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P S Randhawa

Publications and source records attributed to P S Randhawa.

At least 19 recordsLinked to original sources
PubMed2006

Polyomavirus-associated nephropathy: update on antiviral strategies.

Polyomavirus-associated nephropathy (PVAN) is a major complication of kidney transplantation. Many centers respond to PVAN by reducing immunosuppression. Concern over precipitating rejection, as well as situations in which some PVAN-afflicted individuals have multi-organ transplants, can make reduction of immunosuppression undesirable. In these cases, effective antiviral strategies would be useful. This article describes clinical observations and experiences with 3 different antiviral protocols. Two protocols address antiviral treatment of nephropathy (cidofovir in one, and leflunomide in the other). The third protocol examines fluoroquinolone control of polyoma urinary excretion. Patients responded to all 3 strategies. These promising approaches deserve further evaluation with prospective controlled studies.

Animals↗
PubMed2000

Biopsy of marginal donor kidneys: correlation of histologic findings with graft dysfunction.

BACKGROUND: Kidney biopsies are being used to evaluate marginal donors, but rigorous statistical validation of this practice with multivariate analysis has not been performed. METHODS: To analyze histologic parameters in 78 donor biopsies for their ability to predict graft dysfunction, we used a proportional odds model that included both donor and recipient factors. Glomerulosclerosis was categorized into grades 0, 1, 2, and 3, corresponding to 0, 1-10%, 11-20%, and 21-30% global sclerosis, respectively. The degrees of interstitial fibrosis, tubular atrophy, arteriosclerosis, and arteriolar hyalinosis were graded from 0 to 3+, using definitions suggested by the Banff Schema of allograft pathology. RESULTS: Increasing donor age was associated with higher glomerulosclerosis, tubular atrophy, and arteriosclerosis. Kidneys with any degree of interstitial fibrosis were 2.6 times [odds ratio (OR)] more likely to experience a worse outcome at 6 months (P = 0.02). This association held up after correction for acute rejection (OR 2.5, P = 0.03) and high panel-reactive antibody (OR 3.4, P = 0.006), However, the OR was reduced to 1.9 (P = 0.15) after controlling for recipient age. With each increment in the grade of glomerulosclerosis, the odds for a worse outcome at 12 months increased to 2.3 (P = 0.005). The value for OR became 2.0 (P = 0.03) when controlling for recipient age (P = 0.01), 2.4 (P = 0.005), when controlling for acute rejection, and 2.3 (P = 0.006) when controlling for high panel-reactive antibody. CONCLUSIONS: Histopathological parameters present in donor biopsies can independently predict post-transplant graft function. Implications for the pool of donor organs available for transplantation are discussed.

Adolescent↗
PubMed2000

Arteriolitis in renal transplant biopsies is associated with poor graft outcome.

AIMS: The Banff 1997 classification of renal allograft pathology identifies arteriolitis as a finding of uncertain significance. We sought to improve our understanding of arteriolitis by correlating its occurrence with histopathological and clinical parameters. METHODS AND RESULTS: Twenty allograft kidney biopsies from 19 patients, showing arteriolitis, were identified. Arterioles were defined as small vessels with: (1) wall thickness of 1-3 myocytes; (2) diameter less than one-third of an adjacent glomerulus; and (3) discontinuous or absent elastica. Arteriolitis was defined as mural infiltration by lymphocytes. Other histological findings were categorized according to the Banff 1997 working formulation. Ten biopsies (50%) showed type IIA rejection, seven (35%) showed type I rejection, and three (15%) showed borderline change. Two patients with borderline change had acute rejection in the next biopsy. None of the seven patients with type I rejection had previous or subsequent type II rejection on biopsy. A total 11/20 biopsies (10/19 patients) showing arteriolitis had type IIA rejection in the index or next biopsy. On follow-up, graft loss due to rejection occurred in 5/19 (26%) patients (median 126 days); all had shown type IIA rejection on a previous biopsy. Chronic allograft nephropathy developed in a further 4/19 (21%) patients (median 157 days), of whom three had shown only type I rejection on biopsy. CONCLUSION: Arteriolitis is associated with acute rejection, often type II rejection, and is associated with poor graft outcome. Other causes of arteriolitis were not encountered in this series.

Adult↗
PubMed2000

Familial nephrotic syndrome: clinical spectrum and linkage to chromosome 19q13.

BACKGROUND: Familial nephrotic syndrome (NS) has both autosomal dominant and recessive forms of inheritance. Recent studies in families with an autosomal dominant form of focal segmental glomerulosclerosis (FSGS) have been at odds concerning linkage to chromosome 19q13 (Mathis et al, Kidney Int 53:282-286, 1998; Winn et al, Kidney Int 55:1241-1246, 1999), suggesting genetic heterogeneity. This study examines the clinical features and confirms linkage to chromosome 19q13 in a family with autosomal dominant NS. METHODS: DNA samples were obtained from 16 of 17 family members. Genomic DNA was isolated, and polymerase chain reaction was performed for five markers spanning the area of interest on chromosome 19q13. Data were evaluated using two- and six-point linkage analysis. RESULTS: Clinical features included presentation of NS in childhood, steroid unresponsiveness, and slow progression to renal failure. Renal biopsy in affected family members showed lesions ranging from minimal change to mesangial proliferative glomerulonephritis to FSGS. Linkage was confirmed between the disease state and chromosome 19q13, with a maximum logarithm of odds (LOD) score of 2.41. Linkage was observed for a 7 cM region on chromosome 19q13, defined by markers D19S425 and D19S220. CONCLUSIONS: This study confirms the Mathis et al report of linkage to chromosome 19q13 in a family with autosomal dominant NS. However, there were notable differences in the presenting clinical and histopathologic features of our affected family members compared with those of Mathis et al. This suggests that the gene on chromosome 19q13 may be responsible for considerable phenotypic heterogeneity and variable expression in both clinical presentation and renal histopathology.

Adolescent↗
PubMed2000

Acute renal allograft rejection with severe tubulitis (Banff 1997 grade IB).

Recent studies have correlated renal allograft function with individual histologic lesions defined in the Banff schema of kidney transplantation pathology. The clinical significance of severe tubulitis (Banff 97 grade t3) has not been specifically examined. We compared the clinical course and response to antirejection therapy in 36 patients with t3 tubulitis, and 137 patients with milder grades of tubulitis and varying grades of intimal arteritis. Rejection associated with severe tubulitis (grade t3) was associated with graft outcome that was worse than mild to moderate tubulitis (grades t1 or t2) and approached that seen in grade v1 intimal arteritis. Rejection characterized by grade v2 or v3 intimal arteritis had worse prognosis than v1 intimal arteritis and all grades of tubulitis without coexisting intimal arteritis. These observations validate the Banff 97 recommendation that the severity of both tubulitis and intimal arteritis needs to be graded in renal allograft biopsies. In addition, grade t3 tubulitis is identified as a lesion which should be a cause for clinical concern.

Acute Disease↗
PubMed1999

"Striped" pattern of medullary ray fibrosis in allograft biopsies from kidney transplant recipients maintained on tacrolimus.

BACKGROUND: A striped pattern of fibrosis has been described in the kidneys of patients undergoing long-term cyclosporine or tacrolimus therapy. This lesion is frequently misconstrued as being specific for drug toxicity. METHODS: We performed clinicopathologic correlation on 18 patients with striped fibrosis identified by reviewing 61 biopsies from kidney transplant recipients maintained with tacrolimus. RESULTS: Acute rejection was identified in 14 of 18 patients, chronic rejection in 9 of 18 patients, potential diabetic microvascular injury in 8 of 18, and pre-existing donor disease in 2 of 18. In only one patient could striped fibrosis be ascribed primarily to tacrolimus. Striped fibrosis could also be demonstrated in 6 of 10 late allograft biopsy specimens from patients maintained with only azathioprine, and 8 of 10 native biopsies from patients with advanced diabetes mellitus. CONCLUSION: Multiple insults contribute to the pathogenesis of striped fibrosis in the kidney. This lesion can be attributed entirely to chronic drug toxicity in only a minority of allografts.

Adult↗
PubMed1999

Clinical significance of renal biopsies showing concurrent acute rejection and tacrolimus-associated tubular vacuolization.

BACKGROUND: The clinical significance of biopsies showing both rejection and isometric tubular vacuolization has not been well defined in the literature. METHODS: The clinical picture, sequential histopathologic findings, and response to therapy were compared between 24 renal allograft biopsies showing both tubular vacuolization and rejection and 14 biopsies showing vacuolization alone. RESULTS: The rejection was categorized as grade 1 in 4/24 (16.6%), grade 2A in 10/24 (41.6%), and grade 2B in 10/24 (41.6%) cases (Banff schema, 1993-1995). Treatment with additional steroids and tacrolimus led to a decrease in the interstitial inflammation score (2.6+/-0.1 to 1.3+/-0.1, P<0.001), tubulitis score (2.6+/-0.1 to 1.1+/-0.1, P<0.001), and serum creatinine (4.4+/-2.2 mg/dl to 3.3+/-2.6 mg/dl, P=0.001). Complete response, partial response and no response to antirejection therapy were observed in 16/24 (66.7%), 3/24 (12.5%), and 5/24 (20.8%) patients, respectively. Although there was a rise in the plasma (1.4+/-0.2 ng/ml to 2.8+/-0.3 ng/ml, P<0.001) and whole blood (16.5+/-2.8 ng/ml to 31.2+/-5.7 ng/ml, P<0.001) tacrolimus levels, repeat biopsy showed no change in the size or extent of tubular vacuolization (mean score 2.88+/-0.19 vs. 2.83+/-0.21). The morphologic characteristics of the tubular vacuoles in these cases did not differ from those observed in 14 cases of tacrolimus nephrotoxicity not complicated by rejection. CONCLUSION: Patients with concurrent acute rejection and tubular vacuolization usually benefit from increased immunosuppression. The pathogenesis of the vacuolization in this clinical setting is not clear, but may reflect immune-mediated tubular injury.

Acute Disease↗
PubMed1999

The clinical significance of cytomegaloviral inclusions in the allograft kidney.

BACKGROUND: Renal allografts are a frequent site of subclinical cytomegalovirus (CMV) infection diagnosed by culture, but histologic inclusions occur in less than 1% of biopsies. The natural history of this subgroup of patients has been reported only occasionally, mostly before the availability of ganciclovir therapy. METHODS: We analyzed the clinical parameters and pathologic findings in 10 patients with CMV inclusions at allograft biopsy. RESULTS: The patients were 29-72 years old, and 9 of 10 (90%) had previous episodes of acute rejection, 3 of whom needed OKT3 administration. Histopathologic examination of the allografts showed interstitial inflammation with tubulitis in 7 of 10 (70%) patients; in 3 of 10 (30%) patients, viral inclusions were present in the glomerular capillary endothelia without any associated inflammatory response. Morphologic criteria for acute transplant glomerulopathy or proliferative glomerulonephritis were not satisfied. Extrarenal viral inclusions were documented in the gastrointestinal tracts of 2 of 10 (20%) patients. The patients were treated with reduced immunosuppression and ganciclovir. Five patients lost their grafts 56.6+/-86.6 days (range, 4-210 days; median, 21 days) after initial diagnosis. The serum creatinine in the remaining five patients was 3.3+/-2.0 mg/dl (range, 1.2-6.5 mg/dl; median, 2.5 mg/dl) 77+/-16 days (range, 56-101 days; median, 77 days) after transplantation. Histopathologic examination showed no residual viral inclusions in 5 of 7 (71.4%) follow-up specimens available for examination. CONCLUSIONS: CMV inclusions in renal allograft biopsies typically occur after treatment for rejection. Ganciclovir eradicates replicative virus, but graft outcome is determined by coexisting acute rejection and chronic allograft nephropathy. Graft loss primarily attributable to CMV was not observed.

Adult↗
PubMed1999

Human polyoma virus-associated interstitial nephritis in the allograft kidney.

BACKGROUND: Asymptomatic polyoma virus infection documented by urine cytology or serology is well known, but the clinical course of biopsy-proven interstitial nephritis is not well defined. METHODS: Twenty-two cases were identified by histology, immunostaining, in situ hybridization, electron microscopy, or polymerase chain reaction. RESULTS: The clinical features mimicked acute rejection (n=19), chronic rejection with incidental diagnosis at nephrectomy (n=2), or drug toxicity (n=1). Histology showed homogenous intranuclear inclusions. In situ hybridization showed BK virus (BKV) to be the predominant species, but polymerase chain reaction documented JC virus co-infection in one of five cases so tested. Electron microscopy in seven cases showed 20-51-nm virions. The two cases diagnosed at nephrectomy received no therapy. Initial antirejection therapy in 12 cases led to clearance of the virus in 1/12 (8%), partial therapeutic response in 3/12 (25%), and graft loss in 8/12 (67%) cases. The last recorded creatinine in patients with functional grafts ranged from 1.9 to 7.0 (median: 4.5) mg/dl, 0.4-45 (median: 4.0) months after initial diagnosis. The remaining eight cases treated by reduction of immunosuppression at the outset have been free of graft loss for 0.2-10.0 (median: 4.8) months since diagnosis, and clearance of virus has been documented in three of six (50%) cases. The serum creatinine in these patients is 1.7-6.0 (median: 2.4) mg/dl, 0.2-10 (median: 4.8) months after diagnosis. Follow-up biopsies performed 1-23.5 months after diagnosis show chronic allograft nephropathy. CONCLUSIONS: Polyoma virus tubulo-interstitial nephritis-associated graft dysfunction usually calls for judicious decrease in immunosuppression and monitoring for acute rejection. Development of methods to serially quantify the viral load in individual patients could potentially improve clinical outcome.

Adolescent↗
PubMed1999

Cytokine mRNA profiles in Epstein-Barr virus-associated post-transplant lymphoproliferative disorders.

Cytokine mRNA patterns were analyzed in 11 post-transplant lymphoproliferative disorder (PTLD) specimens using qualitative reverse-transcriptase polymerase chain reaction (RT-PCR). In each case, a pattern of IL2-, IFN gamma-, IL4+, IL10+ was seen. A similar pattern was observed in a spleen sample from 1 patient with contemporaneous PTLD elsewhere. Semiquantitative RT-PCR for cytokine message was performed using RNA from bronchoalveolar lavage (BAL) specimens obtained from 2 patients with pulmonary PTLD. In both cases, IL4 message predominated. Reduction of message coincided with resolution of the tumors. The pattern differed from that seen in 1 patient with acute pulmonary rejection, in which RT-PCR of BAL cells showed predominance of IL6 and IFN gamma. We conclude that at least some PTLDs exist within a T-helper cell type 2 (Th2)-like cytokine microenvironment. The presence of a similar mRNA pattern in an extratumoral specimen at the time of PTLD suggests that it may reflect a systemic phenomenon. Disappearance of this pattern following PTLD resolution indicates its dynamic nature and is consistent with the hypothesis that specific cytokines contribute to the development of PTLDs.

Bronchoalveolar Lavage Fluid↗
PubMed1998

Effects of immunotherapy on experimental immunodeficiency-related lymphoproliferative disease.

BACKGROUND: Human lymphokine-activated cells (LAK cells) and interferon alpha (IFN-alpha) have been used clinically in the therapy of posttransplant lymphoproliferative disease (PTLD). However, the efficacy of such therapy has not been extensively tested under controlled experimental conditions. METHODS: A B-cell line, derived from PTLD tissue and clonally related to the parent lesion, was tested for its response to IFN-alpha in vitro. The effects of LAK cells and IFN-alpha therapy were examined in a severe combined immunodeficiency disease (SCID) mouse model in vivo. RESULTS: The PTLD cell line studied showed a 30% decrease in the rate of growth upon incubation with 500 U/ml of IFN-alpha. This in vitro response was also reproduced in vivo, in tumor therapy studies conducted in SCID mice. The magnitude of this inhibitory effect in vivo was a function of tumor burden and dose of IFN-alpha. In parallel experiments, LAK cells reduced the tumorigenicity of a lymphoblastoid cell line derived from the peripheral blood of a patient with PTLD, and prolonged the survival of SCID-beige mice with established lymphoproliferative disease. In contrast with two prior studies, in which the use of autologous cytotoxic T cells was found to be necessary, we found the administration of third-party non-HLA-matched LAK cells also to be effective in reducing tumor burden. CONCLUSIONS: These observations demonstrate the efficacy of immunotherapy for lymphoproliferative disease under controlled experimental conditions, and validate currently ongoing efforts exploring the utility of such therapy in the clinical setting.

Animals↗
PubMed1997

Adenovirus hepatitis in the adult allograft liver.

BACKGROUND: Adenovirus hepatitis in the allograft liver is an uncommon condition hitherto recognized only in pediatric patients. We describe two adult cases. METHODS: Clinical information was obtained by reviewing the medical records. The diagnosis of adenoviral infection was made by immunohistochemistry or culture. RESULTS: Both patients had received recent antirejection treatment and presented with fever, hepatic dysfunction, and progressive leukopenia. One patient had some viral inclusions resembling those described in herpes simplex infections. Adenovirus was cultured from the liver in both cases and from the lung in one case. Both patients were treated by decreasing the immunosuppression and intravenous acyclovir, but died. CONCLUSIONS: Adenovirus infection should be considered when evaluating adult liver transplant patients with necrotizing lesions or microabscess formation at allograft biopsy. A review of the literature shows that most previously reported infections have led to graft loss or death, but occasional remissions of disease are also on record.

Adenoviridae Infections↗
PubMed1997

Clinical significance of renal allograft biopsies with "borderline changes," as defined in the Banff Schema.

BACKGROUND: The Banff Schema suggests the term "borderline changes" for biopsies showing changes insufficient for a diagnosis of mild acute rejection. The appropriate clinical management for patients showing such changes on biopsy is controversial. METHODS: We reviewed the clinical course and response to antirejection therapy of 24 patients with borderline changes, and compared our findings with those obtained from 14 patients with mild acute rejection. Patients were classified as showing complete response, partial response, or no response to antirejection treatment, depending on whether the posttreatment fall in serum creatinine was >70%, 30-70%, or <30% of the pretreatment rise, respectively. Renal allograft biopsies were systematically evaluated in accordance with the Banff schema. RESULTS: Complete response to antirejection therapy was seen in 15/24 (63%), partial response in 3/24 (13%), and nonresponse in 6/24 (25%) patients with borderline change. Compared with patients showing complete response, nonresponse was associated with higher scores of acute tubular necrosis and chronic allograft nephropathy (P<0.05). By comparison, 12/14 (86%) cases of mild acute rejection showed complete response to antirejection therapy (P=0.25 vs. patients with borderline change), and lack of response was associated with a higher score for chronic allograft nephropathy. CONCLUSION: When biopsies are done in the context of renal allograft dysfunction, borderline changes frequently require increased immunosuppression. These findings should not be extrapolated to protocol biopsies performed in the setting of stable graft function.

Adult↗
PubMed1997

Spontaneous arterioenteric fistula after pancreas transplantation.

Chronic pancreas transplant rejection with enteric exocrine drainage can lead to significant long-term complications. We report a case of a 47-year-old male insulin-dependent diabetic who survived the complications of peripancreatic abscess, enterocutaneous fistula, and arterioenteric fistula related to pancreas transplantation. To avoid these long-term complications, we now recommend elective removal of nonfunctioning, enterically drained pancreas allografts.

Anastomosis, Surgical↗
PubMed1997

Subcutaneous implantation of human post-transplant lymphoproliferative disease lesions in SCID mice.

The tumorigenic potential of six post-transplant B-cell lymphoproliferative disease (PTLD) lesions was evaluated in SCID mice. Three animals developed local subcutaneous B cell tumours, two of which contained Epstein-Barr virus (EBV) DNA. Two animals developed CD3 positive thymic neoplasms, and one mouse developed an uncharacterized spontaneously regressing subcutaneous tumour. Immunoglobulin gene rearrangements studies with a JH probe, and EBV clonality studies with a Bam NJ fused terminal probe, showed only one mouse tumour to be genealogically related to the corresponding clinical lesion. It is concluded that lymphoid clones which constitute human PTLD are not autonomous, but sustained by host-derived growth stimuli distinct from those operating in the SCID mouse mileu.

Adult↗