Management of recurrent focal segmental glomerulosclerosis (FSGS) post renal transplantation.

BACKGROUND: One of the common GN causing ESKD is focal segmental glomerulosclerosis (FSGS). Recurrence of FSGS post-transplantation can lead to graft loss. Data on management either prophylactically or once recurrence occurs are limited. This review article aims to assess the effective management of patients with FSGS recurrence post-transplantation, looking mainly at recurrence post prophylactic treatment and remission in case of treatment post recurrence. METHODS: Twenty-three studies were included using the search MeSH terms "FSGS" "recurrence" "adults" "transplantation" "treatment". Search engines used were Pubmed, clinical key, Scopus and Cochrane library. Inclusion criteria were articles covered adult patients with recurrent FSGS post renal transplantation, treatment with rituximab and plasmapheresis, and articles published from 2000 tt2021. Excluded articles were paediatric population, studies with no reported outcomes of the treatment of FSGS, and Patients who received stem cell transplantation or galactose therapy. RESULTS: Prophylactic PP did not show a reduction in recurrence of FSGS in 2/3 studies. Prophylactic rituximab was shown to reduce recurrence of FSGS in one-study and case reports. Treatment of recurrent FSGS with PP showed responses ranging from 41% to 100%. Only one study did not show improvement with PP use as treatment having a 27% remission. Treatment with rituximab showed variable results, with reports showing remission ranging from 57% to 100%. Whereas other reports showing no response at all. PP prescription reporting was variable. One study suggested intensified PP regimen while in most other studies PP was guided by the response reflected by the reduction of proteinuria. DISCUSSION: Reviewing the treatment of recurrent FSGS is crucial, as there no consensus on treating FSGS as the disease is not very common in the adult population. The evidence of different modalities is based on small cohort studies. This paper supports the use of PP and RTX as treatment of recurrent FSGS. CONCLUSIONS: In conclusion, PP and RTX are the main modalities to treat recurrent FSGS with varying response rates. Prophylactic PP does not play a role in preventing recurrent FSGS. Prophylactic rituximab might play a role in preventing FSGS post-transplantation. PP and RTX, when used as a treatment, show variable response rates. Larger RCTs are needed to have a strong level of evidence to base our clinical management on.

UK experience of ofatumumab in recurrence of focal segmental glomerulosclerosis post-kidney transplant.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS), commonly caused by focal segmental glomerulosclerosis (FSGS), is associated with progression to stage 5 chronic kidney disease, requirement for kidney replacement therapy and a risk of disease recurrence post-kidney transplantation. Ofatumumab (OFA) is a fully humanised monoclonal antibody to CD20, with similar mechanisms of action to rituximab (RTX). METHODS: We report a case series of seven UK patients (five paediatric, two adult), all of whom developed FSGS recurrence after kidney transplantation and received OFA as part of their therapeutic intervention. All also received concomitant plasmapheresis. The 2-year outcome of these seven patients is reported, describing clinical course, kidney function and proteinuria. RESULTS: Four patients (all paediatric) achieved complete urinary remission with minimal proteinuria 12 months post-treatment. Three of those four also had normal graft function. Two patients showed partial remission-brief improvement to non-nephrotic proteinuria (197 mg/mmol) in one patient, maintained improvement in kidney function (estimated glomerular filtration rate 76 ml/min/1.73 m2) in the other. One patient did not demonstrate any response. CONCLUSIONS: OFA may represent a useful addition to therapeutic options in the management of FSGS recurrence post-transplantation, including where RTX has shown no benefit. Concomitant plasmapheresis in all patients prevents any definitive conclusion that OFA was the beneficial intervention.

Rituximab as a Preemptive Treatment to Prevent Recurrence of Primary Focal Segmental Glomerulosclerosis: A Novel Approach.

OBJECTIVES: Primary idiopathic focal segmental glomerulo-sclerosis is a serious disease, frequently progressing to end-stage kidney failure. Management of recurrence after kidney transplant is challenging despite multiple proposed therapeutic approaches. Available treatment for focal segmental glomeru-losclerosis recurrence is plasma exchange, intravenous cyclosporine, and rituximab. In this study, we investigated kidney transplant recipients with focal segmental glomerulosclerosis who were at high risk for recurrence. Patients were given preemptive rituximab at day 0 posttransplant. MATERIALS AND METHODS: Between January 2013 and June 2017, our center had 8 patients with primary focal segmental glomerulosclerosis at high risk for recurrence who were scheduled for kidney transplant. These patients received a single rituximab infusion of 375 mg/m2 on day 0 posttransplant. Recurrence of focal segmental glomerulosclerosis posttransplant was defined as repeated proteinuria > 2 g/day, without evidence of clinical or biopsy-proven rejection. RESULTS: Follow-up showed that none of our patients had immediate posttransplant proteinuria. Only 1 patient developed proteinuria at almost 4 months posttransplant. Mean follow-up duration was 8 months. With regard to complications, 2 patients had serious bacterial infections and 1 patient had cytomegalovirus infection. CONCLUSIONS: Rituximab at day 0 posttransplant may be used safely to prevent focal segmental glomeru-losclerosis recurrence in the graft in the early posttransplant period. However, longer follow-up studies with larger series are needed.

Prevention of chronic renal allograft rejection by AS2553627, a novel JAK inhibitor, in a rat transplantation model.

BACKGROUND: Janus kinase (JAK) inhibitors are thought to be promising candidates to aid renal transplantation. However, the effectiveness of JAK inhibitors against features of chronic rejection, including interstitial fibrosis/tubular atrophy (IF/TA) and glomerulosclerosis, has not been elucidated. Here, we investigated the effect of AS2553627, a novel JAK inhibitor, on the development of chronic rejection in rat renal transplantation. METHODS: Lewis (LEW) to Brown Norway (BN) rat renal transplantation was performed. Tacrolimus (TAC) at 0.1mg/kg was administered intramuscularly once a day for 10 consecutive days starting on the day of transplantation (days 0 to 9) to prevent initial acute rejection. After discontinuation of TAC treatment from days 10 to 28, AS2553627 (1 and 10mg/kg) was orally administered with TAC. At 13weeks after renal transplantation, grafts were harvested for histopathological and mRNA analysis. Creatinine and donor-specific antibodies were measured from plasma samples. Urinary protein and kidney injury markers were also evaluated. RESULTS: AS2553627 in combination with TAC exhibited low plasma creatinine and a marked decrease in urinary protein and kidney injury markers, such as tissue inhibitor of metalloproteinase-1 and kidney injury molecule-1. At 13weeks, histopathological analysis revealed that AS2553627 treatment inhibited glomerulosclerosis and IF/TA. In addition, upregulation of cell surface markers, fibrosis/epithelial-mesenchymal transition and inflammation-related genes were reduced by the combination of AS2553672 and TAC, particularly CD8 and IL-6 mRNAs, indicating that AS2553627 prevented cell infiltration and inflammation in renal allografts. CONCLUSIONS: These results indicate the therapeutic potential of JAK inhibitors in chronic rejection progression, and suggest that AS2553627 is a promising agent to improve long-term graft survival after renal transplantation.

Renoprotective effect of epoetin beta pegol by the prevention of M2 macrophage recruitment in Thy-1 rats.

BACKGROUND: Glomerulonephritis (GN) develops via accumulation of extracellular matrix through macrophage recruitment in glomeruli. It is unclear whether epoetin beta pegol (continuous erythropoietin receptor activator, CERA), a long-acting erythropoiesis-stimulating agent, exerts a renoprotective effect by preventing glomerulosclerosis. We examined the renoprotective effect of CERA in rats with Thy-1 glomerulonephritis (Thy-1-GN), an animal model for mesangial proliferative glomerulonephritis. METHODS: Thy-1-GN was induced in F344 rats by injection of anti-Thy1.1 antibody. CERA (25 µg/kg) was intravenously administered 4 h before anti-Thy1.1 antibody injection. After 6 days, blood and urine was collected for biochemical analysis and kidneys harvested for analysis of histopathology and mRNA expression. RESULTS: In Thy-1-GN rats, CERA suppressed increased urinary total protein, urea nitrogen, and N-acetyl-ß-(D)-glucosaminidase. CERA significantly prevented glomerulosclerosis and expression of α-smooth muscle actin, collagen-1, and fibronectin. Increased macrophage infiltration and up-regulated monocyte chemotactic protein-1 were significantly suppressed by CERA. Furthermore, CERA also suppressed up-regulation of arginase-1, a marker of M2 macrophages. Arginase-1 expression levels strongly correlated with levels of collagen-1 and fibronectin mRNA. CONCLUSIONS: These results suggest that CERA has potential to protect kidney function through the prevention of glomerulosclerosis, accompanied by prevention of M2 macrophage recruitment.

Osthole improves an accelerated focal segmental glomerulosclerosis model in the early stage by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated COX-2 expression and apoptosis.

Inflammatory reactions and oxidative stress are implicated in the pathogenesis of focal segmental glomerulosclerosis (FSGS), a common chronic kidney disease with relatively poor prognosis and unsatisfactory treatment regimens. Previously, we showed that osthole, a coumarin compound isolated from the seeds of Cnidium monnieri, can inhibit reactive oxygen species generation, NF-κB activation, and cyclooxygenase-2 expression in lipopolysaccharide-activated macrophages. In this study, we further evaluated its renoprotective effect in a mouse model of accelerated FSGS (acFSGS), featuring early development of proteinuria, followed by impaired renal function, glomerular epithelial cell hyperplasia lesions (a sensitive sign that precedes the development of glomerular sclerosis), periglomerular inflammation, and glomerular hyalinosis/sclerosis. The results show that osthole significantly prevented the development of the acFSGS model in the treated group of mice. The mechanisms involved in the renoprotective effects of osthole on the acFSGS model were mainly a result of an activated Nrf2-mediated antioxidant pathway in the early stage (proteinuria and ischemic collapse of the glomeruli) of acFSGS, followed by a decrease in: (1) NF-κB activation and COX-2 expression as well as PGE2 production, (2) podocyte injury, and (3) apoptosis. Our data support that targeting the Nrf2 antioxidant pathway may justify osthole being established as a candidate renoprotective compound for FSGS.

Plasmapheresis and immunoadsorption for treatment and prophylaxis of recurrent focal segmental glomerulosclerosis in adult recipients of deceased donor renal grafts.

Recurrent focal segmental glomerulosclerosis has a great impact on kidney graft survival. This retrospective study presents immunoadsorption-plasmapheresis treatment and outcome in our renal graft recipients with significant post-transplant proteinuria (>1 g/day) and focal segmental glomerulosclerosis in native kidneys. Recurrence was defined as occurrence of nephrotic range proteinuria or biopsy-confirmed diagnosis. Successful treatment was defined as sustained reduction of proteinuria to <1 g/day. From 2000 through 2011, 548 adult patients received kidney grafts from deceased donors. In 20 of these patients (3.6%) end-stage renal disease was a consequence of focal segmental glomerulosclerosis. Recurrence was confirmed in five of seven treated patients. Immunoadsorption-plasmapheresis treatment was successful in five patients (70%). Their age at disease diagnosis in native kidneys was 12 to 44 years. Time to end-stage renal disease was 3 to 14 years. Recipient age at transplantation was 21 to 61 years. Onset of significant proteinuria was 2 to 87 days after transplantation. Immunoadsorption or plasmapheresis started 1 to 7 days after recurrence of significant proteinuria. Treatment period was 1 to 103 months and 12 to 206 procedures were performed per patient. Follow-up period after cessation of plasmapheresis was 11 to 58 months. Final urine protein/creatinine ratio was 8.8 to 98.0 mg/mmol and final serum creatinine was 63 to 148 µmol/L. Follow-up after transplantation was 18 to 135 months. One patient was still on treatment. One graft was lost to recurrence. No serious adverse effects occurred during immunoadsorption and plasmapheresis. Immunoadsorption and plasmapheresis appears to be successful in the majority of patients, probably due to their early start.

Impact of the National Institutes of Health Focal Segmental Glomerulosclerosis (NIH FSGS) clinical trial on the treatment of steroid-resistant FSGS.

Idiopathic focal segmental glomerulosclerosis (FSGS) is among the most common, morbid and treatment-resistant conditions faced by nephrologists. While glucocorticoids have traditionally been the mainstay of initial treatment, they induce remission in only a minority of patients. A variety of other immunosuppressants have been utilized against steroid-resistant FSGS, but few have been rigorously examined in well-controlled trials. Recently, the results were published from a National Institutes of Health (NIH)-sponsored multicenter randomized trial comparing cyclosporine (CSA) with a combination of mycophenolate mofetil (MMF) and pulse dexamethasone (DEX) for the treatment of steroid-resistant FSGS. No difference in treatment effectiveness was shown between the two groups, and adverse effects were comparable. This was the largest randomized trial ever undertaken in FSGS, but it was unfortunately underpowered to show clinically relevant differences in response rates. This shortcoming, along with particularities of the study population and outcome measures, makes it challenging to draw definitive conclusions from the trial results. Despite these limitations, the trial does provide valuable insights into treatment strategies for FSGS and offers important lessons for planning future research.

IL-2/IL-2Ab complexes induce regulatory T cell expansion and protect against proteinuric CKD.

Regulatory T cells (Tregs) help protect against autoimmune renal injury. The use of agonist antibodies and antibody/cytokine combinations to expand Tregs in vivo may have therapeutic potential for renal disease. Here, we investigated the effects of administering IL-2/IL-2Ab complexes in mice with adriamycin nephropathy, a model of proteinuric kidney disease that resembles human focal segmental glomerulosclerosis. Injecting IL-2/IL-2Ab complexes before or, to a lesser extent, after induction of disease promoted expansion of Tregs. Furthermore, administration of this complex was renoprotective, evidenced by improved renal function, maintenance of body weight, less histologic injury, and reduced inflammation. IL-2/IL-2Ab reduced serum IL-6 and renal expression of IL-6 and IL-17 but enhanced expression of IL-10 and Foxp3 in the spleen. In vitro, the addition of IL-2/IL-2Ab complexes induced rapid STAT-5 phosphorylation in CD4 T cells. In summary, these data suggest that inducing the expansion of Tregs by administering IL-2/IL-2Ab complexes is a possible strategy to treat renal disease.

Divergent roles of Smad3 and PI3-kinase in murine adriamycin nephropathy indicate distinct mechanisms of proteinuria and fibrogenesis.

Multiple transforming growth factor (TGF)-ß-induced fibrogenic signals have been described in vitro. To evaluate mechanisms in vivo, we used an adriamycin nephropathy model in 129x1/Svj mice that display massive proteinuria by days 5 to 7 and pathological findings similar to human focal segmental glomerulosclerosis by day 14. TGF-ß mRNA expression increased after day 7 along with nuclear translocation of the TGF-ß receptor-specific transcription factor Smad3. Inhibiting TGF-ß prevented both pathological changes and type-I collagen and fibronectin mRNA expression, but proteinuria persisted. Renal Akt was phosphorylated in adriamycin-treated mice, suggesting PI3-kinase activation. Expression of mRNA for the p110γ isozyme of PI3-kinase was specifically increased and p110γ colocalized with nephrin by immunohistochemistry early in disease. Nephrin levels subsequently decreased. Inhibition of p110γ by AS605240 preserved nephrin expression and prevented proteinuria. In cultured podocytes, adriamycin stimulated p110γ expression. AS605240, but not a TGF-ß receptor kinase inhibitor, prevented adriamycin-induced cytoskeletal disorganization and apoptosis, supporting a role for p110γ in podocyte injury. AS605240, at a dose that decreased proteinuria, prevented renal collagen mRNA expression in vivo but did not affect TGF-ß-stimulated collagen induction in vitro. Thus, PI3-kinase p110γ mediates initial podocyte injury and proteinuria, both of which precede TGF-ß-mediated glomerular scarring.

Rituximab therapy prevents focal and segmental glomerulosclerosis recurrence after a second renal transplantation.

Preventive treatment of focal and segmental glomerulosclerosis (FSGS) allograft recurrence in high risk recipients having a prior history of graft loss caused by FSGS recurrence is still a challenging question. We retrospectively identified four patients who underwent a second renal transplantation because of recurrent FSGS and who received Rituximab therapy as a prophylactic treatment. Loss of their first allograft was directly related to an early (<3 months) recurrence of FSGS that was either resistant to plasmapheresis therapy in two cases or had escaped to this therapeutic management in the two others. After the second renal transplantation, all patients were free of FSGS recurrence during follow-ups that were between 12 and 54 months long. These preliminary results demonstrate for the first time that Rituximab therapy may constitute an attractive prophylactic option for patients being considered for a second renal transplantation because of recurrent FSGS in their first graft.

Angiotensin receptor blockade attenuates glomerulosclerosis progression by promoting VEGF expression and bone marrow-derived cells recruitment.

BACKGROUND: Previous studies have demonstrated that angiotensin Type I receptor blockade (ARB) reduces proteinuria, reverses glomerular injury and glomerulosclerosis in rat models of diabetic nephropathy and glomerulonephritis. However, the cellular and molecular mechanisms are unclear. To investigate the role of cells of the bone marrow (BM) in glomerular repair seen during ARB administration, we induced progressive glomerulosclerosis in enhanced green fluorescent protein BM chimeric rats by a single injection of anti-Thy 1.1 monoclonal antibody, followed by unilateral nephrectomy. METHODS: Cohorts of rats received valsartan or no treatment from Week 2 to Week 8 after induction of disease. Renal function, urinary protein excretion and histological changes were examined 8 weeks after anti-Thy-1.1 monoclonal antibody injection. RESULTS: Valsartan administration improved renal function, reduced severity of glomerulosclrosis and markedly reduced mortality. Valsartan administration promoted regeneration of the glomerular tuft, lowered proteinuria and resulted in enhanced vascular endothelial growth factor (VEGF) expression in the cortex and glomerular tuft. In addition, valsartan promoted increased recruitment of BM-derived cells (BMDCs) many of which expressed VEGF and likely contributed directly to glomerular repair. Nearly all BMDCs recruited to the glomerulus expressed the monocyte/macrophage marker CD68. CONCLUSIONS: In conclusion, the data shows that ARB by valsartan prevents glomerulosclerosis progression by enhancing glomerular capillary repair which is associated with the recruitment of VEGF producing 'reparative' monocytes and macrophages from the BM.

Bradykinin receptor 1 activation exacerbates experimental focal and segmental glomerulosclerosis.

Focal and segmental glomerulosclerosis (FSGS) is one of the most important causes of end-stage renal failure. The bradykinin B1 receptor has been associated with tissue inflammation and renal fibrosis. To test for a role of the bradykinin B1 receptor in podocyte injury, we pharmacologically modulated its activity at different time points in an adriamycin-induced mouse model of FSGS. Estimated albuminuria and urinary protein to creatinine ratios correlated with podocytopathy. Adriamycin injection led to loss of body weight, proteinuria, and upregulation of B1 receptor mRNA. Early treatment with a B1 antagonist reduced albuminuria and glomerulosclerosis, and inhibited the adriamycin-induced downregulation of podocin, nephrin, and α-actinin-4 expression. Moreover, delayed treatment with antagonist also induced podocyte protection. Conversely, a B1 agonist aggravated renal dysfunction and even further suppressed the levels of podocyte-related molecules. Thus, we propose that kinin has a crucial role in the pathogenesis of FSGS operating through bradykinin B1 receptor signaling.

Tumor necrosis factor-alpha antagonist etanercept decreases blood pressure and protects the kidney in a mouse model of systemic lupus erythematosus.

Chronic inflammation has been implicated in the pathology of hypertension; however, the role for specific cytokines remains unclear. We tested whether tumor necrosis factor-α blockade with etanercept (Etan) reduces mean arterial pressure in a female mouse model of systemic lupus erythematosus (SLE). SLE is a chronic inflammatory disorder with prevalent hypertension. Thirty-week-old SLE (NZBWF1) and control mice (NZW/LacJ) received Etan (0.8 mg/kg SC weekly) for 4 weeks or vehicle. Mean arterial pressure (in millimeters of mercury) was increased in SLE mice (150±5 versus 113±5 in controls; P<0.05) and was lower in Etan-treated SLE mice (132±3) but not controls (117±5). Albuminuria (in micrograms per milligram of creatinine) was elevated in SLE mice (28 742±9032 versus 1075±883; P<0.05) and was lower in Etan-treated SLE mice (8154±3899) but not control animals (783±226). Glomerulosclerosis (in percentage of glomeruli) was evident in SLE mice (2.5±1.6 versus 0.0±0.0 in controls; P<0.05) and was ameliorated in Etan-treated SLE mice (0.1±0.1). Renal cortex CD68(+) cell staining (in percentage of area) was elevated in SLE mice (4.75±0.80 versus 0.79±0.12 in controls; P<0.05) and was lower in Etan-treated SLE mice (2.28±0.32) but not controls (1.43±0.25). Renal cortex NADPH oxidase activity (relative light units per milligram of protein) was higher in SLE mice compared with controls (10 718±1276 versus 7584±229; P<0.05) and lowered in Etan-treated SLE mice (6645±490). Renal cortex nuclear factor κB (phosphorylated and nonphosphorylated) was increased in SLE mice compared with controls and lower in Etan-treated SLE mice. These data suggest that TNF-α mechanistically contributes to the development of hypertension in a chronic inflammatory disease through increased renal nuclear factor κB, oxidative stress, and inflammation.

Thiazolidinedione attenuate proteinuria and glomerulosclerosis in Adriamycin-induced nephropathy rats via slit diaphragm protection.

AIM: The slit diaphragm (SD) of podocyte impairment contributes to massive proteinuria and progressive glomerulosclerosis in many human glomerular diseases. The aim of the study was to determine if thiazolidinedione (TZD) reduce proteinuria and glomerulosclerosis in focal segmental glomerulosclerosis (FSGS) by preserving the structure and function of SD. METHODS: Adriamycin-induced FSGS rat models were employed. Urinary protein content was measured dynamically during the experiment. Additional biochemical parameters in serum samples were measured after the animals were killed. Glomerular sclerosis index (SI) and podocyte foot processes fusion rate (PFR) were evaluated. The protein and mRNA expressing levels of nephrin, podocin and CD2-associated protein (CD2AP) in glomeruli were assessed by immunohistochemistry and real-time quantitative polymerase chain reaction, respectively. The density of podocytes was also evaluated after anti-Wilms' tumour-1 immunohistochemical staining. RESULTS: Rosiglitazone treatment partially reduced proteinuria, but did not significantly affect the serum levels of triglyceride, cholesterol, albumin, glucose, urea nitrogen and creatinine in Adriamycin-induced FSGS rats. Glomerular SI and podocyte foot PFR were significantly attenuated by rosiglitazone treatment. Rosiglitazone prevented the reduction of nephrin, podocin and CD2AP protein expression induced by Adriamycin, however, the mRNA expression levels of these SD-related markers did not change significantly. Rosiglitazone therapy did not reverse Adriamycin-mediated reduction of the density of podocytes. CONCLUSIONS: The study data suggest that TZD are promising therapeutic agents on FSGS, and the mechanism may be mediated in part by directly protecting the structure and function of SD.

Renal denervation reduces glomerular injury by suppressing NAD(P)H oxidase activity in Dahl salt-sensitive rats.

BACKGROUND: Renal sympathetic nerve activity has important effects on renal function in chronic kidney disease. Recent studies indicated that beta agonists directly stimulate NAD(P)H oxidase in endothelial cells. Therefore, we investigated whether renal denervation protects renal function through an anti-oxidative effect. METHODS: The right kidney was removed from Dahl salt-sensitive hypertensive rats. Two weeks later, the rats underwent either left renal denervation (Nx-RDNx; n = 10) or a sham operation (Nx-Sham; n = 10). After a further 6 weeks, kidney function and renal tissue were assessed. In this ex vivo study, using isolated glomeruli from Sprague-Dawley rats, the direct effects of catecholamine on NAD(P)H oxidase activity were assessed. RESULTS: After the Nx-RDNx or Nx-Sham surgery, urinary albumin excretion and the histologic glomerular sclerosis index were lower in the Nx-RDNx group than in the Nx-Sham group. Fluorescence staining for reactive oxygen species in isolated glomeruli was significantly weaker in the Nx-RDNx group. A lucigenin assay of NAD(P)H oxidase activity in isolated glomeruli indicated that renal denervation may have caused the reduction in reactive oxygen species through suppression of the activity of NAD(P)H oxidase. The levels of mRNA for NAD(P)H oxidase components and the levels of rac1 were higher in glomeruli from the Nx-Sham group than from the Nx-RDNx group. In this ex vivo study, although the NAD(P)H oxidase activity did not change with administration of either the alpha- or beta2-agonist, it increased with the beta1-agonist. CONCLUSIONS: Renal sympathetic denervation helps to protect against glomerular sclerosis, possibly by suppressing NAD(P)H oxidase activity, thereby decreasing glomerular reactive oxygen species.

N-acetyl-seryl-aspartyl-lysyl-proline attenuates renal injury and dysfunction in hypertensive rats with reduced renal mass: council for high blood pressure research.

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring peptide of which the plasma concentration is increased 4- to 5-fold by angiotensin-converting enzyme inhibitors. We reported previously that, in models of both hypertension and postmyocardial infarction, Ac-SDKP reduces cardiac inflammation and fibrosis. However, it is unknown whether Ac-SDKP can prevent or reverse renal injury and dysfunction in hypertension. In the present study, we tested the hypothesis that, in rats with 5/6 nephrectomy (5/6Nx)-induced hypertension, Ac-SDKP reduces renal damage, albuminuria, and dysfunction by decreasing inflammatory cell infiltration and renal fibrosis and by increasing nephrin protein. Ac-SDKP (800 microg/kg per day, SC via osmotic minipump) or vehicle was either started 7 days before 5/6Nx (prevention) and continued for 3 weeks or started 3 weeks after 5/6Nx (reversal) and continued for another 3 weeks. Rats with 5/6Nx developed high blood pressure, left ventricular hypertrophy, albuminuria, decreased glomerular filtration rate, and increased macrophage infiltration (inflammation) and renal collagen content (fibrosis). Ac-SDKP did not affect blood pressure or left ventricular hypertrophy in either group; however, it significantly reduced albuminuria, renal inflammation, and fibrosis and improved glomerular filtration rate in both prevention and reversal groups. Moreover, slit diaphragm nephrin protein expression in the glomerular filtration barrier was significantly decreased in hypertensive rats. This effect was partially prevented or reversed by Ac-SDKP. We concluded that Ac-SDKP greatly attenuates albuminuria and renal fibrosis and improves renal function in rats with 5/6Nx. These effects may be related to decreased inflammation (macrophages) and increased nephrin protein.

Podocytes and glomerular function with aging.

Kidney function declines with age in association with the development of age-associated glomerulosclerosis. The well-established structural and functional changes with age are reviewed briefly. The modification of aging pathology by calorie restriction is discussed. The role of the podocyte as a critical cell in the aging process is considered, using animal models and human biopsy material. Newer data on changes in gene expression and possible changes in biology in the glomerulus are discussed. There is speculation on the implications of this change in biology for human disease and progression.

[Clinical value of "zero-hour biopsy"]. / A "null-biopszia" klinikai értéke.

In spite of the improving results the long-term benefits of renal transplantation fell behind the expectable potential possibilities. The main cause of kidney graft loss is chronic allograft nephropathy following cardiovascular deaths. This is such a multiple etiologic clinical picture which may occur at any time. When adequate treatment is not available in time repeated development of chronic renal failure is unavoidable. The aim of my study is, how can we rise the number of transplanted kidney and the quality of them.