. Conclusions: The reduction of tacrolimus and mycophenolate dose in patients with histologically verified tacrolimus nephrotoxicity represents a more effective approach to attenuate significant BKV replication than a single-dose reduction of mycophenolate, including the regression of toxic changes. Pre-emptive tacrolimus dose reduction in case of toxicity signs is associated with a lower incidence of significant BKV replication during the first year after transplantation, without increasing the risk of acute rejection. Supported by MH CZ – DRO (FNOl, 00098892) and by grant IGA_LF_2022_03.

Hepatitis B Virus-Related Nephropathy

Viral-associated nephropathy indicates the direct pathogenic relationship between viral status and the development of nephropathy. Hepatitis B virus (HBV) infection (especially chronic) causes different glomerular, tubular, and interstitium damages. Membranous and membranoproliferative are the common HBV-associated nephropathy. The pathogenesis of HBV-associated nephropathy is primarily immune complex mediated; however, direct tubular damage may occur. The virus load and activity are essential risk factors in HBV-associated nephropathy development. Decreasing virus load and early treatment reduce the risk of HBV-associated nephropathy and may prevent the disease progression. Prevention of HBV infection by a worldwide vaccination program governed by the World Health Organization is the prime target to prevent hepatic and extrahepatic HBV-related complications. The authors searched the EMBASE, Google Scholar, Scopus, and Google search engines for articles about HBV-associated nephropathy using phrases, texts, and keywords such as chronic HBV infection and kidney, HBV-associated glomerulonephritis, nephritis in HBV infection, viral nephropathy, and HBV vaccination. Following multiple meetings and discussions, each author was given a section on the topic to search and summarize. Then, this narrative review manuscript has been written and revised to update HBV-associated nephropathy pathogenesis and treatment.

946. Epidemiology and Long-term Outcomes of BK Polyomavirus Nephropathy in Kidney Solid Organ Transplant Recipients at Texas Children’s Hospital

BackgroundBK Polyomavirus (BKPyV) is an important cause of graft dysfunction and premature graft failure in pediatric kidney transplant recipients (PKTR). Contemporary data on BK viral associated nephropathy (BKVAN) in PKTR are limited. We sought to determine the frequency, associations with, and long-term outcomes of BKVAN in PKTR.MethodsA retrospective cohort study of PKTR ≤21 years of age transplanted from 2011-2018 was completed. Primary outcome was BKVAN and secondary outcomes included graft dysfunction and failure. Associations with BKVAN were measured using chi square and Fisher exact tests. Time to BKVAN and graft failure were assessed using Kaplan-Meier plots. ResultsAmong 200 PKTR, 16 (8%) developed BKVAN at a median of 228 days post-transplant. Median (IQR) age at time of transplant for patients with BKVAN was 14 (7-17) years of age. Of those who developed BKVAN, 13/16 (81%) were biopsy proven, 2/16 (13%) were probable and 1/16 (6%) was presumptive. Treatment of BKVAN included reduced immunosuppression (12, 75%), ciprofloxacin (11, 69%), intravenous immunoglobulin (7, 44%), and leflunomide (4, 25%). Simultaneous rejection therapy occurred in two patients (13%). Notably, three patients with BKVAN had negative BKPyV plasma viral loads. Median (IQR) BKPyV viral load in those with positive PCRs was 82,000 (19,315 – 1,106,283) copies/milliliter. Median (IQR) time to clearance of BKPyV from the plasma was 425 (261 – 858) days. There was no association between age at time of transplant, repeat kidney transplant, donor type, underlying diagnosis at time of transplant, HLA mismatch, mode of dialysis, or steroid free immunosuppression and the development of BKVAN. Mean percent change in eGFR yearly post-transplant was -0.066 for those with BKVAN versus -0.091 for those without BKVAN (p=0.35). Graft failure was experienced in 1/16 (6%) PKTR with BKVAN but was not related to BKVAN. There was no difference in time to graft failure (Figure 1, p=0.64) in those who developed BKVAN versus those who did not. ConclusionBKVAN continues to occur in PKTR. No associations were found with the development of BKVAN in our cohort. PKTR with BKVAN did not have an increased rate of eGFR decline nor did they develop graft failure more quickly than those without BKVAN. Disclosures Sarah J. Swartz, MD, Education grant sponsored by Amgen; awarded by Renal Physicians Association (Other Financial or Material Support, Attended Renal Physician Association PAL (Pediatric Advocacy Leadership) Forum in Jun 2019; Program sponsored by Education grant from Amgen, awarded by the Renal Physicians Association for participation)Vifor Fresensius Medical Care Renal Pharma (Scientific Research Study Investigator, Multi-center site PI for phase 3 study to investigate the safety and efficacy of PA21 (Velphoro) and calcium acetate (Phoslyra) sponsored by Vifor Fresensius Medical Care Renal Pharma funded Sept 2016-Oct 2019)

Viral Nephropathies, Adding SARS-CoV-2 to the List.

Viral infections in the immunocompetent host can cause both acute and chronic kidney disease either as a direct damage to the infected kidney cells or as a consequence of systemic immune responses that impact kidney function. Since identifying these entities in the 1970s and 80s, major breakthroughs in the understanding of the viral mechanisms have occurred. Viruses have evolved mechanisms to hijack signaling pathways of infected cells to evade antiviral immune responses by the host. Over time, the clinical presentations and management of these diseases have evolved along with our in-depth understanding of the various pathophysiological mechanisms causing these conditions. Similarly, both at the cellular and systemic levels, the host has evolved mechanisms to counter viral subversion strategies for mutual survival. Since the start of the current COVID-19 pandemic, numerous cases of acute kidney injury have been reported in the literature with various possible pathophysiological mechanisms. In this review, we summarize lessons learned from prior viral pandemics related to viral mechanisms utilized in the pathogenesis of numerous renal manifestations to attempt to utilize this knowledge in predicting post-COVID-19 kidney disease.

Kidney injury and disease in patients with haematological malignancies.

Acute kidney injury (AKI) is common in patients with cancer, especially in those with haematological malignancies. Kidney injury might be a direct consequence of the underlying haematological condition. For example, in the case of lymphoma infiltration or extramedullary haematopoiesis, it might be caused by a tumour product; in the case of cast nephropathy it might be due to the presence of monoclonal immunoglobulin; or it might result from tumour complications, such as hypercalcaemia. Kidney injury might also be caused by cancer treatment, as many chemotherapeutic agents are nephrotoxic. High-intensity treatments, such as high-dose chemotherapy followed by haematopoietic stem cell transplantation, not only increase the risk of infection but can also cause AKI through various mechanisms, including viral nephropathies, engraftment syndrome and sinusoidal obstruction syndrome. Some conditions, such as thrombotic microangiopathy, might also result directly from the haematological condition or the treatment. Novel immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cell therapy, can also be nephrotoxic. As new therapies for haematological malignancies with increased anti-tumour efficacy and reduced toxicity are developed, the number of patients receiving these treatments will increase. Clinicians must gain a good understanding of the different mechanisms of kidney injury associated with cancer to better care for these patients.

An application of the 2018 Banff Classification for BK polyomavirus-associated nephropathy in renal transplantation.

There is still a lack of a recognized morphological classification of BK viral nephropathy (BKVN) which can better reflect the clinical manifestations and prognosis. We retrospectively analyzed the data of 53 patients with BKVN in our center from January 2011 to December 2018 and evaluated the new Banff 2018 classifications' predictive value for the graft prognosis. The period between transplantation and BKVN diagnosis lasted for 10.3months (IQR, 5.3-21.9months). The main reason (92.5%) for puncture was the increase of blood serum creatinine. Of the 53 patients diagnosed with BKVN, 100% were positive for urinary BK virus-DNA, and the viral load was 1.4×108 copies/mL (IQR, 3.7×104 -1.3×1011 copies/mL); 75.5% were positive for blood BK virus-DNA, and the viral load was 3.3×104 copies/mL (IQR, 0-2.8×107 copies/mL). There were five cases in class 1, 31 cases in class 2, and 17 cases in class 3; the viral load of urine BK was 3.3×108 , 1.4×108 , and 6.3×107 copies/mL (P>.05); the viral load of blood BK was 3.3×104 , 3.3×104 , and 3.3×104 copies/mL (P>.05); the 1-year graft survival rates were 100%, 90.3%, and 52.9%, respectively (P<.05). BKVN mostly occurs within 1year after transplantation. There is no correlation between BK virus load in hematuria and pathological damage at the time of diagnosis. The 2018 Banff Classification for BKVN can better indicate the prognosis of graft.

Kidney Involvement in COVID-19: Need for Better Definitions

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus outbreak in China at the end of 2019, increasing interest emerged regarding renal involvement during coronavirus disease 2019 (COVID-19). AKI with or without proteinuria is described in a variable percentage of patients with COVID-19, and several reports outlined an increased mortality risk in those with AKI. The mechanisms of renal injury during COVID-19 are difficult to study due to the interference of several coexisting factors, such as polypharmacy, hypoxia, and cytokine storm. Just like severe acute respiratory syndrome coronavirus, SARS-CoV-2 virus entry into target cells is facilitated by the presence of angiotensin-converting enzyme 2 (ACE2) expressed in respiratory cells as well as renal tubular cells and podocytes, making the hypothesis of a direct renal infection particularly intriguing. Farkash et al.1 observed renal tubular vacuolization and virus-like inclusions in tubular cells by electron microscopy (EM) in the autopsy of a patient with COVID-19. Similar EM findings together with suggestive immunohistochemical stain for SARS-CoV-2 proteins in tubules were shown in a few patients from two independent Chinese COVID-19 autopsy cohorts (Diao B, Wang C, Wang R, Feng Z, Tan Y, Wang H, et al. [2020] Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection. 10.1101/2020.03.04.20031120).2 However, the same immunohistochemical was not considered specific when used by others.3 Of note, when specific and highly sensitive molecular methods for tissue viral identification were used (i.e., RNAscope3 or real-time PCR,4 the presence of SARS-CoV-2 RNA could not be demonstrated within renal tissue, and none of the aforementioned autopsy studies included viral RNA isolation in the kidney. Interestingly, viral nephropathies with direct tubular infection and viral replication within epithelial cells (i.e., BK virus nephropathy) are usually associated with substantial viruria due to the direct release of viral particles in the tubular lumen following cytopathic cell injury. So far, there is no solid evidence of a correlation between urinary levels of SARS-CoV-2 viral copies and the degree of kidney injury in patients with COVID-19.5 Moreover, the presence of viral particles by pure morphologic evaluation (EM) does not demonstrate by itself a direct cytopathic effect nor a replicative potential because it only supports viral entry. More specific morphologic correlates of viral cytopathy (nuclear atypia/dysmorphology and syncytia) have not been shown yet. Three cases of collapsing glomerulopathy during SARS-CoV-2 infection have been reported,6 presenting with severe kidney injury and variable proteinuria: in genetically predisposed subjects, increased levels of cytokines (i.e., IFNs) in patients with COVID-19 are thought to drive podocyte injury, resulting in collapsing glomerulopathy as can be observed in other viral-associated nephropathies. Although in one case, the presence of virus-like particles in podocytes was observed by EM, the hypothesized mechanism of injury does not require direct kidney infection. Taken together, these observations suggest that caution should be used when addressing the etiology of kidney dysfunction in patients with COVID-19 because unequivocal evidence of direct viral infection of the kidney is still lacking in these severe and acutely ill patients. Disclosures All authors have nothing to disclose. Funding None.

Coexistent BK-virus-associated nephropathy and ureteric stenosis in a patient with acute cellular rejection after renal transplantation: A case report and review of literature

BK-virus-associated nephropathy (BKVN) is one of the most common causes of viral nephropathy in renal-transplant recipients. The intensity of immunosuppression is the most important risk factor for BKVN. Combined BKVN and rejection can occur rarely, which is difficult to diagnose and manage. Ureteritis, leading to ureteric stenosis, can result in secondary to both rejection and BK-virus (BKV) infection. We herein report a case of BKVN coexistent with the features of acute cellular rejection in a patient with ureteric stenosis probably induced by BKV infection, which was managed successfully with step-wise modification of immunosuppression along with double–J stenting, leading to stabilization of graft function.

Immunological and biochemical parameters in patients with hepatitis C virus nephropathy before and after direct hepatitis C virus antiviral agents

Immunological and biochemical parameters in patients with hepatitis C virus nephropathy before and after direct hepatitis C virus antiviral agents

Viral nephropathies in renal transplantation with a special emphasis on adenovirus infection

Viral nephropathies in renal transplantation with a special emphasis on adenovirus infection

Antigen-Specificity of T Cell Infiltrates in Biopsies With T Cell-Mediated Rejection and BK Polyomavirus Viremia: Analysis by Next Generation Sequencing.

This study interrogates the antigen-specificity of inflammatory infiltrates in renal biopsies with BK polyomavirus (BKPyV) viremia (BKPyVM) with or without allograft nephropathy (BKPyVN). Peripheral blood mononuclear cells (PBMC) from five healthy HLA-A0101 subjects were stimulated by peptides derived from the BKPYV proteome or polymorphic regions of HLA. Next generation sequencing of the T cell-receptor complementary DNA was performed on peptide-stimulated PBMC and 23 biopsies with T cell-mediated rejection (TCMR) or BKPyVN. Biopsies from patients with BKPyVM or BKVPyVN contained 7.7732 times more alloreactive than virus-reactive clones. Biopsies with TCMR also contained BKPyV-specific clones, presumably a manifestation of heterologous immunity. The mean cumulative T cell clonal frequency was 0.1378 for alloreactive clones and 0.0375 for BKPyV-reactive clones. Samples with BKPyVN and TCMR clustered separately in dendrograms of V-family and J-gene utilization patterns. Dendrograms also revealed that V-gene, J-gene, and D-gene usage patterns were a function of HLA type. In conclusion, biopsies with BKPyVN contain abundant allospecific clones that exceed the number of virus-reactive clones. The T cell component of tissue injury in viral nephropathy appears to be mediated primarily by an "innocent bystander" mechanism in which the principal element is secondary T cell influx triggered by both antiviral and anti-HLA immunity.

Unlocking the code: mining the urinary proteome after renal transplantation

Diagnosis of transplant dysfunction usually requires kidney biopsy. Sidgel etal. compared urinary proteomics with matched kidney biopsies to develop a biomarker panel to differentiate acute rejection, BK viral nephropathy, and chronic allograft nephropathy. The results suggest that monitoring a panel of urinary peptides may ultimately facilitate noninvasive diagnosis and management of common transplant complications.

Elevated Urinary Matrix Metalloproteinase-7 Detects Underlying Renal Allograft Inflammation and Injury.

The urinary CXC chemokine ligand (CXCL)10 detects renal transplant inflammation noninvasively, but has limited sensitivity and specificity. In this study, we performed urinary proteomic analysis to identify novel biomarkers that may improve the diagnostic performance of urinary CXCL10 for detecting alloimmune inflammation in renal transplant patients. In preliminary studies, adult renal transplant patients with normal histology (n = 5), interstitial fibrosis and tubular atrophy (n = 6), subclinical (n = 6) and clinical rejection (n = 6), underwent in-depth urine protein compositional analysis with LC-MS/MS, and matrix metalloproteinase-7 (MMP7) were identified as a potential candidate for the diagnosis of renal allograft inflammation. Urine MMP7 performance was then studied in a larger, prospective adult renal transplant population (n = 148 urines from n = 133 patients) with matched surveillance/indication biopsies. The diagnostic performance of urinary MMP7 and CXCL10 in combination was next evaluated using concordance (C-) statistics, net reclassification improvement and integrated discrimination improvement indices, to determine whether it was better than CXCL10 alone. Urinary MMP7:creatinine (Cr) was lower in normal transplants compared to those with inflammation: glomerulonephritis (P = 0.009), viral nephropathies (P = 0.002), interstitial fibrosis and tubular atrophy and inflammation (P = 0.04), borderline (P = 0.08), subclinical (P = 0.01) and clinical rejection (P = 0.0006), and acute tubular necrosis (P < 0.0001). Urinary MMP7:Cr and CXCL10:Cr significantly distinguished noninflamed from inflamed biopsies (area under the curve, 0.74 and 0.70, respectively). The addition of urinary MMP7:Cr to CXCL10:Cr improved the diagnostic performance for subclinical and clinical inflammation/injury by integrated discrimination improvement (P = 0.002) and net reclassification improvement (P = 0.006) analyses. Urinary MMP7:Cr improves the overall diagnostic performance of urinary CXCL10:Cr for distinguishing normal histology from subclinical and clinical inflammation/injury, but not subclinical inflammation alone.