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Papers by Shane Meehan

Transplantation, 1998

Background. Collapsing glomerulopathy is a recently described form of glomerular injury character... more Background. Collapsing glomerulopathy is a recently described form of glomerular injury characterized by capillary collapse and visceral epithelial hypercellularity associated with nephrotic range proteinuria and a rapid, progressive decline in renal function. The lesion has rarely been described in allografts.

Clinical journal of the American Society of Nephrology : CJASN, Jan 7, 2015

This study examined kidney biopsies with focal segmental glomerular fibrinoid necrosis to identif... more This study examined kidney biopsies with focal segmental glomerular fibrinoid necrosis to identify early features of pauci-immune necrotizing GN and the primary effector cells mediating initial capillary injury. Seventeen consecutive kidney biopsies with focal pauci-immune necrotizing GN, obtained over a 6-year period (2007-2012), were studied. Neutrophils and CD68(+), CD163(+), CD3(+), CD56(+), and CD20(+) cells were scored in paraffin sections counterstained with periodic acid-Schiff. Electron microscopy was performed in 15 of 17 biopsies and additional examples of pauci-immune necrotizing GN (n=25). Biopsies with thin basement membrane nephropathy (n=5) served as immunohistologic normal controls. Biopsies with pauci-immune necrotizing GN had a mean of 10 (range=3-25) normal-appearing glomeruli, a mean of 2 (range=1-5) glomeruli with segmental fibrinoid necrosis, and a mean of 2 (range=1-11) glomeruli with cellular crescents. CD68(+) and CD163(+) macrophages predominated at sites ...

Human Pathology, 2006

This study uses CD10 and epithelial membrane antigen (EMA) as respective proximal and distal tubu... more This study uses CD10 and epithelial membrane antigen (EMA) as respective proximal and distal tubular segment markers to localize polyoma virus replicative activity, as determined by large T antigen (TAg) expression, in allograft polyoma virus nephropathy (PVN). Sixteen biopsies and 2 nephrectomy specimens with PVN had serial 2-mum paraffin sections stained using monoclonal antibodies to polyoma virus TAg by immunoperoxidase with diaminobenzidine as chromogen. A second immunolabeling step used CD10 as a proximal nephron marker or EMA as a distal tubular marker, and alkaline phosphatase with fast red as chromogen. BK viral DNA was detected in blood in 16 of 18 tested. Fourteen of 16 had cortex and medulla, and 2 had cortex only in the biopsy sample. Fourteen (100%) of 14 had double-positive EMA and TAg expression (EMA+TAg+) in medullary collecting ducts. T antigen was evident in loops of Henle in nephrectomies. Thirteen (81.3%) of 16 had EMA+TAg+, and 10 (62.5%) of 16 had CD10+TAg+ cortical tubular segments. CD10+TAg+ cells were observed in the parietal epithelium of Bowman's capsule in 3 biopsies (18.75%). T antigen was observed in 5.1% of CD10+ tubular profiles compared with 21% of EMA+ profiles in renal cortex (P < .0001). Polyoma virus TAg was observed in medullary collecting ducts, in distal and proximal cortical tubules, and in Bowman's capsule, in decreasing order of frequency. Loops of Henle also had TAg. This distribution suggests potential for an ascending route of infection of allograft tubules in PVN.

Advances in Experimental Medicine and Biology, 2006

... Michelle A. Josephson, Basit Javaid, Pradeep V. Kadambi, Shane M. Meehan and James W. William... more ... Michelle A. Josephson, Basit Javaid, Pradeep V. Kadambi, Shane M. Meehan and James W. Williams ... of chronic rejection in rodents; '^ (6) inhibition of CMV replication in vitro and in vivo at concentrations readily attained in humans; ' (7) inhibition of polyoma BK virus replication ...

ChemInform, 2009

ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Transplantation, 2006

Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of re... more Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals. We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 microg/ml to 100 microg/ml (150 microM to 300 microM). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy. In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 microg/ml did not clear the virus until these levels were attained or cidofovir was added. Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Xenotransplantation, 1995

... 1 Dominique latirme,1 Pierre Gianello,1 Michael Bailin,3 Kate Bergen,1 Robert B. Colvin,2 Ali... more ... 1 Dominique latirme,1 Pierre Gianello,1 Michael Bailin,3 Kate Bergen,1 Robert B. Colvin,2 Alicia Foley,1 Han-Zhou Hong,4 Thomas Lorf,1 Shane Meehan,2 Rod ... 9. Kawai T, Cosimi AB, Colvin RB, Powelson J, Eason J, Kozlowski T, Sykes M, Monroy R, Tanaka M, Sachs DH. ...

Virchows Archiv, 2013

The morphology of focal segmental glomerulosclerosis (FSGS) includes collapsing, cellular, and sc... more The morphology of focal segmental glomerulosclerosis (FSGS) includes collapsing, cellular, and sclerosing forms. The Columbia Working Classification of FSGS divides these into collapsing (COLL), cellular (CELL), tip lesion (TIP), perihilar (PH), and not otherwise specified (NOS) morphologic forms. This study examined the ability of renal pathologists to classify FSGS using single light microscopic images of glomeruli as a uniform data set. Sixty-one digital images of individual glomeruli with FSGS, stained by periodic acid-Schiff or Jones methenamine silver methods, were classified independently by six specialist renal pathologists. Diagnostic consistency was quantified using the kappa statistic for nominal categories. Agreement for 366 diagnoses by six observers was 75.2 % with a kappa value of 0.676. Six of six observers agreed in 31 of 61 cases (50.8 %) and four or more in 53 cases (86.9 %). Respective kappa values ranged from moderate to good: COLL 0.77, CELL 0.53, TIP 0.76, PH 0.84, and NOS 0.60. Capillary retraction with lobular expansion, hypercellularity, and sclerosis in the same glomerular segments, and the location of segmental lesions were sources of diagnostic inconsistency. The morphologic forms of FSGS defined by the Columbia system are reproducible between observers and have a low probability of confusion between forms. Individual glomeruli may have overlapping features of more than one form of FSGS.

Virchows Archiv, 2012

The Columbia working classification of focal segmental glomerulosclerosis (FSGS) identifies five ... more The Columbia working classification of focal segmental glomerulosclerosis (FSGS) identifies five types of glomerular lesions, designated collapsing (COLL), cellular (CELL), glomerular tip lesion (GTL), perihilar (PH), and not otherwise specified (NOS) variant lesions. FSGS COLL and non-collapsing variants of FSGS are described in human immunodeficiency virus (HIV)-associated kidney disease. This study examined the range and relationships of Columbia-type segmental sclerosing lesions in biopsies from patients with HIV infection. We identified 47 renal biopsies from 46 patients with HIV infection obtained over an 8-year period. Twenty-seven biopsies from 26 patients had FSGS. Sixteen biopsies had FSGS COLL (59.3%), 3 had CELL (11.1%), 5 had NOS (18.5%), 2 had PH (7.4%), and 1 had GTL (3.7%) by the Columbia classification. Biopsies had more than one type of Columbia FSGS lesion in 63% and one type in 37%. Single types of FSGS lesions were identified in eight of eight biopsies with ≤10 glomeruli. Combinations of lesions were observed in 17 of 19 (89.5%) with >10 glomeruli, and the coincidence of COLL, CELL, and NOS lesions was not random. NOS, COLL, and CELL morphologic lesions of FSGS frequently coexist in kidney biopsies from HIV+ patients. Combined patterns of FSGS suggest that lesions identified by Columbia criteria may be part of a spectrum of responses to injury in the setting of HIV infection.

Transplantation Proceedings, 1997

Antibody-mediated rejection appears to constitute the major difference between concordant xenogra... more Antibody-mediated rejection appears to constitute the major difference between concordant xenografts and allografts in nonhuman primates. Consistent with its known effect on antibody responses, 5-7 addition of DSG to the conditioning regimen has extended concordant primate xenograft survival for up to 6 months after discontinuation of conventional immunosuppression. In contrast to our observations in recipients of renal allografts, donor-specific skin graft rejection can occur and even in long-term recipients may induce rejection of a previously accepted renal xenograft.

Transplantation Proceedings, 1997

A SPONTANEOUSLY remitting allograft reaction occurrs in MHC class II matched, class I mismatched ... more A SPONTANEOUSLY remitting allograft reaction occurrs in MHC class II matched, class I mismatched pig allografts after short-term, high-dose Cyclosporin A (CyA) treatment.' This animal model provides an ideal opportunity to study the morphological correlates of graft acceptance and has potential relevance to the subclinical reactions seen in human transplant biopsies. We have studied the intragraft cellular events associated with graft acceptance, focusing on the activation, proliferation, and apoptosis in graft infiltrating cells and cell-mediated apoptotic graft cell injury.

Transplantation Proceedings, 1997

ABSTRACT Background. Recent studies in young (5-7 months) miniature swine have demonstrated that ... more ABSTRACT Background. Recent studies in young (5-7 months) miniature swine have demonstrated that the thymus is involved in the rapid induction of stable tolerance to class I mismatched renal allografts after a 12-day course of Cyclosporine (CyA). Because both steroids and age are known to influence the structure and function of the thymus, we have now studied the effects of these two parameters on tolerance induction in this model.1,2,3,4 Materials and Methods. In young swine, the administration of methylprednisolone (MP) during the standard tolerance-inducing regimen (a 12-day course of CyA) produced severe renal dysfunction and acute cellular rejection histologically. However, the renal allografts recovered and were accepted for > 100 days with histological evidence of chronic rejection. To test the effect of age, two relatively old swine (55 and 71 months) received transplants of class I mismatched renal allografts and the standard 12-day course of CyA. One animal rejected the allograft acutely on post-operative day 22, and the second also rejected, but more slowly, with manifestations of chronic rejection. Conclusion. These findings suggest that both MP and old age interfere with the induction of stable tolerance in a fashion similar to the previously described effect of thymectomy. These results may have important implications for the mechanism of thymic-dependent tolerance, for the use of steroids in clinical protocols for the induction of allograft tolerance, and for the application of such protocols to adult patients.

Transplantation, 1997

In recent years, hepatitis C virus infection has been reported to be typically associated with me... more In recent years, hepatitis C virus infection has been reported to be typically associated with membranoproliferative glomerulonephritis and less frequently with membranous nephropathy. Treatment of hepatitis C with interferon-alpha can reduce viremia and improve renal disease. After liver transplantation for hepatitis C virus-associated liver failure, standard immunosuppressive protocols result in a significant increase in hepatitis C viremia. In this report we describe a patient with end-stage liver disease and biopsy-proven hepatitis C-associated glomerulonephritis who underwent liver transplantation. Within 1 month after transplantation, he developed a severe nephrotic syndrome that paralleled a marked increase in viremia. We discuss the possible pathogenic relationship between hepatitis C virus infection and the nephrotic syndrome that followed liver transplantation.

Transplantation, 1998

Background. In clinical transplantation, "passenger" dendritic cells (DCs) in the allograft have ... more Background. In clinical transplantation, "passenger" dendritic cells (DCs) in the allograft have been thought to induce allograft rejection. However, the presence of DCs in the normal human kidney is controversial. Most reports have relied on the examination of MHC class I and II antigen expression in combination with DC morphology for identification of DCs.

Transplantation, 2002

Although polyoma virus infection is being increasingly recognized as a cause of renal allograft d... more Although polyoma virus infection is being increasingly recognized as a cause of renal allograft dysfunction and failure, the risk of polyoma recurrence in a subsequent transplant is unknown. We present the first reported case of successful retransplantation after polyoma virus-induced renal allograft loss. A 40-year-old Caucasian woman received a cadaveric kidney transplant. Baseline immunosuppression included corticosteroids, mycophenolate mofetil, and tacrolimus. Her post-transplant clinical course was complicated by an early acute rejection episode on posttransplant day (PTD) 6, that warranted treatment with OKT3. A biopsy performed on PTD 154 to evaluate a rise in creatinine revealed polyoma virus interstitial nephritis. Despite reduction in immunosuppression, the renal function progressively worsened and dialysis was initiated by PTD 160, followed by transplant nephrectomy on PTD 184. Four months later, she received a living related kidney from her sister. Immunosuppression was initiated with prednisone, azathioprine, and tacrolimus. She had immediate graft function with a decrease in serum creatinine from 12.8 to 1.1 mg/dl. Three and one-half years after her second renal transplant, her allograft functions well, with a serum creatinine of 1 mg/dl. Both quantitative and qualitative assays of blood and urine (by PCR) remain negative for BK virus, indicating the absence of virus reactivation. Judicious retransplantation should be considered as a therapeutic option in the management of polyoma virus induced graft failure. Previous graft loss secondary to polyoma virus infection is not a contraindication to retransplantation.

Transplantation, 1999

We have previously demonstrated that induction of mixed lymphohematopoietic chimerism resulted in... more We have previously demonstrated that induction of mixed lymphohematopoietic chimerism resulted in donor specific renal allograft tolerance without the need for chronic immunosuppression in nonhuman primates. Here we have tested whether tolerance can be similarly induced for baboon to cynomolgus renal xenografts .

Transplant International, 2012

Surgery, 1997

The intensity of discordant xenograft cellular rejection makes it unlikely that safe doses of imm... more The intensity of discordant xenograft cellular rejection makes it unlikely that safe doses of immunosuppressive drugs will alone be sufficient to permit long-term survival. We have therefore concentrated our efforts on establishing tolerance to xenogeneic organs through lymphohematopoietic chimerism and the elimination of preformed natural antibodies (nAbs). Here we report the most recent series of 11 technically successful porcine to nonhuman primate transplantation procedures. In eight experimental animals induction therapy consisted of (1) 3 x 100 cGy nonlethal whole body irradiation (day -6 and day -5) to all animals, (2) horse anti-human thymocyte globulin (day -2, day -1, and day 0) to seven of the animals, (3) 700 cGy thymic irradiation (day -1) to five of the animals, and (4) pig bone marrow infused on day 0 (2-9 x 10(8)/cells/kg). On day 0, just before the renal xenograft, the recipient was splenectomized, and antipig nAbs were removed by means of perfusion of the monkey's blood through either a pig liver (n = 6) or a Gal-alpha (1,3)-Gal adsorption column (n = 5). There control animals did not receive this pretransplantation induction therapy but did undergo hemoperfusion and posttransplantation immunosuppression identical to the experimental animals. All 11 recipients were treated after transplantation with cyclosporin A and 15-deoxyspergualin. Recombinant pig-specific growth factors (interleukin-3 and stem cell factor) were given to six experimental animals from day 0 until the termination of the experiment. Analysis of recipients' sera by means of flow cytometry indicated the effective removal of immunoglobulin M and immunoglobulin G nAbs by either liver perfusion or column adsorption. In the eight experimental animals, nAb titers remained low until death (up to 15 days), but in the three control animals nAb titers increased substantially with time. The longest surviving recipient maintained excellent kidney function with creatinine levels at 0.8 to 1.3 mg/dl throughout its course. Death occurred at day 15 from complications caused by a urinary leak and pancytopenia. Histologic examination of the xenograft revealed only focal tubular necrosis and cytoplasmic vacuolization, with trace amounts of fibrin and C3 in peritubular capillaries. In this animal a fraction of the peripheral blood cells (3%) at day 7 were of pig origin as detected by pig-specific monoclonal antibodies. In addition, colony-forming assays performed on a bone marrow biopsy specimen taken at day 14 indicated that approximately 30% of the relatively few myeloid progenitors detected were of swine origin. We have demonstrated that our protocol is effective in the prevention of hyperacute rejection and in the maintenance of excellent function of the renal xenograft for up to 15 days. These results also indicate that at least short-term engraftment of the xenogeneic donor bone marrow cells is possible to achieve in this discordant large animal combination. Longer survivals will be required to assess the possible effect of this engraftment on induction of tolerance.

Pediatric Transplantation, 2009

Transplantation, 1998

Background. Collapsing glomerulopathy is a recently described form of glomerular injury character... more Background. Collapsing glomerulopathy is a recently described form of glomerular injury characterized by capillary collapse and visceral epithelial hypercellularity associated with nephrotic range proteinuria and a rapid, progressive decline in renal function. The lesion has rarely been described in allografts.

Clinical journal of the American Society of Nephrology : CJASN, Jan 7, 2015

This study examined kidney biopsies with focal segmental glomerular fibrinoid necrosis to identif... more This study examined kidney biopsies with focal segmental glomerular fibrinoid necrosis to identify early features of pauci-immune necrotizing GN and the primary effector cells mediating initial capillary injury. Seventeen consecutive kidney biopsies with focal pauci-immune necrotizing GN, obtained over a 6-year period (2007-2012), were studied. Neutrophils and CD68(+), CD163(+), CD3(+), CD56(+), and CD20(+) cells were scored in paraffin sections counterstained with periodic acid-Schiff. Electron microscopy was performed in 15 of 17 biopsies and additional examples of pauci-immune necrotizing GN (n=25). Biopsies with thin basement membrane nephropathy (n=5) served as immunohistologic normal controls. Biopsies with pauci-immune necrotizing GN had a mean of 10 (range=3-25) normal-appearing glomeruli, a mean of 2 (range=1-5) glomeruli with segmental fibrinoid necrosis, and a mean of 2 (range=1-11) glomeruli with cellular crescents. CD68(+) and CD163(+) macrophages predominated at sites ...

Human Pathology, 2006

This study uses CD10 and epithelial membrane antigen (EMA) as respective proximal and distal tubu... more This study uses CD10 and epithelial membrane antigen (EMA) as respective proximal and distal tubular segment markers to localize polyoma virus replicative activity, as determined by large T antigen (TAg) expression, in allograft polyoma virus nephropathy (PVN). Sixteen biopsies and 2 nephrectomy specimens with PVN had serial 2-mum paraffin sections stained using monoclonal antibodies to polyoma virus TAg by immunoperoxidase with diaminobenzidine as chromogen. A second immunolabeling step used CD10 as a proximal nephron marker or EMA as a distal tubular marker, and alkaline phosphatase with fast red as chromogen. BK viral DNA was detected in blood in 16 of 18 tested. Fourteen of 16 had cortex and medulla, and 2 had cortex only in the biopsy sample. Fourteen (100%) of 14 had double-positive EMA and TAg expression (EMA+TAg+) in medullary collecting ducts. T antigen was evident in loops of Henle in nephrectomies. Thirteen (81.3%) of 16 had EMA+TAg+, and 10 (62.5%) of 16 had CD10+TAg+ cortical tubular segments. CD10+TAg+ cells were observed in the parietal epithelium of Bowman's capsule in 3 biopsies (18.75%). T antigen was observed in 5.1% of CD10+ tubular profiles compared with 21% of EMA+ profiles in renal cortex (P < .0001). Polyoma virus TAg was observed in medullary collecting ducts, in distal and proximal cortical tubules, and in Bowman's capsule, in decreasing order of frequency. Loops of Henle also had TAg. This distribution suggests potential for an ascending route of infection of allograft tubules in PVN.

Advances in Experimental Medicine and Biology, 2006

... Michelle A. Josephson, Basit Javaid, Pradeep V. Kadambi, Shane M. Meehan and James W. William... more ... Michelle A. Josephson, Basit Javaid, Pradeep V. Kadambi, Shane M. Meehan and James W. Williams ... of chronic rejection in rodents; '^ (6) inhibition of CMV replication in vitro and in vivo at concentrations readily attained in humans; ' (7) inhibition of polyoma BK virus replication ...

ChemInform, 2009

ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Transplantation, 2006

Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of re... more Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals. We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 microg/ml to 100 microg/ml (150 microM to 300 microM). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy. In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 microg/ml did not clear the virus until these levels were attained or cidofovir was added. Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Xenotransplantation, 1995

... 1 Dominique latirme,1 Pierre Gianello,1 Michael Bailin,3 Kate Bergen,1 Robert B. Colvin,2 Ali... more ... 1 Dominique latirme,1 Pierre Gianello,1 Michael Bailin,3 Kate Bergen,1 Robert B. Colvin,2 Alicia Foley,1 Han-Zhou Hong,4 Thomas Lorf,1 Shane Meehan,2 Rod ... 9. Kawai T, Cosimi AB, Colvin RB, Powelson J, Eason J, Kozlowski T, Sykes M, Monroy R, Tanaka M, Sachs DH. ...

Virchows Archiv, 2013

The morphology of focal segmental glomerulosclerosis (FSGS) includes collapsing, cellular, and sc... more The morphology of focal segmental glomerulosclerosis (FSGS) includes collapsing, cellular, and sclerosing forms. The Columbia Working Classification of FSGS divides these into collapsing (COLL), cellular (CELL), tip lesion (TIP), perihilar (PH), and not otherwise specified (NOS) morphologic forms. This study examined the ability of renal pathologists to classify FSGS using single light microscopic images of glomeruli as a uniform data set. Sixty-one digital images of individual glomeruli with FSGS, stained by periodic acid-Schiff or Jones methenamine silver methods, were classified independently by six specialist renal pathologists. Diagnostic consistency was quantified using the kappa statistic for nominal categories. Agreement for 366 diagnoses by six observers was 75.2 % with a kappa value of 0.676. Six of six observers agreed in 31 of 61 cases (50.8 %) and four or more in 53 cases (86.9 %). Respective kappa values ranged from moderate to good: COLL 0.77, CELL 0.53, TIP 0.76, PH 0.84, and NOS 0.60. Capillary retraction with lobular expansion, hypercellularity, and sclerosis in the same glomerular segments, and the location of segmental lesions were sources of diagnostic inconsistency. The morphologic forms of FSGS defined by the Columbia system are reproducible between observers and have a low probability of confusion between forms. Individual glomeruli may have overlapping features of more than one form of FSGS.

Virchows Archiv, 2012

The Columbia working classification of focal segmental glomerulosclerosis (FSGS) identifies five ... more The Columbia working classification of focal segmental glomerulosclerosis (FSGS) identifies five types of glomerular lesions, designated collapsing (COLL), cellular (CELL), glomerular tip lesion (GTL), perihilar (PH), and not otherwise specified (NOS) variant lesions. FSGS COLL and non-collapsing variants of FSGS are described in human immunodeficiency virus (HIV)-associated kidney disease. This study examined the range and relationships of Columbia-type segmental sclerosing lesions in biopsies from patients with HIV infection. We identified 47 renal biopsies from 46 patients with HIV infection obtained over an 8-year period. Twenty-seven biopsies from 26 patients had FSGS. Sixteen biopsies had FSGS COLL (59.3%), 3 had CELL (11.1%), 5 had NOS (18.5%), 2 had PH (7.4%), and 1 had GTL (3.7%) by the Columbia classification. Biopsies had more than one type of Columbia FSGS lesion in 63% and one type in 37%. Single types of FSGS lesions were identified in eight of eight biopsies with ≤10 glomeruli. Combinations of lesions were observed in 17 of 19 (89.5%) with >10 glomeruli, and the coincidence of COLL, CELL, and NOS lesions was not random. NOS, COLL, and CELL morphologic lesions of FSGS frequently coexist in kidney biopsies from HIV+ patients. Combined patterns of FSGS suggest that lesions identified by Columbia criteria may be part of a spectrum of responses to injury in the setting of HIV infection.

Transplantation Proceedings, 1997

Antibody-mediated rejection appears to constitute the major difference between concordant xenogra... more Antibody-mediated rejection appears to constitute the major difference between concordant xenografts and allografts in nonhuman primates. Consistent with its known effect on antibody responses, 5-7 addition of DSG to the conditioning regimen has extended concordant primate xenograft survival for up to 6 months after discontinuation of conventional immunosuppression. In contrast to our observations in recipients of renal allografts, donor-specific skin graft rejection can occur and even in long-term recipients may induce rejection of a previously accepted renal xenograft.

Transplantation Proceedings, 1997

A SPONTANEOUSLY remitting allograft reaction occurrs in MHC class II matched, class I mismatched ... more A SPONTANEOUSLY remitting allograft reaction occurrs in MHC class II matched, class I mismatched pig allografts after short-term, high-dose Cyclosporin A (CyA) treatment.' This animal model provides an ideal opportunity to study the morphological correlates of graft acceptance and has potential relevance to the subclinical reactions seen in human transplant biopsies. We have studied the intragraft cellular events associated with graft acceptance, focusing on the activation, proliferation, and apoptosis in graft infiltrating cells and cell-mediated apoptotic graft cell injury.

Transplantation Proceedings, 1997

ABSTRACT Background. Recent studies in young (5-7 months) miniature swine have demonstrated that ... more ABSTRACT Background. Recent studies in young (5-7 months) miniature swine have demonstrated that the thymus is involved in the rapid induction of stable tolerance to class I mismatched renal allografts after a 12-day course of Cyclosporine (CyA). Because both steroids and age are known to influence the structure and function of the thymus, we have now studied the effects of these two parameters on tolerance induction in this model.1,2,3,4 Materials and Methods. In young swine, the administration of methylprednisolone (MP) during the standard tolerance-inducing regimen (a 12-day course of CyA) produced severe renal dysfunction and acute cellular rejection histologically. However, the renal allografts recovered and were accepted for > 100 days with histological evidence of chronic rejection. To test the effect of age, two relatively old swine (55 and 71 months) received transplants of class I mismatched renal allografts and the standard 12-day course of CyA. One animal rejected the allograft acutely on post-operative day 22, and the second also rejected, but more slowly, with manifestations of chronic rejection. Conclusion. These findings suggest that both MP and old age interfere with the induction of stable tolerance in a fashion similar to the previously described effect of thymectomy. These results may have important implications for the mechanism of thymic-dependent tolerance, for the use of steroids in clinical protocols for the induction of allograft tolerance, and for the application of such protocols to adult patients.

Transplantation, 1997

In recent years, hepatitis C virus infection has been reported to be typically associated with me... more In recent years, hepatitis C virus infection has been reported to be typically associated with membranoproliferative glomerulonephritis and less frequently with membranous nephropathy. Treatment of hepatitis C with interferon-alpha can reduce viremia and improve renal disease. After liver transplantation for hepatitis C virus-associated liver failure, standard immunosuppressive protocols result in a significant increase in hepatitis C viremia. In this report we describe a patient with end-stage liver disease and biopsy-proven hepatitis C-associated glomerulonephritis who underwent liver transplantation. Within 1 month after transplantation, he developed a severe nephrotic syndrome that paralleled a marked increase in viremia. We discuss the possible pathogenic relationship between hepatitis C virus infection and the nephrotic syndrome that followed liver transplantation.

Transplantation, 1998

Background. In clinical transplantation, "passenger" dendritic cells (DCs) in the allograft have ... more Background. In clinical transplantation, "passenger" dendritic cells (DCs) in the allograft have been thought to induce allograft rejection. However, the presence of DCs in the normal human kidney is controversial. Most reports have relied on the examination of MHC class I and II antigen expression in combination with DC morphology for identification of DCs.

Transplantation, 2002

Although polyoma virus infection is being increasingly recognized as a cause of renal allograft d... more Although polyoma virus infection is being increasingly recognized as a cause of renal allograft dysfunction and failure, the risk of polyoma recurrence in a subsequent transplant is unknown. We present the first reported case of successful retransplantation after polyoma virus-induced renal allograft loss. A 40-year-old Caucasian woman received a cadaveric kidney transplant. Baseline immunosuppression included corticosteroids, mycophenolate mofetil, and tacrolimus. Her post-transplant clinical course was complicated by an early acute rejection episode on posttransplant day (PTD) 6, that warranted treatment with OKT3. A biopsy performed on PTD 154 to evaluate a rise in creatinine revealed polyoma virus interstitial nephritis. Despite reduction in immunosuppression, the renal function progressively worsened and dialysis was initiated by PTD 160, followed by transplant nephrectomy on PTD 184. Four months later, she received a living related kidney from her sister. Immunosuppression was initiated with prednisone, azathioprine, and tacrolimus. She had immediate graft function with a decrease in serum creatinine from 12.8 to 1.1 mg/dl. Three and one-half years after her second renal transplant, her allograft functions well, with a serum creatinine of 1 mg/dl. Both quantitative and qualitative assays of blood and urine (by PCR) remain negative for BK virus, indicating the absence of virus reactivation. Judicious retransplantation should be considered as a therapeutic option in the management of polyoma virus induced graft failure. Previous graft loss secondary to polyoma virus infection is not a contraindication to retransplantation.

Transplantation, 1999

We have previously demonstrated that induction of mixed lymphohematopoietic chimerism resulted in... more We have previously demonstrated that induction of mixed lymphohematopoietic chimerism resulted in donor specific renal allograft tolerance without the need for chronic immunosuppression in nonhuman primates. Here we have tested whether tolerance can be similarly induced for baboon to cynomolgus renal xenografts .

Transplant International, 2012

Surgery, 1997

The intensity of discordant xenograft cellular rejection makes it unlikely that safe doses of imm... more The intensity of discordant xenograft cellular rejection makes it unlikely that safe doses of immunosuppressive drugs will alone be sufficient to permit long-term survival. We have therefore concentrated our efforts on establishing tolerance to xenogeneic organs through lymphohematopoietic chimerism and the elimination of preformed natural antibodies (nAbs). Here we report the most recent series of 11 technically successful porcine to nonhuman primate transplantation procedures. In eight experimental animals induction therapy consisted of (1) 3 x 100 cGy nonlethal whole body irradiation (day -6 and day -5) to all animals, (2) horse anti-human thymocyte globulin (day -2, day -1, and day 0) to seven of the animals, (3) 700 cGy thymic irradiation (day -1) to five of the animals, and (4) pig bone marrow infused on day 0 (2-9 x 10(8)/cells/kg). On day 0, just before the renal xenograft, the recipient was splenectomized, and antipig nAbs were removed by means of perfusion of the monkey's blood through either a pig liver (n = 6) or a Gal-alpha (1,3)-Gal adsorption column (n = 5). There control animals did not receive this pretransplantation induction therapy but did undergo hemoperfusion and posttransplantation immunosuppression identical to the experimental animals. All 11 recipients were treated after transplantation with cyclosporin A and 15-deoxyspergualin. Recombinant pig-specific growth factors (interleukin-3 and stem cell factor) were given to six experimental animals from day 0 until the termination of the experiment. Analysis of recipients' sera by means of flow cytometry indicated the effective removal of immunoglobulin M and immunoglobulin G nAbs by either liver perfusion or column adsorption. In the eight experimental animals, nAb titers remained low until death (up to 15 days), but in the three control animals nAb titers increased substantially with time. The longest surviving recipient maintained excellent kidney function with creatinine levels at 0.8 to 1.3 mg/dl throughout its course. Death occurred at day 15 from complications caused by a urinary leak and pancytopenia. Histologic examination of the xenograft revealed only focal tubular necrosis and cytoplasmic vacuolization, with trace amounts of fibrin and C3 in peritubular capillaries. In this animal a fraction of the peripheral blood cells (3%) at day 7 were of pig origin as detected by pig-specific monoclonal antibodies. In addition, colony-forming assays performed on a bone marrow biopsy specimen taken at day 14 indicated that approximately 30% of the relatively few myeloid progenitors detected were of swine origin. We have demonstrated that our protocol is effective in the prevention of hyperacute rejection and in the maintenance of excellent function of the renal xenograft for up to 15 days. These results also indicate that at least short-term engraftment of the xenogeneic donor bone marrow cells is possible to achieve in this discordant large animal combination. Longer survivals will be required to assess the possible effect of this engraftment on induction of tolerance.

Pediatric Transplantation, 2009