Clinicopathologic Features of Antibrush Border Antibody Disease.

Introduction: Antibrush border antibody disease (ABBA) is an autoimmune tubulointerstitial kidney disease that primarily affects older individuals and results in progressive kidney failure. It is rare with only 20 reported cases. Here, we describe a case series to further define the clinicopathologic spectrum and natural history, and to inform management. Methods: We identified 67 patients with ABBA who underwent kidney biopsy, including 65 native and 2 transplants. Demographics, clinical findings, and laboratory data were obtained. Histopathologic data included light microscopy, immunofluorescence, electron microscopy and immunostaining for LRP2, CUBN, and AMN. Follow-up data, including treatment(s), laboratory values, and outcomes, were available from 51 patients. Results: Patients with ABBA were predominantly male with a median age of 72 years. Median serum creatinine was 2.7 mg/dl, proteinuria was 2.8 g/day, and hematuria was present in two-thirds of the patients. Tubular injury with LRP2-positive tubular basement membrane (TBM) deposits were seen in 94.2% of patients. Thirty-eight patients (56.7%) had a second kidney disease, commonly glomerular diseases with high-grade proteinuria. These diseases included podocytopathies, membranous nephropathy (MN), IgA nephropathy, diabetic glomerulopathy, lupus nephritis (LN), crescentic glomerulonephritis (GN), tubulointerstitial nephritis, and involvement by lymphoma. The majority of patients were treated with immunosuppression. Of those patients with follow-up, 29.4% achieved remission, 70.6% had no response, and 52.8% required dialysis or were deceased. Untreated patients were at the highest risk. Conclusion: ABBA is a rare autoimmune kidney disease that often occurs with other kidney diseases. Although the overall prognosis of ABBA is poor, there is potential benefit from immunosuppression.

Post-Streptococcal Glomerulonephritis in Two Patients Following Deceased Donor Kidney Transplant.

BACKGROUND Post-streptococcal glomerulonephritis (PSGN) is a well-known cause of renal injury. This disease is caused by a prior infection with specific nephritogenic strains of group A beta-hemolytic streptococcus resulting in formation of immune complexes in the glomeruli. Clinical presentation can range from asymptomatic, microscopic hematuria to the nephritic syndrome which is defined by red to brown urine, nephrotic range proteinuria, edema, hypertension, and acute kidney injury. A few reports have described PSGN in kidney transplant recipients in the post-transplantation period. However, biopsy-proven, donor-derived, PSGN in kidney transplant recipients has not been described. CASE REPORT Kidneys were donated from a 25-year-old Caucasian female with no history of hypertension or diabetes who had anoxic brain death in the setting of sepsis due to group A Streptococcus pyogenes bacteremia. The recipients were a 55-year-old male and a 68-year-old female, both of whom had end stage renal disease (ESRD) secondary to hypertensive nephrosclerosis. The recipients had kidney biopsies, one at the time of implantation and the other on post-operative day (POD) 2. Both biopsies showed streptococcal-associated glomerulonephritis. The prompt recognition and treatment of this disease in the immediate post-operative period resulted in histological resolution of the disease as well as good graft outcomes. CONCLUSIONS Utilizing kidneys from donors with streptococcal bacteremia is possible while maintaining a high degree of suspicion for possible streptococcal-associated glomerulonephritis.

Genetic testing of complement and coagulation pathways in patients with severe hypertension and renal microangiopathy.

A diagnosis of thrombotic microangiopathy on kidney biopsy in a patient presenting with hypertensive emergency has historically elicited the diagnosis of malignant hypertension-associated thrombotic microangiopathy. Recent studies, however, have raised awareness that a number of these patients may actually represent atypical hemolytic uremic syndrome. To further investigate this premise, we performed next-generation sequencing to interrogate the coding regions of 29 complement and coagulation cascade genes associated with atypical hemolytic uremic syndrome in 100 non-elderly patients presenting with severe hypertension, renal failure and a kidney biopsy showing microangiopathic changes limited to the classic accelerated hypertension-associated lesion of arterial intimal edema ('mucoid intimal hyperplasia') in isolation and without accompanying glomerular microthrombi. No pathogenic or likely pathogenic variants were identified in any of the genes analyzed, although 13 patients had rare variants of uncertain significance predicted to be deleterious by all in-silico prediction methods utilized. Accordingly, this large patient cohort showed no definitive burden of disease secondary to genetic variants involving complement or coagulation pathways, which contrasts sharply with the high frequency of similar mutational events reported for atypical hemolytic uremic syndrome. Our results also inform recent data by suggesting that patients who present with severe or malignant hypertension and renal thrombotic microangiopathy may be at higher risk for atypical hemolytic uremic syndrome only if the biopsy shows more active disease that includes glomerular fibrin thrombi.

Myoglobin casts in renal biopsies: immunohistochemistry and morphologic spectrum.

Five hundred eighty renal biopsies from a pool of 27850 archived cases were identified in which a myoglobin stain was performed because of atypical casts. Two hundred and thirty-eight (41%) of these biopsies were found to be positive for myoglobin casts. The morphology of the myoglobin casts ranged from light, almost translucent and refractile, to pink, to dark red and slightly brown granular casts by hematoxylin and eosin, to beaded globular casts that stained brightly fuchsinophilic with Masson trichrome and partially argyrophilic with silver methenamine. All biopsies displayed acute tubular injury associated with intratubular debris and thinning and vacuolization of tubular epithelium. Approximately 20% of myoglobin-positive biopsies showed calcium oxalate or phosphate deposition. Positive myoglobin staining was present in casts, proximal tubular epithelial cells without casts, and also dehisced epithelial cells. Collecting ducts and occasionally the distal tubular epithelium also stained positive. One case showed concurrent myeloma cast nephropathy with "fractured" casts and translucent myoglobin-positive casts. Herein, we describe the morphologic spectrum of myoglobin-positive casts. We conclude that utilization of myoglobin immunohistochemistry is advantageous and, when not available, knowledge of the morphologic spectrum is important.

Vascular mesangial channels in human nodular diabetic glomerulopathy.

The presence of vascular mesangial channels has been reported in idiopathic nodular glomerulosclerosis and diabetic glomerulopathy. However, only limited information on the morphology and immunohistochemical phenotype of these channels is available. This study aims to describe the light and electron microscopic features of these channels and delineate their immunohistochemical phenotype. Thirty-eight cases of human nodular diabetic glomerulopathy with mesangial channels identified by light microscopy were prospectively selected (2010-2012). The cases were stained with CD31/periodic acid-Schiff combined stain. Selected cases were immunostained for CD34, podoplanin, ERG, and Ki-67. Frequent, small and peripheral vascular mesangial channels were seen in all cases, whereas larger and more centrally located vascular channels were also observed. Communication between peripheral capillary loops and peripheral vascular mesangial channels was seen as was communication between peripheral and central vascular mesangial channels. The vascular mesangial channel lining cells showed a typical endothelial phenotype with strong expression of CD31, CD34, and ERG by immunohistochemistry. The lymphatic channel marker podoplanin was negative in all channels, and the proliferation marker Ki-67 showed no evidence of increased proliferation. By electron microscopy, mesangial channels show angulated, irregular borders with lining cells compatible with endothelium and surrounded by mesangial matrix. No basement membranes were identified surrounding the mesangial channels. These findings support the existence of vascular mesangial channels in nodular diabetic glomerulopathy and suggest neovascularization and altered blood flow within these glomeruli.

The association of bone and osteoclasts with vascular calcification.

The presence of bone tissue in calcified arteries may provide insights into the pathophysiology and potential reversibility of calcification, but the prevalence, distribution, and determinants of bone and osteoclasts in calcified arteries are unknown. Specimens of 386 arteries from lower limb amputations in 108 patients were examined retrospectively. Calcification was present in 282 arteries from 89 patients, which was medial in 64%, intimal in 9%, and both in 27%. Bone was present in 6% of arteries, essentially all of which were heavily calcified. Multiple sampling revealed that the true prevalence of bone in heavily calcified arteries was 25%. Bone was more common in medial rather than intimal calcifications (10% vs 3%, p=0.03) but did not vary with artery location (above vs below the knee). Heavily calcified arteries with bone were more likely to come from patients who were older (p=0.04), had diabetes (p=0.06), or were receiving warfarin (p=0.06), but there was no association with gender or renal failure. Bone was almost always adjacent to calcifications, along the periphery, but never within. Staining for the bone-specific proteins osteocalcin and osterix was noted in 20% and 45% of heavily calcified arteries without visible bone. Osteoclasts were present in 4.9% of arteries, all of which were heavily calcified and most of which contained bone. The frequent absence of bone in heavily calcified vessels and the histologic pattern strongly suggests a secondary rather than primary event. Recruitment of osteoclasts to vascular calcifications can occur but is rare, suggesting a limited capacity to reverse calcifications.

Prevalence of nonatheromatous lesions in peripheral arterial disease.

OBJECTIVE: The histopathology of peripheral arterial disease and the accompanying calcification are poorly defined, and it is not known whether this varies according to different risk factors. APPROACH AND RESULTS: Sections from 176 upper and lower leg arteries were examined histologically in specimens from amputations of 60 patients with peripheral arterial disease, of whom 58% had diabetes mellitus, 35% had end-stage renal disease, and 48% had a history of smoking. The most common findings were calcification of the media (72% of arteries) and intimal thickening without lipid (68% of arteries), with the presence of atheromas in only 23% of arteries. Intimal calcification occurred in 43% and was generally much less extensive than medial calcification. Nonatheromatous intimal thickening was frequently severe, resulting in complete occlusion in some vessels. The absence of lipid and macrophages was confirmed by staining with oil red O and staining for CD68. Other than a greater prevalence and severity of medial calcification in end-stage renal disease, the findings did not differ between diabetics, patients with end-stage renal disease, or smokers. CONCLUSIONS: The results indicate that the majority of arteries in patients with peripheral arterial disease have a vascular lesion that is distinct from atherosclerosis, suggesting a different pathogenesis. This pattern does not differ substantially between patients with different risk factors for peripheral arterial disease. The bulk of vascular calcification in the lower extremities is medial rather than intimal.

Prolonged recovery time from zoledronic Acid induced acute tubular necrosis: a case report and review of the literature.

Acute tubular necrosis (ATN) due to bisphosphonates has been reported with Zoledronic acid but the time to recovery (if any) has been usually less than 4 months. Possible recovery time from ATN of any cause is usually less than 6 months. In this paper, we present the case of a 59-year-old Caucasian female with metastatic breast cancer who had received 16 monthly injections of Zoledronic acid for treatment of tumor induced hypercalcemia and developed several episodes of mild acute kidney injury which resolved by withholding treatment. Unfortunately, after the sixteenth injection, the patient experienced severe acute kidney injury, with a peak serum creatinine of 8.0 mg/dL. Although urinalysis showed muddy brown casts, because of atypical recovery time and presence of eosinophiluria and subnephrotic range proteinuria, a kidney biopsy was performed. Diagnosis of typical acute tubular necrosis was confirmed without any other concomitant findings. The course was remarkable for an unusually slow recovery of renal function over 15 months without need for renal replacement therapy until the patient expired from her metastatic cancer two years later. We reviewed all the published cases of acute kidney injury due to Zoledronic acid and suggest recommendations for clinicians and researchers.

Prevalence of clinical rejection after surveillance biopsies in pediatric renal transplants: does early subclinical rejection predispose to subsequent rejection episodes?

We analyzed rates of both SCR and CR in children receiving SB at three months post-transplant to determine if SCR predisposed patients to acute CR. Acute rejection was defined according to Banff criteria to include borderline classification or higher. All cases of SCR and CR were treated with anti-rejection protocols. Between October 2004 and July 2008, 89 SB were performed at three months post-transplant. Twenty-six cases of SCR were detected (29%). Sixteen patients experienced 22 episodes of biopsy-proven CR occurring after SB, including seven episodes following SCR and 15 after normal SB. The onset of CR varied from one to 27 months after SB and occurred at similar intervals for cases with SCR and normal SB. The percentage of patients remaining free of CR at 30 months post-transplant was similar in patients with SCR and normal SB. Renal function and graft survival at 30 months also were no different between patients with SCR and those with normal SB. Early-SCR, when treated with rejection protocols, is not a prognostic indicator for subsequent CR episodes.

Extravasations and emigration of neutrophils to the inflammatory site depend on the interaction of immune-complex with Fcgamma receptors and can be effectively blocked by decoy Fcgamma receptors.

Extravasation and emigration of neutrophils to the site of inflammation are essential early steps in the initiation of many antibody-mediated autoimmune diseases. The Fc domains of cell bound autoantibodies or immune-complexes (IC) are capable of triggering the neutrophil emigration via complement and FcgammaRs-mediated mechanisms. To define the clinical relevance and the relative contribution of these 2 pathways in IC-mediated neutrophil emigration, we have neutralized the FcgammaR-binding activity of IC with a recombinant dimeric Fc receptor, CD16A-Ig, and investigated the early events of IC-induced inflammation in mice. Systemic administration of purified CD16A-Ig blocked IC-induced inflammation, mast- cell degranulation, and extravasation of neutrophils in a reversed Arthus reaction. Although the binding of CD16A-Ig to IC did not alter the complement-activating properties of IC, no evidence for complement-dependent neutrophil emigration was observed. These results suggest that interaction of IC with cells expressing FcgammaRs at the inflammatory site results in the secretion of chemoattractants, which mediate complement-independent emigration of neutrophils in this cutaneous acute inflammation model. Furthermore, blocking the interaction of IC to FcgammaRs expressed on inflammatory cells by administering high-avidity Fc fusion dimers of low-affinity FcgammaRs is an effective way of preventing IC-induced acute inflammation in autoimmune diseases.

Idiopathic IgA nephropathy: pathogenesis, histopathology, and therapeutic options.

IgA nephropathy is one of the most common causes of glomerulonephritis in the world. Proliferative and crescentic forms of IgA are found in up to 30% of cases and are associated with nephrotic-range proteinuria, accelerated hypertension, and accelerated decline toward ESRD. Despite its prevalence and clinical importance, there is no unifying nomenclature or consensus for the treatment of specific histologic subgroups. As a consequence, the development of clinically effective treatment regimens for IgA nephropathy have lagged behind other, less common forms of glomerulonephritis. Herein is reviewed the pathogenesis and histologic subtypes of IgA nephropathy and how conventional and immunosuppressive therapies have an impact on renal survival and recurrence rates. The use of known clinical risk factors for disease progression in conjunction with specific histologic features can be a guide to both induction and consolidation therapies for individual patients with IgA nephropathy.

MRNA stability and overexpression of fatty acid synthase in human breast cancer cell lines.

BACKGROUND: Elevation of fatty acid synthase (FAS) in human cancers is often associated with increased tumor aggression. The basic genetic mechanisms leading to increased enzyme content in cancer cells were investigated using cell lines derived from human metastatic breast carcinomas (T47D, Zr75 and SKBr3) and normal human breast epithelium (184A1). MATERIALS AND METHODS: Western analysis, Northern blotting, [2-(14)C]malonyl-CoA incorporation assays, nuclear run-off transcription assays, mRNA decay assays, and poly(A) tail assays were used to measure and compare transcription rates of the FAS gene among the four cell lines. RESULTS: By Western analysis, FAS levels in T47D were 2.6 times lower than ZR75 and SKBr3, but 6.7 times greater than non-neoplastic 184A1 cells. FAS mRNA levels and specific activity correlated with protein content. In contrast, relative rates of FAS gene transcription were significantly higher in non-neoplastic 184A1 cells than T47D, ZR75 and SKBr3. Stability of message was investigated to explain this discrepancy. The half-life of FAS mRNA in 184A1 cells was 5.6 h, or 4-5-fold less than ZR75 and SKBr3. Poly(A) tail assays showed that FAS mRNA species from 184A1 cells tended to be longer than those of breast cancer cell lines (500-1500 nt versus 500-800 nt, respectively). CONCLUSION: Breast cancer cell lines contained significantly more FAS enzyme, message and activity than non-neoplastic 184A1 cells. Yet, 184A1 cells exhibited higher rates

A prospective, open-label trial of sirolimus in the treatment of focal segmental glomerulosclerosis.

Calcineurin inhibitors are effective therapy for steroid-resistant focal segmental glomerulosclerosis (FSGS) but are associated with significant morbidity and nephrotoxicity. Sirolimus is a novel immunosuppressive agent that is structurally related to tacrolimus but demonstrates no long-term nephrotoxicity. For determination of the efficacy of sirolimus in reducing proteinuria, a prospective, open-label trial was conducted of 21 patients with idiopathic, steroid-resistant FSGS. A complete response was defined as <300 mg protein/24 h after 6 mo, whereas a partial response was defined as a 50% reduction in baseline proteinuria. After 6 mo of therapy, sirolimus induced complete remission in four (19%) of 21 patients and partial remissions in eight (38%). Among sirolimus-responsive patients, 6 mo of therapy decreased proteinuria from a mean of 8.8 +/- 1.7 to 2.1 +/- 0.5 g/24 h (P = 0.0003). In responsive patients, GFR was maintained (45 +/- 6 versus 47 +/- 7 ml/min per 1.73 m2 at 6 mo) throughout the study, whereas nonresponders tended to decrease (31 +/- 4 versus 28 +/- 5 ml/min per 1.73 m2). Using dextran sieving analysis, complete or partial response was associated with an increase in the glomerular ultrafiltration coefficient (K(f), 7 +/- 1. versus 8 +/- 0.9 units at 6 mo; P < 0.05). Glomerular permselectivity and K(f) tended to decrease in nonresponders (8.2 +/- 1.9 versus 6.2 +/- 1.3 units at 6 mo; P = 0.07). Patients with complete remission had a higher GFR (45 +/- 6 versus 31 +/- 4 ml/min per 1.73 m2) at the end of 6 mo compared with nonresponders. In patients with steroid-resistant FSGS, sirolimus reduced proteinuria and glomerular pore size and increased K(f) in patients with steroid-resistant FSGS.

Distribution of cytokeratins and vimentin in adult renal neoplasms and normal renal tissue: potential utility of a cytokeratin antibody panel in the differential diagnosis of renal tumors.

Adult renal epithelial neoplasms (RENs) comprise several distinct clinicopathologic entities with potential prognostic and therapeutic differences. Individual cases can show overlapping morphologic features, necessitating the use of ancillary methods. The purpose of this study was to determine the diagnostic utility of cytokeratin (CK) subtype expression pattern in a wide range of adult RENs. RENs (including clear cell [conventional] renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, renal oncocytoma, collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), urothelial carcinoma, metanephric adenoma (MA), tubulocystic carcinoma (TC) (also known as low-grade collecting duct carcinoma), and mucinous tubular and spindle cell carcinoma) were immunostained for CK subtypes (CK5/CK6, 7, 8, 13, 14, 17, 18, 19, 20), high molecular weight CKs 1, 5, 10, 14 (HMWCK), and vimentin (Vim). The expression pattern of normal kidney was also examined and correlated with RENs. Although there is some overlap, subtypes of RENs show distinctive CK expression profiles that may be useful in several differential diagnostic settings. Clear cell RCCs typically showed a restricted expression pattern of CK8, CK18 and Vim. Papillary RCCs typically expressed CK7, CK8, CK18, CK19, and Vim and could be distinguished from MA (CK7-). Chromophobe RCCs were typically CK7+, CK8+, CK18+, and Vim-, and could be distinguished from oncocytomas (typically CK7-). In oncocytomas, nonspecific staining of unblocked endogenous biotin is a potentially significant diagnostic pitfall. CDC, RMC, and TC demonstrated similar CK expression profiles (with the exception of HMWCK expression limited to CDC), supporting a close relationship between these entities. A panel of CK5/CK6, CK17, and Vim may be helpful in distinguishing CDC (typically CK5/CK6-, CK17-, Vim+) and urothelial carcinoma (typically CK5/CK6+, CK17+, Vim-). In conclusion, CK expression patterns may be helpful in several differential diagnostic situations when dealing with adult RENs.

Correlation of renal histopathology with sonographic findings.

BACKGROUND: Judgments about irreversible renal disease are frequently based on the sonographic appearance of the kidneys. However, the sensitivity and specificity of sonography in identifying chronic, irreversible disease have never been determined, and the specific pathologic changes that increase renal cortical echogenicity have not been defined. METHODS: We retrospectively compared sonographic parameters (length, quantitative echogenicity, cortical thickness, and parenchymal thickness) to biopsy findings of glomerular sclerosis, tubular atrophy, interstitial fibrosis, and interstitial inflammation in 207 patients. RESULTS: Echogenicity showed the strongest correlation with all 4 histologic parameters (r= 0.28-0.35). Renal size was significantly correlated with glomerular sclerosis (r=-0.26) and tubular atrophy (r= 0.20). Parenchymal thickness, but not cortical thickness, correlated with tubular atrophy (r=-0.23). By multivariate analysis, tubular atrophy and interstitial inflammation, but not interstitial fibrosis, were significant determinants of cortical echogenicity. Severe chronic disease (>50% sclerosed glomeruli or a score of 3 out of 5 or greater for tubular atrophy or interstitial fibrosis) was present in 69% and 47% of patients with combined renal length <20 cm and >20 cm, respectively (P= <0.05). For cortical echogenicity >1.0 (>liver echogenicity) and 1.0. CONCLUSION: Cortical echogenicity is the sonographic parameter that correlates best with renal histopathology. Although size or echogenicity alone are poor predictors of chronic irreversible disease, the likelihood of treatable disease in small kidneys with increased cortical echogenicity is very low.

Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin.

Hyperphosphatemia is thought to underlie medial vascular calcification in advanced renal failure, but calcification can occur in other conditions in the absence of hyperphosphatemia, indicating that additional factors are important. To identify these factors, a model of medial calcification in rat aorta in vitro was developed. Aortic rings from rats were incubated in serum-free medium for 9 d, and calcification was measured as incorporation of (45)Ca and confirmed by histology and x-ray diffraction. No calcification occurred in normal vessels despite elevated free Ca(2+) and PO(4)(3-) concentrations of 1.8 mM and 3.8 mM, respectively, but mechanical injury resulted in extensive calcification in the media. Co-incubation studies revealed that normal aortas produced a soluble inhibitor of calcification in injured vessels that was destroyed by alkaline phosphatase. Culture of normal aortas with alkaline phosphatase resulted in calcification of the elastic lamina identified as hydroxyapatite by x-ray diffraction. This effect of alkaline phosphatase was not due to dephosphorylation of osteopontin (OPN), and calcification was not increased in aortas from OPN-deficient mice. The inhibitor was identified as pyrophosphate on the basis of the calcification induced in aortas cultured with inorganic pyrophosphatase, the inhibition of calcification in injured aortas by pyrophosphate, and the production of inhibitory levels of pyrophosphate by normal aortas. No calcification occurred under any conditions at a normal PO(4)(3-) concentration. It is concluded that elevated concentrations of Ca(2+) and PO(4)(3-) are not sufficient for medial vascular calcification because of inhibition by pyrophosphate. Alkaline phosphatase can promote calcification by hydrolyzing pyrophosphate, but OPN is not an endogenous inhibitor of calcification in rat aorta.

Fatal West Nile virus encephalitis in a renal transplant recipient.

West Nile virus (WNV), a mosquito-transmitted single-stranded RNA flavivirus, causes human disease of variable severity. We report clinical and pathologic findings of fatal encephalitis from the transmission of WNV from an organ donor to a kidney transplant recipient. The patient developed a febrile illness 18 days after transplantation, which progressed to encephalitis. Postmortem examination demonstrated extensive viral encephalopathic changes. Immunohistochemical studies highlighted WNV antigens within neurons, especially in the cerebellum and brainstem. Flavivirus virions were detected ultrastructurally within the cerebellum, and WNV was isolated from the brain and the brainstem. Thus, this case demonstrates the first death in the first solid organ transplant-associated transmission of WNV. Immunosuppression of the transplant recipient might have been responsible for the fulminant viral effects. The pathologic diagnosis helped guide subsequent epidemiologic and laboratory studies.