Defining the Nature and Clinicopathologic Significance of Mallory-Denk-like Inclusions in Ovarian Fibromas: A Potential Degenerative Phenomenon Associated With Torsion.

Mallory-Denk bodies (MBD), described in alcoholic hepatitis, are composed of intermediate filaments admixed with other proteins. These cytoplasmic inclusions are irregularly shaped and eosinophilic as seen under the light microscope. MBD-like inclusions have rarely been described outside the hepatobiliary tree. Though rare, intracytoplasmic inclusions have been reported in ovarian fibromas. This study evaluates a series of torsed ovarian fibromas with intracytoplasmic inclusions resembling MDBs. Forty-three ovarian fibromas were retrieved from the pathology archives. The H&E slides were evaluated for the presence of MBD-like inclusions and histologic evidence of torsion. The cases with histologic features of torsion were included in the study group while the nontorsed fibromas formed the control group. Among the 15 cases of fibromas with torsion, MBD-like intracytoplasmic inclusions were seen in 5 cases, predominantly in the interface between necrotic areas and viable stroma. None of the cases from the control group showed any inclusions. There was no significant difference in the size of the fibroma or patient demographics between cases with and without inclusions. The inclusions were positive for cytokeratin and ubiquitin while being negative for per acidic Schiff and periodic acid-Schiff with diastase reaction, in the 3 cases selected for immunohistochemistry and special stains. Electron microscopy of the index case revealed a predominance of type 3 Mallory hyaline. This is the first report describing MDB-like inclusions in ovarian fibromas. These MDB-like inclusions appear to be limited to a fraction of ovarian fibromas that underwent torsion, suggesting that these inclusions likely result from subacute hypoxic damage to the cells.

Kidney Tubulointerstitial Fibrosis and Tubular Secretion.

RATIONALE & OBJECTIVE: Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) is associated with lower tubular secretory clearance in persons undergoing kidney biopsy. STUDY DESIGN: Cross-sectional. SETTINGS & PARTICIPANTS: The Boston Kidney Biopsy Cohort is a study of persons undergoing native kidney biopsies for clinical indications. EXPOSURES: Semiquantitative score of IFTA reported by 2 trained pathologists. OUTCOMES: We measured plasma and urine concentrations of 9 endogenous secretory solutes using a targeted liquid chromatography/mass spectrometry assay. We used linear regression to test associations of urine-to-plasma ratios (UPRs) of these solutes with IFTA score after controlling for estimated glomerular filtration rate (eGFR) and albuminuria. RESULTS: Among 418 participants, mean age was 53 years, 51% were women, 64% were White, and 18% were Black. Mean eGFR was 50mL/min/1.73m2, and median urinary albumin-creatinine ratio was 819mg/g. Compared with individuals with≤25% IFTA, those with>50% IFTA had 12%-37% lower UPRs for all 9 secretory solutes. Adjusting for age, sex, race, eGFR, and urine albumin and creatinine levels attenuated the associations, yet a trend of lower secretion across groups remained statistically significant (P<0.05 for trend) for 7 of 9 solutes. A standardized composite secretory score incorporating UPR for all 9 secretory solutes using the min-max method showed similar results (P<0.05 for trend). LIMITATIONS: Single time point and spot measures of secretory solutes. CONCLUSIONS: Greater IFTA severity is associated with lower clearance of endogenous secretory solutes even after adjusting for eGFR and albuminuria.

Plasma Kidney Injury Molecule 1 in CKD: Findings From the Boston Kidney Biopsy Cohort and CRIC Studies.

RATIONALE & OBJECTIVE: Plasma kidney injury molecule 1 (KIM-1) is a sensitive marker of proximal tubule injury, but its association with risks of adverse clinical outcomes across a spectrum of kidney diseases is unknown. STUDY DESIGN: Prospective, observational cohort study. SETTING & PARTICIPANTS: 524 individuals enrolled into the Boston Kidney Biopsy Cohort (BKBC) Study undergoing clinically indicated native kidney biopsy with biopsy specimens adjudicated for semiquantitative scores of histopathology by 2 kidney pathologists and 3,800 individuals with common forms of chronic kidney disease (CKD) enrolled into the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE: Histopathologic lesions and clinicopathologic diagnosis in cross-sectional analyses, baseline plasma KIM-1 levels in prospective analyses. OUTCOMES: Baseline plasma KIM-1 levels in cross-sectional analyses, kidney failure (defined as initiation of kidney replacement therapy) and death in prospective analyses. ANALYTICAL APPROACH: Multivariable-adjusted linear regression models tested associations of plasma KIM-1 levels with histopathologic lesions and clinicopathologic diagnoses. Cox proportional hazards models tested associations of plasma KIM-1 levels with future kidney failure and death. RESULTS: In the BKBC Study, higher plasma KIM-1 levels were associated with more severe acute tubular injury, tubulointerstitial inflammation, and more severe mesangial expansion after multivariable adjustment. Participants with diabetic nephropathy, glomerulopathies, and tubulointerstitial disease had significantly higher plasma KIM-1 levels after multivariable adjustment. In the BKBC Study, CKD in 124 participants progressed to kidney failure and 85 participants died during a median follow-up time of 5 years. In the CRIC Study, CKD in 1,153 participants progressed to kidney failure and 1,356 participants died during a median follow-up time of 11.5 years. In both cohorts, each doubling of plasma KIM-1 level was associated with an increased risk of kidney failure after multivariable adjustment (hazard ratios of 1.19 [95% CI, 1.03-1.38] and 1.10 [95% CI, 1.06-1.15] for BKBC and CRIC, respectively). There was no statistically significant association of plasma KIM-1 levels with death in either cohort. LIMITATIONS: Generalizability and unmeasured confounding. CONCLUSIONS: Plasma KIM-1 is associated with underlying tubulointerstitial and mesangial lesions and progression to kidney failure in 2 cohort studies of individuals with kidney diseases.

PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection.

The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischaemia. Acute kidney injury (AKI) affects 3% of all hospitalized patients. Here we show that the mitochondrial biogenesis regulator, PGC1α, is a pivotal determinant of renal recovery from injury by regulating nicotinamide adenine dinucleotide (NAD) biosynthesis. Following renal ischaemia, Pgc1α(-/-) (also known as Ppargc1a(-/-)) mice develop local deficiency of the NAD precursor niacinamide (NAM, also known as nicotinamide), marked fat accumulation, and failure to re-establish normal function. Notably, exogenous NAM improves local NAD levels, fat accumulation, and renal function in post-ischaemic Pgc1α(-/-) mice. Inducible tubular transgenic mice (iNephPGC1α) recapitulate the effects of NAM supplementation, including more local NAD and less fat accumulation with better renal function after ischaemia. PGC1α coordinately upregulates the enzymes that synthesize NAD de novo from amino acids whereas PGC1α deficiency or AKI attenuates the de novo pathway. NAM enhances NAD via the enzyme NAMPT and augments production of the fat breakdown product ß-hydroxybutyrate, leading to increased production of prostaglandin PGE2 (ref. 5), a secreted autacoid that maintains renal function. NAM treatment reverses established ischaemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of ß-hydroxybutyrate signalling or prostaglandin production similarly abolishes PGC1α-dependent renoprotection. Given the importance of mitochondrial health in ageing and the function of metabolically active organs, the results implicate NAM and NAD as key effectors for achieving PGC1α-dependent stress resistance.

Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis.

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

N-glycosylated IgG in patients with kidney transplants increases calcium/calmodulin kinase IV in podocytes and causes injury.

Transplant glomerulopathy (TG) is a major cause of late allograft loss. Increased urine podocin/creatinine ratio in TG signifies accelerated podocyte loss. The mechanisms that lead to podocyte injury in TG remain unclear. We report that IgG from kidney transplant recipients with TG, but not from those without TG, cause a reduction in the expression of nephrin, significant podocyte actin cytoskeleton, and motility changes. These changes are preceded by increased expression of calcium/calmodulin kinase IV (CAMK4). Mechanistically, we found that CAMK4 phosphorylates GSK3ß (glycogen synthase kinase 3 beta), activates the Wnt pathway and stabilizes the nephrin transcriptional repressor SNAIL. Silencing neonatal Fc Receptor (FcRn) or CAMK4 prevented the podocyte-damaging effects of IgG from patients with TG. Furthermore, we show that removal of N-linked glycosyl residues from these IgG did not interfere with its entry into the podocytes but eliminated its ability to upregulate CAMK4 and cause podocyte injury. The translational value of these findings is signified by the fact that CAMK4 is increased in podocytes of patients with TG but not in those without TG despite other forms of renal dysfunction. Our results offer novel considerations to limit podocyte injury in patients with kidney transplants, which may lead to eventual glomerular destabilization and transplant glomerulopathy.

T Cell-Specific Adaptor Protein Regulates Mitochondrial Function and CD4+ T Regulatory Cell Activity In Vivo following Transplantation.

The T cell-specific adaptor protein (TSAd), encoded by the SH2D2A gene, is an intracellular molecule that binds Lck to elicit signals that result in cytokine production in CD4+ T effector cells (Teff). Nevertheless, using Sh2d2a knockout (KO; also called TSAd-/-) mice, we find that alloimmune CD4+ Teff responses are fully competent in vivo. Furthermore, and contrary to expectations, we find that allograft rejection is accelerated in KO recipients of MHC class II-mismatched B6.C-H-2bm12 heart transplants versus wild-type (WT) recipients. Also, KO recipients of fully MHC-mismatched cardiac allografts are resistant to the graft-prolonging effects of costimulatory blockade. Using adoptive transfer models, we find that KO T regulatory cells (Tregs) are less efficient in suppressing Teff function and they produce IFN-γ following mitogenic activation. In addition, pyrosequencing demonstrated higher levels of methylation of CpG regions within the Treg-specific demethylated region of KO versus WT Tregs, suggesting that TSAd, in part, promotes Treg stability. By Western blot, Lck is absent in the mitochondria of KO Tregs, and reactive oxygen species production by mitochondria is reduced in KO versus WT Tregs. Full transcriptomic analysis demonstrated that the key mechanism of TSAd function in Tregs relates to its effects on cellular activation rather than intrinsic effects on mitochondria/metabolism. Nevertheless, KO Tregs compensate for a lack of activation by increasing the number of mitochondria per cell. Thus, TSAd serves as a critical cell-intrinsic molecule in CD4+Foxp3+ Tregs to regulate the translocation of Lck to mitochondria, cellular activation responses, and the development of immunoregulation following solid organ transplantation.

FSGS-Causing INF2 Mutation Impairs Cleaved INF2 N-Fragment Functions in Podocytes.

BACKGROUND: Mutations in the gene encoding inverted formin-2 (INF2), a member of the formin family of actin regulatory proteins, are among the most common causes of autosomal dominant FSGS. INF2 is regulated by interaction between its N-terminal diaphanous inhibitory domain (DID) and its C-terminal diaphanous autoregulatory domain (DAD). INF2 also modulates activity of other formins, such as the mDIA subfamily, and promotes stable microtubule assembly. Why the disease-causing mutations are restricted to the N terminus and how they cause human disease has been unclear. METHODS: We examined INF2 isoforms present in podocytes and evaluated INF2 cleavage as an explanation for immunoblot findings. We evaluated the expression of INF2 N- and C-terminal fragments in human kidney disease conditions. We also investigated the localization and functions of the DID-containing N-terminal fragment in podocytes and assessed whether the FSGS-associated R218Q mutation impairs INF2 cleavage or the function of the N-fragment. RESULTS: The INF2-CAAX isoform is the predominant isoform in podocytes. INF2 is proteolytically cleaved, a process mediated by cathepsin proteases, liberating the N-terminal DID to function independently. Although the N-terminal region normally localizes to podocyte foot processes, it does not do so in the presence of FSGS-associated INF2 mutations. The C-terminal fragment localizes to the cell body irrespective of INF2 mutations. In podocytes, the N-fragment localizes to the plasma membrane, binds mDIA1, and promotes cell spreading in a cleavage-dependent way. The disease-associated R218Q mutation impairs these N-fragment functions but not INF2 cleavage. CONCLUSIONS: INF2 is cleaved into an N-terminal DID-containing fragment and a C-terminal DAD-containing fragment. Cleavage allows the N-terminal fragment to function independently and helps explain the clustering of FSGS-associated mutations.

Phosphorylation of ACTN4 Leads to Podocyte Vulnerability and Proteinuric Glomerulosclerosis.

BACKGROUND: Genetic mutations in α-actinin-4 (ACTN4)-an important actin crosslinking cytoskeletal protein that provides structural support for kidney podocytes-have been linked to proteinuric glomerulosclerosis in humans. However, the effect of post-translational modifications of ACTN4 on podocyte integrity and kidney function is not known. METHODS: Using mass spectrometry, we found that ACTN4 is phosphorylated at serine (S) 159 in human podocytes. We used phosphomimetic and nonphosphorylatable ACTN4 to comprehensively study the effects of this phosphorylation in vitro and in vivo. We conducted x-ray crystallography, F-actin binding and bundling assays, and immunofluorescence staining to evaluate F-actin alignment. Microfluidic organ-on-a-chip technology was used to assess for detachment of podocytes simultaneously exposed to fluid flow and cyclic strain. We then used CRISPR/Cas9 to generate mouse models and assessed for renal injury by measuring albuminuria and examining kidney histology. We also performed targeted mass spectrometry to determine whether high extracellular glucose or TGF-ß levels increase phosphorylation of ACTN4. RESULTS: Compared with the wild type ACTN4, phosphomimetic ACTN4 demonstrated increased binding and bundling activity with F-actin in vitro. Phosphomimetic Actn4 mouse podocytes exhibited more spatially correlated F-actin alignment and a higher rate of detachment under mechanical stress. Phosphomimetic Actn4 mice developed proteinuria and glomerulosclerosis after subtotal nephrectomy. Moreover, we found that exposure to high extracellular glucose or TGF-ß stimulates phosphorylation of ACTN4 at S159 in podocytes. CONCLUSIONS: These findings suggest that increased phosphorylation of ACTN4 at S159 leads to biochemical, cellular, and renal pathology that is similar to pathology resulting from human disease-causing mutations in ACTN4. ACTN4 may mediate podocyte injury as a consequence of both genetic mutations and signaling events that modulate phosphorylation.

Mitochondrial transplantation by intra-arterial injection for acute kidney injury.

Acute kidney injury is a common clinical disorder and one of the major causes of morbidity and mortality in the postoperative period. In this study, the safety and efficacy of autologous mitochondrial transplantation by intra-arterial injection for renal protection in a swine model of bilateral renal ischemia-reperfusion injury were investigated. Female Yorkshire pigs underwent percutaneous bilateral temporary occlusion of the renal arteries with balloon catheters. Following 60 min of ischemia, the balloon catheters were deflated and animals received either autologous mitochondria suspended in vehicle or vehicle alone, delivered as a single bolus to the renal arteries. The injected mitochondria were rapidly taken up by the kidney and were distributed throughout the tubular epithelium of the cortex and medulla. There were no safety-related issues detected with mitochondrial transplantation. Following 24 h of reperfusion, estimated glomerular filtration rate and urine output were significantly increased while serum creatinine and blood urea nitrogen were significantly decreased in swine that received mitochondria compared with those that received vehicle. Gross anatomy, histopathological analysis, acute tubular necrosis scoring, and transmission electron microscopy showed that the renal cortex of the vehicle-treated group had extensive coagulative necrosis of primarily proximal tubules, while the mitochondrial transplanted kidney showed only patchy mild acute tubular injury. Renal cortex IL-6 expression was significantly increased in vehicle-treated kidneys compared with the kidneys that received mitochondrial transplantation. These results demonstrate that mitochondrial transplantation by intra-arterial injection provides renal protection from ischemia-reperfusion injury, significantly enhancing renal function and reducing renal damage.

The utility of magnetic resonance imaging for noninvasive evaluation of diabetic nephropathy.

BACKGROUND: Noninvasive quantitative measurement of fibrosis in chronic kidney disease (CKD) would be desirable diagnostically and therapeutically but standard radiologic imaging is too variable for clinical usage. By applying a vibratory force, tissue shear wave stiffness can be measured by magnetic resonance elastography (MRE) that may correlate with progression of kidney fibrosis. Since decreased kidney perfusion decreases tissue turgor and stiffness, we combined newly available three-dimensional MRE shear stiffness measurements with MR arterial spin labeling (ASL) kidney blood flow rates to evaluate fibrosis in diabetic nephropathy. METHODS: Thirty individuals with diabetes and Stage 0-5 CKD and 13 control individuals without CKD underwent noncontrast MRE with concurrent ASL blood flow measurements. RESULTS: MRE cortical shear stiffness at 90 Hz was decreased significantly below controls in all CKD stages of diabetic nephropathy. Likewise, ASL blood flow decreased progressively from 480 ± 136 mL/min/100 g of cortical tissue in controls to 302 ± 95, 229 ± 7 and 152 ± 32 mL/min/100 g in Stages 3, 4 and 5 CKD, respectively. A magnetic resonance imaging (MRI) surrogate for the measured glomerular filtration fraction [surrogate filtration fraction = estimated glomerular filtration rate (eGFR)/ASL] decreased progressively from 0.21 ± 0.07 in controls to 0.16 ± 0.04 in Stage 3 and 0.10 ± 0.02 in Stage 4-5 CKD. CONCLUSIONS: In this pilot study, MRI with ASL blood flow rates can noninvasively measure decreasing kidney cortical tissue perfusion and, with eGFR, a decreasing surrogate filtration fraction in worsening diabetic nephropathy that appears to correlate with increasing fibrosis. Differing from the liver, MRE shear stiffness surprisingly decreases with worsening CKD, likely related to decreased tissue turgor from lower blood flow rates.

Complement 7 Is Up-Regulated in Human Early Diabetic Kidney Disease.

There is a temporal window from the time diabetes is diagnosed to the appearance of overt kidney disease during which time the disease progresses quietly without detection. Currently, there is no way to detect early diabetic nephropathy (EDN). Herein, we performed an unbiased assessment of gene-expression analysis of postmortem human kidneys to identify candidate genes that may contribute to EDN. We then studied one of the most promising differentially expressed genes in both kidney tissue and blood samples. Differential transcriptome analysis of EDN kidneys and matched nondiabetic controls showed alterations in five canonical pathways, and among them the complement pathway was the most significantly altered. One specific complement pathway gene, complement 7 (C7), was significantly elevated in EDN kidney. Real-time PCR confirmed more than a twofold increase of C7 expression in EDN kidneys compared with controls. Changes in C7 gene product level were confirmed by immunohistochemistry. C7 protein levels were elevated in proximal tubules of EDN kidneys. Serum C7 protein levels were also measured in EDN and control donors. C7 levels were significantly higher in EDN serum than control serum. This latter finding was independently confirmed in a second set of blood samples from a previously collected data set. Together, our data suggest that C7 is associated with EDN, and can be used as a molecular target for detection and/or treatment of EDN.

Acute Kidney Injury Associated With Human Granulocytic Anaplasmosis: A Case Report.

Tick-borne illnesses are a growing problem in the United States. Human granulocytic anaplasmosis (HGA), carried by the Ixodes scapularis tick, is caused by Anaplasma phagocytophilum. While the clinical manifestations of HGA may be protean, ranging from asymptomatic infection to life-threatening multiorgan failure, renal involvement is uncommon. We report a case of a 64-year-old man presenting with a febrile illness and acute nephritis in the setting of HGA infection. The patient's kidney biopsy was characterized by a membranoproliferative glomerulonephritis pattern and acute interstitial inflammation. After appropriate antibiotic treatment and high-dose steroids, the patient had a marked improvement in kidney function, although a subsequent recrudescence of nephritis required a 6-month course of additional steroids. As the prevalence of tick-borne diseases continues to spread across the United States, raising awareness of the potential for atypical presentations is important, particularly because early diagnosis and treatment can be curative and prevent further complications.

Disruption of Renal Arginine Metabolism Promotes Kidney Injury in Hepatorenal Syndrome in Mice.

Tubular dysfunction is an important feature of renal injury in hepatorenal syndrome (HRS) in patients with end-stage liver disease. The pathogenesis of kidney injury in HRS is elusive, and there are no clinically relevant rodent models of HRS. We investigated the renal consequences of bile duct ligation (BDL)-induced hepatic and renal injury in mice in vivo by using biochemical assays, real-time polymerase chain reaction (PCR), Western blot, mass spectrometry, histology, and electron microscopy. BDL resulted in time-dependent hepatic injury and hyperammonemia which were paralleled by tubular dilation and tubulointerstitial nephritis with marked upregulation of lipocalin-2, kidney injury molecule 1 (KIM-1) and osteopontin. Renal injury was associated with dramatically impaired microvascular flow and decreased endothelial nitric oxide synthase (eNOS) activity. Gene expression analyses signified proximal tubular epithelial injury, tissue hypoxia, inflammation, and activation of the fibrotic gene program. Marked changes in renal arginine metabolism (upregulation of arginase-2 and downregulation of argininosuccinate synthase 1), resulted in decreased circulating arginine levels. Arginase-2 knockout mice were partially protected from BDL-induced renal injury and had less impairment in microvascular function. In human-cultured proximal tubular epithelial cells hyperammonemia per se induced upregulation of arginase-2 and markers of tubular cell injury. CONCLUSION: We propose that hyperammonemia may contribute to impaired renal arginine metabolism, leading to decreased eNOS activity, impaired microcirculation, tubular cell death, tubulointerstitial nephritis and fibrosis. Genetic deletion of arginase-2 partially restores microcirculation and thereby alleviates tubular injury. We also demonstrate that BDL in mice is an excellent, clinically relevant model to study the renal consequences of HRS. (Hepatology 2018; 00:000-000).

Cathepsin K Deficiency Ameliorates Systemic Lupus Erythematosus-like Manifestations in Faslpr Mice.

Cysteinyl cathepsin K (CatK) is expressed in osteoclasts to mediate bone resorption, but is also inducible under inflammatory conditions. Faslpr mice on a C57BL/6 background develop spontaneous systemic lupus erythematosus-like manifestations. Although normal mouse kidneys expressed negligible CatK, those from Faslpr mice showed elevated CatK expression in the glomeruli and tubulointerstitial space. Faslpr mice also showed elevated serum CatK levels. CatK deficiency in Faslpr mice reduced all tested kidney pathologies, including glomerulus and tubulointerstitial scores, glomerulus complement C3 and IgG deposition, chemokine expression and macrophage infiltration, and serum autoantibodies. CatK contributed to Faslpr mouse autoimmunity and pathology in part by its activity in TLR-7 proteolytic processing and consequent regulatory T (Treg) cell biology. Elevated TLR7 expression and proteolytic processing in Faslpr mouse kidneys and Tregs showed significantly reduced levels in CatK-deficient mice, leading to increased spleen and kidney Treg content. Purified CD4+CD25highFoxp3+ Tregs from CatK-deficient mice doubled their immunosuppressive activity against T effector cells, compared with those from CatK-sufficient mice. In Faslpr mice, repopulation of purified Tregs from CatK-sufficient mice reduced spleen sizes, autoantibody titers, and glomerulus C3 and IgG deposition, and increased splenic and kidney Treg contents. Tregs from CatK-deficient mice had significantly more potency than CatK-sufficient Tregs in reducing spleen sizes, serum autoantibody titers, and glomerulus C3 deposition, and in increasing splenic and kidney Treg content. This study established a possible role of CatK in TLR7 proteolytic activation, Treg immunosuppressive activity, and lupus autoimmunity and pathology.

CD74 Deficiency Mitigates Systemic Lupus Erythematosus-like Autoimmunity and Pathological Findings in Mice.

CD74 mediates MHC class-II antigenic peptide loading and presentation and plays an important role in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus. C57BL/6 Faslpr mice that develop spontaneous lupus-like autoimmunity and pathology showed elevated CD74 expression in the inflammatory cell infiltrates and the adjacent tubular epithelial cells (TECs) in kidneys affected by lupus nephritis but negligible levels in kidneys from age-matched wild-type mice. The inflammatory cytokine IFN-γ or IL-6 induced CD74 expression in kidney TECs in vitro. The presence of kidney TECs from Faslpr mice, rather than from wild-type mice, produced significantly stronger histones, dsDNA, and ribonucleoprotein-Smith Ag complex-induced CD4+ T cell activation. Splenocytes from CD74-deficient FaslprCd74-/- mice had muted responses in a MLR and to the autoantigen histones. Compared with FaslprCd74+/+ mice, FaslprCd74-/- mice had reduced kidney and spleen sizes, splenic activated T cells and B cells, serum IgG and autoantibodies, urine albumin/creatinine ratio, kidney Periodic acid-Schiff score, IgG and C3 deposition, and serum IL-6 and IL-17A levels, but serum IL-2 and TGF-ß levels were increased. Study of chronic graft-versus-host C57BL/6 mice that received donor splenocytes from B6.C-H2bm12 /KhEg mice and those that received syngeneic donor splenocytes yielded similar observations. CD74 deficiency reduced lupus-like autoimmunity and kidney pathology in chronic graft-versus-host mice. This investigation establishes the direct participation of CD74 in autoimmunity and highlights a potential role for CD74 in kidney TECs, together with professional APCs in systemic lupus erythematosus.

The Prognostic Value of Histopathologic Lesions in Native Kidney Biopsy Specimens: Results from the Boston Kidney Biopsy Cohort Study.

Background Few studies have evaluated whether histopathologic lesions on kidney biopsy provide prognostic information beyond clinical and laboratory data.Methods We enrolled 676 individuals undergoing native kidney biopsy at three tertiary care hospitals into a prospective, observational cohort study. Biopsy specimens were adjudicated for semiquantitative scores in 13 categories of histopathology by two experienced renal pathologists. Proportional hazards models tested the association between histopathologic lesions and risk of kidney disease progression (≥40% eGFR decline or RRT).Results Mean baseline eGFR was 57.5±36.0 ml/min per 1.73 m2 During follow-up (median, 34.3 months), 199 individuals suffered kidney disease progression. After adjustment for demographics, clinicopathologic diagnosis, and laboratory values, the following lesions (hazard ratio; 95% confidence interval) were independently associated with progression: inflammation in nonfibrosed interstitium (0.52; 0.32 to 0.83), moderate and severe versus minimal interstitial fibrosis/tubular atrophy (2.14; 1.24 to 3.69 and 3.42; 1.99 to 5.87, respectively), moderate and severe versus minimal global glomerulosclerosis (2.17; 1.36 to 3.45 and 3.31; 2.04 to 5.38, respectively), moderate and severe versus minimal arterial sclerosis (1.78; 1.15 to 2.74 and 1.64; 1.04 to 2.60, respectively), and moderate and severe versus minimal arteriolar sclerosis (1.63; 1.08 to 2.46 and 2.33; 1.42 to 3.83, respectively). An 11-point chronicity score derived from semiquantitative assessments of chronic lesions independently associated with higher risk of kidney disease progression (hazard ratio per one-point increase, 1.19; 95% confidence interval, 1.12 to 1.27).Conclusions Across a diverse group of kidney diseases, histopathologic lesions on kidney biopsy provide prognostic information, even after adjustment for proteinuria and eGFR.

A Case Report and Literature Review: Intraneural Ganglion Cyst Causing Tarsal Tunnel Syndrome.

Intraneural ganglion cysts are benign mucinous lesions that form within joints and enter adjacent nerves via an articular branch. Despite being morphologically characterized as benign, they can demonstrate considerable intrafascicular destruction and expansion, resulting in worsening compressive neuropathies or nerve injury. There have been several suggested theories of pathogenesis, but the most widely accepted articular (synovial) theory describes a capsular defect in a neighboring joint that allows joint fluid to egress and track along the epineurium of the innervating articular branch. In this case report, we describe an intraneural ganglionic cyst located in the tarsal tunnel with extensive involvement of the tibial nerve. We describe the symptoms, diagnosis, and treatment as well as review the current literature on intraneural ganglionic cysts.