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Biomedical subjects

V R Dharnidharka

Publications and source records attributed to V R Dharnidharka.

At least 19 recordsLinked to original sources
PubMed2001

Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is an important complication of transplantation. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database has documented 56 cases of PTLD, the largest such series to date. METHODS: We analyzed the available longitudinal and multicenter data in the NAPRTCS database to evaluate the demographic and therapeutic risk factors and the temporal trends for PTLD in children after renal transplantation. RESULTS: The overall incidence of PTLD was 1.2% of all patients or 298/100,000 posttransplantation years of follow-up. However, this incidence increased from 254/100,000 years between 1987 and 1991 to 395/100,000 years from 1992 onwards. In the same periods, the time to PTLD decreased from a median of 356 days (range 843048) to a median of 190 days (range 42-944). PTLD occurred with greater frequency in white children (P=0.003) and in cadaver donor transplants (P=0.019), but there was no significant predilection for gender, younger children (0-5 years), or primary diagnosis. No significant difference was found in the use of anti-T-cell antibodies or in doses of CsA, azathioprine, or prednisone at 1 month, 6 months, and 1 year. Between 1996 and 1997, 69 patients were initiated with tacrolimus. Eight cases of PTLD were identified in these recipients to date (prevalence rate 11.5%), compared with 46/4084 (1.1%) where cyclosporine was used (P<0.0001). CONCLUSIONS: There is a trend towards increasing incidence and earlier occurrence of PTLD in the pediatric renal transplant population. White race and cadaver donor sources are risk factors not reported before. Continued monitoring of tacrolimus immunosuppression is important.

Black or African American↗
PubMed2001

Pulmonary dysplasia, Denys-Drash syndrome and Wilms tumor 1 gene mutation in twins.

While a genetic basis for the association of developmental lung and kidney defects has been suspected, the involvement of specific genes in this process is under active investigation. We report such a possible genetic linkage present in identical twins with a mutant Wilms tumor (WT1) gene. Twin girls, born at 35 weeks gestation, manifested symptoms of congenital nephrotic syndrome, renal failure, and severe respiratory abnormalities refractory to assisted ventilation. Both died at 1 month of age. Renal biopsies and autopsy kidney tissue from both the girls revealed diffuse mesangial sclerosis (DMS). Autopsy lung tissue revealed pulmonary dysplasia and hypoplasia in both twins. The WT1 gene from renal tissue in both twins was analyzed for mutations using polymerase chain reaction (PCR) amplification and the single-strand conformation polymorphism (SSCP) technique. Both twins possessed an identical missense mutation in exon 8 of the WT1 gene, resulting in replacement of arginine by histidine at amino acid 366 (arg366his) in the WTI protein. This mutation has previously been described in Denys-Drash syndrome. The WT1 gene plays a role in mesenchymal epithelial (ME) interactions in the developing urogenital system, and possibly has a similar role during lung morphogenesis. We propose that this WT1 gene mutation contributes to both DMS and developmental pulmonary abnormalities by altering ME interactions in both organs.

Female↗
PubMed2001

Management of pediatric postrenal transplantation infections.

Infections are the leading cause of hospitalization and death after renal transplantation in children. Various agents are implicated in posttransplantation infections. Viral infections due to the cytomegalovirus and Epstein-Barr virus have assumed greater importance as other infections such as pneumocystis pneumonia have come under control. Multiple factors contribute to the difficulty in the prevention, diagnosis, and treatment of pediatric postrenal transplantation infections. Prevention of infections by adequate preparation before transplantation and the use of chemoprophylaxis should be made a priority. An aggressive approach to diagnosis is required when investigating fever in children. It is hoped that the use of more specific immunosuppressive agents that block only the alloactivated T cells and leave the rest of the immune response intact may result in a reduction in the number and frequency of infections.

Anti-Bacterial Agents↗
PubMed2000

Reduced susceptibility of nonobese diabetic mice to TNF-alpha and D-galactosamine-mediated hepatocellular apoptosis and lethality.

Nonobese diabetic (NOD/LtJ or NOD) mice are resistant to doses of LPS and D-galactosamine that uniformly produce lethality in C57BL/6J (B6) mice (p < 0.01). Liver caspase-3-like activity, serum transaminase levels (both p < 0.05), and the numbers of apoptotic liver nuclei were also reduced in NOD compared with B6 mice treated with LPS (100 ng) and D-galactosamine (8 mg). NOD mice were also at least 100-fold more resistant to recombinant human TNF-alpha and D-galactosamine treatment than B6 mice (p < 0.001). Binding of recombinant human TNF-alpha to splenocytes from NOD mice was similar to that seen in B6 mice, suggesting that the defect in responsiveness was not due to an inability of recombinant human TNF-alpha to bind the NOD TNF type 1 (p55) receptor. Because the TNF type 1 (p55) receptor shares a common signaling pathway with Fas (CD95), NOD and B6 mice were treated with the Fas agonist antibody, Jo-2. Surprisingly, NOD mice were as sensitive as B6 mice to Fas-induced lethality and hepatic injury. In addition, primary hepatocytes isolated from NOD mice and cultured in vitro in the presence of D-galactosamine with or without TNF-alpha were found to be resistant to apoptosis and cytotoxicity when compared with B6 mice. In contrast, Jo-2 treatment produced similar increases in caspase-3 activity and cytotoxicity in primary hepatocytes from NOD and B6 mice. The resistance to LPS- and TNF-alpha-mediated lethality and hepatic injury in D-galactosamine-sensitized NOD mice is apparently due to a post-TNFR binding defect, and independent of signaling pathways shared with Fas.

Animals↗
PubMed1999

The allogeneic response to cultured human skin equivalent in the hu-PBL-SCID mouse model of skin rejection.

BACKGROUND: Engineered tissues have been proposed for the treatment of a variety of conditions including the partial or complete replacement of human organs. To determine the basis for the rejection of these tissues, we analyzed the immune response to allogeneic human skin equivalent (HSE, also called Apligraf) in the humanized SCID mouse (hu-PBL-SCID). METHODS: Two models of hu-PBL-SCID were used for these studies. In one model, human skin or HSE was transplanted onto humanized mice so that graft survival could be analyzed. In the other model, skin grafts were allowed to heal on naive mice before humanization. This model was used to analyze the immunologic response to the vascularized skin allograft. Humanization was performed by adoptive transfer of human PBL into SCID mice by i.p. injection. RESULTS: Both human foreskin and HSE successfully engrafted onto naive SCID mice and remained stable for more than 6 months. In contrast, human foreskin was rejected by 21 days posttransplant in hu-PBL-SCID, whereas HSE consistently engrafted for more than 28 days. Treatment of HSE grafts with interferon-y for 5 days to induce maximal MHC class II molecule expression before grafting failed to induce rejection. HSE also engrafted onto hu-PBL-SCID mice that were exposed to alloantigen by prior injection with interferon-gamma-treated keratinocytes identical to those used to generate the HSE. In addition, we determined that humanization of SCID mice following engraftment and vascularization of human foreskin resulted in marked CD3+ T cell infiltrates and a lymphocyte-induced vasculitis. In contrast, the response in vascularized HSE was associated with minimal CD3+ T cell infiltration in the absence of vasculitis or morphological features of rejection. CONCLUSION: These results support the use of HSE and other allogeneic engineered tissues in humans provided that such tissues are limited in their antigen presenting capabilities. In addition, our findings suggest a critical function for the donor endothelial cell in rejection.

Animals↗
PubMed1999

Angiogenesis in the huPBL-SCID model of human transplant rejection.

BACKGROUND: Angiogenesis is characteristic of chronic inflammatory reactions. The process of angiogenesis is reported to be proinflammatory in part due to enhanced adhesion events and in part due to increased perfusion and permeability to sites of inflammation. However, little is known about the association between angiogenesis and rejection. METHODS: Severe combined immune deficient mice are permissive for the growth of human skin allografts and human peripheral blood mononuclear cells (PBMC). Human PBMC were injected into mice by intravenous or intraperitoneal injection. The infiltration of cells and the associated angiogenesis reactions in the skin allografts were analyzed temporally by videomicroscopy and spatially by immunohistochemistry. RESULTS: Human alloreactive mononuclear cells migrated to human skin but not mouse skin within hours after the intravenous infusion of PBMC. Within 3 days, areas of angiogenesis were observed in the skin grafts at the sites of infiltrates. The vessel densities in skin grafts were 24+/-6 vessels per calibrated grid at baseline on the day of the infusion and increased to 55+/-16 vessels per calibrated field by day 10. Skin grafts harvested from humanized severe combined immune deficient mice 7-14 days after the intraperitoneal infusion of human PBMC showed a similar increased density of vessels that were spatially associated with mononuclear cell infiltrates. CONCLUSIONS: A significant angiogenesis response was associated with the cell infiltrates in the human skin allografts. The onset of angiogenesis appeared after the initial development of localized infiltrates and preceded the development of microvascular destruction. These findings suggest that alloreactive T cells and/or monocytes mediate the angiogenesis response in skin allografts.

Adoptive Transfer↗
PubMed1998

Prevalence of microalbuminuria in children with sickle cell disease.

Renal involvement is common in homozygous sickle cell disease (HbSS), including glomerular hypertension and hypertrophy similar to that seen in rodent models of ablative nephrectomy and stage I diabetic nephropathy (DN). The proteinuria in the rodent models is attenuated by angiotensin converting enzyme inhibition (ACEI). Microalbuminuria (MA) is a sensitive marker for renal involvement in DN prior to the development of proteinuria, and is also attenuated with ACEI. Elevated urinary microalbumin/creatinine ratios (U Alb/Cr) >20 mg/g Cr are reported in 39%-43% of adults with HbSS, and studies are ongoing in this age group to assess the effect of attenuated proteinuria by ACEI on long-term renal function. The purpose of this study was to prospectively investigate the prevalence of MA in children with HbSS and determine factors which affect its expression. U Alb/Cr values were measured on spot urine samples in 102 children (aged 2-18 years, mean 9.47+/-4.62, M:F=53:49) by rate nephelometry. Children with prior known proteinuria, hypertension, or fever/pain episode in the last 15 days were excluded. MA was present in 26.5% of all children with HbSS. However, in children between the ages of 10 and 18 years, the prevalence was 46% (similar to the prevalence in adults). There was a strong correlation between patient age and prevalence of MA (P<0.0001) by both univariate and multivariate analysis. However, pain frequency, hospitalization, transfusion program, ferritin levels, and Cr clearance (C(Cr)) did not correlate with prevalence, although C(Cr) (as estimated by Schwartz formula) was elevated in all. We conclude that the prevalence of MA in the 2nd decade of life is similar to that in adults.

Adolescent↗
PubMed1998

Acute interstitial nephritis presenting as presumed minimal change nephrotic syndrome.

Nephrotic syndrome (NS) secondary to drug-induced acute interstitial nephritis (AIN) is well described in adult but is very rare in children. We report an unusual case of AIN mimicking prototypical childhood minimal change NS. A 2-year-old girl on long-standing amoxicillin therapy for vesicoureteral reflux presented with the acute onset of generalized edema, proteinuria, hypoalbuminemia, hypercholesterolemia, and an inactive urinary sediment. She was placed on empiric steroid therapy for presumed minimal change NS. When she did not respond to steroids, a renal biopsy was performed and revealed AIN. Her NS resolved completely with cessation of her amoxicillin therapy and concomitant tapering of her steroids. This patient demonstrates that the association of AIN with NS should be carefully considered in children on antimicrobials who develop NS, even in the absence of the classic clinical features of AIN. In addition to the usual work-up and care of a child with NS, in these patients consideration may also need to be given to withdrawal of the potential precipitating agent.

Acute Disease↗
PubMed1998

Membranous glomerulonephritis and nephrosis post factor IX infusions in hemophilia B.

Children with hemophilia B who receive exogenous factor IX infusions may rarely develop inhibitors to the exogenous factor IX and require desensitization. Nephrotic syndrome has recently been described in some of these children. We report the renal clinicopathological findings in a child with severe factor IX deficiency, requiring induction of an immune tolerance protocol, who developed nephrotic syndrome. Renal biopsy revealed peripheral capillary wall thickening and a spike appearance consistent with membranous glomerulonephritis. Electron microscopy showed prominent deposits throughout the thickness of the basement membrane. Factor IX dose reduction was accompanied by reversal of the child's nephrotic syndrome without relapses.

Child, Preschool↗
PubMed1998

Ciprofloxacin overdose: acute renal failure with prominent apoptotic changes.

Acute renal failure due to ciprofloxacin has been well described. The previously reported cases have been consistent both clinically and pathologically with tubulointerstitial nephritis (TIN). We report a case of ciprofloxacin overdose leading to acute renal failure characterized by acute tubular necrosis (ATN). The outstanding features in the patient's renal biopsy were those of distal nephron apoptosis, best seen in plastic-embedded sections and electron microscopy. This report shows that the distal nephron can be singularly involved in acute renal failure and that electron microscopy or plastic-embedded sections may be necessary to define its involvement.

Acute Kidney Injury↗
PubMed1998

Central role for CD40/CD40 ligand (CD154) interactions in transplant rejection.

Major advances have been made in understanding the expression and function of CD40 and its ligand CD154. It is now clear that CD40/CD154 interactions are critical in many aspects of the immune response, including T cell activation, T cell-dependent macrophage activation, T cell-B cell interactions and endothelial activation. Moreover, increasing evidence supports a central role for CD40/CD154 interactions in the immune processes of allograft rejection. Functional studies using blocking monoclonal antibodies have revealed beneficial effects of interupting CD40/CD154 co-stimulation in animal models of transplantation, particularly in association with interuption of the CD28/B7 pathway. A next step is to develop new therapeutic approaches to interrupting this pathway in humans, either through the development of receptor antagonists or through the understanding of intracellular signaling pathways utilized by these molecules.

Animals↗
PubMed1997

Sporadic Stiffman syndrome in a young girl.

A 14-month-old girl had experienced sudden episodes of breath-holding and spasms of the trunk and limb muscles, leading to cyanosis and loss of consciousness since 3 months of age. Her clinical features and electromyography suggested Stiffman syndrome, and her response to high-dose diazepam and baclofen confirmed the diagnosis. Stiffman syndrome is a rare entity, rarer still in childhood. This is the youngest case of sporadic Stiffman syndrome reported in literature. Distinguishing Stiffman syndrome from similar conditions such as Schwartz-Jampel syndrome or neuromyotonia is important because administration of GABAergic agents (valproate, baclofen, diazepam) elicits a good response.

Baclofen↗
PubMed1997

Extra and central pontine myelinolysis in a child with adrenal insufficiency.

We report a 5-year-old patient with adrenal insufficiency (AI) who had a subacute monophasic neurologic illness and brainstem and striatal lesions on brain imaging. The prominent electrolyte abnormalities in AI indicate that extra and central pontine myelinolysis is the likely cause. An association between AI and extra pontine myelinolysis has not previously been reported in children.

Adrenal Insufficiency↗
PubMed1996

A child with cardiogenic shock and supraventricular tachycardia presenting in normal sinus rhythm.

We report a case of an infant who presented in profound cardiovascular collapse with a normal sinus rhythm initially. A diagnosis of supraventricular tachycardia (SVT) was established only after hemodynamic stabilization. The possibility of SVT being masked because of severe metabolic derangements and/or painful therapeutic procedures should be kept in mind when managing cardiogenic shock in children. Such a consideration is of practical significance in planning therapy, such as the avoidance of digitalis in a patient with Wolf-Parkinson-White syndrome.

Electrocardiography↗