The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of biopsies from solid organ transplants. Since its initial conception in 1991 for renal ...transplants, it has undergone review every 2 years, with attendant updated publications. The rapid expansion of knowledge in the field has led to numerous revisions of the classification. The resultant dispersal of relevant content makes it difficult for novices and experienced pathologists to faithfully apply the classification in routine diagnostic work and in clinical trials. This review shall provide a complete and simple illustrated reference guide of the Banff Classification of Kidney Allograft Pathology based on all publications including the 2017 update. It is intended as a concise desktop reference for pathologists and clinicians, providing definitions, Banff Lesion Scores and Banff Diagnostic Categories. An online website reference guide hosted by the Banff Foundation for Allograft Pathology (www.banfffoundation.org) is being developed, which will be updated with future refinement of the Banff Classification from 2019 onward.
Seeding strategies have strong influences on the success of viral marketing campaigns, but previous studies using computer simulations and analytical models have produced conflicting recommendations ...about the optimal seeding strategy. This study compares four seeding strategies in two complementary small-scale field experiments, as well as in one real-life viral marketing campaign involving more than 200,000 customers of a mobile phone service provider. The empirical results show that the best seeding strategies can be up to eight times more successful than other seeding strategies. Seeding to well-connected people is the most successful approach because these attractive seeding points are more likely to participate in viral marketing campaigns. This finding contradicts a common assumption in other studies. Well-connected people also actively use their greater reach but do not have more influence on their peers than do less well-connected people.
Progressive renal diseases are associated with rarefaction of peritubular capillaries, but the ultrastructural and functional alterations of the microvasculature are not well described. To study ...this, we analyzed different time points during progressive kidney damage and fibrosis in 3 murine models of different disease etiologies. These models were unilateral ureteral obstruction, unilateral ischemia-reperfusion injury, and Col4a3-deficient mice, we analyzed ultrastructural alterations in patient biopsy specimens. Compared with kidneys of healthy mice, we found a significant and progressive reduction of peritubular capillaries in all models analyzed. Ultrastructurally, compared with the kidneys of control mice, focal widening of the subendothelial space and higher numbers of endothelial vacuoles and caveolae were found in fibrotic kidneys. Quantitative analysis showed that peritubular capillary endothelial cells in fibrotic kidneys had significantly and progressively reduced numbers of fenestrations and increased thickness of the cell soma and lamina densa of the capillary basement membrane. Similar ultrastructural changes were also observed in patient's kidney biopsy specimens. Compared with healthy murine kidneys, fibrotic kidneys had significantly increased extravasation of Evans blue dye in all 3 models. The extravasation could be visualized using 2-photon microscopy in real time in living animals and was mainly localized to capillary branching points. Finally, fibrotic kidneys in all models exhibited a significantly greater degree of interstitial deposition of fibrinogen. Thus, peritubular capillaries undergo significant ultrastructural and functional alterations during experimental progressive renal diseases, independent of the underlying injury. Analyses of these alterations could provide read-outs for the evaluation of therapeutic approaches targeting the renal microvasculature.
The Oxford Classification of IgA nephropathy does not account for glomerular crescents. However, studies that reported no independent predictive role of crescents on renal outcomes excluded ...individuals with severe renal insufficiency. In a large IgA nephropathy cohort pooled from four retrospective studies, we addressed crescents as a predictor of renal outcomes and determined whether the fraction of crescent-containing glomeruli associates with survival from either a ≥50% decline in eGFR or ESRD (combined event) adjusting for covariates used in the original Oxford study. The 3096 subjects studied had an initial mean±SD eGFR of 78±29 ml/min per 1.73 m
and median (interquartile range) proteinuria of 1.2 (0.7-2.3) g/d, and 36% of subjects had cellular or fibrocellular crescents. Overall, crescents predicted a higher risk of a combined event, although this remained significant only in patients not receiving immunosuppression. Having crescents in at least one sixth or one fourth of glomeruli associated with a hazard ratio (95% confidence interval) for a combined event of 1.63 (1.10 to 2.43) or 2.29 (1.35 to 3.91), respectively, in all individuals. Furthermore, having crescents in at least one fourth of glomeruli independently associated with a combined event in patients receiving and not receiving immunosuppression. We propose adding the following crescent scores to the Oxford Classification: C0 (no crescents); C1 (crescents in less than one fourth of glomeruli), identifying patients at increased risk of poor outcome without immunosuppression; and C2 (crescents in one fourth or more of glomeruli), identifying patients at even greater risk of progression, even with immunosuppression.
Geographic proximity has become increasingly relevant due to the growing number of marketing services that use consumers' geographic locations, thus increasing the importance of gaining insights from ...this information. In five studies (both field and experimental), the authors analyze the effect of geographic proximity on social influence and demonstrate that not only social proximity but also perceived homophily can trigger social influence. They find that this effect holds under alternative representations of geographic distance and is confirmed for a range of different services and even for physical goods. Furthermore, the authors show that geographic proximity has a relative effect because the social influence of a closer sender is stronger than that of a more distant sender, regardless of the absolute distances. They present managerially relevant conditions under which the influence of geographic proximity not only is comparable to other types of information such as age or gender but also provides sufficient informational value for customers to offset differences among alternatives (e.g., due to higher prices) in trade-off decisions.
Serum oxalate levels suddenly increase with certain dietary exposures or ethylene glycol poisoning and are a well known cause of AKI. Established contributors to oxalate crystal-induced renal ...necroinflammation include the NACHT, LRR and PYD domains-containing protein-3 (NLRP3) inflammasome and mixed lineage kinase domain-like (MLKL) protein-dependent tubule necroptosis. These studies examined the role of a novel form of necrosis triggered by altered mitochondrial function.
To better understand the molecular pathophysiology of oxalate-induced AIK, we conducted
studies in mouse and human kidney cells and
studies in mice, including wild-type mice and knockout mice deficient in peptidylprolyl isomerase F (Ppif) or deficient in both Ppif and Mlkl.
Crystals of calcium oxalate, monosodium urate, or calcium pyrophosphate dihydrate, as well as silica microparticles, triggered cell necrosis involving PPIF-dependent mitochondrial permeability transition. This process involves crystal phagocytosis, lysosomal cathepsin leakage, and increased release of reactive oxygen species. Mice with acute oxalosis displayed calcium oxalate crystals inside distal tubular epithelial cells associated with mitochondrial changes characteristic of mitochondrial permeability transition. Mice lacking Ppif or Mlkl or given an inhibitor of mitochondrial permeability transition displayed attenuated oxalate-induced AKI. Dual genetic deletion of
and
or pharmaceutical inhibition of necroptosis was partially redundant, implying interlinked roles of these two pathways of regulated necrosis in acute oxalosis. Similarly, inhibition of mitochondrial permeability transition suppressed crystal-induced cell death in primary human tubular epithelial cells. PPIF and phosphorylated MLKL localized to injured tubules in diagnostic human kidney biopsies of oxalosis-related AKI.
Mitochondrial permeability transition-related regulated necrosis and necroptosis both contribute to oxalate-induced AKI, identifying PPIF as a potential molecular target for renoprotective intervention.
First-principles calculations and molecular-dynamics simulations are employed in this study to further our understanding of the crystal structure and orientational order of carbonate ions in ...vaterite, which is the least stable polymorph of calcium carbonate. The structural details of vaterite have been controversial but they are prerequisite for investigating and understanding the processes involving vaterite crystal nucleation, growth, and stabilization at a molecular level. The first-principles calculations, using density functional theory with the plane-wave pseudopotential method, are carried out to calculate relative thermodynamic stabilities of proposed structures. Molecular-dynamics simulations with classical empirical potentials, larger computational cells, and fully flexible models at different temperatures are performed to investigate the orientation and order-disorder of the carbonate ions. The results show that the previously accepted structure with disordered CO3 ions, which are randomly distributed over three orientations parallel to the c axis, is only metastable. By applying a temperature annealing technique to the molecular dynamics simulations, a more stable structure with fully ordered carbonate ions is found that has a hexagonal superstructure. The space group of this newly derived vaterite structure is P6522 (no. 179) with Z = 18 and cell dimensions of √3 times in a, and 3 times in c of the previous suggested disordered structure. Comparison of experimental observations of X-ray diffraction patterns, enthalpies of transformation to calcite, and volume change by heat treatment with our theoretical calculations indicates that freshly made vaterite is often carbonate-disordered and metastable and can fully or partially transform to a carbonate-ordered structure by aging and heating.
Acute kidney injury (AKI) leads to significant morbidity and mortality; unfortunately, strategies to prevent or treat AKI are lacking. In recent years, several preconditioning protocols have been ...shown to be effective in inducing organ protection in rodent models. Here, we characterized two of these interventions—caloric restriction and hypoxic preconditioning—in a mouse model of cisplatin-induced AKI and investigated the underlying mechanisms by acquisition of multi-layered omic data (transcriptome, proteome, N-degradome) and functional parameters in the same animals. Both preconditioning protocols markedly ameliorated cisplatin-induced loss of kidney function, and caloric restriction also induced lipid synthesis. Bioinformatic analysis revealed mRNA-independent proteome alterations affecting the extracellular space, mitochondria, and transporters. Interestingly, our analyses revealed a strong dissociation of protein and RNA expression after cisplatin treatment that showed a strong correlation with the degree of damage. N-degradomic analysis revealed that most posttranscriptional changes were determined by arginine-specific proteolytic processing. This included a characteristic cisplatin-activated complement signature that was prevented by preconditioning. Amyloid and acute-phase proteins within the cortical parenchyma showed a similar response. Extensive analysis of disease-associated molecular patterns suggested that transcription-independent deposition of amyloid P-component serum protein may be a key component in the microenvironmental contribution to kidney damage. This proof-of-principle study provides new insights into the pathogenesis of cisplatin-induced AKI and the molecular mechanisms underlying organ protection by correlating phenotypic and multi-layered omics data.
Display omitted
Autosomal dominant polycystic kidney disease (ADPKD) is typically a late-onset disease caused by mutations in PKD1 or PKD2, but about 2% of patients with ADPKD show an early and severe phenotype that ...can be clinically indistinguishable from autosomal recessive polycystic kidney disease (ARPKD). The high recurrence risk in pedigrees with early and severe PKD strongly suggests a common familial modifying background, but the mechanisms underlying the extensive phenotypic variability observed among affected family members remain unknown. Here, we describe severely affected patients with PKD who carry, in addition to their expected familial germ-line defect, additional mutations in PKD genes, including HNF-1β, which likely aggravate the phenotype. Our findings are consistent with a common pathogenesis and dosage theory for PKD and may propose a general concept for the modification of disease expression in other so-called monogenic disorders.
Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the ...pore-forming protein gasdermin D (GSDMD). Here, we report a specific pattern of GSDMD-protein expression in the peritubular compartment of mice that underwent bilateral ischemia and reperfusion injury (IRI). Along similar lines, the GSDMD-protein expression in whole kidney lysates increased during the first 84 h following cisplatin-induced AKI. Importantly, unlike whole kidney lysates, no GSDMD-protein expression was detectable in isolated kidney tubules. In IRI and cisplatin-induced AKI, GSDMD-deficient mice exhibited hypersensitivity to injury as assessed by tubular damage, elevated markers of serum urea, and serum creatinine. This hypersensitivity was reversed by a combined deficiency of GSDMD and the necroptosis mediator mixed lineage kinase domain-like (MLKL). In conclusion, we demonstrate a non-cell autonomous role for GSDMD in protecting the tubular compartment from necroptosis-mediated damage in IRI.
PDF
