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Mark Haas

Publications and source records attributed to Mark Haas.

At least 19 recordsLinked to original sources
PubMed2007

Unrestricted C3 activation occurs in Crry-deficient kidneys and rapidly leads to chronic renal failure.

Deficiency of the C3 convertase regulator Crry is embryonic lethal in mice unless C3 also is absent. For evaluation of the effect of local kidney Crry deficiency in the setting of an intact complement system, Crry(-/-)C3(-/-) mouse kidneys were transplanted into syngeneic C57BL/6 wild-type mice. These Crry-deficient kidneys developed marked inflammatory cell infiltration, tubular damage, and interstitial fibrosis, whereas similar changes were absent in control transplanted kidneys. Strong C3 deposition in the vessels and tubules that correlated significantly with measures of disease supported that complement activation was pathogenic in this model. Microarray studies showed upregulation of a number of chemokine and extracellular matrix genes, which were validated for CCL2 and CXCL10 mRNA and collagen III protein. The functional significance of these pathophysiologic findings was evaluated by removing both native kidneys, so the transplanted kidney alone provided renal function. Within 21 d of transplantation, seven of eight Crry-deficient kidneys in complement-sufficient wild-type hosts failed, compared with two of 13 controls (P = 0.001), with final blood urea nitrogen levels of 133.9 +/- 33.0 and 55.6 +/- 8.3 mg/dl, respectively (P = 0.015). These data show that mouse Crry is a critical complement regulator in the kidney. When absent, unrestricted complement activation occurs and quickly leads to marked inflammation and progressive renal failure, with features relevant to human diseases with underlying defects in complement regulation, such as hemolytic uremic syndrome.

Animals↗
PubMed2006

Renal biopsy in lupus patients with low levels of proteinuria.

OBJECTIVE: Early and accurate detection of kidney involvement in systemic lupus erythematosus (SLE) improves outcomes. Renal biopsy is required for definitive diagnosis of lupus nephritis (LN). In the absence of acute renal failure (ARF), moderate levels of proteinuria (> 1000 mg/24 h) have been recommended by some to justify biopsy. We investigated whether patients with lower levels of proteinuria without ARF have significant renal disease and should be routinely biopsied. METHODS: We retrospectively evaluated 21 SLE patients with 24-h urine protein < 1000 mg who underwent kidney biopsies. Indications for biopsy included new-onset proteinuria, increasing proteinuria, or hematuria (> 5 red blood cells per high power field). No patient had ARF. RESULTS: Sixteen of 21 (77%) biopsies were diagnostic of LN: 3 class II, 10 class III (5 superimposed class V), 2 class IV (one superimposed class V), and one with class V. One patient had thrombotic microangiopathy. The remaining 4 (23%) patients had non-lupus renal disease. Thirteen patients with class III or greater LN required alterations in therapeutic regimen because of biopsy findings. Of 7 patients without hematuria at the time of biopsy, 4 (57%) had class III, IV, or V LN. One patient without hematuria and < 500 mg/24 h proteinuria had class III LN. CONCLUSION: We found significant renal involvement (Class III, IV, or V LN) in SLE patients with < 1000 mg proteinuria with or without hematuria. Our findings suggest that biopsy be strongly considered in this patient population.

Adolescent↗
PubMed2006

Distinct and separable roles of the complement system in factor H-deficient bone marrow chimeric mice with immune complex disease.

Plasma complement factor H (Cfh) is a potent complement regulator, whereas Cfh on the surface of rodent platelets is responsible for immune complex processing. For dissection between the two, bone marrow chimeras between Cfh-deficient (Cfh(-/-)) and wild-type C57BL/6 mice were created. Platelet Cfh protein was tracked with the Cfh status of the bone marrow donor, indicating that platelet Cfh is of intrinsic origin. In an active model of immune complex disease, Cfh(-/-) mice that were reconstituted with wild-type bone marrow had levels of platelet-associated immune complexes comparable to those of wild-type mice and were protected against the excessive glomerular deposition of immune complexes seen in Cfh(-/-) mice, yet these mice still developed glomerular inflammation. In contrast, wild-type mice with Cfh(-/-) bone marrow had reduced platelet-associated immune complexes and extensive glomerular deposition of complement-activating immune complexes, but they did not develop glomerular pathology. The large quantities of glomerular C3 in wild-type mice with Cfh(-/-) bone marrow were in the form of iC3b and C3dg, whereas active C3b remained in Cfh(-/-) recipients of wild-type bone marrow. These data show that plasma Cfh limits complement activation in the circulation and other accessible sites such as the glomerulus, whereas platelet Cfh is responsible for immune complex processing.

Animals↗
PubMed2006

Glycogen pseudoground glass change in hepatocytes.

Ground glass cytoplasmic change in hepatocytes is typically associated with chronic hepatitis B infection. We report 12 cases of glycogen pseudoground glass change that closely mimics hepatitis B inclusions. Nine individuals were immunosuppressed secondary to liver or kidney transplant (N=3), bone marrow transplant (N=2), HIV infection (N=2), kidney dialysis (N=1), or chronic inflammatory bowel disease (N=1). Medication history was available in 10 individuals and all were on multiple medications (range 2 to 33). Histologically, the pseudoground glass change was identical to the ground glass change seen in chronic hepatitis B infection, with distinct, circumscribed, gray-glassy inclusions surrounded by a rim of cytoplasm. The background livers showed mild or no inflammation and mild or no fibrosis. All cases were negative for chronic hepatitis B infection. The pseudoground glass change was PAS positive and diastase sensitive. Electron microscopy of the inclusions showed glycogen in 3/3 cases. No evidence for viral particles or significant endoplasmic reticulum proliferation was seen. Three cases had follow-up biopsies (1, 1, and 36 mo), and the pseudoground glass was persistent in 2 cases and showed partial resolution in 1 case (1 mo biopsy interval). We conclude that glycogen pseudoground glass change is typically seen in immunosuppressed individuals on numerous medications. The changes are generally seen in the background of mild chronic hepatitis with mild or no fibrosis. Glycogen pseudoground glass change can resolve, but may also persist for years.

Adult↗
PubMed2006

Thin glomerular basement membrane nephropathy: incidence in 3471 consecutive renal biopsies examined by electron microscopy.

CONTEXT: Thin glomerular basement membrane (GBM) nephropathy is often equated with benign familial hematuria, although it may occur sporadically and may not always be benign. Thin GBM nephropathy is reported to occur in at least 1% of the population, although its reported incidence varies considerably in different studies because there are presently no uniform criteria for its diagnosis by electron microscopy (EM). OBJECTIVE: To determine the incidence of thin GBM nephropathy in a large sample of renal biopsies using a basic methodology that can easily be applied in any diagnostic EM laboratory. DESIGN: Direct measurements of GBM thickness were made from electron micrographs at 3 specified points along each of 10 randomly selected glomerular capillaries to determine an average GBM thickness for each of 50 males and 50 females, ages 9 to 80 years, with minimal-change nephropathy or acute interstitial nephritis, without hematuria. The means of the average GBM thickness values were 330 +/- 50 (SD) nm in the males and 305 +/- 45 nm in the females; normal ranges for each sex were defined as being within 2 SD of these means. The average GBM thickness was then similarly determined for renal biopsies with suspected thin GBMs examined from January 2000 to December 2004; a total of 3471 renal biopsies were examined by EM during this period. SETTING: Academic medical center renal pathology/EM laboratory. RESULTS: Excluding biopsies with immunoglobulin A nephropathy, which is known to be frequently associated with thin GBMs, and biopsies with Alport syndrome, 67 biopsies (1.9% of total) had an average GBM thickness below the sex-specific normal range. Of these, 37 biopsies were performed specifically because of hematuria and had an average GBM thickness of 121 to 215 nm (mean, 185 +/- 20 nm). The remaining 30 (0.9%) biopsies, with average GBM thicknesses of 143 to 227 nm (mean, 190 +/- 20 nm), represent cases of incidentally discovered thin GBM nephropathy. CONCLUSIONS: Based on the frequency of incidentally discovered cases and taking into account excluded cases and biopsies (eg, with diabetic nephropathy) in which diagnosis of incidental thin GBM nephropathy by EM is not possible, the incidence of thin GBM nephropathy in our population is estimated to be between 1% and 2%. Diseases most often associated with incidental thin GBM nephropathy were focal segmental glomerulosclerosis (10 cases) and minimal-change nephropathy (5 cases).

Acute Disease↗
PubMed2005

Excellent outcomes after transplantation of deceased donor kidneys with high terminal creatinine and mild pathologic lesions.

BACKGROUND: Outcomes after kidney transplantation using deceased donors with high terminal creatinine are not well described but potentially represent an underutilized source of renal allografts. Utility of renal biopsy of these kidneys is similarly not well established. METHODS: To better understand the posttransplant function of kidneys from donors with high terminal creatinine, we reviewed our database of almost 500 cadaveric kidney transplants. We compared the 65 nonexpanded criteria donors with a final donor creatinine > or = 2.0 mg/dl (range 2.0-4.9 mg/dl) with kidneys procured from donors with terminal creatinine of <1.5. Biopsy results were correlated with graft function. RESULTS: Kidneys from deceased donors with high terminal creatinine performed as well as kidneys from donors with a normal terminal creatinine with respect to primary non-function, acute rejection, 6-year graft and patient survival, and function over the first 48 months. High creatinine kidneys with moderate or severe lesions on biopsy demonstrated poorer function at 6 months and 1 year as compared to those with mild or no histological lesions. CONCLUSIONS: Under select conditions, kidneys from donors with high terminal creatinine can be used safely with excellent results.

Acute Disease↗
PubMed2005

Signaling through up-regulated C3a receptor is key to the development of experimental lupus nephritis.

Signaling of the C3a anaphylatoxin through its G protein-coupled receptor, C3aR, is relevant in a variety of inflammatory diseases, but its role in lupus nephritis is undefined. In this study, we show that expression of C3aR was significantly increased in prediseased and diseased kidneys of MRL/lpr lupus mice compared with MRL/+ controls. To investigate the role of C3aR in experimental lupus, a small molecule antagonist of C3aR (C3aRa) was administered continuously to MRL/lpr mice from 13 to 19 wk of age. All 13 C3aRa-treated mice survived during the 6-wk treatment compared with 9 of 14 (64.3%) control animals given vehicle (p = 0.019). Relative to controls, C3aRa-treated animals were protected from renal disease as measured by albuminuria (p = 0.040) and blood urea nitrogen (p = 0.021). In addition, there were fewer neutrophils, monocytes, and apoptotic cells in the kidneys of C3aRa-treated mice. C3aRa treatment also led to reduced renal IL-1beta and RANTES mRNA and phosphorylated phosphatase and tensin homologue deleted on chromosome 10 protein, whereas the mass of phosphorylated protein kinase B/Akt was increased by C3aRa. Thus, C3aR antagonism significantly reduces renal disease in MRL/lpr mice, which further translates into prolonged survival. These data illustrate that C3aR is relevant in experimental lupus nephritis and may be a target for therapeutic intervention in the human disease.

Animals↗
PubMed2005

C5a promotes development of experimental lupus nephritis which can be blocked with a specific receptor antagonist.

The MRL/lpr murine SLE model has widespread complement activation and deposition of complement fragments in affected tissues. The potent anaphylatoxin C5a has the potential to play a key role in the pathogenesis of lupus nephritis. We found that renal expression of C5aR mRNA and protein was significantly increased in MRL/lpr mice compared to control MRL/+ mice. To examine the role of C5a signaling through C5aR, a specific small molecule antagonist (a) of C5aR was administered continuously to MRL/lpr mice from 13 to 19 wks of age. Littermate controls were given vehicle alone. The progressive impairment in renal function exhibited in the control group was prevented by C5aRa treatment. Infiltration of neutrophils and macrophages into kidneys was significantly reduced in animals treated with C5aRa compared to controls. Furthermore, renal expression of IL-1beta and MIP-2 mRNA as well as the extent of apoptosis were significantly decreased with blockade of C5aR, indicating their dependence upon signals delivered through C5aR. Thus, pharmacological blockade of C5aR reduces disease manifestations in experimental lupus nephritis. These data support an important role for the C5a anaphylatoxin in lupus nephritis, and that blockade of C5aR represents a potentially viable treatment for human lupus nephritis.

Age Factors↗
PubMed2005

Monomorphous angiocentric glioma: a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma.

We present 8 examples of a neoplasm with features of both astrocytoma and ependymoma that may represent a distinct clinicopathologic entity. The cerebral hemispheric tumors occurred in patients that were 3, 4, 12, 14, 15, 26, 30, and 37 years of age. All presented with seizures that, with the exception of 2, began in childhood. Magnetic resonance imaging studies showed ill-defined, T2-hyperintense, generally noncontrast-enhancing lesions that, although centered on the cortex or amygdala, extended into the underlying white matter for a short distance. Histologically, the variably infiltrative tumors were distinctively angiocentric with well-developed perivascular pseudorosettes in some cases. Longitudinal and/or circumferential orientations of perivascular cells were common also. The cells were uniform in their cytologic features from case to case and were bipolar in all but one case. A glial nature was inferred from immunoreactivity for GFAP, and ependymal differentiation was suggested by positivity for EMA in three cases and ultrastructural features in one. Overall, the tumors were biologically indolent except for one that recurred and ultimately proved fatal.

Adolescent↗
PubMed2005

HIV-associated immune complex glomerulonephritis with "lupus-like" features: a clinicopathologic study of 14 cases.

BACKGROUND: While the most common glomerular lesion associated with human immunodeficiency virus (HIV) infection is collapsing focal segmental glomerulosclerosis (FSGS) [HIV-associated nephropathy (HIVAN)], immune complex-mediated forms of glomerulonephritis have been increasingly reported. One form of glomerulonephritis that has been described in the HIV-infected population is immune complex glomerulonephritis with "lupus-like" features, characterized by histologic, immunohistologic, and ultrastructural features resembling lupus nephritis, but occurring in patients without evidence of systemic lupus erythematosus (SLE). Data regarding clinical outcomes in patients with this form of glomerulonephritis are very limited. METHODS: We reviewed pathology reports for all native renal biopsy specimens from HIV-positive patients processed at our center from January 1999 through December 2003. Of 77 total specimens, 14 met the following criteria for lupus-like glomerulonephritis: (1) immunofluorescence microscopy showed granular glomerular staining for IgG, IgA, IgM, C3 and C1q, with > or=1+ (0 to 4+ scale) staining for C1q; and (2) the patient's serum was negative for antinuclear antibodies (ANA), or weakly positive (titer < or =1:80) for ANA and negative for antidouble-stranded DNA. RESULTS: Clinically, ten of the 14 patients with lupus-like glomerulonephritis presented with nephrotic syndrome, all had microscopic hematuria, and nine had serum creatinine >3.0 mg/dL. All but one were African American. Histologically, seven biopsies showed diffuse proliferative glomerulonephritis, six focal proliferative glomerulonephritis, and one membranous nephropathy. All but two biopsies showed moderate or severe chronic change, and three showed concurrent HIVAN. Ten of the 14 patients developed end-stage renal disease (ESRD) within 1 year of the biopsy. Nine of these ten patients presented with proteinuria >5.0 g/24 hours and nephrotic syndrome, while three of four patients who did not develop ESRD had proteinuria < or =3.0 g/24 hours. CONCLUSION: Lupus-like glomerulonephritis, defined by immunohistologic features and absence of serologic evidence of SLE, is not an uncommon form of glomerular disease in HIV-infected patients undergoing a renal biopsy. Renal outcomes in these patients were poor, although this may be due largely to most patients presenting with advanced disease.

AIDS-Associated Nephropathy↗
PubMed2005

Primary alveolar soft part sarcoma (ASPS) of the breast: report of a deceptive case with xanthomatous features confirmed by TFE3 immunohistochemistry and electron microscopy.

Alveolar soft part sarcoma (ASPS) is a rare neoplasm that most commonly presents in the lower extremities. Although ASPS has distinctive histologic features, it may cause diagnostic problems when it arises in unusual locations. To our knowledge, only 1 case of ASPS arising within the breast has previously been reported. Here, we report a second case of primary mammary ASPS. The patient was a 44-year-old woman who presented with a breast mass. Needle biopsy was performed, yielding a polygonal cell lesion with abundant, predominantly xanthomatous cytoplasm. The cells labeled strongly for the histiocytic marker CD68, suggesting a benign macrophage-rich lesion. However, the unusual nature of the lesion as well as the prominence of nucleoli prompted suggestion for an excision. The excision more clearly revealed the lesion's alveolar architecture and demonstrated cells with more eosinophilic cytoplasm, along with the xanthomatous cells. The diagnosis of ASPS was confirmed by electron microscopy, which revealed characteristic membrane-bound rhomboidal crystals, as well as by nuclear labeling for TFE3 protein by immunohistochemistry. With this report, we confirm the utility of a novel immunohistochmical technique for the identification of an ASPS presenting in an unusual locale.

Adult↗
PubMed2004

Complement factor h limits immune complex deposition and prevents inflammation and scarring in glomeruli of mice with chronic serum sickness.

Factor H is the major complement regulator in plasma. Abnormalities in factor H have been implicated in membranoproliferative glomerulonephritis in both humans and experimental animals. It has been shown that factor H on rodent platelets functions analogously to human erythrocyte complement receptor 1 in its role to traffic immune complexes to the mononuclear phagocyte system. C57BL/6 factor H-deficient mice (Cfh(-/-)) and wild-type (wt) controls were immunized daily for 5 wk with heterologous apoferritin to study the chronic serum sickness GN model. Immunizations were started in 6- to 8-wk-old mice, which was before the development of spontaneous membranoproliferative glomerulonephritis in some Cfh(-/-) animals. Glomerular deposition of IgG immune complexes in glomeruli was qualitatively and quantitatively increased in Cfh(-/-) mice compared with wt mice. Consistent with the increase in glomerular immune complexes and possibly because of alternative pathway complement activation, Cfh(-/-) mice had increased glomerular C3 deposition. Wt mice developed no glomerular pathology. In contrast, Cfh(-/-) mice developed diffuse proliferative GN with focal crescents and glomerulosclerosis. In addition, there was significantly increased expression of collagen IV, fibronectin, and laminin mRNA in Cfh(-/-) glomeruli. These data show a role for platelet-associated factor H to process immune complexes and limit their accumulation in glomeruli. Once deposited in glomeruli, excessive complement activation can lead to glomerular inflammation and the rapid development of a scarring phenotype.

Animals↗
PubMed2004

Isometric tubular epithelial vacuolization in renal allograft biopsy specimens of patients receiving low-dose intravenous immunoglobulin for a positive crossmatch.

BACKGROUND: Perioperative treatment with plasmapheresis and intravenous immunoglobulin (IVIG), combined with a tacrolimus-based immunosuppressive regimen, has been used successfully to allow renal transplantations in cross-match-positive recipients. A common finding in biopsy specimens of these allografts is isometric vacuolization of proximal tubular epithelium. This finding presents a diagnostic dilemma because it may occur secondary to IVIG treatment or tacrolimus nephrotoxicity. METHODS: We compared the frequency and severity of isometric tubular vacuolization in renal allograft biopsy specimens obtained during the first 10 days after transplantation in 24 patients who received one or more postoperative treatments with IVIG (100 mg/kg; as part of a desensitization protocol also involving plasmapheresis) with specimens obtained in 91 patients who did not receive IVIG. All patients received tacrolimus. Isometric vacuolization was graded on a 0 to 4 scale based on the fraction of proximal tubules involved: 0, none; 1, less than 10%; 2, 10% to 25%; 3, 26% to 50%; 4, more than 50%. RESULTS: There was a higher frequency of isometric tubular vacuolization (71 % vs. 31%) and more widespread involvement in patients who received IVIG and tacrolimus versus tacrolimus alone, although mean tacrolimus levels were not significantly different between these groups. In control, but not IVIG, biopsy specimens, there was a significant association between vacuolization score and blood tacrolimus level on the day of biopsy. CONCLUSIONS: Isometric tubular vacuolization is a common finding in renal transplant biopsy specimens of patients who receive low-dose IVIG and in many cases is likely to be related, at least in part, to IVIG. In these patients, this finding should not necessarily be interpreted as indicative of tacrolimus (or cyclosporine) nephrotoxicity.

Biopsy↗
PubMed2004

CR1/CR2 deficiency alters IgG3 autoantibody production and IgA glomerular deposition in the MRL/lpr model of SLE.

CR1 and CR2 expression is decreased by approximately 50% on B cells of patients with systemic lupus erythematosus (SLE). Expression is also decreased in the MRL/lpr murine model of SLE prior to the development of clinical disease, suggesting that this alteration may play a role in pathogenesis. To determine whether the decrease in receptor levels affects the development of SLE, we analyzed MRL/lpr mice in which CR1/CR2 expression was altered by gene targeting. Mice from each cohort (Cr2+/+, Cr2+/-, and Cr2-/-) were analyzed biweekly for the development of proteinuria and autoantibodies. Kidneys were examined at 12 and 16 weeks for evidence of immune complex deposition and renal disease. Deficiency of CR1/CR2 did not affect survival or development of renal disease as measured by proteinuria. Mice deficient in CR1/CR2 had significantly lower levels of IgG3 rheumatoid factor (RF) and total serum IgG3, suggesting a specific defect in production of IgG3 in response to endogenous autoantigens. Since IgG3 RF has been associated with the development of vasculitis in this model, we examined the mice for alterations in development of this clinical manifestation. Although there was no difference in the development of ear necrosis among the three groups, renal arteritis was not identified in any of the Cr2+/- mice, whereas it was present in 20% of the Cr2+/- and 40% of the Cr2+/+ mice. Finally, significantly higher levels of IgA were seen in the glomeruli of Cr2+/- mice compared to Cr2+/- or Cr2+/+ mice, suggesting that CR1/CR2 are involved in either the regulation of IgA production or the clearance of IgA immune complexes. Together these data support the concept that alterations in CR1/CR2 expression or function affect the regulation of autoantibody production and/or clearance and may have clinical consequences.

Animals↗