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Biomedical subjects

Prasad Devarajan

Publications and source records attributed to Prasad Devarajan.

At least 37 records · Page 2Linked to original sources
PubMed2004

Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity.

BACKGROUND: Cisplatin is one of the most widely used chemotherapeutic agents, but the risk of nephrotoxicity frequently hinders the use of higher doses to maximize its antineoplastic effects. The lack of early biomarkers has impaired our ability to initiate potential therapeutic or preventive interventions in cisplatin nephrotoxicity in a timely manner. In this study, we have explored the expression and urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in a mouse model of cisplatin-induced nephrotoxic injury. METHODS: Mice were subjected to intraperitoneal injections of 20 mg/kg (high dose) or 5 mg/kg (low dose) cisplatin. The expression of NGAL was measured in the kidney and urine by Western analysis and immunofluorescence, and compared to changes in serum creatinine and urinary N-acetyl-beta-D-glucosaminidase (NAG). RESULTS: Cisplatin resulted in tubule cell necrosis and apoptosis following the high dose, but not the low dose. By Western analysis, NGAL protein was rapidly induced in the kidney within 3 h of high-dose cisplatin. By immunofluorescence, NGAL was induced predominantly in proximal tubule cells in a punctate cytoplasmic distribution, reminiscent of a secreted protein. NGAL was easily detected in the urine by Western analysis within 3 h of cisplatin administration in a dose- and duration-dependent manner. By comparison, changes in urinary NAG or serum creatinine were not evident until 96 h after cisplatin. Using defined concentrations of purified recombinant NGAL, urinary NGAL excretion following cisplatin administration was quantified to be in the 20-80 ng/ml range. CONCLUSION: The results indicate that NGAL represents an early and quantitative urinary biomarker for cisplatin nephrotoxicity.

Acute-Phase Proteins↗
PubMed2004

Human PRMT5 expression is enhanced during in vitro tubule formation and after in vivo ischemic injury in renal epithelial cells.

BACKGROUND: The interactions between cells and the extracellular matrix (ECM) are important in the regulation of cell growth and differentiation. Cells cultured in ECM differentiate and develop tubular structures. The kidney has the ability to partially recover function after an ischemic insult through repairing its tubular epithelium. The factors that contribute to tubule formation in vitro may mediate tubule regeneration in the recovery stage of acute tubular necrosis. METHODS: RNA purified from cells grown on plastic, on Matrigel and in Matrigel matrix were subjected to differential display analysis to identify the transcripts that are differentially expressed during in vitro tubulogenesis. RESULTS: Protein arginine methyltransferase 5 (PRMT5) expression increased in renal epithelial cells undergoing tubule formation. PRMT5 expression is developmentally regulated and ubiquitously expressed in a variety of adult tissues. We also demonstrated that expression of PRMT5 is enhanced in the renal tubular epithelium of animals subjected to ischemic reperfusion injury (IRI). CONCLUSION: The role of PRMT5 in the regulation of mitosis, its induction in renal epithelial cells undergoing tubule formation in vitro and its expression in the tubules of the kidneys subjected to IRI suggest that it functions in the regulation of cell growth and differentiation during tubule formation and regeneration.

Cells, Cultured↗
PubMed2004

The death domain of kidney ankyrin interacts with Fas and promotes Fas-mediated cell death in renal epithelia.

Ankyrins are a ubiquitously expressed family of conserved proteins that mediate the linkage of integral membrane proteins such as transporters and channels with the underlying cytoskeleton. Ankyrins possess a conserved death domain, the functional significance of which has remained puzzling. In this study, the death domain of AnkG190, the isoform of ankyrin expressed in kidney tubules, was used as bait in a yeast two-hybrid screen to identify interacting partners. One of these interactions was with the proapoptotic molecule Fas. This was confirmed by coimmunoprecipitation, colocalization, and glutathione S-transferase pull-down assays in cultured renal epithelial (MDCK) cells. Site-directed mutagenesis of a conserved arginine (R1496 in AnkG190), previously shown to be critical for the binding of Fas (R234 in Fas) to FADD, abolished the interaction of ankyrin's death domain with Fas. Overexpression of constructs containing ankyrin's death domain promoted Fas-mediated apoptosis in MDCK cells. The linkage between ankyrin and Fas was confirmed in vivo in mouse kidney tubule cells by coimmunoprecipitation and colocalization. In an established mouse model of renal ischemia-reperfusion injury characterized by apoptotic tubule cell death, the expression of both ankyrin and Fas was markedly induced, and the interaction between these molecules remained intact. The results identify a novel tethering interaction between ankyrin and Fas in kidney epithelia and suggest that AnkG190 may play a role as an adapter molecule in renal tubule cell death.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin.

Acute renal failure secondary to ischemic injury remains a common problem, with limited and unsatisfactory therapeutic options. Neutrophil gelatinase-associated lipocalin (NGAL) was recently shown to be one of the maximally induced genes early in the postischemic kidney. In this study, the role of NGAL in ischemic renal injury was explored. Intravenous administration of purified recombinant NGAL in mice resulted in a rapid uptake of the protein predominantly by proximal tubule cells. In an established murine model of renal ischemia-reperfusion injury, intravenous NGAL administered before, during, or after ischemia resulted in marked amelioration of the morphologic and functional consequences, as evidenced by a significant decrease in the histopathologic damage to tubules and in serum creatinine measurements. NGAL-treated animals also displayed a reduction in the number of apoptotic tubule cells and an increase in proliferating proximal tubule cells after ischemic injury. The results indicate that NGAL may represent a novel therapeutic intervention in ischemic acute renal failure, based at least in part on its ability to tilt the balance of tubule cell fate toward survival.

Acute Kidney Injury↗
PubMed2003

Activation of mitochondrial apoptotic pathways in human renal allografts after ischemiareperfusion injury.

BACKGROUND: Ischemia-reperfusion injury in cadaveric (CAD) kidney allografts is associated with tubular cell injury, delayed graft function, and an increased incidence of acute and chronic rejection. We tested the hypothesis that activation of specific apoptotic pathways represents a mechanism for tubular cell death after CAD kidney transplantation. METHODS: Serial tissue sections from paraffin-embedded needle biopsy specimens obtained at approximately 1 hr of reperfusion after transplantation of 13 CAD and 12 living-related donor (LRD) renal allografts were examined by using the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay to detect apoptosis and by immunohistochemistry for expression of key pro-apoptotic molecules (Bax, Bak, tumor necrosis factor receptor [TNFR]-1, Fas, and cytochrome c). RESULTS: Apoptosis was detected primarily in tubular cells, with a mean+/-standard deviation of 6.8+/-2.2 apoptotic cells per 100 cells examined in CAD renal allografts compared with 1.8+/-2.7 cells per 100 in LRD (P<0.001) renal allografts. There was a significant correlation between apoptosis rate and cold ischemia time in CAD (r=0.86, P<0.001) renal allografts. Bax was expressed in 100% of CAD versus 17% of LRD renal allografts (P<0.001), Bak in 92% of CAD versus 17% of LRD renal allografts (P<0.001), and TNFR-1 in 100% of CAD versus 58% of LRD renal allografts (P<0.05). Fas was expressed in only a small number of samples (23% of CAD and 17% of LRD renal allografts, P=not significant). Bax and Bak were expressed predominantly in apoptotic cells. Cytochrome c was detected as a mitochondrial pattern in LRD renal allografts, but in a diffuse cytosolic distribution in CAD renal allografts. CONCLUSIONS: Ischemia-reperfusion injury in CAD kidney transplants is associated with a duration-dependent increase in tubular cell apoptosis, mediated at least in part by activation of mitochondrial pathways.

Biopsy, Needle↗
PubMed2003

Angiotensin-converting enzyme inhibition induces death receptor apoptotic pathways in erythroid precursors following renal transplantation.

BACKGROUND: Posttransplant erythrocytosis (PTE) is a condition that occurs in kidney transplant patients and is characterized by increase in hematocrit above 51%. While its pathogenesis remains unclear, angiotensin-converting enzyme inhibitors (ACEI) have been used successfully in the treatment of PTE. We have previously shown that ACEI induce apoptosis in the peripheral erythroid precursors from patients with PTE. In the current study we elucidate the molecular mechanisms of ACEI-induced apoptosis. METHODS: Peripheral CD34+ cells were obtained from four normal controls, five normal kidney transplants, and six kidney transplants with PTE, before and after treatment with ACEI. We evaluated the expression of a variety of apoptotic factors by quantitative reverse transcription-multiplex polymerase chain reaction, Western blot and immunocytochemistry. RESULTS: ACEI resulted in a significant induction of Fas, FADD, and TRADD mRNAs in renal transplant patients with or without PTE. No changes were noted in the expression of mRNAs encoding Bcl-2, Bcl-xL, Bax, caspase 8, caspase 3, or GAPDH. ACEI also resulted in a significant upregulation of Fas, FADD and TRADD protein expression, and their localization predominantly at the plasma membrane. CONCLUSIONS: Our results suggest that ACEI therapy induces apoptosis in erythrocyte progenitor cells of renal transplant patients at least in part via induction of death receptor apoptotic cascades.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Gene expression in early ischemic renal injury: clues towards pathogenesis, biomarker discovery, and novel therapeutics.

Acute renal failure (ARF) represents a common and serious problem in clinical medicine. Renal ischemia-reperfusion injury (IRI) is the major cause of ARF in the native and transplanted kidney. Several decades of research have provided successful therapeutic approaches in animal models, but translational efforts in humans have yielded disappointing results. The major reasons for this include a lack of early markers for ARF (and hence a delay in initiating therapy), and the multi-factorial nature of the disease. This review focuses on the use of cDNA microarrays to elucidate the molecular genetic mechanisms underlying tubule cell apoptosis, and to identify novel biomarkers for early renal IRI. Also presented is a comparative temporal analysis of cDNA microarray results from mature kidneys following IRI and during normal nephrogenesis. Molecular genetic evidence for the notion that regeneration recapitulates development in the kidney, and that injured tubule cells possess the capacity to de-differentiate to the earliest stages of development, is presented. The implications of these findings to the ability of the kidney to repair itself and potential strategies for accelerating recovery are briefly discussed.

Acute Kidney Injury↗
PubMed2003

Differential gene expression following early renal ischemia/reperfusion.

BACKGROUND: Acute renal failure from ischemia/reperfusion injury is associated with tubule cell apoptosis, the molecular mechanisms of which remain under active investigation. The purpose of this study was to identify apoptosis-related genes that are differentially expressed in the early periods following renal ischemia. METHODS: Mice underwent unilateral renal artery clamping for 45 minutes and were sacrificed at 0, 3, 12, or 24 hours of reperfusion. Tubule cell apoptosis was confirmed by DNA laddering and terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL) assay. We employed cDNA microarrays to define global changes in renal gene expression. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry were used as confirmatory tools. RESULTS: By microarray analysis, we identified consistent patterns of altered gene expression, including transcription factors, growth factors, signal transduction molecules, and apoptotic factors. Prominent among the last category included FADD, DAXX, BAD, BAK, and p53. Up-regulation of these proapoptotic genes was confirmed by semiquantitative RT-PCR and immunohistochemistry. CONCLUSION: The results indicate that apoptosis may represent an important mechanism for the early loss of tubule cells following ischemia/reperfusion injury. Both the death receptor-dependent (FADD-DAXX) and mitochondrial (BAD-BAK) pathways are activated. The results also provide a molecular basis for the previous findings that significant intrarenal mechanisms exist to enable tubule cell repair and regeneration, as evidenced by the up-regulation of genes such as growth, proliferation, transcription, and cytoskeletal factors.

Animals↗
PubMed2003

Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury.

Acute renal failure (ARF) secondary to ischemic injury remains a common and potentially devastating problem. A transcriptome-wide interrogation strategy was used to identify renal genes that are induced very early after renal ischemia, whose protein products might serve as novel biomarkers for ARF. Seven genes that are upregulated >10-fold were identified, one of which (Cyr61) has recently been reported to be induced after renal ischemia. Unexpectedly, the induction of the other six transcripts was novel to the ARF field. In this study, one of these previously unrecognized genes was further characterized, namely neutrophil gelatinase-associated lipocalin (NGAL), because it is a small secreted polypeptide that is protease resistant and consequently might be readily detected in the urine. The marked upregulation of NGAL mRNA and protein levels in the early postischemic mouse kidney was confirmed. NGAL protein expression was detected predominantly in proliferating cell nuclear antigen-positive proximal tubule cells, in a punctate cytoplasmic distribution that co-localized with markers of late endosomes. NGAL was easily detected in the urine in the very first urine output after ischemia in both mouse and rat models of ARF. The appearance of NGAL in the urine was related to the dose and duration of renal ischemia and preceded the appearance of other urinary markers such as N-acetyl-beta-D-glucosaminidase and beta2-microglobulin. The origin of NGAL from tubule cells was confirmed in cultured human proximal tubule cells subjected to in vitro ischemic injury, where NGAL mRNA was rapidly induced in the cells and NGAL protein was readily detectable in the culture medium within 1 h of mild ATP depletion. NGAL was also easily detectable in the urine of mice with cisplatin-induced nephrotoxicity, again preceding the appearance of N-acetyl-beta-D-glucosaminidase and beta2-microglobulin. The results indicate that NGAL may represent an early, sensitive, noninvasive urinary biomarker for ischemic and nephrotoxic renal injury.

Acute Kidney Injury↗
PubMed2002

Dissociation of spectrin-ankyrin complex as a basis for loss of Na-K-ATPase polarity after ischemia.

The polarized distribution of Na-K-ATPase at the basolateral membranes of renal tubule epithelial cells is maintained via a tethering interaction with the underlying spectrin-ankyrin cytoskeleton. In this study, we have explored the mechanism underlying the loss of Na-K-ATPase polarity after ischemic injury in Madin-Darby canine kidney (MDCK) cells, utilizing a novel antibody raised against a recently described kidney-specific isoform of ankyrin. In control MDCK cells, ankyrin was colocalized with Na-K-ATPase at the basolateral membrane. ATP depletion resulted in a duration-dependent mislocation of Na-K-ATPase and ankyrin throughout the cytoplasm. Colocalization studies showed a partial overlap between the distribution of ankyrin and Na-K-ATPase at all periods after ATP depletion. By immunoprecipitation with anti-ankyrin antibody, the mislocated Na-K-ATPase remained bound to ankyrin at all time points after ATP depletion. However, the interaction between ankyrin and spectrin was markedly diminished within 3 h of ATP depletion and was completely lost after 6 h. In solution binding assays using a fusion peptide of glutathione S-transferase with the ankyrin binding domain of Na-K-ATPase, a complex with ankyrin was detected at all time points after ATP depletion, but spectrin was lost from the complex in a duration-dependent manner. The loss of spectrin binding was not attributable to spectrin degradation but was associated with hyperphosphorylation of ankyrin. The results suggest that a dissociation of the membrane-cytoskeleton complex at the spectrin-ankyrin interface may contribute to the loss of Na-K-ATPase polarity after ischemic injury and reaffirm a critical adapter role for ankyrin in the normal maintenance of Na-K-ATPase polarity.

Adenosine Triphosphate↗
PubMed2002

Cisplatin-induced apoptosis in auditory cells: role of death receptor and mitochondrial pathways.

Cisplatin, a commonly used chemotherapeutic agent, has a major limitation due to its ototoxicity. Previous studies have shown that cisplatin induces apoptosis in auditory sensory cells, but the underlying mechanisms remain to be elucidated. In this study, cisplatin was found to induce apoptosis in a cochlear cell line, in a dose- and duration-dependent manner. Specific caspase assays revealed an early (6 h) but transient increase in caspase 8 activity, and a delayed (12 h) increase in caspase 9 activity. The enhanced caspase 8 activity was preceded by upregulation of p53 expression, and coincided with cleavage of Bid to its truncated form. This was followed temporally by activation and mitochondrial translocation of Bax, induction of mitochondrial permeability transition, release of cytochrome c into the cytosol, activation of caspase 9, and entry into the execution phase of apoptosis. Our results indicate the involvement of both the death receptor mechanisms as well as mitochondrial pathways in cisplatin-induced apoptosis of auditory cells in an in vitro model system.

Animals↗
PubMed2002

Estradiol reverses TGF-beta1-induced mesangial cell apoptosis by a casein kinase 2-dependent mechanism.

BACKGROUND: The slower rate of progression of chronic renal disease in women than in men is explained in part by the ability of estradiol to reverse the stimulatory effect of transforming growth factor-beta1 (TGF-beta1) on collagen IV synthesis at the level of casein kinase 2 activation. Casein kinase 2 also phosphorylates and activates the pro-apoptotic protein, p53. We hypothesized that estradiol would reverse TGF-beta1-induced mesangial cell apoptosis by antagonizing the stimulatory effects of TGF-beta1 on casein kinase 2 activity, thereby preventing p53 activation. METHODS: The effects of TGF-beta1 on mesangial cell apoptosis, p53 phosphorylation, Bax and Bcl-2 levels, caspase 9 activity, and cleavage of PARP were examined. The abilities of estradiol and a specific inhibitor of CK2 (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) (DRB) to modulate the effects of TGF-beta1 on these processes were also examined. RESULTS: TGF-beta1 (2 ng/mL), which up-regulates CK2 activity, induces apoptosis in murine mesangial cells together with p53 serine389 phosphorylation, up-regulation of Bax, suppression of Bcl-2, destabilization of mitochondrial permeability transition pores, stimulation of caspase 9 activity and activation of PARP. TGF-beta1-induced p53 activation and all the intermediary steps leading to mesangial cell apoptosis were reversed by estradiol (10-9 mol/L) and by DRB, potent inhibitors of CK2 activity, but not by inhibitors of the p38 MAPK, ERK or JNK signaling cascades. In contrast, TGF-beta1 failed to induce apoptosis in p53 knockout mesangial cells. CONCLUSIONS: Our data suggest that CK2 mediates the stimulatory effects of TGF-beta1 on mesangial cell apoptosis via a p53-dependent mechanism. The ability of estradiol to reverse TGF-beta1-induced apoptosis may contribute to the protective effects of female gender on the course of chronic renal disease.

Animals↗
PubMed2002

Towards a biological characterization of focal segmental glomerulosclerosis.

The primary form of focal segmental glomerulosclerosis (FSGS) has become one of the most common causes of end-stage renal disease in children and adolescents. FSGS was initially considered to be the histological expression of a single disease entity. However, evidence accumulated during the past four decades indicates that FSGS is heterogeneous in nature. It therefore is not surprising that the many therapeutic combinations and permutations that have been tried have yielded variable results in different hands. This has generated substantial confusion and frustration among physicians and patients alike. Recent progress in genetics and molecular biology has opened promising new vistas of investigation. Identification of genes that control components of the glomerular capillary, proteins that form the structural basis of podocytes, and genetic mutations that affect the integrity of these structures has revolutionized our understanding of the glomerular filtration barrier. Substantial progress also has been made in understanding the mechanisms that lead to progression of renal disease and, ultimately, sclerosis. Studies of these factors are likely to yield a mechanistic-based classification of FSGS that will allow us to design therapeutic regimens suited to specific subtypes of this disease.

Adolescent↗
PubMed2002

Role of nitric oxide, endothelin-1, and inflammatory cytokines in blood pressure regulation in hemodialysis patients.

BACKGROUND: Altered regulation of blood pressure (BP) in hemodialysis patients is associated with increased morbidity and mortality. Regulation of BP is dependent in part on such vasoactive agents as nitric oxide (NO) and endothelin-1 (ET-1). Cytokine-mediated NO synthase activation during dialysis previously has been reported. The purpose of this study is to investigate the relationship between cytokine-mediated activation of the NO and ET-1 systems and BP regulation in hemodialysis patients. METHODS: Nine patients with chronic hypotension (predialysis systolic BP < 110 mm Hg, duration > 1 month), nine patients with hypertension (predialysis systolic BP > or = 180 mm Hg), and nine age- and sex-matched normotensive controls were enrolled. RESULTS: Predialysis NO end product levels in the hypotensive group were greater than in controls (17.63 +/- 5.9 versus 11.06 +/- 2.12 microm/mL; P = 0.01), whereas the hypertensive group showed lower levels (4.76 +/- 2.33 microm/mL; P < 0.01). The hypotensive group had low postdialysis levels (3.45 +/- 1.11 microm/mL; P = 0.01). Predialysis ET-1 levels in the hypotensive and hypertensive groups were greater in comparison to the normotensive group (7.54 +/- 4.52 and 8.95 +/- 3.52 versus 4.41 +/- 0.6 pg/mL; P < 0.01). Postdialysis endothelin levels increased in both the control and hypertensive groups (P < 0.01). Interleukin-1 and tumor necrosis factor-alpha levels increased postdialysis in all groups, but not significantly. CONCLUSION: High levels of NO end products in hypotensive patients and low levels in hypertensive patients suggest a critical influence of NO in BP control. In addition, elevated ET-1 levels in hypertensive patients may contribute to systemic vasoconstriction and may suggest vascular dysfunction in this patient population.

Adolescent↗
PubMed2002

Cisplatin induces apoptosis in LLC-PK1 cells via activation of mitochondrial pathways.

Cisplatin, a commonly used chemotherapeutic agent, has a major limitation because of its nephrotoxicity. Recent studies have shown that cisplatin causes apoptotic cell death in renal tubule cells, but the underlying molecular mechanisms remain to be elucidated. In this study, cisplatin was found to induce apoptosis in a dose- and duration-dependent manner in cultured proximal tubule (LLC-PK1) cells, as evidenced by DNA laddering and TdT-mediated dUTP nick end-labeling assay. Pretreatment with the specific caspase 9 inhibitor LEHD-CHO completely prevented the apoptosis, whereas the caspase 8 inhibitor IETD-fmk had no effect. Furthermore, the activity of caspase 9 was upregulated about sixfold by cisplatin in a dose-dependent manner. These results implicated the caspase 9-dependent mitochondrial apoptotic pathways. Indeed, cisplatin triggered a duration-dependent translocation of cytochrome c from the mitochondria to the cytosol, by immunofluorescence and Western blots. Cisplatin treatment also resulted in the duration-dependent activation and mitochondrial translocation of the pro-apoptotic molecule Bax, by immunofluorescence. Finally, cisplatin induced a duration-dependent onset of the mitochondrial permeability transition. Our results indicate that cisplatin induces apoptosis in LLC-PK1 cells via activation of mitochondrial signaling pathways. The sequence of events may be summarized as follows: activation of Bax induces mitochondrial permeability transition, leading to release of cytochrome c, activation of caspase 9, and entry into the execution phase of apoptosis. Inhibition of this specific pathway may provide a strategy to minimize cisplatin-induced nephrotoxicity.

Animals↗
PubMed2001

Angiotensin-converting enzyme inhibition induces apoptosis in erythroid precursors and affects insulin-like growth factor-1 in posttransplantation erythrocytosis.

A number of studies suggest that erythropoietin (Ep), angiotensin II, and insulin-like growth factor (IGF-1) are involved in the pathogenesis of posttransplantation erythrocytosis (PTE). Angiotensin-converting enzyme inhibitors (ACEI) are the treatment of choice in PTE, but their mechanism of action is unclear. It was shown previously that ACEI added directly to cultures of erythroid precursors from patients with PTE inhibit colony growth. In this report, the effect of ACEI on CD34+ erythroid precursor apoptosis was studied, as were hematocrit (Hct), Ep, IGF-1, and IGF-binding protein 3 (IGF-BP3) levels. Ten patients with PTE, 10 transplant control patients, and 7 normal control subjects were studied. Peripheral blood CD34+ cells were isolated, and apoptosis was assessed by annexin assay and DNA laddering before and during ACEI therapy. At the same time, Hct, Ep, IGF-1, and IGF-BP3 levels were measured. Baseline CD34+ cell number, CD34+ apoptosis, Ep, IGF-1, and IGF-BP3 levels were the same between PTE and transplant control subjects. ACEI therapy was associated with a striking increase in CD34+ cell apoptosis and a decrease in Hct in both groups. In contrast to control subjects, patients with PTE on ACEI showed a significant decrease in IGF-1 levels and a greater percentage decrease in Hct. In normal control subjects, ACEI therapy was associated with a fall in Hct but no change in CD34+ cell apoptosis. In PTE, ACEI-related increase in erythroid progenitor apoptosis may partially explain the ACEI-associated decrease in Hct. However, it is not clear that erythroid precursor apoptosis is related to changes in IGF-1 or IGF-BP3.

Adolescent↗
PubMedDate not supplied

Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery.

BACKGROUND: The scarcity of early biomarkers for acute renal failure has hindered our ability to launch preventive and therapeutic measures for this disorder in a timely manner. We tested the hypothesis that neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for ischaemic renal injury after cardiopulmonary bypass. METHODS: We studied 71 children undergoing cardiopulmonary bypass. Serial urine and blood samples were analysed by western blots and ELISA for NGAL expression. The primary outcome measure was acute renal injury, defined as a 50% increase in serum creatinine from baseline. FINDINGS: 20 children (28%) developed acute renal injury, but diagnosis with serum creatinine was only possible 1-3 days after cardiopulmonary bypass. By contrast, urine concentrations of NGAL rose from a mean of 1.6 microg/L (SE 0.3) at baseline to 147 microg/L (23) 2 h after cardiopulmonary bypass, and the amount in serum increased from a mean of 3.2 microg/L (SE 0.5) at baseline to 61 microg/L (10) 2 h after the procedure. Univariate analysis showed a significant correlation between acute renal injury and the following: urine and serum concentrations of NGAL at 2 h, and cardiopulmonary bypass time. By multivariate analysis, the amount of NGAL in urine at 2 h after cardiopulmonary bypass was the most powerful independent predictor of acute renal injury. For concentration in urine of NGAL at 2 h, the area under the receiver-operating characteristic curve was 0.998, sensitivity was 1.00, and specificity was 0.98 for a cutoff value of 50 microg/L. INTERPRETATION: Concentrations in urine and serum of NGAL represent sensitive, specific, and highly predictive early biomarkers for acute renal injury after cardiac surgery.

Acute Kidney Injury↗