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Osmotic nephrosis describes a morphological pattern with vacuolization and swelling of the renal proximal tubular cells. The term refers to a nonspecific histopathologic finding rather than defining a specific entity. Osmotic nephrosis can be induced by many different compounds, such as sucrose, hydroxyethyl starch, dextrans, and contrast media. It has a broad clinical spectrum that includes acute kidney injury and chronic kidney failure in rare cases. This article discusses the pathological characteristics, pathogenesis, and various clinical entities of osmotic nephrosis. [ABSTRACT FROM AUTHOR]

Key words: acute renal failure; anorexia nervosa; intravenous immunoglobulin; refeeding syndrome [ABSTRACT FROM PUBLISHER]

Background: Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder., Methods: Mice with targeted disruption of the molybdenum cofactor sulfurase ( Mocos ) gene were generated to enable an integrated understanding of purine disorders and evaluate pathophysiologic functions of this gene which is found in a large number of pathways and is known to be associated with autism., Results: Mocos -deficient mice die with 4 weeks of age due to renal failure of distinct obstructive nephropathy with xanthinuria, xanthine deposits, cystic tubular dilation, Tamm-Horsfall (uromodulin) protein (THP) deposits, tubular cell necrosis with neutrophils, and occasionally hydronephrosis with urolithiasis. Obstructive nephropathy is associated with moderate interstitial inflammatory and fibrotic responses, anemia, reduced detoxification systems, and important alterations of the metabolism of purines, amino acids, and phospholipids. Conversely, heterozygous mice expressing reduced MOCOS protein are healthy with no apparent pathology., Conclusions: Mocos -deficient mice develop a lethal obstructive nephropathy associated with profound metabolic changes. Studying MOCOS functions may provide important clues about the underlying pathogenesis of xanthinuria and other diseases requiring early diagnosis., Competing Interests: All authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

Antisense oligonucleotides (ASOs) are chemically modified nucleic acids with therapeutic potential, some of which have been approved for marketing. We performed a study in rats to investigate mechanisms of toxicity after administration of 3 tool locked nucleic acid (LNA)-containing ASOs with differing established safety profiles. Four male rats per group were dosed once, 3, or 6 times subcutaneously, with 7 days between dosing, and sacrificed 3 days after the last dose. These ASOs were either unconjugated (naked) or conjugated with N-acetylgalactosamine for hepatocyte-targeted delivery. The main readouts were in-life monitoring, clinical and anatomic pathology, exposure assessment and metabolite identification in liver and kidney by liquid chromatography coupled to tandem mass spectrometry, ASO detection in liver and kidney by immunohistochemistry, in situ hybridization, immune electron microscopy, and matrix-assisted laser desorption/ionization mass spectrometry imaging. The highly toxic compounds showed the greatest amount of metabolites and a low degree of tissue accumulation. This study reveals different patterns of cell death associated with toxicity in liver (apoptosis and necrosis) and kidney (necrosis only) and provides new ultrastructural insights on the tissue accumulation of ASOs. We observed that the immunostimulatory properties of ASOs can be either primary from sequence-dependent properties or secondary to cell necrosis.

Poor solubility of drug candidates mainly affects bioavailability, but poor solubility of drugs and metabolites can also lead to precipitation within tissues, particularly when high doses are tested. RO0728617 is an amphoteric compound bearing basic and acidic moieties that has previously demonstrated good solubility at physiological pH but underwent widespread crystal deposition in multiple tissues in rat toxicity studies. The aim of our investigation was to better characterize these findings and their underlying mechanism(s), and to identify possible screening methods in the drug development process. Main microscopic features observed in rat RO0728617 toxicity studies were extensive infiltrates of crystal-containing macrophages in multiple organs. Matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry revealed that these crystals contained the orally administered parent compound, and locality was confirmed to be intracytoplasmic and partly intralysosomal by electron microscopic examination. Crystal formation was explained by lysosomal accumulation of the compound followed by precipitation of the hydrochloride salt under physiological conditions in the lysosomes, which have a lower pH and higher chloride concentration in comparison to the cytosol. This study demonstrates that risk of drug precipitation can be assessed by comparing the estimated lysosomal drug concentration at a given dose with the solubility of the compound at lysosomal conditions., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology.)

Introduction: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the world. While the first case was recorded in Hubei in December 2019, the extent of early community spread in Central Europe before this period is unknown. A high proportion of asymptomatic cases and undocumented infections, high transmissibility, and phylogenetic genomic diversity have engendered the controversial possibility of early international community spread of SARS-CoV-2 before its emergence in China., Methods: To assess the early presence of lethal COVID-19 in Switzerland, we retrospectively performed an analysis of deaths at University Hospital Basel between October 2019 and February 2020 (n = 310), comparing the incidence of clinical causes of death with March 2020 (n = 72), the month during which the first lethal COVID-19 cases in Basel were reported. Trends of COVID-19-suggestive sequelae, such as bronchopneumonia with organization, acute respiratory distress syndrome (ARDS), or pulmonary embolisms (PE) were evaluated. In cases where autopsy was performed (n = 71), analogous analyses were conducted on the cause of death and pulmonary histological findings. Eight cases with a COVID-19-suggestive clinical history and histopathology between October 2019 and February 2020, and 3 cases before October 2019, were selected for SARS-CoV-2 RT-PCR., Results: A statistically significant rise in pulmonary causes of death was observed in March 2020 (p = 0.03), consistent with the reported emergence of lethal COVID-19 in Switzerland. A rise in lethal bronchopneumonia was observed between December 2019 and January 2020, which was likely seasonal. The incidence of lethal ARDS and PE was uniformly low between October 2019 and February 2020. All autopsy cases analyzed by means of SARS-CoV-2 RT-PCR yielded negative results., Conclusion: Our data suggest the absence of early lethal community spread of COVID-19 in Basel before its initial reported emergence in Switzerland in March 2020., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Introduction: In effusion cytology, mesothelial cells can occasionally present with striking intracytoplasmic accumulation of rod- and crystal-like cytoplasmic lamellar inclusions (LIs). Their nature and function are poorly understood, and their diagnostic relevance is unknown., Objective: The aim of this study was to explore the nature of LIs in mesothelial cells and determine their prevalence and diagnostic utility in routine practice., Material and Method: We reviewed a consecutive series of cytological specimens of reactive (n = 102) and malignant effusions (n = 90), respectively. Malignant effusions included malignant mesotheliomas (n = 63) and carcinomas (n = 27). LIs of one effusion were analyzed by electron microscopy (EM)., Results: LIs were found exclusively in benign mesothelial cells in 14% (14/102) of reactive and in 4% (1/27) of malignant effusions with carcinomatosis. They were absent in effusions of malignant mesothelioma. EM revealed mainly straight lamellar, less tubular, structures in cisternae of the hyperplasic rough endoplasmic reticulum (rER)., Conclusion: Cytoplasmic LIs located within hyperplastic rER can be found in up to 14% of effusions restricted to benign mesothelial cells. They can be used as an indirect morphological clue favoring the diagnosis of benign effusion and helping the cytologist to differentiate between reactive and malignant mesothelial cells in daily practice., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Polyomavirus nephropathy (PVN) is a common viral infection of renal allografts, with biopsy-proven incidence of approximately 5%. A generally accepted morphologic classification of definitive PVN that groups histologic changes, reflects clinical presentation, and facilitates comparative outcome analyses is lacking. Here, we report a morphologic classification scheme for definitive PVN from the Banff Working Group on Polyomavirus Nephropathy, comprising nine transplant centers in the United States and Europe. This study represents the largest systematic analysis of definitive PVN undertaken thus far. In a retrospective fashion, clinical data were collected from 192 patients and correlated with morphologic findings from index biopsies at the time of initial PVN diagnosis. Histologic features were centrally scored according to Banff guidelines, including additional semiquantitative histologic assessment of intrarenal polyomavirus replication/load levels. In-depth statistical analyses, including mixed effects repeated measures models and logistic regression, revealed two independent histologic variables to be most significantly associated with clinical presentation: intrarenal polyomavirus load levels and Banff interstitial fibrosis ci scores. These two statistically determined histologic variables formed the basis for the definition of three PVN classes that correlated strongest with three clinical parameters: presentation at time of index biopsy, serum creatinine levels/renal function over 24 months of follow-up, and graft failure. The PVN classes 1-3 as described here can easily be recognized in routine renal biopsy specimens. We recommend using this morphologic PVN classification scheme for diagnostic communication, especially at the time of index diagnosis, and in scientific studies to improve comparative data analysis., (Copyright © 2018 by the American Society of Nephrology.)

Non-human primates (NHPs) are currently considered to be the non-rodent species of choice for the preclinical safety assessment of single-stranded oligonucleotide (SSO) drugs. We evaluated minipigs as a potential alternative to NHPs to test the safety of this class of compounds. Four different phosphorothioated locked nucleic acid-based SSOs (3 antisense and 1 anti-miR), all with known safety profiles, were administered to minipigs using similar study designs and read-outs as in earlier NHP studies with the same compounds. The studies included toxicokinetic investigations, in-life monitoring, clinical and anatomic pathology. In the minipig, we demonstrated target engagement by the SSOs where relevant, and a similar toxicokinetic behavior in plasma, kidney, and liver when compared with NHPs. Clinical tolerability was similar between minipig and NHPs. For the first time, we showed similar and dose-dependent effects on the coagulation and complement cascade after intravenous dosing similar to those observed in NHPs. Similar to NHPs, morphological changes were seen in proximal tubular epithelial cells of the kidney, Kupffer cells, hepatocytes, and lymph nodes. Minipigs appeared more sensitive to the high-dose kidney toxicity of most of the selected SSOs than NHPs. No new target organ or off-target toxicities were identified in the minipig. The minipig did not predict the clinical features of human injection site reactions better than the NHPs, but histopathological similarities were observed between minipigs and NHPs. We conclude that there is no impediment, as default, to the use of minipigs as the non-rodent species in SSO candidate non-clinical safety packages., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.)

Background: The ABO blood group is a major determinant in living donor kidney transplantation since AB antigens are expressed on renal tissue. Little attention has been directed to the ABH-secretor status of the donor kidney. As renal tissue is capable of secreting soluble ABH antigens in secretors, we examined the influence of the ABH-secretor status of kidney donors on outcome in ABO-mismatched living donor kidney transplantation., Study Design and Methods: We retrospectively analyzed all patients who underwent ABO-mismatched kidney transplantation at the University Hospital Basel from September 2005 to October 2013. The ABH-secretor status was determined in all donors by molecular genetic analysis., Results: Of all 55 patients who received transplants, we excluded all patients with donor-specific antibodies (n = 4). Forty-one donors were secretors (78%) and 11 were nonsecretors (22%). Recipients of ABH-secretor donor organs showed a significantly higher glomerular filtration rate throughout the first 6 months posttransplant, whereas no significant influence on posttransplant anti-A/B titers was found. Regression analysis revealed a significant impact on humoral rejection, whereas not on vascular or interstitial rejection in protocol kidney biopsies., Conclusion: The donor ABH-secretor status may have an influence on early posttransplant renal function in patients undergoing ABO-mismatched living donor kidney transplantation. Further prospective studies with long-term follow-up are needed to elucidate involved pathomechanisms., (© 2016 AABB.)

Control of polyomavirus BK (BKV) is achieved by reducing immunosuppression allowing an effective BKV-specific T-cell response. The morphology of resolving BKV-associated nephropathy (PyVAN) has not been systematically investigated. Ninety-nine surveillance biopsies of 35 patients with BKV viremia treated exclusively by immunosuppression reduction were scored according to Banff criteria and grouped relative to BKV viremia as pre-, increasing, decreasing and post-BKV viremia. Thirty-four of 35 patients (97%) cleared BKV viremia after a median of 9 months posttransplantation. The tubulitis score, extent of tubules with intraepithelial lymphocytes, and interstitial inflammation significantly increased from the time of increasing to decreasing viremia. Tubulointerstitial inflammation, to a lower extent, persisted after clearance. The number of SV40+ tubules correlated with the BKV load in plasma, but SV40 immunohistochemistry was frequently negative (60%). During decreasing viremia, 31% of PyVAN cases were plasma cell-rich and 40% showed tubular HLA-DR expression. Compared to baseline 1 month posttransplantation, allograft function remained stable or improved in 29/35 patients (83%) after a median follow-up of 48 months. Within 1 year after clearance of BKV viremia, clinical rejection occurred in 2/35 patients (6%). Our data suggest that resolving PyVAN is typically characterized by a self-limiting acute interstitial nephritis, morphologically indistinguishable from interstitial rejection., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Immunosuppressive maintenance therapy after kidney transplantation leads to various undesired side effects such as calcineurin inhibitor (CNI)-associated nephrotoxicity or elevated cardiovascular risk due to posttransplantation diabetes and hypertension. These effects show negative impacts on long-term allograft function as well as patient morbidity and mortality. Therefore, we used an immunosuppressive regimen with early corticosteroid withdrawal (ESW), maintenance therapy containing tacrolimus, sirolimus (SRL), and mycophenolate sodium for 3 months followed by a prospective randomized trial comparing a CNI free versus a low-dose CNI therapy. The primary endpoint was 6-month graft function. Among 75 patients, ESW was performed after 4 days in 65 patients. Over the following 3 months before randomization to CNI-free maintenance therapy, we experienced a high number (25%) of SRL discontinuations due to adverse events, including leukopenia, anemia, arthritis, and pneumonitis. In addition there were significantly more allograft rejection episodes in the CNI-free group (P = .017) during the study period leading to a switch from SRL to a CNI. Despite the higher rate of rejection episodes in the CNI-free groups, glomerular filtration rates (GFR) at 6 months were comparable between the study groups (P = .25). After 1 year only 9.2% (6/65) of all patients treated with SRL remained on this drug. Conclusion, there was an unacceptably high rate of SRL intolerance using an ESW and CNI-free immunosuppressive regimen combined with a significantly higher rate of rejection episodes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD.

Fibronectin glomerulopathy (FNG) is a rare, autosomal dominant renal disease with massive mesangial, and subendothelial fibronectin deposits. It presents proteinuria, often in the nephrotic range in the third to fourth decade, and slow progression to end-stage renal disease. The risk of recurrent disease in renal allograft is uncertain. A Japanese female with end-stage renal disease because of unknown origin received a renal transplant and was referred with proteinuria and mild deterioration of renal function four months after transplantation. Five allograft biopsies were underwent from one h to 12 months after the transplantation, including a biopsy 19 d after the transplantation, which revealed dense deposits suggesting fibronectin. A biopsy 134 d after the transplantation showed a feature of lobular glomerulonephritis corresponding FNG. The diagnosis was confirmed by IST4 positive and IST9 negative immunostaining together with typical fibrillary dense deposits in the mesangium and subendothelial spaces in electron microscopy. This is the first report of recurrent FNG in Japan., (© 2012 John Wiley & Sons A/S.)

Background: Protocol biopsies are assigned to fixed points in time after transplantation irrespective of renal function. Usually, it is not known whether there is graft dysfunction at the time of biopsy. This study analyzes repeat protocol biopsies in the absence of any clinical signs of graft dysfunction at the time of biopsy (i.e., "true surveillance biopsy")., Methods: Observational single center study. Kidney transplant recipients with protocol biopsies after 3 and 6 months were analyzed., Results: Three hundred seventy patients had protocol biopsies after 3 and 6 months. One hundred forty-eight patients (40%; 296 biopsies) with a median follow-up of 3.4 years (range, 0.95-7.7 years), fulfilled the criteria of repeat true surveillance biopsies. Graft survival censored for death was 100% at 1 year, 96% at the end of follow-up. One hundred eighty-four biopsies (62%) revealed pathological findings, mainly subclinical rejection (3/6 months: 41% vs. 45%; P = 0.2) and chronic lesions (3/6 months: 22% vs. 44%; P<0.001). Grafts with repeat pathological findings at 3 and 6 months had a significant decline in graft function at end of follow-up compared with grafts with no or only singular pathology (median delta estimated glomerular filtration rate: -10.24 vs. -0.19; P = 0.005). Ninety-three of 148 patients (63%) had a therapeutic intervention as a consequence of the biopsy., Conclusions: Less than 50% of protocol biopsies were performed in the absence of any clinical signs of graft dysfunction. A high proportion of these biopsies revealed pathological findings that were associated with a significant decrease in long-term graft function.

Background: The etiology of nephrocalcinosis is variable. In this study, we wanted to elucidate whether the histopathological appearance of calcium phosphate deposits provides information about possible etiology., Methods: Autopsy cases from the years 1988 to 2007 and native kidney biopsies from a 50-year period (1959-2008) with nephrocalcinosis were identified. The biopsy cases were re-evaluated by light microscopy. The autopsy cases were analysed according to the underlying disease. The biopsy cases were grouped with respect to the likely etiology of nephrocalcinosis. Total number, density, localization, size and pattern of all calcification foci were documented and correlated with clinical and laboratory data., Results: About 223 of 12,960 autopsy cases (1.7%) had nephrocalcinosis, 111 of which (49.8%) suffered from advanced malignant tumours. Nephrocalcinosis was the main diagnosis in 48 of 12,480 native kidney biopsies (0.4%). Clinicopathological correlation revealed a specific pattern of calcification associated with hyperphosphataemia and/or hyperphosphaturia: these cases showed predominant globular or shell-like calcifications (phosphate type). In contrast, the biopsies of the hypercalcaemic/hypercalciuric group had a different predominant pattern with clumpy or finely granular calcifications (calcium type)., Conclusions: Our results indicate that hyperphosphaturia-associated cases of nephrocalcinosis can be distinguished from hypercalciuria-associated cases histopathologically.

From 1995 Polyomavirus (PyV) nephropathy (PVN) has played an important role in solid organ transplant recipients. The disease is caused by a DNA virus, usually the BK variant, more rarely JC virus. In immune incompetent patients either latent endogenous virus is reactivated, or donated virus can multiply. The frequency of PVN nephropathy (previously 10% or higher) is declining. The disease follows a stepwise course: viruria, viraemia, nephropathy. Nephropathy usually manifests itself during the first year after transplantation. The disease remains clinically silent for long periods, later progressive loss of renal function and renal failure occur. A major risk factor is therapy with potent immune suppressive agents. Morphologically, viral replication produces nuclear inclusions and necrosis, predominantly in the urothelium and tubular epithelium. Inflammation (T and B lymphocytes, monocytes/macrophages and granulocytes) accompanies necrosis. Progression is marked by tubular atrophy, interstitial fibrosis and transplant loss. The virus can be detected by the electron microscope and, better, by immunohistology (preferentially mAb against SV40 Large T antigen). It is often hard to differentiate PVN from an interstitial cellular rejection reaction (Banff 1 A/B). As no effective drug treatment exists, the disease must be diagnosed as early as possible and immune suppression reduced. Screening for polyomavirus reactivation is best done stepwise: search for urinary "Decoy cells" (PyV infected cells), PCR for PyV in the blood and in the case of reduced renal function, renal biopsy. Compliance with a stringent screening algorithm allows early detection and adequate treatment and prevents organ loss.

Background: Renal amyloidosis results from protein misfolding and leads to progressive renal insufficiency. Few data are available concerning the relevance of the histomorphological patterns and the dynamics of the disease process., Methods: Cases of renal amyloidosis in native kidney biopsies (n = 203) were retrospectively evaluated for the pattern of amyloid distribution, the extent of glomerular amyloid deposition and the amount of interstitial fibrosis and tubular atrophy. One hundred and fifty-eight cases were characterized by immunohistochemistry to determine the biochemical amyloid type. Morphological findings were correlated with available clinical data., Results: According to the predominant site of amyloid deposition, 84.6% showed a glomerular, 9.4% a vascular and 6% a tubulointerstitial distribution pattern. Within the glomeruli, amyloid was initially deposited in a focal segmental fashion that became diffuse and global in later stages. Most cases were identified as AL lambda (84/158) or AA (68/158). There was no correlation between the biochemical type and the distribution pattern. Serum creatinine correlated well with interstitial fibrosis and tubular atrophy and proteinuria with the glomerular amyloid load., Conclusions: The relevance of the different distribution patterns is unclear at the moment, but they may be due to the physicochemical properties of the amyloid fibrils in a given patient. This may become important in future anti-fibrillar therapies.

The virtual crossmatch (virtual-XM) has been proposed for accurate identification of donor-specific HLA-antibodies, but large prospective studies assessing its value for pretransplant risk stratification are lacking. A total of 233 consecutive renal allograft recipients were prospectively stratified according to the virtual-XM. In patients with a negative virtual-XM (n=190, 82%), prospective cytotoxicity crossmatches (CDC-XM) were omitted, and they received standard immunosuppression. Virtual-XM positive patients were only transplanted if CDC-XM were negative. They received additional induction with anti-T-lymphocyte-globulin and intravenous immunoglobulins (n=43, 18%). The cumulative incidence of clinical/subclinical antibody-mediated rejection (AMR) at 1 year was lower in the negative virtual-XM than in the positive virtual-XM group [15/190 (8%) vs. 18/43 (42%); P<0.0001]. After a median follow-up of 2.6 years, allograft loss because of AMR occurred less often in the negative virtual-XM group (1% vs. 7%; P=0.04) and death-censored allograft survival at 2 years was higher (98% vs. 91%; P=0.02). Serum creatinine was not different at the last follow-up (129 μm vs. 130 μm; P=0.58). We conclude that a negative virtual-XM defines patients at low risk for AMR and early allograft loss, while a positive virtual-XM represents a significant risk for AMR despite enhanced induction therapy. This supports the utility of the virtual-XM for risk stratification and treatment allocation., (© 2011 The Authors. Transplant International © 2011 European Society for Organ Transplantation.)

Background: In systemic lupus erythematosus patients, a strong association between the occurrence of antibodies against complement C1q (anti-C1q) and lupus nephritis can be observed. However, the predictive value of anti-C1q titres for a renal flare remains to be determined. Increasing titres of anti-C1q before the occurrence of clinical apparent nephritis might not only serve as a clinical parameter but also indicate a direct pathogenic mechanism of anti-C1q., Methods: The aim of this study was to analyse the occurrence of anti-C1q before the onset of experimental lupus nephritis in MRL/MpJ +/+ mice and to correlate anti-C1q titres with the type and severity of glomerulonephritis (GN) developing at advanced age., Results: As judged by a number of morphological and immunological analyses, GN in MRL/MpJ +/+ mice resembled human lupus nephritis and occurred in variable degrees of severity. We also observed an abundant and early presence of anti-C1q. However, anti-C1q neither correlated with overall survival nor with any histological marker of severity of GN., Conclusions: The absence of a correlation between the presence of anti-C1q and the occurrence of experimental lupus nephritis contradicts the hypothesis that anti-C1q are pathogenic. However, different pathogenic mechanisms of experimental lupus nephritis and human proliferative lupus nephritis cannot be excluded.

Early detection of polyomavirus BK (BKV) viremia and reduction of immunosuppression is recommended for preventing polyomavirus-associated nephropathy (PyVAN), but systematic histological evaluations were not performed in previous studies. We routinely screen for decoy cells and, if positive, measure plasma BKV-loads. In a cohort of 203 consecutive renal transplantations performed from 2005-2008, 38 patients (19%) developed BKV-viremia and were treated with reduction of immunosuppression. Based on subsequent allograft biopsy results and peak BKV-viremia, patients were assigned to three groups: (i) definitive PyVAN (n = 13), (ii) presumptive PyVAN defined by plasma BKV-loads of ≥ 4 log(10) copies/ml (n = 17) and (iii) low BKV-viremia (n = 8). Clearance of BKV-viremia was achieved in 35/38 patients (92%) and subsequent clinical rejection occurred in 3/35 patients (8.6%), both without any difference among the groups. Patients with definitive PyVAN had higher peak plasma BKV-loads and required longer time for clearance (8.8 vs. 4.6 vs. 2.9 months; p = 0.001). However, allograft function remained stable from baseline to last follow-up at 34 months (range 18-60) in all three groups with median serum creatinine of 1.6 mg/dl, 1.6 mg/dl and 1.3 mg/dl, respectively. We conclude that screening for BKV-replication and reduction of immunosuppression is an effective strategy to preserve medium-term allograft function even in patients developing definitive PyVAN., (©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Low-level donor-specific HLA-antibodies (HLA-DSA) (i.e. detectable by single-antigen flow beads, but negative by complement-dependent cytotoxicity crossmatch) represent a risk factor for early allograft rejection. The short-term efficacy of an induction regimen consisting of polyclonal anti-T-lymphocyte globulin (ATG) and intravenous immunoglobulins (IvIg) in patients with low-level HLA-DSA is unknown. In this study, we compared 67 patients with low-level HLA-DSA not having received ATG/IvIg induction (historic control) with 37 patients, who received ATG/IvIg induction. The two groups were equal regarding retransplants, HLA-matches, number and class of HLA-DSA. The overall incidence of clinical/subclinical antibody-mediated rejection (AMR) was lower in the ATG/IvIg than in the historic control group (38% vs. 55%; p = 0.03). This was driven by a significantly lower rate of clinical AMR (11% vs. 46%; p = 0.0002). Clinical T-cell-mediated rejection (TCR) was significantly lower in the ATG/IvIg than in the historic control group (0% vs. 50%; p < 0.0001). Within the first year, allograft loss due to AMR occurred in 7.5% in the historic control and in 0% in the ATG/IvIg group. We conclude that in patients with low-level HLA-DSA, ATG/IvIg induction significantly reduces TCR and the severity of AMR, but the high rate of subclinical AMR suggests an insufficient control of the humoral immune response.

Polyomavirus (PV) associated nephropathy (PVAN) has become an important cause of allograft dysfunction. We studied plasma cells (PCs) - which have not yet been characterized - present in the cellular infiltrate of 20 PVAN cases using immunohistochemistry and morphometry. The results were correlated with morphological, clinical and anti-BK virus serological findings. PC-rich cellular infiltrates occurred in 50% of cases (>15% PCs in the cellular infiltrate) and in these IgM producing PCs were commonly seen (70%): IgM PC predominance in 50% of cases and a comparable number of IgM and IgG PCs in 20% of cases. We found a significant correlation not just between the absolute numbers (P < 0.034) and the percentage values of IgM PCs (P < 0.004 in relation to all cells) and the serum IgM-Ab anti-BKV activity, but also between the ratio of IgG/IgM PCs and the ratio of serum IgG/IgM-Ab activities (P < 0.0001). We showed that IgM PC counts in biopsies correlate with titers of circulating anti-BK virus IgM antibodies. Every case except one was C4d negative in peritubular capillaries (PTC). As IgG PCs characterize PC-rich rejection cases, we suggest that in the presence of IgM PCs in PC-rich infiltrate with PTC C4d negativity, a search for possible PVAN infection should be initiated.

Background: The impact of different therapy modalities on the outcome of Immunoglobulin A glomerulonephritis (IgAGN) in individual patient is not clear. We present preliminary results from the sequential application of renin-angiotensin system (RAS) inhibition and corticosteroids to discriminate the individual effect of both therapies., Methods: Regardless of the degree of proteinuria, renal function and histological grading, patients with biopsy-proven IgAGN were treated with a standardized protocol. RAS inhibition was performed for 3 months. Thereafter, immunosuppressive therapy with prednisone (0.5 mg/kg body weight) on alternate days for 6 months was started. The primary endpoint was a maximal reduction of proteinuria (spot urine protein/ creatinine ratio (uPCR)), by RAS inhibition and by the combination of RAS inhibition and steroids., Results: 10 patients were treated according to the protocol. During a median follow-up of 18 months, uPCR decreased from initial 230 mg/mmol (2 g/g) (median, interquartile range (IQR) 146 - 396) to 154 mg/mmol (1.4 g/g) (IQR 88 - 190) at 3 months during the RAS inhibition period (33% reduction, p = 0.01) and further to 31 mg/mmol (0.3 g/g) (IQR 21 - 71) until end of the steroid period at 9 months (80% reduction compared to uPCR at 3 month, p < 0.001). At the last F/U, uPCR (median) remained stable at 41 mg/mmol (0.4 g/g). The estimated glomerular filtration rate was stable during the whole observation period., Conclusions: Sequential RAS inhibition and steroid treatment leads to a continuous decrease in proteinuria, beyond the decrease produced by isolated RAS inhibition. Our data suggest independent effects of both, RAS inhibition and steroids, on the reduction of proteinuria in a small, non selected group of patients with IgAGN. The hypothesis that patients with IgAGN, regardless of the degree of proteinuria, renal function and histological grading, may benefit from combination therapy with maximal RAS inhibition and low dose corticosteroids now has to be confirmed in a randomized study.

Background: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed on various cell types and mediates homophilic cell adhesion. CEACAM1 plays an important role in cell morphogenesis and angiogenesis. Furthermore, CEACAM1 regulates adhesive activity of immune-competent cells, suggesting an additional role in inflammatory processes., Methods: Therefore, in the present study the expression of CEACAM1 was analysed retrospectively in renal biopsies from kidney transplant recipients (stable graft [Ctr; n = 18], acute vascular rejection [AVR; n = 14], acute tubulointerstitial rejection [AIR; n = 9], and combined vascular and interstitial rejection [AVIR; n = 7]). Expression patterns of CEACAM1 were determined using immunohistochemistry and quantitative morphometry., Results: All biopsy specimens from patients with stable grafts showed low CEACAM1 levels, suggesting a constitutive expression in renal transplants. In patients with acute rejection, CEACAM1 was markedly up-regulated. AVR revealed the highest tubular CEACAM1 levels (4.9 +/- 0.5% [AVR] vs 2.2 +/- 0.3% [Ctr] of tubular area; P < .05), whereas interstitial rejections showed the highest glomerular expressions (4.5 +/- 0.5% [AIR] vs 0.9 +/- 0.1% [Ctr] of glomerular area; P < .05)., Conclusions: An up-regulated expression of CEACAM1 in tubular and/or glomerular cells is an indicator of acute inflammatory processes in biopsy specimens from patients with acute renal allograft rejections and, therefore, might be used as a new clinical marker.

Accurate prognostic parameters in prostate biopsies are needed to better counsel individual patients with prostate cancer. We evaluated the prognostic impact of morphologic and immunohistochemical parameters in preoperative prostate cancer biopsies. A consecutive series of prostate biopsies of 279 men (72% with clinical stage T1c and 23% with T2) who subsequently underwent radical prostatectomy was prospectively analysed for Gleason score, number and percentage of positive cores (NPC, PPC), total percentage of biopsy tissue with tumour (TPT), maximum tumour percentage per core (MTP), and expression of Ki67, Bcl-2 and p53. All biopsy features were significantly associated with at least one feature of the radical prostatectomy specimen. pT stage was independently predicted by PSA, seminal vesicle invasion by Ki67 LI, positive margins by PSA and MTP, large tumour diameter by PSA and PPC, and Gleason score by biopsy Gleason score, MTP, and Ki67 LI, respectively. Biopsy Gleason score, NPC (1 vs. >1), TPT (<7 vs. >or=7%), and Ki67 LI (<10 vs. >or=10%) were significant predictors of biochemical recurrence after radical prostatectomy (p < 0.01, each). KI67 LI was the only independent prognostic factor in case of a low TPT (<7%) or low Gleason score (<7), the hazard ratio being 6.76 and 6.44, respectively. In summary, preoperative Gleason score, NPC, TPT and Ki67 LI significantly predict the risk of recurrence after radical prostatectomy, and Ki67 is an independent prognosticator in biopsies with low-volume or low-grade prostate cancer. Analysis of Ki67 LI in these biopsies may help to better identify patients with clinically insignificant prostate cancer., ((c) 2008 Wiley-Liss, Inc.)