Biomedical subjects

Minnie M Sarwal

Publications and source records attributed to Minnie M Sarwal.

At least 19 recordsLinked to original sources

PubMed2013

The identification of novel potential injury mechanisms and candidate biomarkers in renal allograft rejection by quantitative proteomics.

Early transplant dysfunction and failure because of immunological and nonimmunological factors still presents a significant clinical problem for transplant recipients. A critical unmet need is the noninvasive detection and prediction of immune injury such that acute injury can be reversed by proactive immunosuppression titration. In this study, we used iTRAQ -based proteomic discovery and targeted ELISA validation to discover and validate candidate urine protein biomarkers from 262 renal allograft recipients with biopsy-confirmed allograft injury. Urine samples were randomly split into a training set of 108 patients and an independent validation set of 154 patients, which comprised the clinical biopsy-confirmed phenotypes of acute rejection (AR) (n = 74), stable graft (STA) (n = 74), chronic allograft injury (CAI) (n = 58), BK virus nephritis (BKVN) (n = 38), nephrotic syndrome (NS) (n = 8), and healthy, normal control (HC) (n = 10). A total of 389 proteins were measured that displayed differential abundances across urine specimens of the injury types (p < 0.05) with a significant finding that SUMO2 (small ubiquitin-related modifier 2) was identified as a "hub" protein for graft injury irrespective of causation. Sixty-nine urine proteins had differences in abundance (p < 0.01) in AR compared with stable graft, of which 12 proteins were up-regulated in AR with a mean fold increase of 2.8. Nine urine proteins were highly specific for AR because of their significant differences (p < 0.01; fold increase >1.5) from all other transplant categories (HLA class II protein HLA-DRB1, KRT14, HIST1H4B, FGG, ACTB, FGB, FGA, KRT7, DPP4). Increased levels of three of these proteins, fibrinogen beta (FGB; p = 0.04), fibrinogen gamma (FGG; p = 0.03), and HLA DRB1 (p = 0.003) were validated by ELISA in AR using an independent sample set. The fibrinogen proteins further segregated AR from BK virus nephritis (FGB p = 0.03, FGG p = 0.02), a finding that supports the utility of monitoring these urinary proteins for the specific and sensitive noninvasive diagnosis of acute renal allograft rejection.

Acute Kidney Injury↗

PubMed2006

Designer genes: Filling the gap in transplantation.

Accelerated evolution of the field of functional genomics has been greatly facilitated by high-throughput microarray-based gene function studies, relating to the parallel and serial expression measurements of genomes. Microarray experimentation is being applied for the study of basic research questions, drug target discovery, pharmacology, toxicogenomics, target selectivity, disease biomarker determination, development of prognostic tests, and disease subclass determination. This article will review the current applications of microarray technology in the field of organ transplantation and discuss the potential impact of this technology on transplantation medicine.

Genetic Engineering↗

PubMed2006

Chipping into the human genome: novel insights for transplantation.

High throughput, high density platforms for transcriptional, proteomic, and metabonomic analyses are opening new doors for improving our understanding of the complexity and redundancy of the immune system in the interplay of the innate and allo-immune responses in organ transplantation. New insights are being obtained into the possible discrepancies between the gold standard of tissue pathological diagnosis and clinical graft outcomes, as new transcriptional categories of transplant rejection evolve. The bystander effects of chronic immunosuppression underlying the complexities of graft dysfunction are beginning to be understood. Non-invasive mechanisms to monitor transplants, by following 'footprints' of biomarker sets that reflect the disease phenotype, are being pursued for their clinical application for direct patient care. Utilization of these same biomarker sets may also offer a unique means to titrate immunosuppression and predict specific graft dysfunction events prior to clinical decline, thus bringing in the potential to reduce patient morbidity from infection and malignancy, preserve graft integrity, and limit the progression of chronic graft injury. Bioinformatics support is integral to the unraveling of the mysteries of the human genome, proteome, and metabolome in disease and in health.

Genome, Human↗

PubMed2006

Option of pre-emptive nephrectomy and renal transplantation for Bartter's syndrome.

Bartter's syndrome (BS) is an incurable genetic disease, with variable response to supportive therapy relating to fluid and electrolyte management. Poor control or therapy non-compliance may result in frequent life threatening episodes of dehydration, acidosis and hypokalemia, with resultant adverse effects on patient quality of life (QOL). We report, for the first time, pre-emptive bilateral native nephrectomies and successful renal transplantation, prior to the onset of ESRD, for severe, clinically brittle, neonatal BS, resulting in correction of metabolic abnormalities and excellent graft function. We propose that fragile BS should be considered as a possible indication for early native nephrectomies and pre-emptive renal transplantation, procedures that results in a 'cure' for the underlying disease and significant improvements in patient QOL.

Bartter Syndrome↗

PubMed2006

Proteinuria in pediatric renal transplant recipients during the first 60 post-transplant days.

Although normative values of post-transplant proteinuria have been reported in adults, data for pediatric renal transplant recipients have not been previously published. We hypothesized that pediatric renal transplant recipients achieve normal urinary protein to creatinine (UProt/UCr) ratios (<0.2) by 60 days post-transplant in the absence of early recurrent disease. Retrospective chart review of 108 consecutive pediatric renal transplant recipients at Stanford University was performed. Thirty-two (30%) patients who were eligible had > or = 1 UProt/UCr ratio obtained during the first 60 post-transplant days. Mean age at transplant was 13.9 +/- 4.2 yr. UProt/UCr ratios were grouped by week post-transplant for quantile analysis. Mean weekly UProt/UCr values were not lower than 0.2 until the ninth post-transplant week. No difference in post-transplant proteinuria existed between nephrectomized and non-nephrectomized transplant recipients. Experience with a single patient with proven focal segmental glomerulosclerosis (FSGS) recurrence suggests that normative UProt/UCr data may be useful in early identification of patients experiencing disease recurrence. Univariate correlations demonstrated that UProt/UCr negatively correlated with serum albumin levels (-0.415, p < 0.0001) and days post-transplant (-0.531, p < 0.0001). Independent of primary diagnosis, proteinuria persists throughout the first 60 days in most pediatric renal transplant patients, decreasing relative to time post-transplant.

Adolescent↗

PubMed2006

Microarrays: a monitoring tool for transplant patients?

Microarray technology holds a distinct advantage over traditional genomic methods, with the unique capability to rapidly generate multiple global gene expression profiles in parallel. This technology is quickly gaining widespread use in many areas of science and medicine because it can be easily adapted to study many experimental questions, particularly relating to disease heterogeneity. Microarray experiments have begun to advance our understanding of the underlying molecular processes in solid organ transplantation; however, several obstacles must be overcome before this technology is ready for application in the clinical setting. This article will review the current applications of microarray technology in the field of transplantation, and discuss the potential impact of this technology on monitoring of solid organ transplant recipients.

Humans↗

PubMed2005

Mycophenolate mofetil in pediatric renal transplantation.

Mycophenolate mofetil (MMF) has become a popular immunosuppressive agent in pediatric renal transplantation and has helped to address the unique challenges of transplantation in this population. This paper reviews the early studies that proved MMF's efficacy in reducing the risk of acute renal rejection, as well as its safety and tolerability in comparison to azathioprine. Key conclusions about the pharmacokinetics of MMF from studies of MMF alone and in combination with other immunosuppressive therapies are outlined. The importance of therapeutic drug monitoring (TDM) in this population is also explored in this review. Finally, recent studies showing that newer agents used in combination with MMF can further increase efficacy and reduce the risk of adverse events such as posttransplant lymphoproliferative disease are discussed.

Child↗

PubMed2005

Expression profiling of murine double-negative regulatory T cells suggest mechanisms for prolonged cardiac allograft survival.

Recent studies have demonstrated that both mouse and human alpha beta TCR(+)CD3(+)NK1.1(-)CD4(-)CD8- double-negative regulatory T (DN Treg) cells can suppress Ag-specific immune responses mediated by CD8+ and CD4+ T cells. To identify molecules involved in DN Treg cell function, we generated a panel of murine DN Treg clones, which specifically kill activated syngeneic CD8+ T cells. Through serial cultivation of DN Treg clones, mutant clones arose that lost regulatory capacity in vitro and in vivo. Although all allogeneic cardiac grafts in animals preinfused with tolerant CD4/CD8 negative 12 DN Treg clones survived over 100 days, allograft survival is unchanged following infusion of mutant clones (19.5 +/- 11.1 days) compared with untreated controls (22.8 +/- 10.5 days; p < 0.001). Global gene expression differences between functional DN Treg cells and nonfunctional mutants were compared. We found 1099 differentially expressed genes (q < 0.025%), suggesting increased cell proliferation and survival, immune regulation, and chemotaxis, together with decreased expression of genes for Ag presentation, apoptosis, and protein phosphatases involved in signal transduction. Expression of 33 overexpressed and 24 underexpressed genes were confirmed using quantitative real-time PCR. Protein expression of several genes, including Fc epsilon RI gamma subunit and CXCR5, which are >50-fold higher, was also confirmed using FACS. These findings shed light on the mechanisms by which DN Treg cells down-regulate immune responses and prolong cardiac allograft survival.

Animals↗

PubMed2005

Corticosteroid avoidance in pediatric renal transplantation.

Corticosteroids have played a central role in the evolution of renal transplant as the modality of choice for renal replacement in end stage kidney disease. Their use is associated with significant, dose related morbidity including osseous, cardiovascular, metabolic complications, body disfigurement and growth retardation in children. The strategies that have been employed to minimize these side effects include reduction in the daily administered dose of steroids, use of alternate day dosing regimens, steroid withdrawal post-transplantation and complete steroid avoidance. Steroid dose minimization has been associated with increased rates of acute rejection, though introduction of newer and more potent immunosuppressives has helped reduce the incidence of this complication. Steroid minimization will benefit patient morbidity due to cataracts, cardiovascular and osseous complications, but may offer little benefit towards improving linear growth. Alternate day steroid therapy may have a greater impact on growth improvement, but may be troubled by regimen non-adherence. Steroid withdrawal post-transplant, the ultimate target, is successful in a cohort of patients, but overall, has been historically associated with unacceptably high rates of clinical acute rejection, and has thus been used sparingly in adults and even less so in children. Complete corticosteroid avoidance, using newer induction and immunosuppressive agents, has been associated with an 8-23% incidence of acute rejection in pediatric renal transplant patients, significant catch-up growth post-transplant, improvements in post-transplant hypertension and hyperlipidemia, and a high safety profile at current follow-up. Newer induction protocols may allow complete steroid-free immunosuppression thus offering significant advantages in preventing the above-mentioned steroid related morbidity, which could also possibly be applicable to other areas of solid organ transplantation in all age groups.

Adrenal Cortex Hormones↗

PubMed2005

Gastrointestinal leukocytoclastic vasculitis: an adverse effect of sirolimus.

An 18-yr-old Hispanic female with end-stage renal disease secondary to chronic glomerulonephritis of unknown etiology underwent cadaveric renal transplantation. She was placed on a steroid-free protocol with tacrolimus and mycophenolate mofetil (MMF) for maintenance immunosuppression. Approximately 8 months post-transplantation, MMF was replaced by sirolimus (SRL) because of persistent leukopenia. Four months after the initiation of SRL, the patient began to experience chronic, constant periumbilical abdominal pain in the absence of vomiting, diarrhea or melena. Esophagogastroduodenoscopy and CT scans revealed significant diffuse mucosal thickening of the antrum, duodenum, and jejunum; leukocytoclastic vasculitis was identified on antral biopsy. A repeat biopsy after reduction of sirolimus dose by 50% over 6 months showed mild chronic inflammation of stomach and duodenum with some improvement in abdominal pain. Discontinuation of SRL and replacement with low dose MMF resulted in complete resolution of pain and normalization of gastrointestinal anatomy by imaging studies within 2 months. In light of this report, drug-induced leukocytoclastic vasculitis caused by SRL should be considered in the differential diagnosis of chronic abdominal pain in a patient with organ transplantation.

Abdominal Pain↗

PubMed2005

Transcriptional analysis of the molecular basis of human kidney aging using cDNA microarray profiling.

BACKGROUND: The molecular basis of renal aging is not completely understood. METHODS: We used global gene expression monitoring by cDNA microarrays to identify age associated genes in human kidney samples. Our samples included young (8 weeks-8 years, N= 4), adult (31-46 years, N= 7), and old kidneys (71-88 years, N= 9). RESULTS: Old kidneys had more glomerulosclerosis, tubular atrophy, interstitial fibrosis, and fibrous intimal thickening in small arteries. We identified approximately 500 genes that were differentially expressed among the three age groups. Old kidneys appeared to have increased extracellular matrix turnover and a nonspecific inflammatory response, combined with a reduction in processes dependent on energy metabolism and mitochondrial function. Quantitative supervised bioinformatics analyses of adult and old kidney expression data correlated the expression of 255 gene profiles with renal pathology scores. Microarray class prediction analysis (PAM) identified 50 unique genes that segregated old kidneys into two distinct clusters: those more similar within age class (OO, N= 5) versus old kidneys more similar to adult kidneys (OA, N= 4). The expression of six functionally significant genes was further validated by quantitative reverse transcription-polymerase chain reaction (RT-PCR) (FN1, MMP7, TNC, SERPIN3A, BPHL, CSPG2) in the experiment group and, subsequently, confirmed independently in 17 additional old and adult age-stratified test kidney samples. The p53 inducible gene, CSPG2, performed best in separating OO kidneys from adults and OA samples in this analysis. CONCLUSION: The method described in this study using independent validation samples can be envisioned to test utility of the identified genes in assessing age-related changes that contribute to decline in renal function.

Adult↗

PubMed2004

Arraying the orchestration of allograft pathology.

Microarrays, or gene chips, are exciting investigative tools for analyzing expression changes across thousands of genes in concert in tissues and cells of interest. Despite the relatively recent application of microarrays to transplant research, they hold great promise for unraveling the staging of rejection, stratifying patients towards more individualized treatment regimes, and discovering noninvasive biomarkers for monitoring of intragraft events. Bioinformatics tools are being developed to sift through the large data sets generated as "genomic fingerprints" of the underlying biologic pathways. Gene clustering and class prediction tools allow discovery of diagnostic and prognostic molecular signatures of health and disease. Oligonucleotide-based microarrays also have utility in genotyping polymorphic markers. This report reviews the current literature of microarray use in transplantation research, compares currently available array platforms, and discusses future application of this technology to clinical organ transplantation.

Biomarkers↗

PubMed2004

Microangiopathy of brain, retina, and inner ear (Susac's syndrome) in an adolescent female presenting as acute disseminated encephalomyelitis.

Susac's syndrome is a rare disorder that consists of microangiopathy of the brain, retina, and inner ear and usually affects young women in young adulthood. The triad of clinical manifestations consists of acute encephalopathy with neurologic signs, branch retinal artery occlusion (BRAO), and sensorineural hearing loss. We present a case of an adolescent female who presented at age 16 years with clinical and neuroimaging features of acute disseminated encephalomyelitis (ADEM). The full triad did not develop until 2.5 years after the initial neurologic presentation.

Adolescent↗

PubMed2004

Corticosteroid avoidance in pediatric renal transplantation: can it be achieved?

Corticosteroids have been a cornerstone therapy in renal transplantation, which is the treatment modality of choice for adult and pediatric end-stage renal disease. Their use is associated with significant morbidity, notably cardiovascular, endocrine, and bone complications, body disfiguration, and almost universal growth retardation in children. While newer immunosuppressants have reduced the incidence of these adverse effects, they continue to pose significant post-transplant challenges. There are various strategies that can be used to avoid these adverse effects including the use of an alternative corticosteroid such as deflazacort, minimization of corticosteroid dosage, corticosteroid withdrawal after a period of early use, and more recently complete corticosteroid avoidance. Recent randomized studies have demonstrated significant improvement in growth parameters, lipid profile, and in the amount of bone loss in patients treated with deflazacort, an oxazoline analog of prednisone, compared with methylprednisone.Corticosteroid minimization has been associated with an increased rate of acute rejection. While augmentation with newer immunosuppressants has helped reduce the incidence of acute rejection, significant improvements in growth have not been demonstrated. Alternate-day corticosteroid therapy has been shown to have a beneficial effect on growth but regimen compliance has limited its widespread applicability. Studies of corticosteroid withdrawal have met with varied success. Early corticosteroid withdrawal has been associated with rejection rates ranging from 10% to 81% and late corticosteroid withdrawal, from 13% to 68.8%, with acute rejection episodes occurring as late as 4 years after corticosteroid withdrawal. The rates of clinical acute rejection have been unacceptably high, and corticosteroid withdrawal is thus used very sparingly in adults and even less so in children. Complete corticosteroid avoidance as reported by an initial study has been associated with a 23% incidence of acute rejection and 'catch-up' growth post-transplantation in 14 pediatric recipients, as measured by the change in height standard deviation scores post-transplantation. A second renal transplant study, in adults, demonstrated similar rejection rates of 25% with improvement in post-transplant hypertension and lipid profiles. A more recent pediatric study using a novel extended daclizumab induction protocol demonstrated an 8% incidence of clinical acute rejection with significant improvements in graft function, hypertension, and growth, without an increased incidence of infectious complications. Renal transplantation with a corticosteroid-free protocol may offer significant advantages in the incidence of acute rejection, graft function, growth, blood pressure, lipidemia, and body appearance and appears to be well tolerated when used with a variety of current induction protocols to replace early corticosteroid use. This protocol may also be applicable to other areas of solid organ transplantation in all age groups.

Adrenal Cortex Hormones↗

PubMed2004

Microarrays: interrogating the transplant transcriptosome.

The use of DNA microarrays as a hypothesis generation tool for determining gene expression differences across thousands of genes in a data set is increasing. Recently, the use of microarrays has been applied to the transplant field and holds great promise for unraveling the mechanisms at play in various transplant processes and for identifying new tissue-specific and noninvasive biomarkers predictive of clinical outcomes. As microarrays produce large amounts of data, bioinformatics tools are being developed to determine gene expression patterns. Gene clustering and class prediction tools aid in the discovery of molecular signatures in different disease processes while literature mining, gene family analysis and pathway analysis helps in understanding the biological relevance of these signatures. This chapter focuses on DNA microarrays, their application to transplantation, and reviews key research studies where DNA microarrays are applied to understand acute rejection, chronic rejection and tolerance in human transplantation.

Graft Rejection↗

PubMed2003

One hundred percent patient and kidney allograft survival with simultaneous liver and kidney transplantation in infants with primary hyperoxaluria: a single-center experience.

BACKGROUND: Combined liver-kidney transplantation is the definitive treatment for end-stage renal disease caused by primary hyperoxaluria type I (PH1). The infantile form is characterized by renal failure early in life, advanced systemic oxalosis, and a formidable mortality rate. Although others have reported on overall results of transplantation for PH1 covering a wide age spectrum, none has specifically addressed the high-risk infantile form of the disease. METHODS: Six infants with PH1 underwent simultaneous liver-kidney transplantation at our center between May 1994 and August 1998. Diagnosis was made at 5.2+/-3.3 months of age, they were on dialysis for 11.8+/-2.3 months, and they underwent transplantation at 14.8+/-3.0 months of age when they weighed 10.6+/-1.7 kg. RESULTS: At a mean follow-up of 6.4+/-1.7 years (range, 3.9-8.1 years), we report 100% patient and kidney allograft survival. There were no cases of acute tubular necrosis. Long-term kidney allograft function remained stable in all patients, with serum creatinine values of less than 1.1 mg/dL and a mean creatinine clearance of 99 mL/min/1.73 m2 at follow-up. Those who received combined hemodialysis and peritoneal dialysis pretransplant had lower posttransplant urinary oxalate values than those receiving peritoneal dialysis alone. There was improvement in growth and psychomotor and mental developmental scores after transplantation. CONCLUSIONS: Combined liver-kidney transplantation for the infantile presentation of PH1 is associated with excellent outcome when the approach includes early diagnosis and early combined transplantation, aggressive pretransplant dialysis, and avoidance of posttransplant renal dysfunction.

Body Constitution↗

PubMed2003

Continued superior outcomes with modification and lengthened follow-up of a steroid-avoidance pilot with extended daclizumab induction in pediatric renal transplantation.

BACKGROUND: Corticosteroids have been invariant transplant immunosuppressives with numerous adverse effects. We previously reported 6-month results in 10 patients using extended daclizumab induction to safely eliminate steroid use in pediatric renal transplantation. This expanded pilot series discusses immunosuppression dosing modification to further minimize drug toxicity without sacrificing regimen efficacy. METHODS: Fifty-seven pediatric renal transplant recipients were enrolled in the pilot steroid-free protocol. Extended daclizumab induction, tacrolimus, and mycophenolate mofetil (MMF) were intended maintenance drugs. Fourteen patients were equal to or younger than 5 years, and 43 patients were older than 5 years of age at transplantation. There were seven protocol breaks. Study patients underwent serial protocol transplant biopsies (n=246), and serum daclizumab and mycophenolic acid (MPA) trough levels were evaluated. In this efficacy study, controls were 50 historical-matched steroid-based children receiving tacrolimus with 100% 2-year graft survival and without delayed graft function. RESULTS: Mean follow-up was 20 (range, 4.5-41) months with 98% overall graft and patient survival. At 1 year of analysis, steroid-free recipients showed significant improvements for clinical acute rejection (8%), graft function, hypertension, and growth, without increased infectious complications. Leukopenia, anemia, and allograft nephrotoxicity were addressed by solely decreasing MMF and tacrolimus dosing and/or by replacing MMF with sirolimus, without increasing acute rejection. Early daclizumab levels of more than 5 microg/mL were observed for the first time in children of all ages. CONCLUSIONS: Pediatric renal transplantation is safe without steroids. Daclizumab first-dose doubling and extended use for 6 months replaces steroids effectively without evidence of overimmunosuppression and may be the pivotal cause for the reduced acute rejection seen in this trial. This pilot study provides preliminary data to test this protocol in a prospective, multicenter randomized study.

Antibodies, Monoclonal↗

PubMed2003

Microarrays: new tools for transplantation research.

The advent of DNA microarray technology has greatly enhanced our potential to understand the molecular basis of human diseases and to aid in more accurate classification, diagnosis and/or prognosis. This powerful, flexible and highly informative technique has been adopted by many biomedical research disciplines. The use of DNA microarrays for gene expression profiling of patients undergoing organ transplantation has diagnostic and therapeutic potential. By generating global views of the gene expression changes in renal graft function post transplantation, DNA microarray technology will provide important information to improve our understanding of the molecular basis of various causes of graft dysfunction, and therefore suggest improved diagnosis, disease classification, and treatment.

Child↗