Stepwise Reduction of Dietary Phosphorus in Diets for Piglets and Fattening Pigs of Different Genetic Origin Housed under Various Station Environments-A Ringtest.

The reduction of emissions of nutrients from livestock is one of the main topics in areas with intensive animal husbandry. In order to minimize the loss of nutrients into the environment, it is common practice to feed animals as close as possible to metabolic demands. For phosphorus (P), there are various studies for swine and poultry, which showed that a reduction of dietary P levels is possible, if a sufficient level of phytase is added to the diet. The supplementation of a sufficient dosage of phytase to plant-based diets leads to an increase in digestible phosphorus (dP) upon the hydrolisation of phytate (InsP6) to P and lower inositol-phosphates. However, most of these studies were conducted under standardized experimental conditions. In terms of transfer to practical conditions with varying housing, management and genetics, there are concerns that have led to speculation by farmers and veterinarians whether the reduction of dietary P could negatively affect bone health and therefore animal welfare. In order to test whether a reduction of dietary P according to the recommendations for dP of the German Society of Nutrition Physiology (GfE) affects bone mineralization and growth performance, a ringtest was conducted where piglets and fattening pigs were fed at four experimental stations with three centrally produced diets from the same batches. The diets contained three different levels of P and were designed to reflect practical diets. The P level decreased from diet one to three, respectively. Diets one and two were calculated to contain P levels, which are typically fed under practical conditions in Germany. The third diet was optimized to fulfill the requirements of dP by the GfE. The animals were fed in two phases as post-weaning piglets (8-15 kg and 15-28 kg BW) followed by a three-phase fattening regime (28-60 kg, 60-90 kg and 90-120 kg BW). Individual body weight and feed consumption (pen basis or individually, depending on the experimental station) were recorded for every feeding phase. At the end of the experiment, animals were slaughtered. At one experimental station, additional blood serum, metatarsi of the left leg and kidney tissue were sampled to analyze serum P concentration, expression of P transporters in the kidney and bone traits. In two experimental stations, femur and vertebra were sampled, and bone ash was determined. Overall, animal performance and all other traits analyzed did not differ between the treatment with the highest and the treatment with the lowest dietary P concentration. The results demonstrate that it is possible to decrease dietary P according to the recommendations for dP of the GfE, without impairing the animals' performance or mineral homeostasis and health. A reduction of total P by reducing mineral P to the levels of the present study require the supplementation of phytase to achieve sufficient concentrations of dP.

Prospective study on the potential of RAAS blockade to halt renal disease in Alport syndrome patients with heterozygous mutations.

BACKGROUND: Patients with autosomal or X-linked Alport syndrome (AS) with heterozygous mutations in type IV collagen genes have a 1-20 % risk of progressing to end-stage renal disease during their lifetime. We evaluated the long-term renal outcome of patients at risk of progressive disease (chronic kidney disease stages 1-4) with/without nephroprotective therapy. METHODS: This was a prospective, non-interventional, observational study which included data from a 4-year follow-up of AS patients with heterozygous mutations whose datasets had been included in an analysis of the 2010 database of the European Alport Registry. Using Kaplan-Meier estimates and logrank tests, we prospectively analyzed the updated datasets of 52 of these patients and 13 new datasets (patients added to the Registry after 2011). The effects of therapy, extrarenal symptoms and inheritance pattern on renal outcome were analyzed. RESULTS: The mean prospective follow-up was 46 ± 10 months, and the mean time on therapy was 8.4 ± 4.4 (median 7; range 2-18) years. The time from the appearance of the first symptom to diagnosis was 8.1 ± 14.2 (range 0-52) years. At the time of starting therapy, 5.4 % of patients had an estimated glomerular filtration rate of <60 ml/min, 67.6 % had proteinuria and 27.0 % had microalbuminuria. Therapeutic strategies included angiotensin-converting enzymer inhibitors (97.1 %), angiotensin receptor antagonists (1 patient), dual therapy (11.8 %) and statins (8.8 %). Among patients included in the prospective dataset, prevented the need for dialysis. Among new patients, no patient at risk for renal failure progressed to the next disease stage after 4 years follow-up; three patients even regressed to a lower stage during therapy. CONCLUSIONS: Treatment with blockers of the renin-angiotensin-aldosterone system prevents progressive renal failure in AS patients with heterozygous mutations in the genes causing AS. Considerable numbers of aging AS patients on dialysis may have heterozygous mutations in these genes (present in 1 % of total population) as underlying disease. Hence, greater alertness towards timely diagnosis and therapy has the potential to prevent progressive renal failure in most-if not all-AS patients with heterozygous mutations in the causal genes.

Vasoactive Therapy in Systemic Sclerosis: Real-life Therapeutic Practice in More Than 3000 Patients.

OBJECTIVE: Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry. METHODS: The data of 3248 patients with SSc were analyzed. RESULTS: Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005. CONCLUSION: These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.

Influence of dietary amino acid level on chemical body composition and performance of growing-finishing boars of two sire lines.

There is only little information available concerning the chemical body composition of growing-finishing boars. For that reason, a total of 26 entire male pigs (boars) of two different Piétrain sire lines were fed with different levels of dietary essential amino acids (EAA) and the influence of this treatment on performance and chemical body composition was evaluated. In addition, an initial group of eight boars (n = 4 per sire line) was slaughtered at approximately 21 kg live weight (LW). The other 26 boars were fed three different diets containing 11.5, 13.2 and 14.9 g lysine/kg during the grower period and 9.0, 10.4, 11.7 g lysine/kg during the finisher period, respectively. Other EAA were added in relation to lysine (Lys: Met + Cys: Thr: Trp: Val = 1: 0.60: 0.65: 0.18: 0.75). At a LW of approximately 122 kg these 26 boars (six groups with three to seven animals each) were also slaughtered. The effects of EAA level and sire line on fattening and slaughter performance was recorded, and body and weight gain composition were analysed. There were no significant effects of EAA level on performance or on chemical body composition. Boars sired with Piétrain line 1 demonstrated increased lean meat content and protein body content (p < 0.05) as compared to Piétrain line 2-sired boars.

Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations.

We studied here the clinical course of heterozygous carriers of X-linked Alport syndrome and a subgroup of patients with thin basement membrane disease due to heterozygous autosomal recessive Alport mutations whose prognosis may be worse than formerly thought. We analyzed 234 Alport carriers, including 29 with autosomal recessive mutations. Using Kaplan-Meier estimates and log-rank tests, autosomal and X-linked carriers were found to have similar incidences of renal replacement therapy, proteinuria, and impaired creatinine clearance. Further, age at onset of renal replacement therapy did not differ between X-chromosomal and autosomal carriers. Both groups showed an impaired life expectancy when reaching renal replacement therapy. RAAS inhibition significantly delayed the onset of end-stage renal failure. Not only carriers of X-linked Alport mutations but also heterozygous carriers of autosomal recessive mutations were found to have an increased risk for worse renal function. The risk of end-stage renal disease in both groups affected life expectancy, and this should cause a greater alertness toward patients presenting with what has been wrongly termed 'familial benign hematuria.' Timely therapy can help to delay onset of end-stage renal failure. Thus, yearly follow-up by a nephrologist is advised for X-linked Alport carriers and patients with thin basement membrane nephropathy, microalbuminuria, proteinuria, or hypertension.

Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.

Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.

Loss of collagen-receptor DDR1 delays renal fibrosis in hereditary type IV collagen disease.

Alport syndrome is a hereditary type IV collagen disease leading to progressive renal fibrosis, hearing loss and ocular changes. End stage renal failure usually develops during adolescence. COL4A3-/- mice serve as an animal model for progressive renal scarring in Alport syndrome. The present study evaluates the role of Discoidin Domain Receptor 1 (DDR1) in cell-matrix interaction involved in pathogenesis of Alport syndrome including renal inflammation and fibrosis. DDR1/COL4A3 Double-knockouts were compared to COL4A3-/- mice with 50% or 100% expression of DDR1, wildtype controls and to DDR1-/- COL4A3+/+ controls for over 6years. Double-knockouts lived 47% longer, mice with 50% DDR1 lived 29% longer and showed improved renal function (reduction in proteinuria and blood urea nitrogen) compared to animals with 100% DDR1 expression. Loss of DDR1 reduced proinflammatory, profibrotic cells via signaling of TGFbeta, CTGF, NFkappaB and IL-6 and decreased deposition of extracellular matrix. Immunogold-staining and in-situ hybridisation identified podocytes as major players in DDR1-mediated fibrosis and inflammation within the kidney. In summary, glomerular epithelial cells (podocytes) express DDR1. Loss of DDR1-expression in the kidney delayed renal fibrosis and inflammation in hereditary type IV collagen disease. This supports our hypothesis that podocyte-matrix interaction via collagen receptors plays an important part in progression of renal fibrosis in Alport disease. The blockade of collagen-receptor DDR1 might serve as an important new therapeutic concept in progressive fibrotic and inflammatory diseases in the future.

High frequency of corticosteroid and immunosuppressive therapy in patients with systemic sclerosis despite limited evidence for efficacy.

INTRODUCTION: In systemic sclerosis (SSc) little evidence for the effectiveness of anti-inflammatory and immunosuppressive therapy exists. The objective of this study was to determine the extent to which SSc patients are treated with corticosteroids and immunosuppressive agents. METHODS: Data on duration and dosage of corticosteroids and on the type of immunosuppressive agent were analyzed from 1,729 patients who were registered in the German Network for Systemic Scleroderma (DNSS). RESULTS: A total 41.3% of all registered SSc patients was treated with corticosteroids. Corticosteroid use was reported in 49.1% of patients with diffuse cutaneous SSc and 31.3% of patients with limited cutaneous SSc (P < 0.0001). Among patients with overlap disease characteristics, 63.5% received corticosteroids (P < 0.0001 vs. limited cutaneous SSc). A total 16.1% of the patients received corticosteroids with a daily dose >or= 15 mg prednisone equivalent. Immunosuppressive therapy was prescribed in 35.8% of patients. Again, among those patients with overlap symptoms, a much higher proportion (64.1%) was treated with immunosuppressive agents, compared with 46.4% of those with diffuse cutaneous SSc sclerosis and 22.2% of those with limited cutaneous SSc (P < 0.0001). The most commonly prescribed drugs were methotrexate (30.5%), cyclophosphamide (22.2%), azathioprine (21.8%) and (hydroxy)chloroquine (7.2%). The use of these compounds varied significantly between medical subspecialties. CONCLUSIONS: Despite limited evidence for the effectiveness of corticosteroids and immunosuppressive agents in SSc, these potentially harmful drugs are frequently prescribed to patients with all forms of SSc. Therefore, this study indicates the need to develop and communicate adequate treatment recommendations.

Living donor kidney transplantation from relatives with mild urinary abnormalities in Alport syndrome: long-term risk, benefit and outcome.

BACKGROUND: Alport syndrome is a hereditary nephropathy leading to renal failure during adolescence. This study evaluates the outcome of living donor transplantation (Tx) from heterozygous mothers to their affected children. METHODS: Seven mothers were evaluated, and donation was refused in one because of proteinuria. RESULTS: All of the remaining six donors had microhaematuria, and one had proteinuria. Renal function was monitored after Tx (average 6.7 years in donors and 5.3 years in acceptors). Three of six donors developed new onset hypertension, and two new onset of proteinuria. Renal function declined significantly in four donors: (1) -35% after 2 years; (2) -25% after 3 years; (3) -30% after 4 years and (4) -60% after 14 years versus before Tx. However, creatinine clearance remained >40 ml/min in all donors. All transplanted kidneys worked well 1 and 5 years after Tx, and one failed after 10 years. One patient died from meningitis, and the remaining four remained stable. CONCLUSION: Living donor Tx from relatives in Alport families is an ambivalent option. Proteinuria should be an exclusion criterion. Yet, even in donors with isolated microhaematuria, families and their physicians should be aware of an increased risk of renal failure in donor and recipient. This risk might be minimized by careful donor evaluation including biopsy and nephroprotective strategies after Tx in both donor and recipient.

Nephroprotective effect of the HMG-CoA-reductase inhibitor cerivastatin in a mouse model of progressive renal fibrosis in Alport syndrome.

BACKGROUND: Alport syndrome is caused by mutations in genes encoding for the alpha3, alpha4 or alpha5 chain of type IV collagen leading to excessive production of fibrotic tissue and end-stage renal failure. HMG-CoA-reductase-inhibitors exhibit pleiotropic effects by which they modulate the production of connective tissue. The aim of this study was to examine the anti-fibrotic effect of the HMG-CoA-reductase-inhibitor, cerivastatin, in COL4A3 knockout mice, an animal model of Alport syndrome with progressive renal fibrosis. METHODS: Forty homozygous COL4A3 knockout mice received cerivastatin, starting 28 or 49 days after birth. Mice were sacrificed at day 52 or 66 after birth. Immunohistochemistry against laminin and fibronectin was performed. Inflammatory cell infiltration was determined by F4/80- and CD3-staining. Myofibroblasts were identified by an alpha-smooth muscle actin staining. Expression of the profibrotic cytokines, TGF-beta1 and CTGF, were determined by immunoblot. RESULTS: The lifespan of treated COL4A3 knockout mice was increased by 28% compared with untreated animals (71+/-6 vs 91+/-9 days, P<0.01). Early cerivastatin treatment reduced cholesterol levels (113+/-13 vs 141+/-19 mmol/l in untreated animals, P<0.05) and serum urea (164 vs 235 mmol/l, day 66, P<0.05). Treatment also decreased proteinuria (5.5 vs 12 g/l at day 66, P<0.05). Deposition of laminin and fibronectin, expression of TGF-beta and CTGF was reduced. Infiltration of T-cells and macrophages as well as myofibroblasts appeared to be reduced in kidneys from cerivastatin-treated mice. CONCLUSION: Cerivastatin prolongs the lifespan of COL4A3 knockout mice, reduces proteinuria and delays uraemia. These effects are associated with decreased renal fibrosis and a reduction of inflammatory cell infiltration.

[Characterization of proteinuria in patients with ulcerative colitis and therapy with aminosalicylates]. / Charakterisierung der Proteinurie bei Patienten mit Colitis ulcerosa unter der Behandlung mit Aminosalicylaten.

BACKGROUND AND PURPOSE: Patients with ulcerative colitis have a higher rate of tubular nephropathies. Data concerning the cause of these lesions is rare and inconsistent, the occurrence may be part of the disease itself or a side effect of 5-aminosalicylates (5-ASA). This study investigated proteinuria and eosinophiluria in patients with moderate ulcerative colitis under treatment with 5-ASA. PATIENTS AND METHODS: Urine specimens (microelectrophoresis and eosinophiluria) of 34 patients with acute onset of moderate ulcerative colitis who were treated only with 5-ASA as active drug were analyzed. RESULTS: Data of 27 patients could be evaluated. Twelve patients had tubular proteinuria previous to treatment. By the end of the study, urine specimens normalized in six, in further six the proteinuria remained unaltered, two patients developed proteinuria under treatment. In 14 patients, proteinuria was not detectable at any time. Eosinophiluria was found in none of the specimens. CONCLUSION: Under treatment with 5-ASA no toxic or allergic nephropathy developed. One initially pathologic urine specimen normalized under treatment coming along with remission of the intestinal symptoms and histological findings. This indicates an association between the activity of the ulcerative colitis and might be caused by renal excretion of pro-inflammatory cytokines.

Rho/Rho kinase pathway regulates maintenance of the differentiated tubular epithelial cell phenotype on laminin-1.

BACKGROUND: Maintenance of a polarized tubular epithelium by appropriate intracellular signaling and extracellular matrix is critical both in normal renal function as well as in acute and chronic tubular injury. We examined the hypothesis that maintenance of a differentiated epithelial phenotype on the basement membrane glycoprotein laminin-1 is controlled by the Rho/Rho kinase pathway. METHODS: Using the tubular epithelial cell lines LLC-PK1 and MDCK which were cultured on laminin-1 vs. collagen IV, we analyzed cell morphology and motility (cohort migration assay) as well as expression of differentiation and dedifferentiation markers (immunofluorescence microscopy). RESULTS: Cohort migration of LLC-PK1 cells was significantly slowed down on laminin-1 (10.7 +/- 2.2 m.u. (migratory units)) compared with collagen IV (16.6 +/- 2.3 m.u.; BSA control: 2.8 +/- 2.5 m.u.). Inhibition of the Rho/Rho kinase pathway by C3 exotoxin (1 mug/ml) or the Rho kinase inhibitor Y27632 (10 microM) significantly augmented cohort migration on laminin-1 (14.5 +/- 1.4 and 16.0 +/- 1.8 m.u. vs. 10.7 +/- 2.2 m.u.). In parallel to the increased migratory activity, inhibition of the Rho/Rho kinase pathway resulted in a more mesenchymal phenotype of LLC-PK1 cells on laminin-1 with increased formation of lamellopodia and filopodia, distinct loss of focal contacts and stress fibers, upregulation of the dedifferentiation marker vimentin, and loss of cell-cell contacts with translocation of beta-catenin from the adherens junctions to the cytosol and nucleus. Similarly, cohort migration of MDCK cells was retarded on laminin-1 when compared with collagen IV, and addition of the Rho kinase inhibitor Y27632 resulted in enhanced motility and a change in cell morphology. CONCLUSION: The study demonstrates that the Rho/Rho kinase pathway is required to maintain a non-migratory epithelial phenotype of cultured renal tubular LLC-PK1 and MDCK cells on the basement membrane glycoprotein laminin-1.

Cost effectiveness of enoxaparin as prophylaxis against venous thromboembolic complications in acutely ill medical inpatients: modelling study from the hospital perspective in Germany.

OBJECTIVE: To estimate, from the hospital perspective in Germany, the cost effectiveness of the low-molecular-weight heparin (LMWH) subcutaneous enoxaparin sodium 40 mg once daily (ENOX) relative to no pharmacological prophylaxis (NPP) and relative to subcutaneous unfractionated heparin (UFH) 5,000 IU three times daily (low-dose UFH [LDUFH]). Each is used in addition to elastic bandages/compression stockings and physiotherapy in the prevention of venous thromboembolic events (VTE) in immobilised acutely ill medical inpatients without impaired renal function or extremes of body weight. METHODS: The incremental cost-effectiveness ratios (ICERs) of the 'additional cost for ENOX per clinical VTE avoided versus NPP' and 'additional cost for ENOX per episode of major bleeding avoided versus LDUFH' were chosen as target variables. The target variables were quantified using a modelling approach based on the decision-tree technique. Resource use during thromboprophylaxis, diagnosis and treatment of VTEs, episode of major bleeding and secondary pneumonia after pulmonary embolism (PE) was collected from a hospital survey. Costs were exclusively those to hospitals incurred by staff expenses, drugs, devices, disposables, laboratory tests and equipment for diagnostic procedures. These costs were determined by multiplying utilised resource items by the price or tariff of each item as of the first quarter of 2003. Safety and efficacy values of the comparators were taken from the MEDENOX (prophylaxis in MEDical patients with ENOXaparin) and the THE-PRINCE (THromboEmbolism-PRevention IN Cardiac or respiratory disease with Enoxaparin) trials and from a meta-analysis. The evaluation encompassed 8 (6-14) days of thromboprophylaxis plus time to treat VTE and episode of major bleeding in hospital. Point estimates of all model parameters were applied exclusively in the base-case analysis. RESULTS: There were incremental costs of euro 1,106 for ENOX per clinical VTE avoided versus NPP (1 euro approximately equals 1.07 US dollars; average of the first quarter of 2003). ENOX dominated LDUFH: cost savings of euro 55,825 were obtained and 7.7 episodes of major bleeding were avoided by ENOX compared with LDUFH, each per 1000 patients. In comprehensive sensitivity analyses, the robustness of the model and its results was shown. CONCLUSIONS: Results of this evaluation suggest that, in immobilised acutely ill medical inpatients, ENOX may offer hospitals in Germany a very cost-effective option for thromboprophylaxis compared with NPP and a cost-saving alternative compared with LDUFH.

Chronic renal failure and shortened lifespan in COL4A3+/- mice: an animal model for thin basement membrane nephropathy.

A heterozygous mutation in autosomal Alport genes COL4A3 and COL4A4 can be found in 20 to 50% of individuals with familial benign hematuria and diffuse glomerular basement membrane thinning (thin basement membrane nephropathy [TBMN]). Approximately 1% of humans are heterozygous carriers of mutations in the autosomal Alport genes and at risk for developing renal failure as a result of TBMN. The incidence and pathogenesis of renal failure in heterozygous COL4A3/4 mutation carriers is still unclear and was examined further in this study using COL4A3 knockout mice. In heterozygous COL4A3(+/-) mice lifespan, hematuria and renal function (serum urea and proteinuria) were monitored during a period of 3 yr, and renal tissue was examined by light and electron microscopy, immunohistochemistry, and Western blot. Lifespan of COL4A3(+/-) mice was found to be significantly shorter than in healthy controls (21.7 versus 30.3 mo). Persistent glomerular hematuria was detected starting in week 9; proteinuria of > 0.1 g/L started after 3 mo of life and increased to > 3 g/L after 24 mo. The glomerular basement membrane was significantly thinned (167 versus 200 nm in wild type) in 30-wk-old mice, coinciding with focal glomerulosclerosis, tubulointerstitial fibrosis, and increased levels of TGF-beta and connective tissue growth factor. The renal phenotype in COL4A3(+/-) mice resembled the clinical and histopathologic phenotype of human cases of TBMN with concomitant progression to chronic renal failure. Therefore, the COL4A3(+/-) mouse model will help in the understanding of the pathogenesis of TBMN in humans and in the evaluation of potential therapies.

Nephroprotection by antifibrotic and anti-inflammatory effects of the vasopeptidase inhibitor AVE7688.

BACKGROUND: Chronic renal disease substantially increases the risk of cardiovascular events and death. Vasopeptidase inhibitors are known to show a strong antihypertensive effect. In the present study, we investigated the nephroprotective potential of the vasopeptidase inhibitor AVE7688 beyond its antihypertensive effects in a mouse model of progressive renal fibrosis. METHODS: COL4A3 -/- mice received 25 mg AVE7688 per kg body weight. Treatment was initiated in week 4 (early) and week 7 (late). Eight mice per group were sacrificed after 7.5 or 9.5 weeks, and serum levels of urea, systemic blood pressure, and proteinuria were measured. Renal tissue was investigated by routine histology, electron microscopy, immunohistochemistry, and Western blotting. Lifespan until death from renal fibrosis was monitored. RESULTS: Lifespan of treated mice increased by 143% (early therapy) and by 53% (late therapy) compared to untreated animals (172 +/- 19 vs. 109 +/- 15 vs. 71 +/- 6 days, P < 0.01). Untreated COL4A3 -/- mice did not develop severe hypertension (mean systolic blood pressure 116 +/- 14 vs. 111 +/- 9 mm Hg in wild-type mice), and both therapies mildly reduced systemic blood pressure (107 +/- 13 and 105 +/- 14 mm Hg, data not significant). AVE7688 decreased proteinuria from 12 +/- 3 g/L in untreated mice to 2 +/- 1 g/L (early) and to 4 +/- 1 g/L (late therapy, P < 0.05), as well as serum-urea from 247 +/- 27 to 57 +/- 10 and to 105 +/- 20 mmol/L (P < 0.05). Extent of fibrosis, inflammation, and profibrotic cytokines was reduced by AVE7688 therapy. CONCLUSION: The results indicate a strong nephroprotective effect of the vasopeptidase inhibitor in this animal model of progressive renal fibrosis. Besides the antihypertensive action of AVE7688, its antifibrotic, anti-inflammatory, and antiproteinuric effects demonstrated in the present study may serve as an important therapeutic option for chronic inflammatory and fibrotic diseases in man.