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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.

Background T helper (Th) type 17 and Th2 cells mediate psoriasis and eczema, respectively. Some dermatoses exhibit overlapping clinicopathologic features, and their immunopathology is relatively unexplored. Objective To determine whether Th17 and Th2 subsets and interleukin (IL) 36 and β-defensin 2 (BD-2) markers of IL-17 signaling expression can discriminate between biopsy samples of psoriasis and eczematous/spongiotic dermatitis and to use those markers to immunophenotype cases with clinicopathologic overlap. Methods A retrospective study was performed on biopsy samples of psoriasis, eczema/spongiotic dermatitis, sebopsoriasis, tumor necrosis factor α inhibitor–associated psoriasiform dermatitis, and ambiguous cases diagnosed as spongiotic psoriasiform dermatitis. Dual CD4/GATA3 and CD4/RORC, IL-36, and BD-2 immunohistochemistry was performed. Results IL-36 and BD-2 were strongly expressed in biopsy samples of psoriasis compared with eczema/spongiotic dermatitis. No significant differences were observed in the percentages of Th2 and Th17 cells between disease types. Strong expression of IL-36 and BD-2 was observed in a subset of spongiotic psoriasiform dermatitis, sebopsoriasis, and tumor necrosis factor α inhibitor–associated psoriasiform dermatitis biopsy samples. Limitations This was an exploratory study with a small sample size. No multiple testing adjustment was done. Clinical follow-up was limited. Conclusions In cases with clinicopathologic overlap between psoriasis and spongiotic dermatitis, IL-36, and to a lesser extent BD-2, may be used to assess for a psoriasis-like/IL-17 phenotype, which could inform therapeutic clinical decisions.

Purpose Rejection and infection can be antecedents of chronic lung allograft dysfunction (CLAD), the major limitation to long term survival for lung transplant recipients. BAL cytology is routinely performed but recently some have advocated abandoning this practice because of the low diagnostic yield. We hypothesized that inflammation observed on BAL cytology would predict CLAD risk. Methods We categorized diagnostic findings on BAL cytology between 2012 and 2019. Bronchoscopy indication, infection treatment, BAL and biopsy results, and CLAD-free survival were abstracted from medical records. Cytology associations with clinical outcomes were compared using generalized-estimating equation-adjusted logistic regression. The association between BAL inflammation and CLAD or death were determined using time-dependent Cox proportional hazards models adjusted for age, gender, diagnosis, lung allocation score, and transplant type. Results We evaluated 3,578 cytology reports from 491 subjects. Inflammation was the most common finding (6.4%), followed by fungi (5.2%). There were 5 cases of malignancy and 2 cases of CMV. Inflammation on BAL cytology was more common in procedures performed for symptoms, associated with antimicrobial initiation (a proxy for clinically significant infection), associated with acute rejection, and linked to increased BAL neutrophil and lymphocyte concentrations (Figure 1A). Inflammation on BAL cytology was present for 32% of subjects on at least one sample, more frequent around the time of CLAD onset, and associated a 2.6-fold hazard ratio (CI 1.2-5.3) for CLAD or death (Figure 1B). However, this association was not significant after adjusting for BAL cell counts and acute rejection. Conclusion Inflammation on BAL cytology specimens is clinically significant, suggesting acute rejection or infection and increased risk of CLAD or death. However, other indicators of allograft inflammation can substitute for some of the information provided by BAL cytology.

The use of digital whole slide images (WSI) in the field of pathology has become feasible for routine diagnostic purposes and has become more prevalent in recent years. This type of technology offers many advantages but must show the same degree of diagnostic reliability as conventional glass slides. Several studies have examined this issue in various settings and indicate that WSI are a reliable method for diagnostic pathology. Since transplant pathology is a highly specialized field that requires not only accurate but rapid diagnostic evaluation of biopsy materials, this field may greatly benefit from the use of WSI. In this study, we assessed the reliability of using WSI compared to conventional glass slides in renal allograft biopsies. We examined morphologic features and diagnostic categories defined by the Banff 07 Classification of Renal Allograft Pathology as well as additional morphologic features not included in this classification scheme. We found that intraobserver scores, when comparing the use of glass slides versus WSI, showed substantial agreement for both morphologic features (κ = 0.68) and acute rejection diagnostic categories (κ = 0.74). Furthermore, interobserver reliability was comparable for morphologic features (κ = 0.44 [glass] vs 0.42 [WSI]) and acute rejection diagnostic categories (κ = 0.49 [glass] vs 0.51 [WSI]). These data indicate that WSI are as reliable as glass slides for the evaluation of renal allograft biopsies.

Immunofluorescence detection of the complement split product C4d along peritubular capillaries in renal allograft biopsies is the mainstay for the diagnosis of antibody-mediated rejection. The extent of peritubular capillary C4d positivity may have significant clinical ramifications; however, peritubular capillary density in the renal cortex is often difficult to assess with single-channel immunofluorescence. In this study, we report a C4d/CD34 double-immunofluorescence staining protocol for renal allograft frozen sections that allows rapid and sensitive detection of C4d positivity, as well as improved accuracy in estimating the C4d-positive fraction of peritubular capillaries. In addition, this method aids in determining whether C4d-positive structures correspond to peritubular capillaries or whether they represent common mimics of peritubular capillaries such as tubular basement membranes. C4d/CD34 double immunofluorescence provides rapid, convenient, and low-cost implementation for laboratories currently utilizing single-channel C4d immunofluorescence.

We present an 11 yr old girl who received 3 kidney transplants (KTx). She received 1st-KTx from a living donor at age 4 due to the end-stage renal disease. She had no HLA antibodies (Ab) at pre-1st-KTx, and thus pre-tx crossmatch (XM) and donor-specific HLA antibodies (DSA) were −ve. Six weeks later, the allograft was removed due to torsion (twisting of blood vessels) and thrombosis (formation of a blood clot). The C4d staining of Tx-biopsy was −ve indicating no antibody-mediated rejection (ABMR). She was relisted for the 2nd-KTx. Two-mo post tx-nephrectomy sample revealed Abs to all 10 mismatched (MM) donor’s HLA types (and associated CREG) resulting in 97% CPRA. After a 3 yr wait, she received 2nd-KTx from a deceased donor (DD) with −ve XM and DQ8 DSA (MFI = 1961). Shortly, she developed complications by BK viremia/nephropathy and immunosuppression was reduced, which potentially increased alloimmune activation. At 2-mo post-2nd-KTx, she developed de novo DSAs directed against 4 mismatched HLAs of 2nd-KTx (1600–14600 MFI). She was treated with multiple rounds of eculizumab, plasmapheresis and IVIG until Dec. 2015, when she presented with an acute increase in serum creatinine to 8.7 mg/dL. KTx biopsy showed acute ABMR. She was relisted for 3rd-KTx on Feb. 2016 with a cPRA 100%. After 2 yr wait, she received 3rd-KTx on Feb. 2018 from a DD with −ve XM and no DSA. The 3rd donor was mismatched by 8 HLA antigens - 1 of them was a repeat-MM with 1st donor and another was repeat-MM with both 1st and 2nd donors. However, Abs to 5 mismatched HLAs of the 3rd-KTx (B8, B37, Cw6, DP2, DP4) found in the historical sera (MFIs 1000–16,000) were completely −ve in multiple sera tested during 2 mo post-3rd-KTx (Fig.). No rejection was noted. Lessons learned from this case were: A 4-yr old human immune system can recognize and respond to alloantigens, and can trigger HLA-Abs production efficiently. However, acquired memory response, an integral component of adaptive immunity is not fully developed until 11 yr of age. These findings have vital implications in pediatric KTxs. Download : Download high-res image (508KB) Download : Download full-size image

Aim Over 50% of kidney transplant (Ktx) candidates with 100% CPRA display HLA-DP antibodies, which impair the chances of finding a compatible deceased donor (DD) despite national sharing. Herein, we assessed the impact of donor-specific HLA-DP antibodies (DP-DSA) on Ktx outcome. Methods DD Ktxs performed at UCSF (n = 569) from 2013 to 16 were analyzed. Based on pre-tx DSA status, recipients were divided into 3 groups: DSA −ve (n = 465), non-DP DSA +ve (n = 81), and DP-DSA +ve (n = 23). All recipients received standard immunosuppression, and DP-DSA +ve recipients received additional 1 dose IVIG at day-1 post-tx. Grafts were evaluated by 6 mo protocol biopsies (Bx) and cause Bx. HLA antibodies were tested using single antigen bead assay (One Lambda). Results There were more highly sensitized patients (CPRA > 97%) and well-matched Ktx in DP-DSA +ve group compared to the other 2 groups (Table). All recipients in DSA −ve and non-DP DSA +ve groups had a −ve T and B cell pronase flow-crossmatch (FXM), while 30% (n = 7) of DP-DSA +ve group that had a DP-DSA of >10,000 MFI, displayed a +ve B-FXM (MCS ∼ 200; 120 cutoff). There were no hyper acute rejection episodes in all 3 groups. The DP-DSAs were self-decayed overtime post-tx in all 23 recipients transplanted with pre-formed DP-DSAs (Figure). The Bx findings revealed no significant difference in the rate of antibody-mediated rejection (ABMR) or in acute cellular rejection (ACR) between the 3 groups. Two recipients transplanted with DP-DSAs but −ve XMs lost their grafts: one was a 46F re-tx recipient with 100% CPRA, 1/12 HLA-mismatch, DP4 DSA (MFI = 6956), lost due to ACR in 4 months; another was 62 M, 19% CPRA, 7/12 HLA-mismatch, DP1 DSA (MFI = 4165), suffered Polyomavirus nephropathy at 5 months. Conclusions Kidneys can be transplanted across DP-DSAs with no apparent effect on graft survival. This strategy increases the DD Ktx in highly sensitized patients without pre-tx desensitization. The long-term outcome studies are ongoing.

Aim We developed a reliable virtual crossmatch (VXM) method for use as pre-transplant XM for deceased donor (DD) kidney transplantation (Ktx). Here we report the outcomes of 248 Ktx performed based on VXM. Methods Our VXM method includes 3 integral processes: accurate identification of HLA antibodies (Ab) using right tools and principles, assessment of correlation between the strength of donor specific Ab (DSA) and T and B cell bindings by flow XM (FXM), and listing of clinically relevant unacceptable antigens that will not impact DD offers or graft survival. From the start of the new KAS through Dec. 2016, 434 DD-Ktx were performed at UCSF, of which 375 (86%) were performed based on VXM (350 were VXM−ve with DSA+/− and 25 were VXM+ve with DP/DQα DSA+). 59/434 (14%) of the Ktxs were performed based on pre-tx FXM (54 were FXM−ve with DSA+/− and 5 were FXM+ve with DP-DSA+). Six month protocol biopsy (Bx) and cause Bx were evaluated for C4d rejection. Results All 350 pre-tx VXM−ve assessments were negative by retrospective FXM. There were no hyper acute rejections in these 350 Ktx. Biopsies of 273 negative VXM-based Ktx revealed no significant difference in the rate of antibody-mediated rejection (ABMR) or in acute cellular rejection (ACR) between 3 distinct CPRA groups (Table). Females, re-tx, well-matched tx, and de nova DSA producers were more frequent in both high CPRA groups compared to 0–79% CPRA group. Pre-tx DSA was more common in 99–100% CPRA group compared to other groups. Conclusions Our VXM protocol is reliable, has excellent graft survival, and works even for those with 100% CPRA. Accurate VXM method improves organ allocation for broadly sensitized patients, increases the efficiency of regional/national sharing, and avoids reallocation into unintended recipients. Download : Download high-res image (137KB) Download : Download full-size image

Regulatory T cells (Treg) are critical regulators of immune tolerance. Both IL-2 and CD28-CD80/CD86 signaling are critical for CD4(+)CD25(+)FOXP3(+) Treg survival in mice. Yet, both belatacept (a second-generation CTLA-4Ig) and basiliximab (an anti-CD25 monoclonal antibody) are among the arsenal of current immunotherapies being used in kidney transplant patients. In this study, we explored the direct effect of basiliximab and belatacept on the Tregs in peripheral blood both in the short term and long term and in kidney biopsies of patients with acute rejection. We report that the combined belatacept/basiliximab therapy has no long-term effect on circulating Tregs when compared to a calcineurin inhibitor (CNI)-treated group. Moreover, belatacept-treated patients had a significantly greater number of FOXP3(+) T cells in graft biopsies during acute rejection as compared to CNI-treated patients. Finally, it appears that the basiliximab caused a transient loss of both FOXP3(+) and FOXP3(-) CD25(+) T cells in the circulation in both treatment groups raising important questions about the use of this therapy in tolerance promoting therapeutic protocols.

Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is one of the most important causes of progressive kidney failure in HIV-1-seropositive patients. Since the 1980s, much has been published regarding the epidemiology, pathogenesis, and treatment of HIVAN. Our knowledge of the clinical features, pathologic manifestations, course, and potential outcome of HIVAN has increased considerably. The use of highly active antiretroviral therapy has shown significant improvement in the outcome of human immunodeficiency virus infection and is found to be effective in preventing end-stage renal disease. The purpose of this review is to summarize the data about the clinical manifestations, pathogenesis and pathophysiologic mechanisms of HIVAN with particular attention on treatment including pharmaceutical and renal replacement options.

Tamm-Horsfall protein knockout mice are more prone to urinary tract infection. Background Human colon contains many bacteria that commonly colonize the perineum and frequently enter the urinary tract. Uropathogenic Escherichia coli are the most common cause of urinary tract infection. Type 1 fimbriated E. coli have been associated with cystitis, and P fimbriated E. coli with pyelonephritis. Factors involved in clearing bacteria from the urinary tract are poorly understood. Tamm-Horsfall protein (THP), the most abundant protein in mammalian urine, has been postulated to play a role in defense against urinary tract infection but definitive proof for this idea has been lacking. Methods In this study, we generated THP gene knockout mice by the technique of homologous recombination, and examined if the THP-deficient (THP -/- ) mice were more prone to urinary tract infection. Various strains of E. coli expressing type 1 or P fimbriae were introduced transurethrally into the bladders of the THP -/- and genetically similar wild-type (THP +/+ ) mice. Urine, bladder, and kidney tissues were obtained from the mice and cultured for bacterial growth. Results THP -/- mice inoculated with type 1 fimbriated E. coli had a longer duration of bacteriuria, and more intense colonization of the urinary bladder in comparison with THP +/+ mice. When inoculated with a P fimbriated strain of E. coli, the THP -/- mice showed no difference in kidney bacterial load when compared with the THP +/+ mice. Conclusion These findings support the idea that THP serves as a soluble receptor for type 1 fimbriated E. coli and helps eliminate bacteria from the urinary tract.

Coronary atherosclerosis with occlusive thrombosis is the major cause of acute myocardial infarction. Although plaque rupture is usually hypothesized to be the predisposing event in coronary thrombosis, the possibility cannot be excluded that local changes in the anticoagulant properties of the endothelium overlying the plaque contribute to this process. It is evident that thrombomodulin and the endothelial cell protein C receptor are critical players in the control of the thrombogenic process. This study examined whether thrombomodulin and the endothelial cell protein C receptor are down-regulated on endothelial cells overlying the atherosclerotic plaque in coronary arteries and thus could potentially favor local thrombus formation. Sections of archival left and right coronary arteries (n = 18 each) with severe atherosclerosis from the native heart of six patients who underwent heart transplantation were immunostained for CD31, CD34, endothelial cell protein C receptor, and thrombomodulin using a streptavidin-biotin-peroxidase method. Controls included left and right coronary arteries from autopsy cases with no atherosclerosis (n = 6), and also from cases with mild atherosclerosis (n = 5). The apparent density of all of these proteins was much higher in control than in atherosclerotic arteries. Our findings support the hypothesis that both endothelial cell protein C receptor and thrombomodulin are down-regulated in coronary arteries with atherosclerosis. These changes would be expected to result in reduced inhibition of thrombogenic and anti-inflammatory activity on the endothelium overlying atherosclerotic regions and thus could contribute to coronary thrombosis.

Infection with certain strains of Escherichia coli and endotoxemia results in renal glomerular thrombotic microangiopathy (TMA) characterized by endothelial swelling and prominent glomerular microthrombus formation. Nitric oxide (NO) is an endogenous biologic modulator with diverse physiologic functions including vasodilation and inhibition of platelet adhesion and aggregation. NO is synthesized from conversion of L-arginine to L-citrulline by a family of NO synthases (NOS), which include constitutive and inducible isoforms. Indirect evidence supports the hypothesis that TMA is associated with depressed intrarenal NO production. However, the effect of TMA on renal tissue NOS expression has not been fully elucidated. We studied rats with TMA induced by iv bolus injection of high dose (20 mg/kg) E. coli endotoxin. Subgroups of six animals each were sacrificed before or at 30, 90, 180, 360, and 720 minutes after the administration of endotoxin. Renal histology and tissue expression of endothelial and inducible nitric oxide synthases (eNOS and iNOS) were examined. Additionally, we examined the effect of endotoxin on glomerular NO production, and eNOS and iNOS protein expression in vitro. Glomerular capillary thrombosis developed by 180 minutes after endotoxin administration in approximately half of the animals. The glomeruli without thrombotic lesions apparent by light microscopy disclosed early signs of TMA characterized by endothelial swelling, platelet accumulation/adhesion, and patchy fibrinogen deposition. These morphologic changes were associated with a marked reduction of renal tissue eNOS expression beyond 180 minutes after the endotoxin administration. The fall in eNOS expression was coupled with a significant rise in iNOS protein abundance, which was expressed largely by glomerular circulating neutrophils and endothelial cells, peritubular vascular endothelium, and collecting ducts of cortex and medulla. In vitro incubation of isolated glomeruli with endotoxin also resulted in a marked reduction in eNOS expression and a significant rise in iNOS content. Administration of E. coli endotoxin leads to a sustained fall in renal eNOS expression both in vivo and in vitro. The associated decline in intrarenal endothelial NO production/availability may result in renal vasoconstriction and a hypercoagulative state, which may contribute to the pathogenesis of endotoxin-induced TMA.

Fasting induces pancreatic secretory lipase, possibly through an increased utilization of fatty acids and/or ketone bodies by the acinar cells. To test this hypothesis, the effects of l -aminocarnitine (ACA), an inhibitor of mitochondrial β-oxidation and ketone body formation, on the pancreatic enzyme composition were studied in rats. The characteristics and reversibility of the hepatic steatosis produced by ACA in fasted animals were also investigated. In fasted rats, ACA decreased the plasma levels of β-hydroxybutyrate, glucose and insulin, but increased that of glucagon. Fasting for 3 days increased the pancreatic lipase content by 80%. Administration of ACA (3, 10 or 30 mg kg−1daily) for 3 days to fasted rats led to dose-related decreases in pancreatic lipase content, the fasting-induced increase was prevented even by the lowest dose. Nevertheless, ACA in the fasted rats likewise decreased the pancreatic contents of protein, amylase and trypsinogen to varying degrees, suggesting a general defect of protein synthesis. The 3-day treatment with ACA during fasting led to dose-related, marked increases in hepatic weight and triglyceride content. Light and electron microscopy revealed lipid vesicles of varying sizes in the hepatocytes; the fat deposition was predominant in the periportal zones of the hepatic lobules. By means of electron microscopy, lipid vacuoles were observed in the centroacinar cells, but not in the acinar cells of the pancreas. In rats treated with 30 mg kg−1of ACA daily for 3 days while they were fasted, cessation of ACA treatment and refeeding with normal chow led to normalization of the pancreatic enzyme contents within 6 days, and gradual and complete disappearance of the hepatic steatosis within 24 days. Microscopy also demonstrated complete recovery in both the liver and the pancreas. The results indicate that pancreatic secretory lipase induction during the adaptive phase of starvation is dependent on an unhindered mitochondrial β-oxidation of fatty acids and ketogenesis. The dose-related degree of hepatic triglyceride accumulation which can be produced readily by administration of ACA during short-term starvation in the rat may serve as a new, convenient experimental model for studies of fatty liver. 2000 Academic Press@p$hr

To determine the nephron segment distribution of tubular epithelial damage and regeneration and the proliferative activity of various nephron segments in human acute tubular necrosis (ATN) with an antibody to proliferating cell nuclear antigen (PCNA) and to compare the findings in native kidneys with ATN with those in transplant kidneys with ATN, archival tissues from 12 native and 21 transplant kidney biopsy specimens and nine transplant nephrectomy specimens were collected that all showed obvious morphological signs of ATN. Nineteen patients with transplant kidneys with ATN were immunosuppressed with cyclosporine and 11 were immunosuppressed with prednisone and azathioprine. There was a predominance of "regenerating" tubules (tubules with thin epithelium) in the distal nephron in native kidneys with ATN; in the transplant kidneys this was less conspicuous. The number of Tamm-Horsfall protein (THP)-positive tubules was decreased in all kidneys with ATN compared with normal human kidneys. In contrast, the number of THP-positive casts was much higher in all kidneys with ATN than in the normal kidneys. In transplant kidneys with ATN the number of THP-positive casts was substantially lower than in native kidneys with ATN. The macula densa appears to maintain its morphological integrity in kidneys with ATN. Both regenerating and normal appearing tubules expressed vimentin and HLA-DR. The proliferation index (PI; ie, percentage of PCNA-positive nuclei) of the renal tubular epithelium in normal control kidneys varied between 0.22 and 0.33, depending on the tubule segment. The highest PI was noted in the transplant kidneys with ATN not treated with cyclosporine (8.0), followed by the native kidneys with ATN (4.4) and the transplant kidneys with ATN treated with cyclosporine (4.3). We did not find any significant difference in the PI between the regenerating (5.0) and normal appearing (5.6) tubules. Proximal tubules (8.7) showed significantly higher PI values than distal tubules (3.5) in transplant kidneys with ATN. Our results show substantial differences between native kidneys and transplant kidneys with ATN. Tubular epithelial cell proliferation in human ATN is prominent and appears to correlate with the severity of ATN. Light microscopically normal appearing tubules and regenerating tubules participate equally in the regeneration of injured tubules. Cyclosporine may have an inhibitory effect on cell regeneration (proliferation) in human transplant kidneys with ATN.

Atrophic tubules in end-stage renal disease (ESRD) may have various morphologic appearances: some show microscopic features of "classic" atrophic tubules (thick, wrinkled tubular basement membrane and simplified epithelium), others show "thyroidization" (round tubules with simplified epithelium and casts), and many have the appearance of "endocrine" tubules (small tubules with narrow lumina, clear cells, and relatively thin basement membranes). Other tubules in ESRD may be enlarged and dilated with hypertrophic cells ("super" tubules). The exact segment of the nephron from which these tubules arise in ESRD has not been well studied. We examined paraffin sections of 28 end-stage kidneys with a panel of nephron-segment-specific renal epithelial markers (proximal nephron markers: Tetragonolobus purpureas and Phaseolus vulgaris erythroagglutinin lectins; distal nephron markers: antibodies to epithelial membrane antigen, low molecular weight cytokeratin [AE1/AE3], the lectin Arachis hypogaea, and an antibody to Tamm-Horsfall protein labeling the thick ascending limb of Henle). In addition, an antibody to proliferating cell nuclear antigen was applied to determine the proliferation index (proliferating cell nuclear antigen-positive nuclei/all counted nuclei x 100, ie, the percentage of proliferating cell nuclear antigen-positive nuclei) of the various atrophic and "super" tubules in ESRD. Classic atrophic tubules and the "super" tubules showed primarily a proximal phenotype. Tubules showing thyroidization were consistently positive with markers of the distal tubular epithelium. "Endocrine" tubules stained primarily with distal tubular markers; however, some proximal staining also was noted. The widened renal interstitium contained single cells or loosely organized small cell clusters positive with both the AE1/AE3 and the epithelial membrane antigen antibodies. Serial sectioning showed that the majority of these single cells were not forming tubules. The proliferation index of the "classic" atrophic tubules was the highest (3.08%), followed by the "super" tubules (2.39%), the "endocrine" tubules (1.58%), and the "thyroid" tubules (1.09%). These indexes are all considerably higher than the proliferation index of the normal renal tubular epithelium. Our findings suggest that different types of tubular atrophy may arise from different segments of the nephron, and that the renal interstitium in ESRD may harbor isolated cells with epithelial characteristics. Furthermore, the end-stage kidney is not a resting organ; on the contrary, it shows a high proliferative activity, particularly in the epithelium of the "classic" atrophic and the "super" tubules.

Chiari network is a rare vestigial remnant of the right valve of the sinus venosus, located in the right atrium. We report the case of a 41-year-old woman who presented with fever and chills. She had a history of infective endocarditis caused by methicillin-sensitive Staphylococcus aureus a year ago. Echocardiography did not reveal the presence of any vegetation on any of the cardiac valves. She was found to have a mass attached to Chiari network in her right atrium. This was removed surgically and revealed the presence of infective endocarditis on the papillary fibroelastoma attached to the Chiari network. This is the first report of such a case and illustrates that not all endocarditis occurs on cardiac valves.