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Howard Trachtman

Publications and source records attributed to Howard Trachtman.

At least 19 recordsLinked to original sources
PubMed2006

Involvement of the fractalkine pathway in the pathogenesis of childhood hemolytic uremic syndrome.

Thrombotic microangiopathy and acute renal failure are cardinal features of postdiarrheal hemolytic uremic syndrome (HUS). These conditions are related to endothelial and epithelial cell damage induced by Shiga toxin (Stx) through the interaction with its globotriaosyl ceramide receptor. However, inflammatory processes contribute to the pathogenesis of HUS by sensitizing cells to Stx fractalkine (FKN), a CX(3)C transmembrane chemokine expressed on epithelial and endothelial cells upon activation, is involved in the selective migration and adhesion of specific leukocyte subsets to tissues. Here, we demonstrated a selective depletion of circulating mononuclear leukocytes expressing the receptor for FKN (CX(3)CR1) in patients with HUS. We found a unique phenotype in children with HUS distinct from that seen in healthy, uremic, or infected controls, in which monocytes lost CX(3)CR1, down-modulated CD62L, and increased CD16. In addition, the CD56(dim) natural killer (NK) subpopulation was decreased, leading to an altered peripheral CD56(dim)/CD56(bright) ratio from 10.0 to 4.5. It is noteworthy that a negative correlation existed between the percentage of circulating CX(3)CR1(+) leukocytes and the severity of renal failure. Finally, CX(3)CR1(+) leukocytes were observed in renal biopsies from patients with HUS. We suggest that the interaction of CX(3)CR1(+) cells with FKN present on activated endothelial cells may contribute to renal injury in HUS.

Biopsy↗
PubMed2006

Urinary neutrophil gelatinase-associated lipocalcin in D+HUS: a novel marker of renal injury.

BACKGROUND: Diarrhea-associated hemolytic uremic syndrome (D+HUS) causes acute renal failure. Neutrophil gelatinase-associated lipocalcin (NGAL) is an early indicator of kidney injury. OBJECTIVE: To determine if urinary NGAL excretion is a biomarker of severe renal injury and predicts the need for dialysis in D+HUS. METHODS: Patients were randomly selected from among participants in the SYNSORB Pk trial. Urine samples were collected daily if available during the first week of hospitalization. NGAL levels were determined by ELISA. RESULTS: 34 children, age 5.9+/-3.9 yr, were studied; ten (29%) required dialysis. Patients were categorized based on urinary NGAL concentration within five days of hospitalization - <200 ng/ml and >or=200 ng/ml. Twenty patients (58%) had increased urinary NGAL excretion. The severity of D+HUS at enrollment was similar in the two groups. However, children with increased urinary NGAL levels had higher peak BUN and creatinine concentrations (P<0.01) and required dialysis more often, 9/20 versus 1/14 (P=0.024) compared to children with normal excretion. CONCLUSION: The majority of patients with D+HUS have renal tubular epithelial injury, as evidenced by elevated urinary NGAL excretion. Urinary NGAL levels below 200 ng/ml within five days of hospitalization may be an adjunctive marker that defines less severe renal involvement.

Acute-Phase Proteins↗
PubMed2006

Modulating the progression in IgA nephropathy.

IgA nephropathy affects almost 1% of the population and yet the diagnosis is often missed. This significant kidney disease is often progressive with 25% of the patients going on to end-stage kidney disease over the course of 25 years. This minireview describes the clinical presentations in children and young adults. Therapeutic options are discussed including angiotensin-converting enzyme blockade, steroids, cytotoxics, tonsillectomy, fish oil, vitamin E, singly or in combination, in order to modulate the rate of progression.

Adolescent↗
PubMed2006

Nitric oxide and superoxide in rat mesangial cells: modulation by C-reactive protein.

BACKGROUND: C-reactive protein (CRP) has been linked to cardiovascular and renal disease. We evaluated the effects of CRP on the production of nitric oxide (NO) and superoxide by rat mesangial cells (RMC) and the impact on cell function. METHODS AND RESULTS: RMC were incubated with cytokines (IFN-gamma, IL-1beta, and LPS) and CRP (10-100 microg/ml) for 24-72 h. Exposure to CRP resulted in a time- and dose-dependent reduction in NO accumulation (p<0.05). Although inducible nitric oxide synthase (iNOS) protein expression was unaltered after 48 h, CRP stimulated expression of HSP90. Steady state abundance of iNOS mRNA increased nearly threefold after a 24-h exposure to CRP. Incubation with 100 microg/ml CRP for 60-120 min resulted in a 272% increase in superoxide production that was prevented by diphenyleneiodium chloride but not L-NAME (p<0.0001). CONCLUSION: CRP enhances superoxide release in RMC, which in turn inactivates NO and reduces net production. The functional relevance of these CRP-induced changes is supported by increased expression of HSP90 in RMC exposed to the mediator. These findings suggest that systemic inflammation, which contributes to the pathogenesis of atherosclerosis, may play a role in the progression of kidney disease.

Animals↗
PubMed2006

Proteinuria and renal disease: prognostic value of urine dipstick testing for leukocytes.

Proteinuria is utilized to screen for underlying kidney disease and serves as a marker of disease progression. The aim of this study was to test the hypothesis that patients with proteinuria will have a higher frequency of urine dipstick positive for leukocytes as an index of noninfectious renal inflammation. In this retrospective analysis, 1,099 urine specimens were evaluated from 676 patients. Proteinuria was present in 39% of the samples and leukocyturia in 5.1%. The percentage of urines that were dipstick positive for leukocytes was similar in those specimens with or without proteinuria. However, in patients with proteinuria and concomitant leukocyturia, the mean serum creatinine concentration was higher (P=0.003) and the calculated GFR was lower (P=0.01) compared to those without this additional abnormality. These differences were noted despite similar age, gender distribution, and array of underlying diseases in these two groups. Based on these findings, urine dipstick testing for leukocytes as a primary means of screening otherwise healthy children for serious renal disease is of little value. However, in patients with established proteinuria, a positive dipstick result for leukocytes is a simple means of identifying those with more prominent noninfectious renal inflammation, a process which may promote kidney disease progression. This finding may serve as an early marker of the severity of renal injury, regardless of whether the primary process is glomerular or tubular.

Child↗
PubMed2006

Urinary podocyte mRNA excretion in children with D+HUS: a potential marker of long-term outcome.

BACKGROUND: Diarrhea-associated hemolytic uremic syndrome (D+HUS) causes acute renal failure and may lead to podocyte loss. Objective. To determine if the urinary mRNA excretion of podocyte proteins is detectable in children with D+HUS and if it is a biomarker of a poor long-term outcome. METHODS: Patients were randomly selected from participants in the SYNSORB Pk trial. Urine samples were collected daily during the first week of hospitalization. Specimens were also obtained in healthy volunteers. Synaptopodin and nephrin mRNA levels were measured using real-time PCR. RESULTS: Fifteen children, aged 4.9+/-2.8 years, were studied. Patients were categorized based on urinary mRNA levels into normal (marker:GAPDH mean + SD) in controls. Twelve patients (80%) had increased urinary podocyte mRNA excretion; 11 (73%) had high synaptopodin and 5 (33%) had high nephrin mRNA levels. Follow-up data were available in 13/15 patients, all of whom had normal blood pressure, urinalysis, and serum creatinine concentration. CONCLUSION: The isolation of podocyte mRNA from routine urine samples is feasible in children with D+HUS. Most patients have podocyturia based on synaptopodin and nephrin mRNA excretion. Larger studies with extended follow-up are required to determine the relationship of these biomarkers to long-term renal prognosis in D+HUS.

Adolescent↗
PubMed2006

Clinical spectrum of gross hematuria in pediatric patients.

Although isolated gross hematuria is a disturbing symptom, there have been few studies of this finding in pediatric patients. Therefore, this study was performed to examine the associated symptoms and causes of gross hematuria in children and adolescents who presented with this problem as their major clinical manifestation. It also determined the long-term outcome of patients in whom no etiology was found. A retrospective review was performed on the medical records of 100 consecutive patients referred for evaluation of gross hematuria between 1992 and 1999. The etiology was determined based on standard urinalysis methods, clinical laboratory tests, and imaging studies. Patients with gross hematuria in whom an etiology was not found were followed up through 2001. Of the 100 patient records reviewed, 18 were excluded because the clinical evaluation was incomplete. The remaining 82 patients (59 M: 23 F) had a mean age of 9.2 +/- 5.0 years. Glomerular gross hematuria was found in 24 patients. A cause was found in all of these patients, most commonly immunoglobulin A (IgA) nephropathy (n=13) and Alport syndrome (n=6). Nonglomerular gross hematuria was found in 56 patients, and the most common etiologies were hypercalciuria (n=9), urethrorrhagia (n=8), and hemorrhagic cystitis (n=7). No etiology was found in 26 patients with nonglomerular gross hematuria. No diagnosis was made in the case of 2 patients whose hematuria could not be defined as glomerular or nonglomerular. Telephone follow-up was performed in 18 of these children 4.0 +/- 3.2 years (range: 1-9 years) after the initial evaluation and showed that only 3 of these patients had had recurrences of gross hematuria. They and all of the other patients remained otherwise well. The urinalysis, including microscopic examination, was the most important diagnostic test in a patient with isolated gross hematuria. Nonglomerular problems were more than twice as common as glomerular diseases as a cause of isolated gross hematuria in pediatric patients The distribution of the etiologies of gross hematuria was consistent with previous studies. Although nearly half of the patients with nonglomerular gross hematuria could not be given a diagnosis, their long-term prognosis appeared to be good.

Adolescent↗
PubMed2005

Efficacy of mycophenolate mofetil in pediatric patients with steroid-dependent nephrotic syndrome.

Most patients with minimal change nephrotic syndrome are steroid responsive and tolerate this medication. However, a substantial number of patients relapse frequently and become steroid dependent. These patients often require treatment with alternative immunosuppressive drugs to maintain remission and minimize steroid toxicity. Previous studies have suggested that mycophenolate mofetil is effective in treating these patients. However, there are limited data on the effectiveness of this agent in pediatric patients, specifically those with steroid-dependent nephrotic syndrome. The purpose of this study was to assess the efficacy and safety of mycophenolate mofetil therapy in children and adolescents with steroid-dependent nephrotic syndrome who failed other treatments. A retrospective chart review was performed on all patients with steroid-dependent nephrotic syndrome. Clinical characteristics, laboratory data and the relapse rate were assessed prior to and during mycophenolate mofetil treatment. Twenty-one patients, ages 2-17 years, with steroid-dependent nephrotic syndrome who were treated with mycophenolate mofetil between 2001-2005 were included in this review. The indication for mycophenolate mofetil use was steroid dependence in 17 and steroid toxicity in 4 patients. The mean duration of treatment was 1.0+/-0.5 years (range: 0.2-2.0 years). Patients treated with mycophenolate mofetil had a reduction in relapse rate from 0.80+/-0.41 to 0.47+/-0.43 relapses per month ( P <0.02). Side effects were mild and mostly gastrointestinal in nature. In 1 child, mycophenolate mofetil was discontinued due to varicella infection and not restarted. The findings indicate that mycophenolate mofetil is a useful adjunctive therapy in the treatment of patients with steroid-dependent nephrotic syndrome. It lowers the relapse rate by 40% and is well tolerated by patients with steroid-dependent nephrotic syndrome.

Adolescent↗
PubMed2005

Meprin-alpha in chronic diabetic nephropathy: interaction with the renin-angiotensin axis.

Meprin (MEP) A is a metalloendopeptidase that is present in the renal proximal tubule brush-border membrane (BBM) and that colocalizes with angiotensin-converting enzyme (ACE). The MEP beta-chain gene locus on chromosome 18 has been linked to a heightened risk of diabetic nephropathy (DN) in patients with type 2 diabetes. This study evaluated 1) whether MEP-alpha and MEP-beta gene and protein expression are altered in db/db mice before the onset of DN and 2) the role of MEP-alpha in the pathogenesis of DN and the impact of the renin-angiotensin system on this interaction in two experimental models of diabetes. MEP-alpha and MEP-beta gene and protein expression were evaluated in db/db mice, 13-14 wk of age, compared with lean C57BLKS/J littermate animals. A treatment study was then performed in which db/db mice and controls were assigned to one of three groups: control (C) water, no therapy; ACE inhibitor therapy, enalapril (EN)-treated water, 50 mg/l; ANG II receptor type 1 blocker (ARB) therapy, losartan (LOS)-treated water, 500 mg/l. Treatment was started at 8 wk of age and continued for 52 wk. Male Sprague-Dawley rats with diabetes for 52 wk following a single dose of streptozocin (STZ; 60 mg/kg) were also studied. At 13.5 wk of age, MEP-alpha and MEP-beta kidney mRNA abundance and protein expression were significantly lower in db/db mice compared with lean controls, with greater changes in MEP-beta (P < 0.05). In the treatment study, EN ameliorated and LOS exacerbated DN in db/db mice. BBM MEP A enzymatic activity and MEP-alpha protein content were lower in db/db mice vs. control nonobese mice at 52 wk (P < 0.02). EN-treated db/db mice showed increased MEP A activity, MEP-alpha content in BBM, decreased urinary MEP-alpha excretion, and enhanced BBM staining for MEP-alpha protein vs. C and LOS-treated db/db mice. In nonobese mice, EN and LOS treatment had no effect on MEP-alpha expression. In rats with STZ-induced diabetes for 52 wk, urinary MEP-alpha excretion was increased and MEP A activity and MEP-alpha protein content per milligram of BBM protein were decreased compared with age-matched control animals (P < 0.05). These results indicate that db/db mice manifest decreased MEP-alpha and MEP-beta gene and protein expression, before the development of overt kidney disease. Moreover, in db/db mice with DN and rats with STZ-diabetes, there was an inverse relationship between renal MEP-alpha content and the severity of the renal injury. Treatment with an ACE inhibitor was more effective than ARB in ameliorating DN in db/db mice, a change that correlated with alterations in urinary excretion and BBM content of MEP-alpha. MEP-alpha may play a role in the pathogenesis of DN and the benefits of ACE inhibitor therapy on the progression of diabetic kidney disease may be related, in part, to its impact on renal MEP-alpha expression.

Angiotensin Receptor Antagonists↗
PubMed2005

Clinico-pathologic findings in medullary cystic kidney disease type 2.

Medullary cystic kidney disease type 2 is an uncommon autosomal dominant condition characterized by juvenile onset hyperuricemia, precocious gout and chronic renal failure progressing to end-stage renal disease in the 4th through 7th decades of life. A family suffering from this condition is described. The patient in the index case presented with renal insufficiency as a child. A renal biopsy revealed tubular atrophy, and immunohistochemical staining of the tissue for uromodulin (Tamm Horsfall protein) revealed dense deposits in renal tubular cells. Genetic testing revealed a single nucleotide mutation (c.899G>A) resulting in an exchange of a cysteine residue for tyrosine (C300Y). Medullary cystic kidney disease type 2 (also known as uromodulin-associated kidney disease) likely represents a form of endoplasmic reticulum storage disease, with deposition of the abnormal uromodulin protein in the endoplasmic reticulum, leading to tubular cell atrophy and death.

Adenine↗
PubMed2005

Assessing health status and health care utilization in adolescents with chronic kidney disease.

Few validated health status measures have been assessed in children with chronic kidney disease (CKD). The objective was to assess the validity of a generic health status measure, the Child Health and Illness Profile-Adolescent Edition (CHIP-AE), in adolescents with CKD. A case-control study was performed (1) to assess scores on the CHIP-AE in adolescents with CKD compared with two control groups of age-, socioeconomic-, and gender-matched peers and (2) to compare health of patients who had chronic renal insufficiency (CRI), were on dialysis, and were posttransplantation. Seven pediatric nephrology centers recruited 113 patients (mean age, 14 yr; 39 CRI, 21 dialysis, 53 posttransplantation). Compared with 226 control subjects, patients with CKD had lower overall satisfaction with health and more restriction in activity. Positively, patients with CKD had more family involvement, better home safety and health practices, and better social problem-solving skills and were less likely to participate in risky social behaviors or socialize with peers who engaged in risky behavior. Patients who received dialysis were less physically active and experienced more physical discomfort and limitations in activities than did transplant or CRI patients. It is concluded that patients with CKD have poorer functional health status than age-matched peers. Among CKD patients, dialysis patients have the poorest functional health status. These results suggest that the CHIP-AE can be used to measure functional health status in adolescent patients with CKD.

Adolescent↗
PubMed2005

Variants in the Wilms' tumor gene are associated with focal segmental glomerulosclerosis in the African American population.

Wilms' tumor gene (WT1) is important for nephrogenesis and gonadal growth. WT1 mutations cause Denys-Drash and Frasier syndromes, which are characterized by glomerular scarring. To test whether genetic variations in WT1 and WIT1 (gene immediately 5' to WT1) associate with focal segmental glomerulosclerosis (FSGS), patients with biopsy-proven idiopathic and HIV-1-associated FSGS were enrolled in a multicenter study. We genotyped SNP rs6508 located in WIT1 exon 1, three SNPs (rs2301250, rs2301252, rs2301254) in the promoter shared by WT1 and WIT1, rs2234590 in exon 6, rs2234591 in intron 6, rs16754 in exon 7, and rs1799937 in intron 9 of WT1. Cases (n = 218) and controls (n = 281) were compared in the African American population. Stratification by HIV-1 infection status showed that SNPs rs6508, rs2301254, and rs1799937 were significantly associated with FSGS [rs6508 odds ratio (OR) 1.82, P = 0.006; rs2301254 OR 1.65, P = 0.049; rs1799937 OR 1.91, P = 0.005] in the non-HIV-1 group and rs2234591 (OR 0.234, P = 0.011) in the HIV-1 group. Haplotype analyses in the population revealed that seven SNPs were associated with FSGS; five SNPs had the highest contingency score [-log10(P value) = 13.57] in the HIV-1 group. This association could not be explained by population substructure. We conclude that SNPs in WT1 and WIT1 genes are significantly associated with FSGS, suggesting that variants in these genes may mediate pathogenesis by altering WT1 function. Furthermore, HIV-1 infection status interacts with genetic variations in both genes to influence this phenotype. We speculate that nephropathy liability alleles in WT1 pathway genes cause podocyte dysfunction and glomerular scarring.

Black or African American↗