Combined interleukin 1 and tumour necrosis factor α blockade in rat crescentic anti-glomerular basement membrane glomerulonephritis

SUMMARY: Studies in experimental models have established that blockade of either interleukin 1 (IL‐1) or tumour necrosis factor α (TNF‐α) is effective in suppressing crescentic glomerulonephritis. However, it is not known whether simultaneous blockade of both cytokines will provide additional disease suppression compared with that produced by single cytokine blockade. We have addressed this question in a study of accelerated crescentic anti‐glomerular basement membrane (GBM) glomerulonephritis in the rat. Groups of six animals were treated with an IL‐1 receptor antagonist (IL‐1ra), TNF‐α‐binding protein (TNFbp), IL‐1ra + TNFbp (combined) or saline (control) from the time of anti‐GBM serum injection until being killed, 10 days later. Saline‐treated animals developed crescentic glomerulonephritis with tubulointerstitial damage, heavy proteinuria and renal impairment. Compared with saline, treatment with either IL‐1ra or TNFbp alone resulted in significant suppression of crescent formation (3.0% and 3.3%, respectively, vs. 21.0%; both P < 0.001 vs. control), tubulointerstitial leucocytic infiltration (262 ± 31 and 282 ± 32 cells/mm² vs. 481 ± 71 cells/mm²; both P < 0.001 vs. control) and proteinuria (167 ± 44 and 164 ± 23 mg/24 h vs. 279 ± 36 mg/24 h; both P < 0.001 vs. control) and prevented the loss of renal function. Combined IL‐1ra and TNFbp treatment resulted in a virtually identical degree of disease suppression as individual cytokine blockade in terms of crescent formation (2.7%), interstitial leucocytic infiltration (274 ± 45 cells/mm²), proteinuria (190 ± 18 mg/24 h) and renal function preservation. In conclusion, this study has demonstrated that blockade of either IL‐1 or TNF‐α alone substantial suppresses experimental crescentic glomerulonephritis to a similar extent to that achieved by simultaneous blockade of both cytokines. These findings provide a rationale for the use of cytokine monotherapy, rather than multiple cytokine blockade, in the treatment of human crescentic glomerulonephritis.     

The role of platelet‐derived growth factor in a murine model of crescentic nephritis

SUMMARY Platelet‐derived growth factor (PDGF) is a major mesenchymal cell mitogen, with an established role in the pathogenesis of experimental mesangial proliferative nephritis. The role of PDGF in experimental models of crescentic glomerulonephritis is not well defined. To study the role of PDGF in glomerular crescent formation, we induced a model of crescentic glomerulonephritis in transgenic mice expressing high concentrations of the soluble external domain of the PDGFβ receptor (PDGF‐Rβ). Crescentic nephritis was induced by the intraperitoneal injection of antibody to whole rabbit glomeruli. At day 7 of disease, biopsies of transgenic and wild‐type mice were evaluated for crescent frequency, crescent area, and thickness of crescent cell layer. In situ hybridization was performed to evaluate the expression of both PDGF B‐chain and PDGFRβ mRNA within crescents. Delivery of soluble receptor to the urinary space was evaluated by Western blotting. Crescent frequency did not differ between wild type and transgenic mice. However, crescent area quantified by computer image analysis was significantly reduced in transgenic mice (P < 0.015). Transgenic biopsies displayed predominantly crescents composed of two cell layers (P = 0.03 compared with wild type), whereas wild‐type biopsies had significantly more crescents composed of four or more cell layers (P = 0.04). Both PDGF B‐chain and PDGF‐Rβ mRNA were detected within crescents in a heterogeneous fashion. Soluble receptor was detectable in the urine of all transgenic diseased mice. We conclude that PDGF plays a role in modulating crescent size and development in our murine model of crescentic nephritis.     

Effect of Sairei-to on irreversible glomerular sclerotic lesions in rats

The effects of Sairei-to and its active components on a model of irreversible mesangial proliferative glomerulonephritis induced by injecting monoclonal antibody (MoAb) 1-22-3 into uninephrectomized rats were examined. The significant suppressive effects of Sairei-to and its active components on proteinuria were demonstrated on days 7, 14, 21 after MoAb 1-22-3 injection compared with phosphate-buffered saline (PBS)-treated controls. On day 21, light microscopy revealed that the drugs reduced mesangial cell proliferation, mesangial matrix expansion (matrix score: 84.5±41.6 for Sairei-to, 76.1±31.9 for Syo-saiko-to, 66.7±46.3 for its three components vs 162.4±26.1 for PBS, P<0.005) and crescent formation (mean percentage: 2.25% for Sairei-to, 1.71% for Syo-saiko-to, 1.43% for its three components vs 18.86% for PBS, P<0.005). The kidney weights of the groups given the drugs were significantly lower than the PBS group value (1.03±0.08 g with Sairei-to, 1.11±0.12 g with Syo-saiko-to, 1.06±0.12 g with its three components vs 1.39±0.20 g with PBS, P<0.01 or P<0.05). Immunofluorescence analysis revealed that the drugs suppressed the expression of transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA) and collagen type I in the glomeruli, and reduced the numbers of ED1-positive cells in the glomeruli and OX8-positive cells in the glomeruli and in the tubular interstitium. The blood biochemistry results revealed significant differences between the total cholesterol levels (70.0±5.9 mg/dL with Sairei-to, 66.0±6.4 mg/dL with Syo-saiko-to, 76.6±8.4 mg/dL with its three components vs 104.3±26.6 mg/dL with PBS, P<0.05). We conclude that Sairei-to and its active components have suppressive effects on proteinuria and mesangial matrix expansion in rats with irreversible renal sclerosis. Transforming growth factor-β, collagen type I and α-SMA expression and infiltration by ED1- and OX8-positive cells were also suppressed by these drug preparations.     

Smad7 gene therapy ameliorates an autoimmune crescentic glomerulonephritis in mice

Autoimmune crescentic glomerulonephritis is characterized by severe immune response with glomerular crescentic formation and fibrosis in the kidney. Recent studies indicate that overexpression of renal Smad7 attenuates both renal fibrosis and inflammation in rat remnant kidney. However, little attention has been paid to the potential role of TGF-beta/Smad signaling in autoimmune kidney disease. This study tested the hypothesis that blocking TGF-beta signaling by overexpression of Smad7 may have a therapeutic effect in a mouse model of autoimmune crescentic glomerulonephritis that was induced in C57BL/6 x DBA/2J F1 hybrid mice by giving DBA/2J donor lymphocytes. Smad7 gene was transfected into the kidney using the ultrasound-microbubble-mediated system. Results showed that overexpression of Smad7 blocked both renal fibrosis and inflammatory pathways in terms of Smad2/3 and NF-kappaB activation (P < 0.01), thereby inhibiting alpha-smooth muscle actin; collagen I, III, and IV accumulation; and expression of inflammatory cytokines (IL-1beta and IL-6), adhesion molecule/chemokine (intercellular adhesion molecule-1, monocyte chemoattractant protein-1), and inducible nitric oxide synthase (all P < 0.01). Leukocyte infiltration (CD4(+) cells and macrophages) was also suppressed (P < 0.005). Severe histologic damage (glomerular crescent formation and tubulointerstitial injury) and functional injury including proteinuria were significantly improved (all P < 0.05). This study provides important evidence that overexpression of Smad7 may have therapeutic potential for autoimmune kidney disease.     

Plasminogen activator inhibitor-1 is a significant determinant of renal injury in experimental crescentic glomerulonephritis

Crescentic glomerulonephritis is characterized by glomerular fibrin deposition, and experimental crescentic glomerulonephritis has been shown to be fibrin-dependent. Net fibrin deposition is a balance between activation of the coagulation system causing glomerular fibrin deposition and fibrin removal by the plasminogen-plasmin (fibrinolytic) system. Plasminogen activator inhibitor-1 (PAI-1) inhibits fibrinolysis by inhibiting plasminogen activators and has effects on leukocyte recruitment and matrix deposition. To test the hypothesis that the presence of PAI-1 and its levels were a determinant of injury in crescentic glomerulonephritis, accelerated anti-glomerular basement membrane glomerulonephritis was induced in mice genetically deficient in PAI-1 (PAI-1 -/-), PAI-1 heterozygotes (PAI-1 +/-), and mice engineered to overexpress PAI-1 (PAI-1 tg). Compared with strain-matched genetically normal animals, PAI-1 -/- mice with glomerulonephritis developed fewer glomerular crescents, less glomerular fibrin deposition, fewer infiltrating leukocytes, and less renal collagen accumulation at day 14 of disease. The reduction in disease persisted at day 28, when injury had become more established. In contrast, mice overexpressing the PAI-1 gene (PAI-1 tg), that have basal plasma and renal PAI-1 levels several times, normal developed increased glomerular crescent formation, more glomerular fibrin deposition, increased numbers of infiltrating leukocytes, and more renal collagen at both time points. These studies demonstrate that PAI-1 is a determinant of glomerular fibrin deposition and renal injury in crescentic glomerulonephritis.     

Up-regulation of ICAM-1 and VCAM-1 expression during macrophage recruitment in lipid induced glomerular injury in ExHC rats

Summary: A number of studies have demonstrated an important role for macrophages (Mo) in lipid induced glomerular injury; however, little is known of the mechanisms which facilitate Mo infiltration in this disease. the present study examined the expression of adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) during the development of glomerular Mo infiltration in ExHC rats; a strain which is susceptible to lipid induced glomerular injury. Twenty-five male 6 week old ExHC rats were placed on a normal diet supplemented with 3% cholesterol, 0.6% sodium cholate and 15% olive oil (high-cholesterol diet, HCD). Groups of five rats were killed prior to the beginning of the HCD or after 3 days, 1, 2 and 6 weeks on a HCD. A group of five matched ExHC rats on a normal diet served as a control. ExHC rats fed a HCD showed marked hypercholesterolaemia in the absence of any increase in plasma triglyceride levels from day 3 (190 ± 14 vs 42 ± 2 mg/dL in control; mean ± s.e.m., P<0.01), and developed mild proteinuria (21.9 ± 2.7 vs 5.2 ± 0.5 mg/24 h in control; P<0.01) and segmental glomerular lesions at week 6. Immunoperoxidase staining identified a significant increase in glomerular ED1⁺Mo at week 1 (2.0 ± 0.2 vs 1.0 ± 0.1 ED1⁺Mo/glomerular cross-section in control, P<0.01) which was further increased at week 6 (6.9 ± 0.4 ED1⁺Mo/gcs). There was also a significant increase in glomerular cells expressing the adhesion molecule ligands lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4). Coincident with Mo infiltration, there was an increase in the intensity of glomerular ICAM-1 protein expression as shown by antibody staining. In addition, northern blot analysis of cortical RNA and in situ hybridization demonstrated an increase in glomerular ICAM-1 and VCAM-1 mRNA expression from day 3 onwards. In conclusion, these results suggest that both ICAM-1/LFA-1 and VCAM-1/VLA-4 interactions play an important role in Mo recruitment and accumulation during the development of lipid induced glomerular injury.     

Fibrin independent proinflammatory effects of tissue factor in experimental crescentic glomerulonephritis

BACKGROUND: Tissue factor initiated glomerular fibrin deposition is an important mediator of injury in crescentic glomerulonephritis. Recent data have suggested noncoagulant roles for tissue factor in inflammation. METHODS: To test the hypothesis that in addition to its effects in initiating coagulation, tissue factor has proinflammatory effects in glomerulonephritis, rabbits given crescentic anti-glomerular basement membrane (GBM) antibody-induced glomerulonephritis were defibrinogenated with ancrod. One group of defibrinogenated rabbits was also given anti-tissue factor antibodies. Comparisons were made between these groups, as well as a third group that was neither defibrinogenated with ancrod nor given anti-tissue factor antibodies. RESULTS: Defibrinogenation alone abolished glomerular fibrin deposition, reduced crescent formation, and limited renal impairment (ancrod-treated, serum creatinine 274 +/- 37 micromol/L; untreated 415 +/- 51 micromol/L; P < 0.01). Tissue factor inhibition in defibrinogenated rabbits resulted in further protection of renal function (creatinine 140 +/- 19 micromol/L, P < 0.01) and reduced proteinuria (0.4 +/- 0.2g/day, untreated 2.6 +/- 0.4 g/day, P <0.01), which was significantly increased by defibrinogenation alone (ancrod-treated, 5.6 +/- 1.2 g/day). Anti-tissue factor antibodies (but not defibrinogenation alone) attenuated glomerular T-cell and macrophage recruitment, and major histocompatibility complex (MHC) class II expression. CONCLUSION: These results demonstrate important proinflammatory effects of tissue factor in crescentic glomerulonephritis that are fibrin independent and provide in vivo evidence for tissue factor's proinflammatory effects on MHC class II expression and leukocyte accumulation.     

Clinical evaluation of chronic nephrotoxicity of long-term cyclosporine A treatment in adult patients with steroid-dependent nephrotic syndrome

Aim: Chronic nephrotoxicity of long‐term cyclosporine A (CsA) treatment is a matter of concern in patients with steroid‐dependent nephrotic syndrome (SDNS). Methods: Twenty‐eight adult NS patients (25, minimal‐change nephrotic syndrome (NS); three, focal‐segmental glomerulosclerosis) were divided into three groups. Group A was continuously treated with CsA for more than 5 years (143 ± 40 months, 1.3 ± 0.4 mg/kg per day at final analysis, n = 12); group B had been previously treated with CsA (70 ± 27 months, n = 6); and group C had been treated with corticosteroids alone (n = 10). The clinical variables related to chronic CsA nephrotoxicity were examined. Results: In groups A and B, estimated glomerular filtration rate decreased from 86 ± 22 and 107 ± 17 to 83 ± 23 and 88 ± 13 mL/min per 1.73 m², respectively, at final analysis (both P < 0.05). Serum magnesium levels in group A were significantly lower than those in group B or C (A, 1.78 ± 0.16 mg/dL; B, 2.00 ± 0.14 mg/dL; C, 2.03 ± 0.10 mg/dL; A vs B, C, P < 0.01), and a significant correlation between these and the duration of CsA treatment was found (r = ?0.68, P < 0.001). There was a trend towards a correlation between the duration of CsA administration and urinary α1‐microglobulin (r = 0.38, P = 0.07). Conclusion: Mild decrease in renal function and hypomagnesemia were found in adult SDNS patients with long‐term CsA treatment. Careful monitoring of renal function, blood pressure and serum magnesium levels is necessary.     

Comparison of the effects of Puumala and Dobrava viruses on early and long‐term renal outcomes in patients with haemorrhagic fever with renal syndrome

Aim: The clinical course and outcome of patients with haemorrhagic fever with renal syndrome (HFRS) caused by Puumala (PUUV) and Dobrava viruses (DOBV) were analyzed and whether it left long‐term consequences on kidney function after 10 years was evaluated. Methods: Cross‐sectional studies were conducted to test the kidney function and blood pressure of HFRS‐affected patients and to follow them up 10 years after. Eighty‐two PUUV‐ and 53 DOBV‐induced HFRS patients and 14 and 31 participants 10 years after having contracted PUUV‐ and DOBV‐related diseases, respectively were evaluated. Results: Serum creatinine concentrations were 279.5 and 410 mcmol/L in PUUV and DOBV groups, respectively (P = 0.005). There were six and 13 anuric (P < 0.05), none and seven dialysis‐dependant (P < 0.05), and nine and 18 hypotensive patients (P < 0.05) in PUUV and DOBV groups, respectively. After 10 years, glomerular filtration rates were 122.1 ± 11.1 and 104.7 ± 20.2 mL/min (P < 0.05) in PUUV and DOBV groups, respectively. Conclusion: During the acute phase, DOBV causes more severe renal impairment than PUUV infection. After 10 years follow up, renal function was found within normal limits, although after DOBV infection glomerular filtration rate (GFR) was significantly lower than after PUUV infection.     

Antibody blockade of TNF-alpha reduces inflammation and scarring in experimental crescentic glomerulonephritis

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine produced by macrophages, and by renal mesangial and tubular epithelial cells. It stimulates the release of interleukin (IL)-1beta, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta (TGF-beta). Blockade of TNF-alpha is currently used clinically in several autoimmune inflammatory diseases. We hypothesised that blocking TNF-alpha with a monoclonal antibody would prevent inflammation and renal fibrosis in crescentic glomerulonephritis. METHODS: Nephrotoxic nephritis was induced in Wistar Kyoto (WKY) rats by intravenous injection of rabbit antirat glomerular basement membrane (GBM) nephrotoxic serum (NTS). Anti-TNF-alpha monoclonal antibody or saline was given intraperitoneally three times per week in four protocols: experiment 1, days 0 to 7; experiment 2, days 0 to 14 and days 4 to 14; experiment 3, days 4 to 28; and experiment 4, days 14 to 28. RESULTS: In experiment 1, rats treated from disease induction had less glomerular fibrinoid necrosis and fewer glomerular macrophages at day 7. In experiment 2, rats treated from day 0 or day 4 showed improved renal function, as judged by serum creatinine, with a significant reduction in crescents. In experiment 3, anti-TNF-alpha treatment significantly reduced urine protein to creatinine ratio and urinary MCP-1 levels. Serum creatinine was preserved at both day 14 and day 28. Tubulointerstitial inflammation, glomerular and tubulointerstitial scarring, and markers of fibrosis [alpha-smooth muscle actin (alpha-SMA) and type IV collagen] were significantly less in treated rats at day 28. In experiment 4, serum creatinine was higher and tubulointerstitial scarring was less in delayed-treated animals. CONCLUSION: Neutralization of endogenous TNF-alpha reduces glomerular inflammation, crescent formation, and tubulointerstitial scarring, with preservation of renal function, in experimental crescentic glomerulonephritis. TNF-alpha blockade is effective even when introduced at the time of maximum glomerular inflammation.     

Prevention and treatment of experimental crescentic glomerulonephritis by blocking tumour necrosis factor-alpha.

BACKGROUND: The mechanisms controlling progression of glomerulonephritis are poorly understood, but there is increasing evidence that tumour necrosis factor-alpha (TNF-alpha) plays a central role in many aspects of glomerular inflammation and scarring. We investigated the role of TNF-alpha in an experimental model of crescentic glomerulonephritis in Wistar Kyoto (WKY) rats by continuously blocking endogenous TNF-alpha, using its soluble receptor sTNFr p55, both before and after establishment of nephritis. METHODS: Glomerulonephritis was induced by a single intravenous injection of 0.1 ml nephrotoxic serum. In the first experiment, rats were pre-treated with sTNFr p55 2 mg/kg intraperitoneally 1 hour before induction of nephritis and on a daily basis thereafter until day 4. In the second experiment, a similar protocol was followed, but treatment with sTNFr p55 was continued until day 10. In the third experiment, treatment with sTNFr p55 was delayed until 4 days after induction of nephritis and continued until day 10. The effects of treatment on renal function, renal histology, cellular infiltration, activation and proliferation, and IL-1beta expression were assessed by standard methods. RESULTS: In the first experiment, short-term treatment with sTNFr p55 caused a marked reduction in albuminuria and fibrinoid necrosis. It also reduced glomerular cell infiltration, activation and proliferation. In the second experiment, prolonged treatment with sTNFr p55 caused a sustained reduction in albuminuria and all histological and cellular parameters of glomerular inflammation; in particular it completely prevented the development of crescents. In the third experiment, delayed therapy of established nephritis with sTNFr p55 significantly reduced albuminuria and glomerular inflammation, including the prevalence of crescent formation. In both long-term experiments, there was less glomerular expression of IL-1beta and lower serum concentrations of IL-beta in sTNFr p55-treated rats. CONCLUSIONS: This study shows that neutralization of endogenous TNF-alpha is effective in preventing acute glomerular inflammation and crescent formation, and in treating established disease, in a rat model of crescentic nephritis. These results may have therapeutic implications for human glomerulonephritis.     

Pentoxifylline suppresses renal tumour necrosis factor-alpha and ameliorates experimental crescentic glomerulonephritis in rats.

BACKGROUND: Crescentic glomerulonephritis is a rapidly progressive form of glomerulonephritis, but treatment remains non-specific. The methylxanthine derivative pentoxifylline (PTX) is a clinically available phosphodiesterase inhibitor with anti-inflammatory and immunoregulatory activities. This study examined whether PTX has beneficial effects in a rat model of anti-glomerular basement membrane (GBM) crescentic glomerulonephritis. METHODS: Experimental crescentic glomerulonephritis was induced in Wistar rats by intravenous injection of rabbit anti-rat GBM serum and treated with either vehicle (phosphate-buffered saline) or PTX (0.1 g/kg/day) intravenously on a daily basis. Groups of six animals were euthanized at days 3, 7, 14 or 28 after induction of disease. Effects of PTX on renal function, histology and expression of cytokines, chemokines and adhesion molecules were determined. RESULTS: Compared with the vehicle-treated nephritic rats, PTX treatment beginning at the start of the nephritis significantly suppressed mRNA expression of tumour necrosis factor (TNF)-alpha, but not interleukin-1 beta, throughout the course of nephritis. Moreover, PTX decreased renal mRNAs for intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted (RANTES) and osteopontin (OPN) at all time points examined. These effects were associated with a significant inhibition of macrophage and T-cell infiltration, a reduction of 24-h urinary protein excretion (50-75%, P<0.05), an improvement of histological damage including glomerular crescent formation (60-70%, P<0.01) and a decrease of cortical mRNAs for type I (alpha 1) collagen and fibronectin. The efficacy of PTX could also be seen, though to a lesser extent, in rats with established nephritis. CONCLUSIONS: PTX is an effective anti-inflammatory and immunomodulatory agent capable of suppressing rat crescentic glomerulonephritis. Inhibition of renal TNF-alpha, ICAM-1, RANTES, MCP-1 and OPN expression may be a mechanism whereby PTX suppresses progressive renal injury in rat crescentic glomerulonephritis.     

Hypertension in stroke patients: Relationship with hyperinsulinaemia

Summary: In an attempt to determine the presence of hypertension in stroke patients and its relationship with hyperinsulinaemia, a case-control study was carried out in the outpatients clinic, Department of Neurology, Sardjito General Hospital, Yogyakarta. Patients included in the study were those who had survived a stroke at least 3 months after the first attack. the exclusion criteria included: diabetes mellitus, renal failure, heart failure, malignancy, myocardial infarction, current antihypertensive and hypolidaemic treatment. Controls were selected from non-stroke patients at the same department matching for sex and age. During the study 51 stroke patients (39 male and 12 female, aged 58.7 ± 10.3 years) and 51 controls (40 male and 11 female, aged 58.6 ± 9.8 years). There were no significant differences in baseline clinical characteristics; namely, smoking, body mass index, blood sugar and blood lipids except triglyceride (169 ± 61 vs 141 ± 60 P<0.05) of cases and controls. Although there was no significant difference of fasting plasma insulin levels (9.3 ± 8.3 vs 8.3 ± 2.6 mU/L, P= >0.05), significantly higher levels of postprandial insulin (94.8 ± 86.7 vs 55.2 ± 49.1 mU/L, P<0.05) were found in cases than controls. There were a significantly higher levels of blood pressure, both systolic (160 ± 24 vs 131 ± 11 mmHg, P<0.05) and diastolic (101 ± 13 vs 79 ± 4 mmHg, P<0.05), and more frequent hypertension defined as BP ± 140/90 mmHg (72.5 vs 2.0%, P<0.05) in cases than controls. No significant difference of plasma insulin levels (94.9 ± 82.3 vs 94.3 ± 119.2 mU/L, P>0.05) between hypertensive and normotensive stroke patients. However, significantly higher levels of insulin (94.3 ± 119.2 mU/L vs 55.2 ± 49.1 mU/L, P<0.05) were found in normotensive stroke patients than controls. the relationship between 2 h post-prandial blood sugar levels and post-prandial insulin levels was positive and nearly significant relationship (r=0.62, P=0.05). the relationship between mean arterial pressure (MAP) and post-prandial insulin levels of the whole patients (cases and controls) were poor but significant (r = 0.22, P<0.05). the relationship between MAP and post-prandial insulin levels are poor and not significant both in stroke patients (r = 0.00, P>0.05) and controls (r = 0.17, P>0.05). the slope of both curves in both scattered diagrams seemed to be slightly different. We conclude that hypertension and post prandial hyperinsulinaemia may play a role in the genesis of stroke, while hyperinsulinaemia may an independent factor.     

Dyslipidaemia in patients with lupus nephritis

Aim: There is little data on the prevalence and severity of dyslipidaemia in Asian patients with lupus nephritis (LN). Whether the dyslipidaemia in LN patients differs from subjects with comparable levels of renal impairment also remains undefined. Methods: Lipid profiles of 100 Chinese patients with quiescent LN (age 46.3 ± 9.3 years, 83% female, maintenance prednisolone dose 5.80 ± 2.43 mg/day) were studied and compared with 100 controls who had non‐lupus non‐diabetic chronic kidney diseases (CKD), matched for sex, age and renal function. Results: LN patients and CKD controls had similar renal function and proteinuria, while blood pressure was higher in controls. Twenty‐five percent of LN patients and 17% of controls were receiving statin treatment. Despite this, 59% of LN patients and 46% CKD controls showed abnormal lipid parameters (P = 0.066). LN patients showed higher levels of total cholesterol (TC) and triglycerides (TG) than controls (5.28 ± 0.12 vs 4.86 ± 0.08 mmol/L, P = 0.004; and 1.62 ± 0.12 vs 1.20 ± 0.07 mmol/L, P = 0.002, respectively). More LN patients had abnormal TC, TG or low‐density lipoprotein cholesterol (LDL‐C) (54%, 16% and 38%; P = 0.016, = 0.005 and = 0.021, respectively). Hydroxychloroquine (HCQ) treatment was associated with lower TC, LDL‐C and HDL‐cholesterol. Conclusion: Dyslipidaemia is prevalent in LN patients and is more severe than controls with a similar degree of CKD despite disease quiescence, low steroid dose and low level of proteinuria. Concomitant corticosteroid and renal impairment are likely contributing factors. HCQ treatment is associated with reduced severity of dyslipidaemia in LN patients.     

Prospective study of progression of kidney dysfunction in community-dwelling older adults

Aim: Few prospective studies have assessed renal dysfunction in older persons. We sought to define kidney dysfunction among a community‐based cohort of elderly subjects and to determine the factors for its progression. Mehtods: The Epidemiologia do Idoso (EPIDOSO) Study is a prospective study of individuals ≥65 years old (mean 72.6 ± 0.3), living in the community in the city of São Paulo. The creatinine clearance (CrCl) of 269 individuals of this cohort was estimated during 8 years of follow‐up. The rate of decline in CrCl was calculated using linear regression analysis and dividing the group into tertiles of CrCl change. Results: Overall mean change in CrCl was ?2.37 ± 0.23 mL/min per year. Mean age increased with the greatest degree of decline in renal function (71.1 ± 0.59, 72.5 ± 0.54 and 74.3 ± 0.58, for the first, second and third CrCl change tertiles, respectively, P < 0.01). A higher value of baseline CrCl was associated with progressive decline in CrCl (P < 0.01). Diastolic BP was greater in the second versus the first estimated glomerular filtration rate tertile (83 ± 1 vs 80 ± 1 mmHg, P < 0.05). High‐density lipoprotein (HDL) cholesterol was inversely associated with CrCl decline (P < 0.05). Conclusion: Progression of kidney dysfunction occurs in most community‐dwelling elderly. Strategies aimed at slowing the progression should be considered for possible risk factors of older age, baseline CrCl, BP and HDL.     

Type IV phosphodiesterase inhibitor is effective in prevention and treatment of experimental crescentic glomerulonephritis

BACKGROUND: Tumour necrosis factor alpha (TNF-alpha) has an important role in acute glomerular inflammation. Rolipram, a type IV phosphodiesterase inhibitor, has multiple anti-inflammatory effects including inhibition of TNF-alpha synthesis. METHODS: We investigated the effects of rolipram in prevention and delayed treatment of crescentic glomerulonephritis in Wistar Kyoto rats. Glomerulonephritis was induced by injection of nephrotoxic serum. RESULTS: In the preventive study, rolipram (6.25 mg/kg i.p. twice daily) was started 2.5 h before injection of nephrotoxic serum. Rolipram reduced the expression of TNF-alpha in glomeruli and renal tubules and abrogated glomerular injury on day 4 (99.7% reduction in albuminuria and 96.4% reduction in fibrin deposition). In the delayed-treatment experiment, rolipram was started 4 days after injection of nephrotoxic serum. Rolipram reduced renal excretion of TNF-alpha by 63% on day 7. TNF-alpha was not detected in the sera of treated or control rats. Delayed treatment was effective in crescentic glomerulonephritis, as shown by reduction in albuminuria by 38.1%, fibrin deposition by 60.8%, and crescent formation by 67% on day 7. CONCLUSIONS: Rolipram is effective both in prevention and treatment of experimental crescentic glomerulonephritis. This was associated with a reduction of renal production of TNF-alpha.     

Paraneoplastic polymyositis associated with crescentic glomerulonephritis

A female concurrently developed polymyositis (PM), lung cancer, and nephrotic range proteinuria. Renal biopsy revealed crescentic glomerulonephritis. Pathology of lung cancer was proved to be adenocarcinoma. After surgical treatment of lung cancer, the symptoms of PM-associated crescentic glomerulonephritis disappeared. PM is associated with a higher risk of malignancy, though renal involvement in patients with PM is thought to be uncommon. In patients with PM, there have been few reports concerning the coexistence of glomerular disease, including crescent glomerulonephritis. Herein we report a case of crescentic glomerulonephritis-associated PM that was successfully treated after the surgical removal of lung cancer. We consider that such association of PM and crescent glomerulonephritis is rare in adults. Careful evaluation of underlying malignancy is important. The definite treatment is adequate management of underlying malignancy.