Biomedical subjects

Robert C Atkins

Publications and source records attributed to Robert C Atkins.

At least 73 records · Page 4Linked to original sources

PubMed2003

Activation of the ERK pathway precedes tubular proliferation in the obstructed rat kidney.

BACKGROUND: In vitro studies suggest that activation of the extracellular signal-regulated kinase (ERK) pathway plays a critical role in the proliferation of tubular epithelial and myofibroblast-like cells. However, little is known of ERK activation in individual cell types in normal or diseased kidney. The aims of this study were to (1) localize ERK activation within the kidney, and (2) examine the relationship between ERK activation and cell proliferation in the injured kidney. METHODS: Unilateral ureteric obstruction (UUO) was induced in groups of six Wistar rats, which were killed at 30 minutes, 6 hours, and 1, 4, or 7 days after obstruction. Activation of ERK was identified using antibodies specific for the phosphorylated form of ERK (pERK) in Western blots and immunostaining. Proliferating cells were detected using bromodeoxyuridine (BrdU). RESULTS: Western blotting showed abundant expression of the two ERK isoforms, ERK-1 and ERK-2, in normal rat kidney. Low levels of activated ERK (pERK-2> pERK-1) were detected in normal rat kidney by Western blotting. Immunostaining showed that ERK activation in normal kidney was largely restricted to collecting ducts in the outer medulla. Within 30 minutes of ureter obstruction, Western blotting showed a sixfold increase in ERK activation followed by a second peak (14-fold increase) on days 4 and 7. The initial peak of ERK activation was localized to medullary collecting ducts and the thick ascending limb of Henle (TALH), whereas the second peak corresponded to a progressive increase in ERK activation in dilated collecting ducts and in interstitial cells in the cortex. Proliferation of tubular epithelial cells closely followed the pattern of ERK activation, being evident first in medullary collecting ducts and TALH on day 1, and then in cortical collecting ducts from day 4. CONCLUSION: This study has identified a discrete pattern of ERK activation in normal rat kidney and an increase in ERK activation following obstruction. The temporal and spatial relationship in which ERK activation preceded tubular cell proliferation suggest that ERK signaling plays a key role in tubular epithelial cell proliferation in the injured kidney.

Animals↗

PubMed2003

Induction of MIF synthesis and secretion by tubular epithelial cells: a novel action of angiotensin II.

BACKGROUND: Angiotensin II (Ang II) plays an important role in the development of renal injury through its vasoactive and proinflammatory activities. We investigated whether some of the effects of Ang II could be mediated through the production of macrophage migration inhibitory factor (MIF). METHODS: Groups of rats underwent sham surgery (sham), subtotal nephrectomy (STNx), or STNx plus treatment with irbesartan. Renal tissue was examined 12 weeks postsurgery for MIF mRNA expression and leukocyte accumulation. To determine whether Ang II had a direct effect on MIF production, mRNA synthesis and protein secretion were examined in proximal tubular epithelial (NRK52E and MCT) cell lines. RESULTS: MIF mRNA was strongly expressed in 5.4%+/- 1.1% (mean +/- SD) of cortical tubules of sham-operated rats. This was significantly up-regulated in STNx rats (44.9%+/- 22.6%) and was abrogated by administration of irbesartan (2.8%+/- 2.4%). STNx resulted in significant glomerular and interstitial accumulation of macrophages and T cells, which correlated with glomerular and tubular MIF mRNA expression, respectively. In vitro studies of tubular epithelial cells revealed that Ang II caused a twofold increase in MIF mRNA expression in NRK52E and MCT cells, which was abrogated by irbesartan. In addition, Ang II induced a rapid release of 50% of MIF protein from NRK52E cells within 20 minutes. CONCLUSION: This study has demonstrated that Ang II up-regulates MIF mRNA production and MIF protein secretion by tubular epithelial cells. Ang II may promote accumulation and activation of interstitial leukocytes via induction of MIF synthesis and secretion in renal tubular epithelial cells. This may be an important mechanism by which Ang II mediates renal injury.

Angiotensin II↗

PubMed2003

Native arteriovenous fistula blood flow and resistance during hemodialysis.

BACKGROUND: Measurement of vascular access flow (Qa) has been proposed as the ideal method for surveillance of native fistulae. However, debate exists about the influence of blood pressure (mean arterial pressure [MAP]) on Qa during dialysis. METHODS: During three consecutive dialysis treatments, 10 patients had paired measurements of Qa and MAP performed at 30, 60, 120, 180, 210, and 240 minutes. Access resistance (AR; in peripheral resistance units, PRUs) was calculated from MAP and Qa values. RESULTS: Overall pooled coefficients of variation (CVs) for MAP, Qa, and AR were 8.4%, 12.3%, and 12.9%, respectively. A significant reduction in Qa and MAP occurred throughout the dialysis treatment (Qa, 104 mL/min; P = 0.008; MAP, 10.4 mm Hg; P = 0.007). Mean percentages of change in Qa for the first third compared with the middle and last thirds of the session were -4.6% +/- 11.15% (SD) and -9.6% +/- 10.5%, respectively. Thus, Qa varied between 11.4% and -30.6% from baseline during the last hour of dialysis treatments. A stronger correlation between MAP and Qa was seen in radiocephalic (r2 = 0.55; P < 0.0001) compared with brachiocephalic fistulae (r2 = 0.06; P = 0.023). Mean AR was unchanged during the dialysis session (0.23 PRU; P = 0.358). AR for radiocephalic fistulae was significantly greater compared with brachiocephalic fistulae (6.03 +/- 3.90 versus 3.00 +/- 1.11 PRU; P < 0.0001). CONCLUSION: Qa could decrease up to 30% from baseline, potentially impairing the ability of Qa to predict impending vascular access failure. AR remained stable during the treatment and may be a more useful measure of vascular access performance as part of an access surveillance program.

Arm↗

PubMed2003

Health-related quality of life in Australian adults with renal insufficiency: a population-based study.

BACKGROUND: Health-related quality of life is increasingly recognized as an important outcome in clinical research and patient care. Although there are a large number of reports of quality of life in the setting of end-stage renal disease, the impact of lesser degrees of renal impairment in the general population has not been described. METHODS: Data relating to quality of life measured by the Medical Outcomes Study 36-Item Short Form (SF-36) was available for 10,525 participants (93.6%) of the Australian Diabetes, Obesity and Lifestyle Study, a randomly selected representative sample of the Australian population aged 25 years or older. Results are examined by category of renal function (Cockcroft-Gault estimated glomerular filtration rate: normal, > or =60 mL/min/1.73 m2; renal insufficiency, <60 mL/min/1.73 m2). RESULTS: Significant impairment in health-related quality of life was seen with renal insufficiency for all SF-36 scales except Vitality and Mental Health. Adjusting for the substantial comorbidity associated with renal insufficiency, scores for Physical Functioning, Role-Physical, General Health, Vitality, and Role-Emotional were significantly lower. Examination of age-specific effects on health-related quality of life showed that mental health was particularly impaired in the younger age group, and Physical Functioning, in the older age group with renal insufficiency. Patterns of impairment were similar in men and women. CONCLUSION: Results from this study indicate that the current emphasis on clinical interventions aimed at preserving renal function are likely to improve the negative impact of kidney disease on health-related quality of life; however, prospective studies are needed to confirm these findings.

Adult↗

PubMed2003

Heterogeneity of antigen expression explains controversy over glomerular macrophage accumulation in mouse glomerulonephritis.

BACKGROUND: Many antibody labelling studies have suggested that there are few or no glomerular macrophages in mouse models of glomerulonephritis, despite the presence of a prominent interstitial macrophage infiltrate. These findings conflict with studies of human and rat glomerulonephritis. Therefore, we examined whether heterogeneity of macrophage antigen expression could explain this apparent discrepancy. METHODS: Kidneys were collected from normal mice and mice killed at 2 and 10 days after induction of accelerated anti-glomerular basement membrane (GBM) glomerulonephritis. Following fixation, macrophages were detected by immunoperoxidase staining in serial kidney sections using antibodies recognising CD11b, F4/80 and CD68. RESULTS: Induction of anti-GBM nephritis caused a progressive increase in glomerular and interstitial leukocytes. At days 2 and 10, there were more CD68+ macrophages in glomeruli than macrophages expressing CD11b or F4/80. At day 10, CD68+ macrophages accounted for almost all glomerular CD45+ total leukocytes. In contrast, CD11b+ and F4/80+ macrophages at day 10 accounted for only 65 and 13% of glomerular leukocytes, respectively. However, in the interstitium the number of macrophages expressing CD68, CD11b and F4/80 were not different. CONCLUSION: Antibody detection of mouse CD68 identifies all glomerular macrophages in mouse anti-GBM nephritis, indicating a similar infiltrate to that seen in human and rat anti-GBM nephritis. Our finding of substantial heterogeneity in glomerular macrophage antigen expression in this model suggests that previous studies of mouse glomerulonephritis may have underestimated glomerular macrophages and their role in glomerular injury.

Animals↗

PubMed2003

Laboratory assessment of immune function in renal transplant patients.

BACKGROUND: Advances in immunosuppression have made renal transplantation an effective therapy for end stage renal failure; with low rejection rates and long graft survival times. However, the major adverse consequences, infection and malignancy have not diminished. To predict this risk a score of immune competence has been developed from the simultaneous laboratory assessment of multiple parameters of immune function. METHODS: The immune status of 152 transplant recipients (138 renal and 14 pancreas/renal) was assessed by measurement of lymphocyte subsets, mitogen-induced T-cell proliferative responses, neutrophil phagocytic capacity and reactive oxygen species (ROS) generation. A scoring system was devised based on the average number of these parameters below 10th percentile of normal. RESULTS: The most common abnormality was B-cell lymphopenia (85%) followed by reduced neutrophil ROS production (63% of patients), NK cell lymphopenia (50%), lymphocyte mitogen response (49%) and CD4 number (23%). The abnormalities were unrelated to the duration of immunosuppression (up to 15 years), and variable combinations of cyclosporine A, azathioprine, prednisolone and mycophenolate mofetil (MMF) (except for a consistent reduction in lymphocyte mitogen response in MMF treated patients). Retrospective comparison of infective episodes showed a significantly greater index of infections in patients with the worst score compared with a normal score. CONCLUSIONS: The data suggests that this quantification of immune function may allow assessment of the level of host immune defence reflecting the level of drug-induced immunosuppression and thus risks of immunosuppressive complications.

Adult↗

PubMed2003

Association between albuminuria and proteinuria in the general population: the AusDiab Study.

BACKGROUND: The relationship between urinary albumin and total protein excretion and the appropriateness of one test over the other are unclear due to the paucity of large epidemiological studies of albuminuria and proteinuria. In screening for renal and cardiovascular disease, whether to measure albuminuria, proteinuria or both, is currently an unanswered question. METHODS: Random urine samples from 10,596 (94.2%) participants of the Australian Diabetes, Obesity and Lifestyle Study were tested for albuminuria (urine albumin:creatinine > or =30 mg/g) and proteinuria (urine protein:creatinine > or =0.20 mg/mg). This study was a representative sample of the national non-institutionalized population drawn from 42 randomly selected urban and non-urban areas (census collector districts) across Australia. RESULTS: Among a representative cross-section of the Australian adult population, urine albumin excretion was strongly correlated with total protein excretion, particularly among the elderly, and those with diabetes mellitus, hypertension, obesity and renal impairment (P <0.001). Albuminuria performed well as a screening test for proteinuria: sensitivity 91.7% [95% confidence interval (CI) 87.7-94.5%], specificity 95.3% (95% CI 94.9-95.7%) and negative predictive value 99.8% (95% CI 99.7-99.9%). However, among those with proteinuria, 8% excreted albumin within the normal range. CONCLUSIONS: While albuminuria may be a suitable test for general population screening for renal and cardiovascular disease, it should not replace testing for proteinuria in those with known or suspected renal disease.

Adult↗

PubMed2003

Blockade of p38alpha MAPK ameliorates acute inflammatory renal injury in rat anti-GBM glomerulonephritis.

The p38 mitogen-activated protein kinase (MAPK) pathway is a pro-inflammatory signal transduction pathway. The aim of this study was to examine the role of this pathway in acute renal inflammation. Immunostaining localized components of the p38 MAPK pathway (p38alpha, p-p38, p-ATF-2) in normal glomeruli, to podocytes, and occasional endothelial cells. This study identified an eightfold increase in glomerular activation of p38 MAPK (phosphorylated p38, p-p38) within 3 h of the induction of rat anti-glomerular basement membrane (GBM) glomerulonephritis and localized p-p38 and p-ATF-2 to infiltrating neutrophils, with increased staining of podocytes and endothelial cells. The relevance of these findings to human acute inflammatory renal disease was determined by examination of biopsy specimens. In patients with post-infectious glomerulonephritis, there was an increased number of positive p-p38 glomerular cells, including p-p38 staining of infiltrating neutrophils, compared with normal human kidney. In rats, administration of a specific p38 MAPK inhibitor, NPC 31145, before induction of anti-GBM disease prevented a loss of renal function and substantially reduced proteinuria. The reduction in renal injury was attributed to a 55% reduction in glomerular neutrophil infiltration and a 68% reduction in platelet accumulation. This was associated with an abrogation of glomerular P-selectin immunostaining and inhibition of glomerular P-selectin gene expression. In summary, this study has localized the components of the p38 MAPK pathway to cells in normal and diseased rat and human kidney and identified a number of important mechanisms by which signaling through the p38 MAPK pathway induces inflammatory renal disease. Blockade of the p38 pathway may be a novel therapeutic strategy for the treatment of acute renal inflammation.

Activating Transcription Factor 2↗

PubMed2003

Interferon-gamma augments acute macrophage-mediated renal injury via a glucocorticoid-sensitive mechanism.

Macrophages have been implicated in causing renal injury in both human and experimental kidney disease. The aim of the current study was to determine whether modulating the state of macrophage activation directly affects the capacity of these cells to cause renal injury. This was investigated using an adoptive transfer model in which macrophage activation can be manipulated in vitro, using interferon-gamma (IFN-gamma) or dexamethasone (Dex), and then macrophage-mediated renal injury determined in vivo. In this model, rats were made leukopenic by administration of cyclophosphamide (CyPh). Two days later (day 0), animals were injected with sheep anti-GBM serum followed by a single injection of rat NR8383 macrophages on day 1 and then killed 3 or 24 h after cell transfer. NR8383 macrophages were incubated IFN-gamma and/or Dex before adoptive transfer into animals. Induction of proteinuria and glomerular cell proliferation (PCNA+ cells) in this model was dependent on transfer of NR8383 macrophages. Exposure of macrophages to IFN-gamma for 18 h (but not 3 h) before transfer caused a twofold increase in the degree of proteinuria and glomerular cell proliferation compared with unstimulated cells (Nil versus IFN-gamma; P < 0.001). This was due to an increase in the number of transferred macrophages within the glomerulus and a significant increase in degree of renal injury per transferred glomerular macrophage. IFN-gamma increased iNOS and PDGF-B gene expression and upregulated adhesion molecule expression in NR8383 macrophages. In contrast, exposure of NR8383 cells to Dex for 18 h (but not 1 h) abrogated renal injury due to a failure of transferred macrophages to accumulate within the glomerulus. In addition, Dex abrogated renal injury caused by IFN-gamma-stimulated macrophages. In conclusion, activation of macrophages by IFN-gamma, independent of any effect on other leukocytes or renal cells, can substantially augment macrophage-mediated renal injury. This IFN-gamma augmentation of renal injury is sensitive to the action of glucocorticoids, which act directly on macrophages to prevent their recruitment to the inflamed glomerulus. This study provides the first evidence that it is possible to directly modulate macrophage-mediated renal injury.

Adoptive Transfer↗

PubMed2003

Prevalence of kidney damage in Australian adults: The AusDiab kidney study.

The incidence of ESRD is increasing dramatically. Progression to end-stage may be halted or slowed when kidney damage is detected at an early stage. Kidney damage is frequently asymptomatic but is indicated by the presence of proteinuria, hematuria, or reduced GFR. Population-based studies relating to the prevalence of kidney damage in the community are limited, particularly outside of the United States. Therefore, the prevalence of proteinuria, hematuria, and reduced GFR in the Australian adult population was determined using a cross-sectional study of 11,247 noninstitutionalized Australians aged 25 yr or over, randomly selected using a stratified, cluster method. Subjects were interviewed and tested for proteinuria-spot urine protein to creatinine ratio (abnormal: >/=0.20 mg/mg); hematuria-spot urine dipstick (abnormal: 1+ or greater) confirmed by urine microscopy (abnormal: >10,000 red blood cells per milliliter) or dipstick (abnormal: 1+ or greater) on midstream urine sample; and reduced GFR-Cockcroft-Gault estimated GFR (abnormal: <60 ml/min per 1.73 m(2)). The associations between age, gender, diabetes mellitus, and hypertension, and indicators of kidney damage were examined. Proteinuria was detected in 2.4% of cases (95% CI: 1.6%, 3.1%), hematuria in 4.6% (95% CI: 3.8%, 5.4%), and reduced GFR in 11.2% (95% CI: 8.6%, 13.8%). Approximately 16% had at least one indicator of kidney damage. Age, diabetes mellitus, and hypertension were independently associated with proteinuria; age, gender, and hypertension with hematuria; and age, gender, and hypertension with reduced GFR. Approximately 16% of the Australian adult population has either proteinuria, hematuria, and/or reduced GFR, indicating the presence of kidney damage. Identifying and targeting this section of the population may provide a means to reduce the burden of ESRD.

Adult↗

PubMed2003

Haematopoietic cell transplantation in the treatment of sickle cell disease.

Allogeneic haematopoietic cell transplantation (HCT) is presently the only treatment which offers the possibility of a cure for patients with sickle cell disease (SCD). While approximately 84% of patients survive disease-free after human leukocyte antigen (HLA)-identical sibling donor HCT, this therapy has traditionally been reserved for patients who have suffered serious complications due to the risk of transplant-related morbidity and mortality. Typically, these sickle-related complications have included recurrent episodes of acute chest syndrome, recurrent vaso-occlusive episodes and stroke. The future of HCT for haemoglobinopathies undoubtedly will evolve as transplant-related complications are reduced and as the process of selecting patients for HCT is refined.

Anemia, Sickle Cell↗

PubMed2002

Risk of renal allograft loss from recurrent glomerulonephritis.

BACKGROUND: Recurrent glomerulonephritis is a known cause of renal allograft loss; however, the incidence of this complication is poorly defined. We determined the incidence, timing, and relative importance of allograft loss due to the recurrence of glomerulonephritis. METHODS: A total of 1505 patients with biopsy-proved glomerulonephritis received a primary renal transplant in Australia from 1988 through 1997. Recurrence was confirmed by renal biopsy. The Kaplan-Meier method was used to estimate the 10-year incidence of allograft failure due to recurrent glomerulonephritis, and this incidence was compared with the incidence of acute rejection, chronic rejection, and death with a functioning allograft. Characteristics of the recipients and donors were examined as potential predictors of recurrence. RESULTS: Allograft loss due to the recurrence of glomerulonephritis occurred in 52 recipients, with a 10-year incidence of 8.4 percent (95 percent confidence interval, 5.9 to 12.0). The type of glomerulonephritis, the sex of the recipient, and the peak level of panel-reactive antibodies were independent predictors of the risk of recurrence. Recurrence was the third most frequent cause of allograft loss at 10 years, after chronic rejection and death with a functioning allograft. Despite the effect of recurrence, the overall 10-year incidence of allograft loss was similar among transplant recipients with biopsy-proved glomerulonephritis and among those with other causes of renal failure (45.4 percent [95 percent confidence interval, 40.9 to 50.2] vs. 45.8 percent [95 percent confidence interval, 42.3 to 49.3], P=0.09). CONCLUSIONS: Recurrence is an important cause of allograft loss for those with renal failure due to glomerulonephritis. No risk factors for recurrence were identified that warrant altering the approach to transplantation. However, accurate estimates of risk can now be provided to potential recipients of renal allografts.

Actuarial Analysis↗

PubMed2002

Macrophage colony-stimulating factor expression and macrophage accumulation in renal allograft rejection.

BACKGROUND: Studies of infiltrating cells from acutely rejecting renal allografts show that a high proportion of these cells are macrophages, and early macrophage infiltration is a poor prognostic sign for transplant survival. Macrophage colony-stimulating factor (M-CSF), produced by tubular and mesangial cells, has been associated with macrophage infiltration and proliferation in experimental and human kidney diseases. We investigated the expression of M-CSF in a model of acute rejection. METHODS: Lewis rats underwent bilateral nephrectomies and received an orthotopic Dark Agouti allograft or Lewis isograft. Animals received cyclosporine (10 mg/kg/day) from day 0 to day 3 and were killed at days 4, 8, or 14 after transplantation. Macrophages (ED1+) and T cells (W3-13+) were identified by immunohistochemistry, and M-CSF expression was identified by Northern blotting and in situ hybridization. RESULTS: Isografts had normal renal function without histological evidence of rejection. Allografts exhibited a moderate infiltrate at day 4 but progressed to severe rejection at day 14, with elevated serum creatinine level and severe tubulointerstitial damage. Macrophages and T cells were present in equal proportion in the infiltrate at day 4. At day 14, the number of macrophages increased fivefold (2580/mm2), although T cells were unchanged (380/mm2). Proliferating macrophages (ED1+, BrdU+) increased from day 4 (4%) to day 14 (10%). M-CSF mRNA expression was strongly up-regulated in allografts compared with isografts and normal rat. In situ hybridization demonstrated M-CSF expression by resident and infiltrating cells. Renal tubular expression was minimally increased at day 4 but strongly up-regulated at day 14 (more than 50% of tubules positive), particularly in areas of tubular damage. Tubular M-CSF expression colocalized with areas of intense macrophage infiltration and proliferation. Serial sections with double labeling demonstrated that T cells were the dominant source of M-CSF at day 4, yet later in the rejection (day 14) the predominant sites of production were both renal tubular cells and interstitial macrophages. CONCLUSIONS: Renal production of M-CSF by graft-infiltrating (macrophages and T lymphocytes) and resident (tubular) cells was up-regulated during acute rejection. M-CSF promotes macrophage recruitment and proliferation and may thereby play a pathogenic role in acute rejection. The kinetics of M-CSF production during acute rejection suggest that local macrophage proliferation may be initiated by T cells and perpetuated by both renal tubular and autocrine release.

Animals↗

PubMed2002

Increased incidence of benign breast disease in female renal transplant patients receiving cyclosporin.

BACKGROUND: Unlike other cancers, breast cancer does not occur at increased frequency in renal transplant patients but fibroadenomata may be more common as a result of exposure to cyclosporin. In order to determine the incidence of benign breast disease in renal transplant patients at Monash Medical Centre, current female patients were studied. METHODS: The study was divided into two parts: (i) a retrospective review of those who presented with clinically detectable breast lumps; and (ii) mammographic screening of current female transplant patients who had been transplanted for more than 1 year. RESULTS: In the retrospective study there were 11 patients with 16 breast lumps among a total of 85 patients. All were confirmed by biopsy. The mean age at diagnosis of breast lumps was 41.5 years (range 25-70 years). The mean time to presentation was 3.5 years after transplantation. Nine out of 11 patients had benign breast disease including fibroadenoma (six patients), fibrocystic disease (two patients) and intraductal papillomatosis (one patient). Two patients had breast cancer. Five of the patients with fibroadenoma had multiple lumps and a recurrent course. All patients with fibroadenomata had received cyclosporin. In the second part, 54 patients were further screened. The mean duration of transplantation was 6.4 years (range 1.25-18.5 years). Eighty-seven per cent of the patients had received cyclosporin, and 80% had a negative (normal) study. Seven of 54 had abnormalities including cysts and calcification, of whom two patients had fibroadenomata. Four patients had 'dense mammograms', all of whom received cyclosporin as a part of their immunosuppression. No breast cancer was detected during the study. CONCLUSION: The incidence of benign breast disease in the female transplant patients studied was far greater then the general population. The increase in fibroadenomata, in particular, may relate to the use of cyclosporin.

Adult↗

PubMed2002

Smoking is associated with renal impairment and proteinuria in the normal population: the AusDiab kidney study. Australian Diabetes, Obesity and Lifestyle Study.

BACKGROUND: Smoking has been associated with the prevalence, development, and progression of kidney disease. The effect of smoking on kidney function in the healthy population is unclear. We examined the relationship between smoking and indicators of kidney damage in a healthy population without impaired fasting glucose levels, impaired glucose tolerance, diabetes mellitus, or hypertension. METHODS: This is a randomly selected, population-based, cross-sectional study of 11,247 Australian adults. Smoking status was determined by questionnaire. Subjects were tested for indicators of kidney damage: renal impairment by Cockcroft-Gault-estimated glomerular filtration rate less than 60 mL/min/1.73 m2 and proteinuria by urine protein-creatinine ratio of 0.20 mg/mg or greater. RESULTS: After adjusting for potential confounding factors, smoking was significantly associated with renal impairment in men with an odds ratio of 3.59, but not in women. Smoking was significantly associated with proteinuria in subjects with high-normal systolic blood pressure, with odds ratios ranging from 3.64 at 131.5 mm Hg to 5.76 at 139.5 mm Hg, and in subjects with high-normal 2-hour glucose levels, with odds ratios ranging from 1.76 at 7.0 mmol/L to 10.84 at 7.7 mmol/L. Lifetime exposure, but not current level of smoking, correlated with lower estimated glomerular filtration rate and greater urine protein-creatinine ratio. CONCLUSION: Smoking is associated with renal impairment and proteinuria in a population without hypertension or abnormal glucose metabolism. A dose-response relationship was found between cumulative amount of smoking and indicators of kidney damage. In conjunction with other studies and plausible biological mechanisms, this study suggests that smoking may cause kidney damage, even in a healthy population.

Adult↗

PubMed2002

Urine macrophage migration inhibitory factor reflects the severity of renal injury in human glomerulonephritis.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a pathogenic role in experimental crescentic glomerulonephritis (GN). Renal expression of MIF is also upregulated in human GN and correlates with leukocytic infiltration, histologic damage, and renal dysfunction. The study presented here examined whether MIF can be measured in urine and if so, whether the urine MIF concentration reflects the degree of renal injury. Urine and serum MIF was measured by enzyme-linked immunosorbent assay in 10 normal healthy volunteers and in a cohort of 63 patients with GN (2 thin basement membrane disease [TBM], 15 membranous GN, 10 focal segmental glomerular sclerosis, 20 IgA glomerularnephritis, 11 crescentic GN, 10 systemic lupus erythematosis World Health Organization class IV). Renal MIF expression was assessed by immunostaining of biopsy tissue. MIF was detected in urine from normal volunteers (mean +/- SD; 191 +/- 132 pg MIF/micromol creatinine). The urine MIF concentration was unchanged in patients with nonproliferative nephropathies (343 +/- 397 pg MIF/micromol Cr) but was increased 3.4-fold in proliferative nephropathies (645 +/- 527 pg MIF/micromol Cr; P < 0.05 versus normal and nonproliferative). Stratified analysis showed the greatest increase in urine MIF in crescentic GN (4.5-fold). In contrast, serum MIF levels were not different between normal patients and any patient group. Immunostaining demonstrated a significant increase in renal MIF expression in proliferative glomerulonephritides that was associated with macrophage and T cell infiltration. There was a significant correlation between the urine MIF concentration and renal MIF expression, but not with serum MIF, indicating a renal origin for the excreted urine MIF. The urine MIF concentration also correlated with the degree of renal dysfunction, histologic damage, and leukocytic infiltration, but not with the amount of proteinuria. In conclusion, this study shows that the urine MIF concentration is significantly increased in proliferative forms of GN and correlates with the degree of renal injury. Urine MIF levels reflect MIF expression within the kidney and may be a useful noninvasive tool for monitoring patients with crescentic GN, particularly in disease exacerbation.

Adult↗

PubMed2002

Macrophage accumulation at a site of renal inflammation is dependent on the M-CSF/c-fms pathway.

Production of macrophage-colony stimulating factor (M-CSF), the major macrophage growth factor, is increased in tissues during inflammation. Therefore, we determined whether M-CSF, acting through its receptor c-fms, contributes to macrophage accumulation at a site of tissue injury. Daily treatment with anti-c-fms or control antibody was given to mice with renal inflammation resulting from unilateral ureteric obstruction (UUO). Following UUO, kidney M-CSF mRNA increased in association with macrophage accumulation (days 1, 5, and 10) and local macrophage proliferation (days 5 and 10). Anti-c-fms treatment caused a minor inhibition of monocyte recruitment at day 1, reduced macrophage accumulation by 75% at day 10, but did not affect blood monocyte counts or the CD4 and CD8 lymphocytic infiltrate. Prevention of macrophage accumulation by anti-c-fms treatment was associated with a 90% reduction in local macrophage proliferation at days 5 and 10 without evidence of increased macrophage apoptosis. Therefore, M-CSF/c-fms signaling plays a key role in macrophage accumulation during tissue injury.

Animals↗

PubMed2000

In vivo administration of a nuclear transcription factor-kappaB decoy suppresses experimental crescentic glomerulonephritis.

Glomerular expression of cytokines, interleukin-1 (IL-1), and tumor necrosis factor-alpha (TNF-alpha), together with leukocytic infiltration, are prominent features in crescentic glomerulonephritis. Because these cytokines are targets for nuclear transcription factor-kappaB (NF-kappaB), the use of NF-kappaB decoy oligodeoxynucleotide (ODN) treatment was evaluated in an experimental disease model. Crescentic glomerulonephritis was induced in primed Wistar rats by injection of sheep antiglomerular basement membrane serum. Thirty minutes after injection, rats were anesthetized and the left kidney was perfused with NF-kappaB decoy ODN or scrambled ODN control mixed with a virus-liposome complex, and then killed 7 d later. Animals given the scrambled control ODN developed severe glomerulonephritis by day 7 with heavy proteinuria, glomerular crescents and interstitial lesions, marked leukocytic infiltration, and upregulated renal expression of cytokines (IL-1 and TNF-alpha) and adhesion molecules (intercellular adhesion molecule-1). In contrast, NF-kappaB decoy ODN treatment substantially inhibited the disease with a 50% reduction in proteinuria, a threefold reduction in histologic damage, a 50% reduction in leukocytic infiltration, and a 50 to 80% reduction in the renal expression of cytokines and leukocyte adhesion molecules. In conclusion, this study has demonstrated that NF-kappaB plays a key role in cytokine-mediated renal injury and that NF-kappaB decoy ODN treatment has clear therapeutic potential in rapidly progressive glomerulonephritis.

Animals↗