Detection and measurement of microalbuminuria: a challenge for clinical chemistry.
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Albumins↗
Biomedical subjects
Robert C Atkins
Publications and source records attributed to Robert C Atkins.
Blastic NK-cell-like lymphoma with T-cell receptor gene rearrangement.
Blastic natural killer (NK) cell lymphoma is very rare but has been recently classified as a distinct entity in WHO classification. However, the classification remains controversial, and the clinicopathologic spectrum is not completely understood. We report a unique case of cutaneous CD4(+) CD56(+) malignancy with a typical clinical presentation and immunophenotype of blastic NK-cell lymphoma in a 15-year-old Guamanian girl. The skin was the only site involved by the lymphoma. Molecular study showed clonal T-cell receptor gamma gene rearrangement. The patient has been disease-free till now (more than 12 months following bone marrow transplant). This case may represent a tumor at an early stage of a common developmental pathway for T-cells and NK-cells.
Adolescent↗
Time and exercise improve phosphate removal in hemodialysis patients.
BACKGROUND: Control of serum phosphate remains a difficult clinical issue in most hemodialysis (HD) patients. This study examines 2 nonpharmacological approaches to improving phosphate control in HD patients. METHODS: First, 9 stable HD patients underwent dialysis in random fashion for either 4 hours 3 times weekly or 5 hours 3 times weekly. Adjustments were made to blood flow rates such that Kt/V was the same for all sessions, thus allowing independent assessment of the influence of time. The primary end point was weekly dialysate phosphate removal. In the second study, 12 different patients underwent an exercise program in which they pedaled a bicycle ergometer either immediately before or during dialysis. Again, weekly dialysate phosphate removal was measured. RESULTS: In the time study, urea reduction ratio (69% +/- 0.02% versus 68% +/- 0.07, 4 versus 5 hours) and weekly urea removal were no different between the 2 groups. However, weekly phosphate removal (3,007 +/- 641 versus 3,400 +/- 647 mg; P < 0.02) significantly improved with longer dialysis duration. Serum phosphate levels improved, but did not reach statistical significance in this short-term study. In the exercise study, weekly phosphate removal improved with exercise, but did not reach significance (2,741 +/- 715 [no exercise] versus 2,917 +/- 833 [exercise predialysis] versus 2,992 +/- 852 mg [exercise during dialysis]; P = 0.055), although comparing only exercise during dialysis with no exercise reached significance (P = 0.02). There was no significant difference in serum phosphate levels. CONCLUSION: Both increased dialysis time and exercise result in increased dialytic removal of phosphate and could be expected in the long term to improve phosphate control.
Adult↗
Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized controlled trials.
BACKGROUND: In this systematic review of randomized controlled trials (RCTs), we assess the benefits and harm of current treatments for diffuse proliferative lupus nephritis (DPLN). METHODS: The Cochrane Controlled Trial Registry, MEDLINE, and EMBASE were searched for RCTs of treatment for DPLN. All available RCTs of patients with biopsy-proven DPLN were included, and data were extracted for overall mortality, end-stage renal disease, doubling of serum creatinine level, relapse, major infection, herpes zoster infection, ovarian failure, malignancy, and bladder toxicity. Treatment effects on these outcomes were summarized as relative risk (RR) with 95% confidence interval (CI) and pooled by using a random-effects model. RESULTS: Twenty-five of 920 articles identified were eligible RCTs and were included. The majority compared cyclophosphamide or azathioprine plus steroids versus steroids alone. Cyclophosphamide plus steroids reduced the risk for doubling of serum creatinine level (4 RCTs, 228 patients; RR, 0.59; 95% CI, 0.40 to 0.88) compared with steroids alone, but had no impact on overall mortality (5 RCTs, 226 patients; RR, 0.98; 95% CI, 0.53 to 1.82). However, risk for ovarian failure was increased significantly (3 RCTs, 147 patients; RR, 2.18; 95% CI, 1.10 to 4.34). In studies from the 1970s, azathioprine plus steroids reduced the risk for all-cause mortality compared with steroids alone (3 RCTs, 78 patients; RR, 0.60; 95% CI, 0.36 to 0.99), but had no effect on renal outcomes. Neither therapy was associated with increased risk for major infection. The addition of plasma exchange to these treatments offered no benefit, and information on other agents, including mycophenolate mofetil, was insufficient for analysis. CONCLUSION: Until future RCTs of newer agents are completed, the current use of cyclophosphamide combined with steroids remains the best option to preserve renal function in patients with DPLN. The smallest effective dose and shortest duration of treatment should be used to minimize gonadal toxicity without compromising efficacy.
Azathioprine↗
Vascular access practice patterns in the New Zealand hemodialysis population.
BACKGROUND: Native arteriovenous fistula (AVF) prevalence varies significantly among different populations and countries. Physician practice patterns may have a strong influence on access type. We assessed differences in vascular access practice patterns across all treating centers in New Zealand. METHODS: Adult (age > or = 18 years) patients on hemodialysis therapy in the year ending September 30, 2001, were studied from the Australian and New Zealand Dialysis and Transplant Association Registry. Multinomial logistic regression was used to assess factors associated with arteriovenous graft (AVG) and catheter use. RESULTS: Of 772 patients available for analysis, 461 patients (60%) underwent dialysis using an AVF; 122 patients (16%), an AVG; and 189 patients (24%), a catheter. On multivariable analysis, female sex (odds ratio, 5.92; P < 0.001), coronary artery disease (odds ratio, 1.89; P < 0.05), body mass index greater than 30 (odds ratio, 2.55; P < 0.05), and age (odds ratio, 1.03 per year increase; P < 0.001) were associated with an increased likelihood of AVG use. Maori and Pacific Island patients were less likely to use an AVG compared with Caucasians (odds ratio, 0.47; P < 0.05). Predictors of greater likelihood of catheter use were female sex (odds ratio, 3.9; P < 0.001), late referral (odds ratio, 1.60; P < 0.05), and age (odds ratio, 1.02 per year increase; P < 0.001). Proportions of access types varied significantly across the 7 treating centers (AVFs, 32% to 86%; AVGs, 2% to 32%; catheters, 9% to 33%; P < 0.001). After adjusting for confounding factors, significant differences persisted among access types in some centers and the national average. CONCLUSION: Certain patient characteristics, such as age and female sex, are associated strongly with increased AVG and catheter use. However, the significant variation in risk across centers suggests more attention needs to be given to physician practice patterns to increase AVF use rates.
Adult↗
Renal processing of serum proteins in an albumin-deficient environment: an in vivo study of glomerulonephritis in the Nagase analbuminaemic rat.
BACKGROUND: Plasma albumin has been considered as important for governing glomerular permselectivity as well as being tubulotoxic in proteinuric states. The purpose of this study was to examine glomerular permselectivity and protein clearance of plasma albumin-deficient Nagase analbuminaemic rats (NAR) in normal and proteinuric states associated with puromycin aminonucleoside nephrosis (PAN) and anti-glomerular basement membrane glomerulonephritis (anti-GBM GN) and to compare the results with those of previous studies using Sprague-Dawley rats. METHODS: Glomerular permselectivity was measured using tritium-labelled polydisperse Ficoll. In vivo fractional clearance (FC) of albumin, transferrin and immunoglobulin G was measured to include both intact and degraded forms of filtered material. Endogenous protein clearance was analysed using two-dimensional electrophoresis in combination with matrix-assisted laser desorption ionization (MALDI) mass spectrometry. RESULTS: FCs of proteins and Ficoll in control NAR were similar to those found in Sprague-Dawley rats. Despite the lack of serum albumin in NAR, proteinuria and morphological changes observed were also similar to those found in Sprague-Dawley rats, with total protein excretion increasing 6-fold in PAN rats and 4-fold in anti-GBM GN rats with respect to controls. Two-dimensional electrophoresis in combination with MALDI mass spectrometry identified the major proteins being excreted as transferrin and a group of mildly acidic proteins in the MW range 40-50 kDa, namely antithrombin III, kininogen, alpha-1-antiproteinase, haemopexin and vitamin D-binding protein. CONCLUSIONS: Both diseases exhibited similar effects to those observed in Sprague-Dawley rats despite the lack of serum albumin, including inhibition of renal protein degradation. The net changes in protein FC, particularly in the range of radii of 36-55 A, could not be accounted for by changes in size selectivity as Ficoll FC was little affected by the disease states. This emphasizes the need to reassess the relative importance of changes in renal tubular handling vs changes in glomerular capillary barrier in proteinuric states. These studies also demonstrate that albumin is not a critical factor in governing glomerular permselectivity or proteinuria.
Acetylglucosaminidase↗
The role of flow cytometric ANCA detection in screening for acute pauci-immune crescentic glomerulonephritis.
BACKGROUND: Most cases of pauci-immune crescentic glomerulonephritis (PICGN) are associated with serum anti-neutrophil cytoplasmic antibodies (ANCA). This article studied the sensitivity and specificity of serum ANCA, determined by flow cytometry and indirect immunofluorescence (IIF), to identify patients with acute PICGN. METHODS: 577 adults presenting for first biopsy of their native kidneys with serum taken for ANCA (flow cytometry and IIF) determination were studied. A positive ANCA was defined using a flow cytometric ANCA assay as a screening test, followed by a slide-based indirect IIF technique. Pathological confirmation of acute PICGN was used to assess the sensitivity and specificity of this combined approach and its positive predictive value (PPV) and negative predictive value (NPV) in patients presenting for renal biopsy due to abnormal urinary sediment. RESULTS: Forty-nine patients were found to have acute PICGN on renal biopsy. Of these 47 were ANCA positive (sensitivity 95.9%). Overall 93 of the renal biopsy patients were ANCA positive, (specificity 91.3%). A further seven patients (two ANCA positive) had advanced sclerosing disease consistent with PICGN but without evidence of current disease activity. The PPV and NPV of ANCA, assessed by flow cytometry and slide IIF, in predicting that patients presenting with undifferentiated renal disease would have acute PICGN was 50.5 and 99.8%, respectively. CONCLUSIONS: Flow cytometric screening of serum for ANCA in patients undergoing renal biopsy has a high NPV for determining those with acute PICGN. It may provide a rapid, simple screening test for this lesion in laboratories using diagnostic flow cytometry and may complement IIF/ELISA in evaluating ANCA positive patients.
Acute Disease↗
Albumin and glomerular permselectivity.
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Albuminuria↗
Macrophages in streptozotocin-induced diabetic nephropathy: potential role in renal fibrosis.
BACKGROUND: Renal fibrosis is central to the progression of diabetic nephropathy; however, the mechanisms responsible for fibroblast and matrix accumulation in this disease are only partially understood. Macrophages accumulate in diabetic kidneys, but it is unknown whether macrophages contribute to renal fibrosis. Therefore, we examined whether macrophage accumulation is associated with the progression of renal injury and fibrosis in type 1 diabetic nephropathy and whether macrophages exposed to the diabetic milieu could promote fibroblast proliferation. METHODS: Kidney macrophages, renal injury and fibrosis were analysed in diabetic C57BL/6J mice at 2, 8, 12 and 18 weeks after streptozotocin injection. Isolated rat bone marrow macrophages were stimulated with diabetic rat serum or carboxymethyllysine (CML)-bovine serum albumin (BSA) to determine whether macrophage-conditioned medium could promote the proliferation of rat renal (NRK-49F) fibroblasts. RESULTS: Progressive injury and fibrosis in diabetic nephropathy was associated with increased numbers of kidney macrophages. Macrophage accumulation in diabetic mice correlated with hyperglycaemia (blood glucose, HbA1c levels), renal injury (albuminuria, plasma creatinine), histological damage and renal fibrosis (myofibroblasts, collagen IV). Culture supernatant derived from bone marrow macrophages incubated with diabetic rat serum or CML-BSA induced proliferation of fibroblasts, which was inhibited by pre-treating fibroblasts with interleukin-1 (IL-1) receptor antagonist or the platelet-derived growth factor (PDGF) receptor kinase inhibitor, STI-571. CONCLUSION: Kidney macrophage accumulation is associated with the progression of renal injury and fibrosis in streptozotocin-induced mouse diabetic nephropathy. Elements of the diabetic milieu can stimulate macrophages to promote fibroblast proliferation via IL-1- and PDGF-dependent pathways which may enhance renal fibrosis.
Animals↗
p38 Mitogen-activated protein kinase activation and cell localization in human glomerulonephritis: correlation with renal injury.
Activation of the p38 mitogen-activated protein kinase (MAPK) signal transduction pathway plays an important role in the inflammatory response. It was postulated that p38 MAPK is important in the pathogenesis of human glomerulonephritis and contributes to the development of renal injury. p38 MAPK activation was examined by immunodetection for dual phosphorylated p38 (p-p38) in normal human kidney and 77 renal biopsy specimens encompassing a wide spectrum of glomerulonephritides. In normal kidney, p-p38 immunostaining was restricted to the nuclei of a small number of podocytes, parietal epithelial cells, and tubular cells. There was a dramatic increase in the number of p-p38-positive cells in glomeruli and tubules in nonproliferative and proliferative glomerulonephritis and a substantial increase in the number of interstitial p-p38-positive cells in proliferative glomerulonephritis. Double immunostaining identified p38 activation in intrinsic renal cells (podocytes and endothelial and tubular cells), infiltrating macrophage and neutrophils, and myofibroblasts. Renal failure correlated with the number of p-p38-positive glomerular, tubular, and interstitial cells. Proteinuria correlated with the number of p-p38-positive tubular and interstitial cells and the number of p-p38-positive podocytes in nonproliferative glomerulonephritis. Furthermore, glomerular p38 activation correlated with segmental proliferative and necrotic lesions, and interstitial p38 activation correlated with the degree of interstitial inflammation. In conclusion, activation of p38 MAPK in intrinsic renal cells and infiltrating leukocytes correlated with renal dysfunction and histopathology, suggesting an important pathogenic role for p38 MAPK activation in human glomerulonephritis.
Enzyme Activation↗
Vascular access and all-cause mortality: a propensity score analysis.
The native arteriovenous fistula (AVF) is the preferred vascular access because of its longevity and its lower rates of infection and intervention. Recent studies suggest that the AVF may offer a survival advantage. Because these data were derived from observational studies, they are prone to potential bias. The use of propensity scores offers an additional method to reduce bias resulting from nonrandomized treatment assignment. Adult (age 18 yr or more) patients who commenced hemodialysis in Australia and New Zealand on April 1, 1999, until March 31, 2002, were studied by using the Australian and New Zealand Dialysis and Transplant Association (ANZDATA) Registry. Cox regression was used to determine the effect of access type on total mortality. Propensity scores were calculated and used both as a controlling variable in the multivariable model and to construct matched cohorts. The catheter analysis was stratified by dialysis duration at entry to ANZDATA to satisfy the proportional-hazard assumption. There were 612 deaths in 3749 patients (median follow-up, 1.07 yr). After adjustment for confounding factors and propensity scores, catheter use was predictive of mortality. Patients with arteriovenous grafts (AVG) also had a significantly increased risk of death. Effect estimates were also consistent in the smaller propensity score-matched cohorts. Both AVG and catheter use in incident hemodialysis patients are associated with significant excess of total mortality. Reducing catheter use and increasing the proportion of patients commencing hemodialysis with a mature AVF remain important clinical objectives.
Adult↗
The role of p38alpha mitogen-activated protein kinase activation in renal fibrosis.
The p38 mitogen-activated protein kinase (MAPK) pathway transduces external stress stimuli and is important in extracellular matrix synthesis in cell types in vitro; however, its role in renal fibrosis is not known. Explored was the role the p38 MAPK pathway in rat unilateral ureteric obstruction (UUO), a model of renal fibrosis induced by a noninflammatory surgical insult. In a time-course study, a marked increase in phosphorylation (activation) of p38 in both interstitial myofibroblasts and tubules was shown. Rats were then treated daily with a specific inhibitor of p38alpha, NPC 31169, from the time of UUO surgery until being killed 7 d later. Compared with vehicle, NPC 31169-treated rats had a significant reduction in renal fibrosis assessed by interstitial volume, collagen IV deposition, and mRNA levels. This was primarily due to a reduction in the accumulation of interstitial myofibroblasts, as shown by a reduction in the area of immunostaining for alpha-smooth muscle actin and heat shock protein 47. The increase in renal TGF-beta1 mRNA and protein levels in UUO was unaltered with NPC 31169 treatment; however, connective tissue growth factor mRNA was reduced. These results demonstrate that p38alpha MAPK plays an important role in renal fibrosis, acting downstream of TGF-beta1. Blockade of p38 MAPK reduces extracellular matrix production and may be considered a potential therapeutic option in the treatment of renal fibrosis.
Animals↗
Activation of the extracellular-signal regulated protein kinase pathway in human glomerulopathies.
Examined was extracellular-signal regulated kinase (ERK) activation in normal human kidney (n = 2) and a cohort of glomerulopathies by immunohistochemistry staining for the dual-phosphorylated form of ERK (p-ERK). Cell proliferation was determined by expression of the proliferating cell nuclear antigen (PCNA). In normal human kidney, p-ERK was largely restricted to the cytoplasm of cells of the collecting duct (CD). In glomerulopathies, glomerular ERK activation was highly variable. However, there was colocalization of cell proliferation and ERK activation in the glomerular tuft and crescents. Tubular ERK activation in the different glomerulopathies was confined to the CD in areas with normal architecture. In contrast, ERK activation was prominent in tubules and interstitial cells in areas of tubulointerstitial damage. ERK activation was observed in glomerular and interstitial alpha-smooth muscle actin-positive myofibroblasts, but few macrophages or T cells showed ERK activation. There was a significant correlation between glomerular p-ERK+ and PCNA+ cells and between tubular p-ERK+ and PCNA+ cells. Glomerular p-ERK+ cells correlated with glomerular cellularity and the percentage of glomeruli with segmental lesions. Tubular p-ERK+ cells correlated with renal dysfunction and interstitial fibrosis and tubular atrophy. In conclusion, activation of the ERK pathway in human glomerulopathies correlates with cell proliferation, histologic lesions, and renal dysfunction. ERK activation may promote renal repair through tubular proliferation while promoting renal fibrosis via proliferation of glomerular and interstitial myofibroblasts.
Actins↗
Macrophage-mediated renal injury is dependent on signaling via the JNK pathway.
Macrophage accumulation is a prominent feature in most forms of human glomerulonephritis and correlates with renal dysfunction. Macrophages can directly mediate acute renal injury in animal models, but the mechanisms of macrophage activation required for mediating renal injury are unknown. This study examined whether activation of the Jun amino terminal kinase (JNK) signaling pathway is necessary for macrophage-mediated renal injury. An adoptive transfer model was used in which rats were immunized with sheep IgG (day -5), made leukopenic by administration of cyclophosphamide (CyPh) (day -2), and then injected with sheep anti-glomerular basement membrane (GBM) serum (day 0). Animals were then given an intravenous injection of bone marrow-derived macrophages (BMM) (day 1) and killed 24 h later (day 2). The induction of proteinuria and glomerular cell proliferation (PCNA+ cells) in CyPh-treated anti-GBM disease was dependent on transfer of BMM. Exposure of BMM to the specific JNK inhibitor, SP600125, for 3 h before adoptive transfer had no effect on glomerular accumulation of BMM in CyPh-treated anti-GBM disease. However, SP600125 treatment of BMM caused a 75% reduction in proteinuria and a 70% reduction in glomerular cell proliferation (P < 0.01 versus vehicle or untreated BMM). In conclusion, this study has defined a critical role for the JNK signaling pathway in macrophage-mediated renal injury.
Animals↗
Atherosclerosis and folic acid supplementation trial in chronic renal failure: baseline results.
BACKGROUND: Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) is a randomized placebo controlled trial assessing whether high-dose folic acid can reduce cardiovascular events and atherosclerosis progression in patients with chronic renal failure (CRF). Here we report the baseline results and compare indices of arterial structure (carotid intima-medial thickness (IMT)) and function (systemic arterial compliance (SAC)), pressure augmentation index (AI(x)) and pulse wave velocity (PWV a-f and PWV f-d)) to age- and sex-matched controls. METHODS: Three hundred and fifteen subjects with CRF (serum creatinine > or = 0.40 mmol/L) aged 24-79 years (mean +/- SD: 56.6 +/- 13.6 years) and 213 healthy controls (58.2 +/- 10.2 years) were studied. Fasting blood samples were assayed for lipids (both groups), total homocysteine (tHcy), red cell folate, cobalamin and fibrinogen (CRF group). Ultrasound B mode measurements were used to determine mean carotid IMT and applanation tonometry techniques to determine SAC, AI(x), PWV (a-f), PWV (f-d) and central pressures. RESULTS: Ninety-six per cent of the CRF group had at least one of: hypertension, hypercholesterolaemia, diabetes or smoking; 35% had established cardiovascular disease. The mean IMT was greater in CRF patients than in controls (0.86 +/- 0.19 vs 0.68 +/- 0.11 mm, P < 0.001). The SAC was significantly lower, and PWV (a-f) and AI(x) significantly higher. The tHcy was increased in 97% of the CRF group (27.3 +/- 2.9 micromol/L (normal < 13)). Total homocysteine did not correlate with IMT or any other measure of arterial function. However, those in the upper quantile of tHcy (> or =25 micromol/L) did have higher PWV (a-f) and lower SAC than those in the lower quantile. CONCLUSIONS: Compared to normals, patients with CRF exhibited a 10-15-year shift to the right in age-related increases in carotid IMT and PWV (a-f), and significantly increased central pressure augmentation. This 5-year study is examining the impact of high-dose folic acid therapy on cardiovascular end-points, IMT progression and arterial function in CRF.
Adult↗
Determinants of native arteriovenous fistula blood flow.
BACKGROUND: Determinants of native arteriovenous fistula (AVF) placement have been well studied. Little is known on whether these factors impact on subsequent blood flow (Qa) in the mature AVF. METHODS: Arteriovenous fistula Qa and cardiac index (CI) were determined by ultrasound dilution. Multiple linear regression was used to assess independent predictors of AVF Qa. RESULTS: Of the 148 patients available for the analysis, 68% were male, with 61% using a radiocephalic AVF. Aetiology of renal disease was: 38% glomerulonephritis (GN), 22% diabetes mellitus (DM), 9% hypertension/ischaemic (HTN) and 31% other. Thirty per cent had coronary artery disease (CAD), 10% cerebrovascular disease and 11% peripheral vascular disease (PVD). Median (iqr) Qa was 1185 mL/min (790-1650) and CI was 3.15 L/min per 1.73 m(2) (2.60-3.93). On univariable analysis, log CI (0.98, P < 0.001), age (-0.1 per 10 years, P = 0.002), access position (upper vs lower 0.26, P = 0.003, PVD (-0.35, P = 0.015), CAD (-0.25, P = 0.008), and primary renal disease (DM vs GN, -0.35, P = 0.003, HTN vs GN, -0.34, P = 0.04) were associated with Qa. On multivariable analysis, CI (0.84, P < 0.001), access position (upper vs lower, 0.17, P = 0.018) and primary renal disease (DM vs GN, -0.26, P = 0.005, and HTN vs GN, -0.26, P = 0.038) remained significant predictors of AVF Qa. CONCLUSION: Once established, CI, AVF position and primary renal disease (hypertension/ischaemic and diabetes) are the major determinants of AVF Qa while female gender, CAD, PVD and body mass index were not significant determinants of Qa in this cohort.
Aged↗
Macrophage accumulation and renal fibrosis are independent of macrophage migration inhibitory factor in mouse obstructive nephropathy.
BACKGROUND AND AIM: The progression of renal injury, initiated by either an immune or non-immune insult, is closely associated with the accumulation of leucocytes and fibroblasts in the damaged kidney. Macrophage migration inhibitory factor (MIF) regulates leucocyte activation and fibroblast proliferation in vitro. Studies have identified a pathological role for MIF in immune-initiated renal injury in the rat. In this study, we examined the role of MIF in obstructive nephropathy, where renal injury is initiated by a non-immune insult. METHODS AND RESULTS: Unilateral ureteric ligation was performed on MIF wildtype (+/+) and MIF deficient (-/-) mice. Groups of five mice were killed at days 0, 1, 5 or 10 after obstruction, and kidneys were examined via immunohistochemistry and northern blotting. In MIF +/+ mice, expression of the MIF protein increased in obstructed kidneys compared to normal control kidneys. Interstitial macrophage and T cell accumulation was significantly increased in obstructed kidneys at day 5 and 10, but was unaffected by MIF deficiency. Osteopontin and macrophage colony stimulating factor (M-CSF) mRNA expression in obstructed kidneys were equally increased in both genotypes, indicating that expression of these chemokines is not influenced by MIF. No difference was detected in the development of renal fibrosis in obstructed MIF +/+ and MIF -/- kidneys, as assessed by myofibroblast accumulation and proliferation and expression of profibrotic molecules (transforming growth factor-beta 1(TGF-beta1) and collagen). CONCLUSION: These results demonstrate that MIF expression is increased in obstructive nephropathy without affecting kidney leucocyte accumulation or the development of renal fibrosis. This suggests that the progression of renal injury in obstructive nephropathy is independent of MIF.
Animals↗
Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury.
BACKGROUND: Macrophage-mediated renal injury has been implicated in progressive forms of glomerulonephritis; however, a role for macrophages in type 2 diabetic nephropathy, the major cause of end-stage renal failure, has not been established. Therefore, we examined whether macrophages may promote the progression of type 2 diabetic nephropathy in db/db mice. METHODS: The incidence of renal injury was examined in db/db mice with varying blood sugar and lipid levels at 8 months of age. The association of renal injury with the accumulation of kidney macrophages was analyzed in normal db/+ and diabetic db/db mice at 2, 4, 6, and 8 months of age. RESULTS: In db/db mice, albuminuria and increased plasma creatinine correlated with elevated blood glucose and hemoglobin A1c (HbA1c) levels but not with obesity or hyperlipidemia. Progressive diabetic nephropathy in db/db mice was associated with increased kidney macrophages. Macrophage accumulation and macrophage activation in db/db mice correlated with hyperglycemia, HbA1c levels, albuminuria, elevated plasma creatinine, glomerular and tubular damage, renal fibrosis, and kidney expression of macrophage chemokines [monocyte chemoattractant protein-1 (MCP-1), osteopontin, migration inhibitory factor (MIF), monocyte-colony-stimulating factor (M-CSF)]. The accrual and activation of glomerular macrophages also correlated with increased glomerular IgG and C3 deposition, which was itself dependent on hyperglycemia. CONCLUSION: Kidney macrophage accumulation is associated with the progression of type 2 diabetic nephropathy in db/db mice. Macrophage accumulation and activation in diabetic db/db kidneys is associated with prolonged hyperglycemia, glomerular immune complex deposition, and increased kidney chemokine production, and raises the possibility of specific therapies for targeting macrophage-mediated injury in diabetic nephropathy.
Animals↗