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Eberhard Ritz

Publications and source records attributed to Eberhard Ritz.

At least 127 records · Page 7Linked to original sources
PubMed2002

The epidemiology of end-stage renal disease in Iran in an international perspective.

INTRODUCTION: The epidemiology of end-stage renal disease (ESRD) and renal replacement therapy (RRT) is under continuous evolution all over the world. We report here the epidemiological analysis of ESRD and RRT in Iran and discuss it against the background of the international situation. METHODS: This epidemiological report is based on data from centre questionnaires which were collected in Iran from 1997 onwards, with a response rate of 100%. RESULTS: The prevalence/incidence of RRT patients were 238/49.9 p.m.p. in the year 2000. Haemodialysis and kidney transplantation were the most common RRT modalities, accounting for 53.7% and 45.5% of prevalent RRT patients, respectively. The proportion treated by peritoneal dialysis was very low (<1%). Home haemodialysis was not performed. The majority of haemodialysis centres used synthetic membranes (70%) and 100% of the sessions were performed using acetate as a buffer; 42.5% of haemodialysis patients were treated with a twice-weekly regimen, whilst 49.6% were on the standard thrice-weekly regimen. The majority of RRT patients in Iran were young to middle aged. The great majority of renal allografts came from living donors (mainly unrelated to recipients). The main renal diseases leading to ESRD were diabetes and hypertension. The third most common category was "cause unknown". CONCLUSION: The epidemiology of RRT in Iran is characterized by: (i) young patient age (younger than the international average); (ii) high proportion of patients receiving renal allograft; (iii) use of living-unrelated donors as the major source of renal allografts.

Adolescent↗
PubMed2002

Nutritional status in dialysis patients: a European consensus.

BACKGROUND: Malnutrition is common in dialysis patients and closely related to morbidity and mortality. Therefore, assessment of nutritional status and nutritional management of dialysis patients play a central role in everyday nephrological practice. METHODS: Achieving a consensus on key points relating to pathogenesis, clinical assessment, and nutritional management of dialysis patients. RESULTS: The assessment of nutritional status should be based on clinical assessment and biochemical parameters, including history of weight loss, per cent standard weight, body mass index, muscle mass, subcutaneous fat mass, and plasma albumin, creatinine, bicarbonate and cholesterol. Co-morbid conditions should be assessed and C-reactive protein (CRP) measured--as a marker of inflammation--as there is a close relation between malnutrition, on one side, and co-morbid conditions and inflammation on the other. For a more detailed assessment, subjective global assessment of nutritional status is a well-validated tool, and dual-energy X-ray absorptiometry (DEXA) is a useful method for routine assessment of lean body mass. Anthropometric methods are also useful. They are cheap and easy to apply, although less precise than DEXA. The recommended daily protein intake is at least 1.2 g/kg standard body weight and the energy intake 35 kcal/kg standard body weight (BW), in patients <60 years, and 30 kcal/kg standard BW in patients >60 years. The standard bicarbonate level should be at least 22 mmol/l. If CRP is >10 mg/l, it is important to seek and treat the underlying cause. Adequate dialysis (for haemodialysis: Kt/V >1.2) should be ensured and, although no definite evidence of the importance of dialysis water quality is available, the opinion of the authors is that the water quality should be high. The role of the biocompatibility of the dialysis membrane is still not clear. The dietitian plays a pivotal role in the nutritional care of dialysis patients, and patients should be provided with dietary counselling from the start of substitutive treatment in order to meet the recommended nutritional intakes. Dietary counselling can also play an important role in an integrated treatment of hyperphosphataemia, although most patients will also need phosphate binders if they have an adequate protein intake. CONCLUSION: Malnutrition assessment and treatment is a great challenge for nephrological care. Achieving evidence-based consensus can help in implementing the progress of knowledge in clinical practice.

Body Mass Index↗
PubMed2002

Management of disturbances of calcium and phosphate metabolism in chronic renal insufficiency, with emphasis on the control of hyperphosphataemia.

BACKGROUND: Disturbances of calcium-phosphate (Ca-P) metabolism in chronic renal insufficiency (CRI) play an important role not only in bone disease (renal osteodystrophy) but also in soft tissue calcification, with an increased risk of vascular calcification, arterial stiffness, and worsening of atherosclerosis. METHODS: Discussion in order to achieve a consensus on key points relating to pathogenesis, clinical assessment, and management of renal osteodystrophy in dialysis patients. RESULTS: Secondary hyperparathyroidism develops primarily as a consequence of reduced active vitamin D production by the kidneys and phosphate retention, with the development of hyperphosphataemia, hypocalcaemia, and increased parathyroid hormone (PTH) levels. The same factors over the long term cause parathyroid gland hyperplasia and autonomous PTH production (tertiary hyperparathyroidism). As hyperphosphataemia and increased CaxP product have been associated with increased mortality in dialysis patients, hyperparathyroidism should be prevented and managed, starting in the pre-dialysis period, by calcium/vitamin D supplementation. Hyperphosphataemia is usually treated by means of intestinal phosphate binders, but different types of binders have been used. The traditional aluminium-based phosphate binders are certainly effective, but have the drawback of side effects due to aluminium absorption (osteomalacia, encephalopathy, microcytic anaemia). Calcium-containing phosphate binders (calcium carbonate or calcium acetate) have mainly been used for the last 10-15 years. However, they aggravate metastatic calcification, particularly if they are taken together with vitamin D analogues and a high calcium dialysate concentration. New calcium- and aluminium-free phosphate binders have recently been developed and may be useful, particularly in patients with metastatic calcification and/or hypercalcaemic episodes, in order to reduce the phosphate burden in the absence of an additional calcium load. New vitamin D analogues and calcimimetic drugs are also being developed for PTH suppression, with the goal to minimize or even entirely avoid hypercalcaemia and/or hyperphosphataemia. A suitable dialysate calcium concentration is important and must take into consideration the medical therapy and the calcium balance on an individual patient basis. Surgical parathyroidectomy is the ultimate means of treating hypercalcaemic hyperparathyroidism, when medical therapy has failed. CONCLUSION: Achieving an evidence-based consensus can give clinicians a useful tool for the treatment of disturbances of Ca-P metabolism in CRI: this has become an important objective in nephrological care, particularly as ageing and increased risk of atherosclerosis have become major issues in the dialysis population.

Bone Diseases↗
PubMed2002

Combination treatment with an ET(A)-receptor blocker and an ACE inhibitor is not superior to the respective monotherapies in attenuating chronic transplant nephropathy in a 'Fisher-to-Lewis' rat model.

BACKGROUND: Specific endothelin A (ET(A))-receptor blockade and ACE inhibition attenuate chronic transplant nephropathy (CTN) in the 'Fisher-to-Lewis' rat model. It is unknown (i) which of both pharmacological interventions attenuates CTN more effectively and (ii) whether combination therapy exerts additive nephroprotection. METHODS: We compared (i) the effects of specific ET(A)-receptor blockade with LU 302146 (30 mg/kg bw/day) and ACE inhibition with trandolapril (0.3 mg/kg bw/day) and (ii) the effect of a combination therapy of both drugs on the development of CTN. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Untreated 'Fisher-to-Lewis' allografts served as controls (TX). All animals received low-dose cyclosporin A (1.5 mg/kg body weight) for 10 days post-transplant to inhibit early acute rejection episodes. The duration of the experiment was 36 weeks. Blood pressure (BP) was measured every other week by tail plethysmography. Indices of glomerulosclerosis (GS), tubulointerstitial and vascular damage, number of glomeruli, total glomerular volume and mean glomerular volume were measured using morphometric and stereological techniques, respectively. Albuminuria, blood chemistry and haematology were measured at the end of the experiment. RESULTS: LU 302146 did not affect systolic BP. In contrast, trandolapril and combination treatment significantly reduced systolic BP. Histological signs of CTN were almost completely prevented by LU 302146 and trandolapril as compared to TX, e.g. GS=0.8+/-0.08 and 0.9+/-0.20 vs 1.8+/-0.21* (arbitrary unit; *P<0.001 vs treated groups). Allograft weight was significantly lower in treated vs TX animals. Trandolapril and combination therapy, but not LU 302146 alone, abrogated glomerular hypertrophy, i.e. mean glomerular volume: TX 2.22+/-0.43, trandolapril 1.61+/-0.38**, LU 302146 2.22+/-0.11, trandolapril+LU 302146 1.78+/-0.28* (microm(3); *P<0.05 vs control and LU 302146, **P<0.01 vs control and LU 302146). Albuminuria was lower in treated compared to TX animals. Combination therapy did not confer additional benefit compared to the respective monotherapies. CONCLUSIONS: We conclude that ET(A)-receptor blockade abrogates GS, tubulointerstitial and vascular damage in the 'Fisher-to-Lewis' model of CTN to a similar extent as ACE inhibition. However, only ACE inhibition inhibits glomerular hypertrophy. In contrast to ACE inhibition, the effect of ET(A)-receptor blockade is independent of BP. This finding is consistent with the notion that ET(A)-receptor mediated events play a partly BP-independent role in the genesis of CTN. Combination therapy exerts no additive nephroprotection.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

How should we manage anaemia in patients with diabetes?

Anaemia is an important component of diabetic nephropathy but only recently has it attracted the attention of diabetologists and nephrologists. In diabetic patients, anaemia is the result of diminished erythropoietin production and, to a lesser degree, of increased excretion of erythropoietin in the urine, whereas erythropoietin responsiveness remains unchanged. Although erythropoietin concentrations are predictive of the rate of progression of renal disease, epidemiological studies have failed to show lower haemoglobin concentrations in patients with diabetic compared with non-diabetic renal disease with impaired renal function. However, inappropriately low erythropoietin concentrations and anaemia have been reported in subcohorts of diabetic patients. Further studies are required to determine whether reversal of anaemia has beneficial effects on microvascular and macrovascular diabetic complications, particularly cardiac disease, retinopathy and peripheral arterial disease.

Anemia↗
PubMed2002

The renal risks of smoking: an update.

PURPOSE OF REVIEW: Smoking increases the renal risk both in diabetic and in nondiabetic renal disease. The purpose of the present review is to summarize the current state of knowledge about this important remediable renal risk factor. RECENT FINDINGS: The deleterious effect of smoking on renal function extends beyond patients with primary or secondary renal disease and patients with a renal transplant, because recent studies document a relation between smoking and loss of filtration rate, even in cardiovascular high-risk populations without primary renal disease such as the elderly, the patient with severe essential hypertension, or the patient with widespread atherosclerosis. Furthermore, recent studies show that in nondiabetic patients without primary renal disease, albuminuria, a potential surrogate marker of glomerular damage, is correlated with smoking. The mechanisms underlying the adverse renal effects of smoking are still incompletely understood. Beyond its effect on progression of renal failure, smoking is also an important cardiovascular risk factor in the patient with renal failure or the patient with a renal transplant. SUMMARY: Smoking is one of the most important remediable renal risk factors. The exact mechanisms of smoking-induced renal damage remain to be determined. For all the above reasons cessation of smoking should be recommended to renal patients - a recommendation which is infrequently given and even less frequently followed.

Albuminuria↗
PubMed2002

Predictive performance of renal function equations for patients with chronic kidney disease and normal serum creatinine levels.

Accurate renal function measurements are important for the diagnosis and treatment of kidney disease, proper medication dosing, interpretation of possible uremic symptoms, and decision-making regarding when to initiate renal replacement therapy. Because the use of highly accurate filtration markers to measure renal function has traditionally been limited by cumbersome and costly techniques and the involvement of radioactivity (among other factors), renal function is typically estimated by using specially derived prediction equations. These formulae usually use serum creatinine levels, i.e., a marker of filtration that is insensitive to mild/moderate decreases in GFR. Although attempts have been made to validate certain renal function prediction equations among patients with chronic kidney disease (CKD) with abnormal serum creatinine levels, this is the first study to specifically evaluate the predictive performance of these equations for patients with CKD and serum creatinine levels in the normal range. The results of eight prediction equations for 109 patients with CKD and serum creatinine levels of < or =1.5 mg/dl were compared with standard iohexol GFR values. The most accurate results were obtained with the Cockroft-Gault and Bjornsson equations. The most precise formulae were the Modification of Diet in Renal Disease Study equations, although they were highly biased. Even the most accurate results exhibited levels of error that made them suboptimal for clinical treatment of these patients. These results suggest that measurement of GFR with endogenous or exogenous filtration markers might be the most prudent strategy for the assessment of renal function in the CKD population with normal serum creatinine levels. Further studies are needed to confirm the generalizability of these findings for this patient subgroup.

Adult↗
PubMed2002

The effect of donor gender on graft survival.

Differences in actuarial graft survival according to donor gender have been reported for renal allografts and for cardiac and hepatic allografts, but for the latter in small series with limited biostatistical power. Using the large database of the Collaborative Transplant Study (CTS), this study is an evaluation of graft survival according to donor and recipient gender for renal (n = 124,911), cardiac (n = 25,432), and hepatic (n = 16,410) transplants. Confounders, such as calendar year, geographical area, race, donor and recipient age, HLA mismatch, cold ischemia time, and others, as well as interaction terms were taken into consideration. Death-censored actuarial renal allograft survival from female compared with male donors was less in female recipients and even more so in male recipients. The donor gender-associated risk ratio for graft loss was 1.15 in female recipients and 1.22 in male recipients. The age-gender interaction term was statistically significant, the gender effect being more pronounced for younger (16 to 45 yr) compared with older (>45 yr) donors. Serum creatinine concentrations 1 yr after transplantation were also higher for recipients with kidney grafts coming from female donors irrespective of recipient gender. For first cardiac transplants, graft survival was inferior when the donor was female and the recipient male, but no statistical difference according to donor gender was demonstrable in female recipients. For first hepatic transplants overall, no significant differences according to donor gender were noted. The proportion of recipients who had treatment for rejection crisis during the first year was higher for male recipients of kidneys from female donors compared with male donors. No difference according to donor gender was demonstrable in female recipients. For cardiac and hepatic grafts, no significant effect of donor gender on the proportion of patients treated for rejection episodes was noted. The data show that adverse effects of female donor gender for different organs is much less uniform than reported in the past. An important confounder is donor age. A gender effect on graft survival is also observed for cardiac allografts. Therefore, in addition to potential "nephron underdosing," further pathomechanisms must play a role, possibly differences in immunogenicity according to donor gender.

Actuarial Analysis↗
PubMed2002

Retinoid receptor-specific agonists alleviate experimental glomerulonephritis.

Retinoids are potent antiproliferative and anti-inflammatory compounds. We previously demonstrated that the natural pan-agonists all-trans retinoic acid (RA) and 13-cis RA efficiently preserve renal structure and function in rat mesangioproliferative glomerulonephritis. We examine effects of synthetic retinoid receptor-specific agonists 1) to identify common and receptor subtype-specific pathways in this model and 2) to characterize effects of retinoids on the renal endothelin (ET) system. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of agonists specific for retinoid A (Ro-137410) and retinoid X (Ro-257386) receptors and the complex anti-activator protein-1 active retinoid BMS-453 7 days after induction of anti-Thy1.1 nephritis (n = 7-9/group). The different retinoids lowered glomerular ET-1 and ET type A and B receptor gene expression in control and nephritic rats with comparable efficacy. Reduction of glomerular c-Fos and GATA-2 mRNA expression levels suggests downregulation of transcription factors required for ET expression. The different retinoids were similar in their action on the glomerular capillary occlusion score, number of total glomerular cells, and glomerular infiltrating macrophage count. They differed in their ability to normalize blood pressure (Ro-257386 > BMS-453 > arotinoid), albuminuria (BMS-453 > Ro-257386 > arotinoid), and creatinine clearance (arotinoid > BMS-453 > Ro-257386). No signs of toxicity were observed. We conclude that all retinoid agonists with different subtype specificity are highly efficient in reducing renal damage and proliferation of mesangial cells. Retinoid X and A receptor-specific pathways are apparently involved in the antiproliferative, anti-inflammatory, and anti-ET action. Further studies are indicated to define the potential use of retinoid agonists in inflammatory renal disease.

Albuminuria↗
PubMed2002

Altered temporal organization of plasma insulin oscillations in chronic renal failure.

Chronic renal failure (CRF) is associated with mechanistically unexplained impaired insulin sensitivity. Erratic insulin secretory patterns typify other states of insulin resistance. We sought to investigate possible alterations of plasma insulin oscillations in CRF. We assessed high- and low-frequency insulin and glucose oscillations in 7 male CRF patients and 11 controls by multiparametric deconvolution analysis and cluster analysis, approximate entropy (ApEn) statistic, and cross-ApEn statistics. Insulin sensitivity was appraised by euglycemic hyperinsulinemic clamps. Despite impaired glucose disappearance rates in CRF, fasting and 24-h mean insulin and glucose concentrations did not differ between patients and controls. However, patients showed a 2.5-fold increase of insulin elimination half-life, reduced frequency of both rapid (6.1 +/- 0.4 vs. 7.1 +/- 0.2 h(-1), P < 0.001) and slow oscillations of insulin release (0.54 +/- 0.11 vs. 0.71 +/- 0.1 h(-1), P < 0.001), lack of acceleration and paradoxically more orderly slow insulin and glucose pulses after meals, and increased temporal coupling between insulin and glucose patterns (cross-ApEn: 0.58 +/- 0.13 vs. 1.37 +/- 0.23, P < 0.001). Postprandial glucose intolerance was inferable by prolonged and amplified blood glucose excursions despite exaggerated insulin bursts of almost 3-fold higher area. In summary, CRF is associated with a complex disruption of the temporal organization of insulin release, which differs from abnormalities observed to date in other states of insulin resistance.

Adult↗
PubMed2002

Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease.

In patients with uremia, increased blood concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have been linked to the severity of atherosclerosis and to excess cardiovascular mortality. The ADMA levels and several traditional cardiovascular risk factors were assessed in 44 untreated nonsmoking patients with confirmed primary chronic renal disease at different stages of renal disease. True GFR was assessed by means of the inulin-clearance technique. For comparison, nonsmoking subjects matched with respect to age, gender, and body-mass index were examined. Mean plasma ADMA concentration was markedly higher (P < 0.0001) in all patients combined (4.2 +/- 0.9 micromol/L) than in control subjects (n = 16; age 45 +/- 10 yr; serum creatinine 1.0 +/- 0.1 mg/dl; ADMA 1.4 +/- 0.7 micromol/L). However, mean ADMA levels were similar in patients with normal renal function (n = 16; age 41 +/- 9 yr; serum creatinine 1.1 +/- 0.1 mg/dl; GFR 120 +/- 14 ml x min(-1) x 1.73 m2; ADMA 4.0 +/- 0.7 micromol/L), in patients with moderate renal failure (n = 15; 47 +/- 7 yr; 1.8 +/- 0.3 mg/dl; 65 +/- 10 ml x min(-1) x 1.73 m2; 3.8 +/- 0.6 micromol/L) and in patients with advanced renal failure (n = 13; 46 +/- 9 yr; 4.2 +/- 0.9 mg/dl; 25 +/- 4 ml x min(-1) x 1.73 m2; 4.7 +/- 1.2 micromol/L). Furthermore, ADMA levels were increased to the same extent in normotensive (n = 17; 4.0 +/- 0.8 micromol/L) and in hypertensive (n = 27; 4.2 +/- 0.9 micromol/L) patients. In contrast to ADMA, mean total plasma homocysteine concentration were similar in control subjects (10.6 +/- 2.9 micromol/L) and in patients with normal GFR (11.0 +/- 2.9 micromol/L), but were significantly higher in patients with moderate renal failure (17.7 +/- 4.1 micromol/L) and particularly in patients with advanced renal failure (28.2 +/- 10.6 micromol/L). Finally, mean total serum cholesterol concentrations were comparable in the control group and in the three groups of patients with renal disease. In contrast to several traditional cardiovascular risk factors, markedly increased blood concentrations of ADMA, a putative biochemical marker of atherosclerosis, are present even in nonsmoking patients without diabetes with incipient primary renal disease. Thus, the early increase of ADMA levels may be of relevance for the excess cardiovascular morbidity and mortality due to arterio- and atherosclerotic complications in patients with renal disease.

Adult↗
PubMed2002

Apolipoprotein A-IV serum concentrations are elevated in patients with mild and moderate renal failure.

Cell culture studies and investigations in mice that overexpress either human or mouse apolipoprotein A-IV (apoA-IV) revealed anti-atherogenic properties of apoA-IV. An association between low apoA-IV concentrations and coronary artery disease in humans was demonstrated; therefore, apoA-IV may also play an antiatherogenic role in humans. Because apoA-IV is markedly elevated in dialysis patients, patients with the earliest and modest stages of renal impairment were studied to assess the association of apoA-IV with GFR and atherosclerotic complications. GFR was measured by the use of iohexol in 227 non-nephrotic patients with different degrees of renal impairment. ApoA-IV increased significantly with decreasing GFR and was already elevated in earliest stages of renal disease (GFR > 90 ml/min per 1.73 m2). Multiple linear regression analysis identified renal function parameters (GFR, creatinine, and urea) as the most important determinants of apoA-IV levels in serum of these patients. Twenty-six patients had already experienced 36 atherosclerotic events. Logistic regression analysis identified three variables associated with atherosclerotic complications: age, apoA-IV, and gender. Each 1 mg/dl increase of apoA-IV decreased the odds ratio for an atherosclerotic complication by 8% (P = 0.011). The data clearly show that the anti-atherogenic apoA-IV starts to increase during the earliest phases of renal insufficiency, which makes apoA-IV an early marker of renal impairment.

Adult↗
PubMed2001

Remodeling of resistance arteries in renal failure: effect of endothelin receptor blockade.

Remodeling of vessels is a known feature of renal failure, but it is unclear whether this represents an appropriate or inappropriate response to the known changes in blood flow, shear stress, and wall tension. To investigate remodeling in response to variations in blood flow, first-order mesenteric arteries were exposed to high- and low-flow conditions via the ligation of second-order branches, according to the technique described by Pourageaud and De Mey. The resulting changes in vessel geometric features, relative proportions of intima and media, submicroscopic structure, and immunostaining for proliferating cell nuclear antigen (PCNA), endothelin-1 (ET-1), and ET(A) receptors were assessed in first-order mesenteric arteries under low-flow and high-flow conditions. Subtotally nephrectomized (SNX) animals were compared with sham-operated rats. Animals either were left untreated or were treated with the ET(A) receptor antagonist (ET-RA) LU-135252, because of suggestions in the literature that ET is involved in vascular remodeling in uremia. A highly significant increase in intimal thickness was noted in low-flow arteries (4.21 +/- 1.39 microm) of SNX animals, compared with normal-flow arteries (2.06 +/- 0.61 microm), but this increase was not observed in sham-operated rats (1.38 +/- 0.77 in low-flow arteries versus 2.40 +/- 0.35 microm in normal-flow arteries). The increase in intimal thickness in low-flow arteries was abrogated by ET-RA. The medial thickness was increased in untreated SNX animals (19.5 +/- 3.61 microm), compared with sham-operated rats, and this increase was also prevented by ET-RA. The medial thickness was not affected by low flow in either sham-operated or SNX animals. In parallel, the number of PCNA-positive intimal cells was higher in low-flow, but not high-flow, arteries of SNX rats, compared with sham-operated rats. No significant change was observed in sham-operated animals. In the media, the number of PCNA-positive cells was higher in untreated SNX animals than in sham-operated rats. The number was even more markedly increased in high-flow, but not low-flow, vessels. This increase was abrogated by ET-RA. It is concluded that, in uremic animals, the response of the intima to low flow and the response of the media to high flow are exaggerated. Both responses are apparently mediated by ET.

Animals↗
PubMed2001

Effects of retinoids on the TGF-beta system and extracellular matrix in experimental glomerulonephritis.

Transforming growth factor-beta1 (TGF-beta 1) overexpression plays a key role in the glomerular accumulation of extracellular matrix proteins in renal disease. Retinoids have previously been shown to significantly limit glomerular damage in rat experimental glomerulonephritis. Therefore, the effects of all-trans retinoic acid and isotretinoin on the components of the TGF-beta system and extracellular matrix proteins in anti-Thy1.1-nephritis (Thy-GN) were investigated. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of 10 mg/kg body wt all-trans retinoic acid or 40 mg/kg body wt isotretinoin (n = 9 per group) either with a pretreatment (day -2 through 8) or posttreatment protocol (day +3 through 8), i.e., starting before or after induction of Thy-GN, respectively. Urinary TGF-beta 1 excretion was 60% lower in all-trans retinoic acid-treated animals with Thy-GN (P < 0.025). The increase of cortical TGF-beta 1 gene expression in Thy-GN rats was significantly attenuated with all-trans retinoic acid and even more with isotretinoin treatment as compared with untreated animals (P < 0.025). Cortical expression of TGF receptor II, but not receptor I gene expression, was significantly lower in animals treated with all-trans retinoic acid or isotretinoin (P < 0.05). In all-trans retinoic acid-treated animals with Thy-GN, the increase of glomerular TGF-beta 1 protein (P < 0.008) and TGF-beta 1 (P < 0.025) and TGF receptor II mRNA (P < 0.015) was significantly less. Immunohistochemistry revealed less glomerular staining for TGF-beta 1 and TGF receptor II in the presence of all-trans retinoic acid. TGF-beta 1 immunostaining was not restricted to monocytes and macrophages, as indicated by double-staining. Glomerular staining for collagen IV and collagen III was less in animals treated with isotretinoin (P < 0.02 for both) in contrast to all-trans retinoic acid, whereas fibronectin remained unchanged. It was concluded that the beneficial effects of retinoids on glomerular damage are presumably due to a marked reduction in renal TGF-beta 1 and TGF receptor II expression.

Animals↗
PubMed2001

Renal endothelin-1 and endothelin receptor type B expression in glomerular diseases with proteinuria.

The endothelin (ET) system has been studied extensively in experimental models of progressive chronic renal disease, but there is limited information regarding the ET system in renal patients. First, the expression of human ET-1, as well as ET receptor type A (ET-R(A)) and ET-R(B), was studied in 26 renal biopsies from patients with different renal diseases. Gene expression was assessed by quantitative reverse transcription-PCR. Second, ET-1 and ET-R(B) protein expression and localization were examined, by immunohistochemical analyses, among a homogeneous cohort of 16 patients with IgA nephropathy and different degrees of proteinuria. ET-R(B) mRNA expression was threefold higher among patients with higher-grade proteinuria [> or =2 g/24 h, n = 10; OD ratio (ODR), i.e., wild-type/mutant mRNA ratio, 1.81 +/- 0.3], compared with patients with lower-grade proteinuria (<2 g/24 h, n = 8; ODR, 0.63 +/- 0.1; P < 0.01) or control subjects (n = 9; ODR, 0.57 +/- 0.1; P < 0.01). ET-1 gene expression was significantly higher among patients with higher-grade proteinuria, compared with patients with lower-grade proteinuria (P < 0.01) or control subjects (P < 0.05). ET-R(A) mRNA expression was not different among the groups. Patients with higher-grade proteinuria who were receiving angiotensin-converting enzyme inhibitors exhibited significantly (P < 0.05) lower ET-1 and ET-R(B) mRNA expression, which was comparable to that of control subjects. By using immunohistochemical analyses, an association between proteinuria and expression of ET-1 and ET-R(B) in proximal tubular epithelial cells and of ET-1 in glomeruli was confirmed in the separate cohort of patients with IgA nephropathy. It is concluded that the increased ET-R(B) and ET-1 mRNA and protein expression observed in animal models of renal disease is also demonstrable among patients with renal disease and high-grade proteinuria.

Adult↗
PubMed2001

Blood pressure-independent additive effects of pharmacologic blockade of the renin-angiotensin and endothelin systems on progression in a low-renin model of renal damage.

Pharmacologic blockade of the renin and endothelin (ET) systems is an established strategy to interfere with progression of renal failure. In the Heyman nephritis model, additive benefits of decreases in BP with the combination of angiotensin-converting enzyme inhibitors (ACE-i) and ET(A) receptor antagonists (ET-RA) were demonstrated. To further investigate these findings and to exclude confounding effects of BP decreases, this issue was reassessed in a low-renin model of subtotal kidney resection. Subtotally nephrectomized (SNX) and sham-operated rats were left untreated or received an ACE-i, an angiotensin II subtype 1 receptor antagonist (AT1-RA), an ET-RA, or combinations thereof (ACE-i plus ET-RA or AT1-RA plus ET-RA). The parameters studied were the glomerulosclerosis index (GSI), tubulointerstitial index, vascular damage index, glomerular geometry, and albumin excretion. After 12 wk, BP values were comparable. Urinary albumin excretion rates were significantly higher for untreated SNX rats (24.3 +/- 31.3 mg/24 h), compared with untreated sham-operated rats (0.71 +/- 0.40 mg/24 h). Rates were significantly lower for all treated, compared with untreated, SNX groups. GSI values were significantly higher for untreated SNX rats than for untreated sham-operated rats. ACE-i caused significantly lower GSI in SNX rats (0.46 +/- 0.06), compared with AT1-RA (0.60 +/- 0.10) or ET-RA (0.65 +/- 0.10). GSI values were significantly decreased further with ACE-i plus ET-RA (0.29 +/- 0.09) or AT1-RA plus ET-RA (23 +/- 0.05) treatment. Changes in the tubulointerstitial index and vascular damage index proceeded in parallel. The results document BP-independent effects of the ACE-i and AT1-RA on the GSI and urinary albumin excretion and an effect of the ET-RA on the GSI. The contrasting results suggest different pathogenetic pathways for glomerulosclerosis and albuminuria. The combination of treatments provided superior effects on the GSI and tubulointerstitial index but not on urinary albumin excretion.

Albuminuria↗