The Early Diagnosis and Treatment of Chronic Renal Insufficiency.

BACKGROUND: Chronic renal insufficiency (CRI) is becoming more common and has an increasing impact on public health. In Germany, approximately one in ten adults has CRI. Its most serious consequence is generally not the development of end-stage renal failure, but rather the markedly increased cardiovascular risk as kidney function declines. METHODS: This review is based on the findings of a selective search in PubMed for literature about the treatment options for CRI, and on our overview of the existing guideline recommendations on diagnostic testing. RESULTS: Patients with diabetes mellitus and arterial hypertension are at especially high risk of developing CRI. For these patients, some of the guidelines recommend regular testing for albuminuria and measurement of the glomerular filtration rate (GFR), though sometimes only when specific risk constellations are present. The treatment of CRI has evolved in recent years. At first, aside from general measures, only RAS inhibitors were available as a specific therapy for CRI. With the extension of the approval of SGLT-2 inhibitors to non-diabetic CRI patients, the options for treatment have become wider. Two randomized controlled trials have revealed the benefit of SGLT-2 inhibitors with respect to their primary combined endpoints: time to a specified eGFR reduction and renal/cardiovascular death (HR 0.61 [0.51; 0.72] and 0.72 [0.64; 0.82]). The potential side effects and contraindications of SGLT-2 inhibitors must be taken into account. A further treatment option for diabetics with CRI has become available with the approval of the non-steroidal mineralocorticoid receptor antagonist finerenone. CONCLUSION: In patients with risk factors, renal function should be regularly tested.

Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients: A Randomized Clinical Trial.

Importance: Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported. Objective: To evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients. Design, Setting, and Participants: This prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete. Interventions: Randomized 1:1 to daprodustat or darbepoetin alfa. Main Outcomes and Measures: The primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, -0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability. Results: A total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of -0.10 g/dL (95% CI, -0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, -11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa. Conclusions and Relevance: This randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population. Trial Registration: ClinicalTrials.gov Identifier: NCT03029208.

[Autosomal polycystic kidney disease]. / Polyzystische Nierenerkrankungen.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic kidney disease. The clinical course is highly variable, association to certain genetic mutations only weak. Great progress has been made in recent years in determining the pathophysiology of the disease. Diagnosis of ADPKD is almost always possible by ultrasound, genetic examination is confined to selected cases. In addition, imaging is important for prognosis where MRI and computer tomography are superior for determination of total kidney volume. Until recently, supportive therapy has been the only available therapeutic option. This includes optimal antihypertensive therapy with a goal blood pressure below 110/75 mm mercury, at least with normal renal function and without any other contraindication. In addition, fluid intake should be increased to 2.5-4 l per day. Finally, tolvaptan is available as a specific therapy in selected countries. This therapy should be restricted to cases with rapid progressive and early renal failure due to costs and side effects. The value of this agent in later stages of chronic renal failure is currently being evaluated in clinical studies. Additional specific therapies are in early clinical evaluations.

Antitumoral effects of calcitriol in basal cell carcinomas involve inhibition of hedgehog signaling and induction of vitamin D receptor signaling and differentiation.

Activation of the Hedgehog (Hh)-signaling pathway due to deficiency in the Hh receptor Patched1 (Ptch) is the pivotal defect leading to formation of basal cell carcinoma (BCC). Recent reports provided evidence of Ptch-dependent secretion of vitamin D(3)-related compound, which functions as an endogenous inhibitor of Hh signaling by repressing the activity of the signal transduction partner of Ptch, Smoothened (Smo). This suggests that Ptch-deficient tumor cells are devoid of this substance, which in turn results in activation of Hh-signaling. Here, we show that the application of the physiologically active form of vitamin D(3), calcitriol, inhibits proliferation and growth of BCC of Ptch mutant mice in vitro and in vivo. This is accompanied by the activation of the vitamin D receptor (Vdr) and induction of BCC differentiation. In addition, calcitriol inhibits Hh signaling at the level of Smo in a Vdr-independent manner. The concomitant antiproliferative effects on BCC growth are stronger than those of the Hh-specific inhibitor cyclopamine, even though the latter more efficiently inhibits Hh signaling. Taken together, we show that exogenous supply of calcitriol controls the activity of 2 independent pathways, Hh and Vdr signaling, which are relevant to tumorigenesis and tumor treatment. These data suggest that calcitriol could be a therapeutic option in the treatment of BCC, the most common tumor in humans.

Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID).

INTRODUCTION: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. METHODS: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. RESULTS: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm). CONCLUSIONS: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

Fibrosis and evidence for epithelial-mesenchymal transition in the kidneys of patients with staghorn calculi.

OBJECTIVES: • To quantify fibrotic lesions in renal tissues obtained from patients with large calculi and to evaluate association with renal function. • Presence of epithelial-mesenchymal transition (EMT) in stone-containing renal tissues was investigated. PATIENTS, SUBJECTS AND METHODS: • In all, 50 patients with nephrolithiasis with large calculi and matched healthy controls (37) were recruited. • Plasma creatinine (Cr) and corrected Cr clearance (CCr) were determined in all subjects. • Of the 50 patients, 38 had renal tissue available for histological analysis. Fibrosis was assessed by Masson's trichrome staining. Co-expression of epithelial cytokeratins and mesenchymal markers [α-smooth muscle actin (αSMA) and vimentin] in renal tubular cells was detected by dual immunofluorescence staining. • Expression of fibronectin, transforming growth factor ß1 (TGF-ß1) and CD68 were investigated. RESULTS: • Overall, the kidney function of the patients was significantly reduced, indicated by increased plasma Cr and decreased corrected CCr compared with healthy controls. • Inflammation grading in renal tissues of the patients was correlated with the percentage of the fibrotic area. Renal fibrosis was inversely correlated with renal function. • Cytokeratins co-expressed with αSMA and vimentin were found in nephrolithiatic renal tubular cells, and these cells strongly expressed fibronectin and TGF-ß1. • Infiltration of CD68-positive cells was a common finding in the inflamed renal sections. CONCLUSIONS: • Kidneys of large stone-forming patients had robust signs of inflammation and fibrosis, and there was a close correlation of renal fibrosis with renal dysfunction. • This is the first study to show evidence for renal tubular cells showing signs of EMT in large stone-containing kidneys. Plausibly, TGF-ß1 triggers EMT, which at least in part contributes to large stone-induced renal fibrosis.

The role of bone morphogenetic protein-5 (BMP-5) in human nephrosclerosis.

BACKGROUND: Bone morphogenetic protein-5 (BMP-5) has been shown to be essential for nephrogenesis. Its role in adult kidney and in patients with hypertensive nephrosclerosis is still unknown. METHODS: BMP-5 expression was evaluated by immunostaining and real-time PCR in tissue samples from normal and nephrosclerotic human kidneys. The impact of transforming growth factor-ß (TGF-ß), tumor necrosis factor-α (TNF-α) and angiotensin-II (AT-II) on expression of BMP-5 and its receptors was quantified in proximal tubular cells (HK-2). Functional characteristics of BMP-5 were evaluated by testing its influence on TGF-ß-induced epithelial-to-mesenchymal transition (EMT), TNF-α-induced apoptosis of HK-2 cells and inflammatory cell infiltration. RESULTS: BMP-5 expression was localized in tubular epithelial cells and significantly decreased in nephrosclerotic kidneys. Stimulation of HK-2 cells with TGF-ß, TNF-α and AT-II resulted in a significant decreased expression of BMP-5 and its receptors. BMP-5 attenuated TGF-ß-induced EMT, TNF-α-induced apoptosis and migration of mononuclear cells. CONCLUSIONS: BMP-5 is expressed in the tubuli of adult kidneys. Its decreased expression in nephrosclerosis along with its regenerative capabilities in HK-2 cells may point to a protective role in hypertensive nephrosclerosis.

Fulminant plasmapheresis-refractory thrombotic microangiopathy associated with advanced gastric cancer.

We report a case of a 27-year-old female with thrombotic microangiopathy as an initial presentation of an unexpected disseminated gastric carcinoma. Based on clinical features and laboratory findings, thrombotic thrombocytopenic purpura (TTP) was diagnosed and plasma exchange started. However, she had responded poorly to plasmapheresis, developed multiorgan failure and died 72 h after admission. Autopsy revealed a disseminated gastric adenocarcinoma with metastatic infiltration of dura mater and disseminated tumor cell emboli in the microcirculation of the liver and lungs. Genetic analysis revealed amplification of KRAS oncogene and aberrations in DCC tumor suppressor gene, which can explain the young age and advanced disease at presentation. The role of plasmapheresis in cancer-associated TTP is uncertain. Plasmapheresis delivers fresh coagulation factors and may theoretically promote microthrombi formation and lead to worsening of the disease. Thrombotic thrombocytopenic purpura seems to be a late and prognostically poor manifestation of an underlying malignancy, with majority of patients dying soon after diagnosis. It is important to be aware of this possibility in thrombotic microangiopathy, especially with atypical features and poor response to standard treatment.

Retrospective analysis of long-term lipid apheresis at a single center.

We retrospectively analyzed 10 906 lipid apheresis sessions (heparin-induced lipoprotein precipitation, direct adsorption of lipoproteins, double filtration plasmapheresis, dextran sulfate adsorption, and immunoadsorption) in 38 patients who were consecutively treated in our department during the last 20 years. The incidences of major cardiovascular events (MACE) (death, cerebrovascular accident, myocardial infarction, limb amputation, and renal vascular involvement) were taken separately as primary end-points or as a combined end-point. The time-course of secondary end-points (coronary and extracranial status of arteries, left ventricular function, occlusive artery disease, and calculated glomerular filtration rate [cGFR]) were also evaluated, as well as the extent of the reduction in plasma lipids and lipoproteins and the incidence of therapy associated side-effects. MACE decreased from 7.02% events per patient per year at the start of lipid apheresis to 1.17% during lipid apheresis and the rate of myocardial revascularization decreased from 22.8% to 3.8% per patient per year. Classical (diabetes mellitus, arterial hypertension, and smoking history), as well as novel risk factors (cGFR < 60 mL/min, statin withdrawal, mixed hyperlipoproteinemia, and elevated lipoprotein (a)) were associated with an elevated risk for MACE. All applied methods had comparable effects. All lipid apheresis methods proved to be safe and suitable for long-term treatment. The present data demonstrate that treatment with lipid apheresis is very effective and leads to long-term reduction in cardiovascular mortality and morbidity.

Role of CX3C-chemokine CX3C-L/fractalkine expression in a model of slowly progressive renal failure.

BACKGROUND: The chemokine/chemokine receptor pair CX(3)C-L/CX(3)C-R is suspected to play a role in renal fibrogenesis. The aim of this study was to investigate their function in an animal model of slowly progressive chronic renal failure. METHODS: Functional data were analysed in folic acid nephropathy (FAN) at different time points (up to day 142 after induction). Immunostaining for CX(3)C-L, CD3, S100A4, collagen type I, fibronectin, alpha-smooth muscle actin, Tamm-horsfall protein, aquaporin 1 and 2 as well as quantitative real-time PCR (qRT-PCR) for CX(3)C-L, CX(3)C-R and fibroblast-specific protein 1 (FSP-1) were performed. Additionally, regulatory mechanisms and functional activity of CX(3)C-L in murine proximal and distal tubular epithelial cells as well as in fibroblasts were investigated. RESULTS: CX(3)C-L/GAPDH ratio was upregulated in FAN 3.4-fold at day 7 further increasing up to 7.1-fold at day 106. The expression of mRNA CX(3)C-L correlated well with CX(3)C-R (R(2) = 0.96), the number of infiltrating CD3+ cells (R(2) = 0.60) and the degree of tubulointerstitial fibrosis (R(2) = 0.56) and moderately with FSP-1 (R(2) = 0.33). Interleukin-1beta, tumour necrosis factor-alpha, transforming growth factor-beta as well as the reactive oxygen species (ROS) H(2)O(2) were identified by qRT-PCR as inductors of CX(3)C-L/fractalkine (FKN) in tubular epithelial cells. Functionally, CX(3)C-L/FKN chemoattracts peripheral blood mononuclear cells, activates several aspects of fibrogenesis and induces the mitogen-activated protein kinases in renal fibroblasts. CONCLUSIONS: In FAN, there is a good correlation between the expression of CX(3)C-L with markers of interstitial inflammation and fibrosis which may result from upregulation by pro-inflammatory and pro-fibrotic cytokines as well as by ROS in tubular epithelial cells. The FKN system may promote renal inflammation and renal fibrogenesis.

Pathogenesis of tubulointerstitial fibrosis in chronic allograft dysfunction.

The term chronic allograft nephropathy (CAN) was originally coined in 1991 to replace chronic rejection which was used too generalized. However, the revised Banff classification, published in 2007, eliminated the term CAN again because it was felt that the term was used too broadly and prevented the search for the underlying cause. Interstitial fibrosis and tubular atrophy are integral parts of chronic allograft dysfunction and represent in the new classification a separate entity with or without the identification of a specific etiology. Myofibroblasts are the key, albeit not exclusive, effector cells in renal fibrogenesis resulting in upregulated extracellular matrix synthesis and eventually in interstitial fibrosis. These cells are formed mainly by stimulation of resident interstitial fibroblasts but also by differentiation processes of periadventitial cells, bone marrow derived cells and by a process entitled epithelial mesenchymal transition (EMT) of tubular epithelial cells. EMT has been described by many groups to be of high prevalence in renal allograft dysfunction contributing to matrix accumulation and renal function deterioration. This is of particular interest because immunosuppressive therapy has differential effects on EMT with calcineurin inhibitors in particular inducing the process. Moreover, specific therapies inhibiting EMT have been applied in experimental studies although the effects of their application in chronic allograft dysfunction remain to be studied. At the same time, immunosuppression may interfere with physiologic clearance of myofibroblasts by apoptosis, explaining in part the high prevalence of interstitial fibrosis in allograft biopsies. The Fas system has been identified to be mainly responsible for this physiologic apoptosis in non-renal scarring models; however, its relevance for renal fibrosis and particular fibrosis in renal allograft dysfunction remains to be determined. These findings point to a cautious and individualized use of immunosuppressive therapy in patients with allografts and particular those with chronic allograft dysfunction not because of rejection processes. Protocols using CNI-free immunosuppression are interesting options to prevent fibrosis in chronic allograft dysfunction.

Prenatal dexamethasone exposure does not alter blood pressure and nephron number in the young adult marmoset monkey.

The influence of prenatal factors on the development of arterial hypertension has gained considerable interest in recent years. Prenatal dexamethasone exposure was found to induce hypertension and to alter nephron number and size in rodents and sheep. However, it is not clear whether these findings are applicable to nonhuman primates. Thus, we examined the effects of prenatal dexamethasone treatment on blood pressure (BP) and nephron number in marmoset monkeys. Fifty-two marmosets were allotted to 3 groups according to the gestational stage during which their mothers were exposed to oral 5-mg/kg dexamethasone for 7 days (gestation period: 20 weeks): (1) the early dexamethasone group at week 7; (2) the late dexamethasone group at week 13; and (3) the control group. BP was determined by telemetric (n=12) or cuff measurements (n=30), along with cystatin C, proteinuria, and body weight. All of the animals were euthanized at the age of 24 months, and glomerular number and volume were determined. Prenatal exposure to dexamethasone did not lead to a significant difference between the groups with regard to BP, kidney morphology and function, or body weight. BP correlated significantly with body weight, relative kidney weight, and mean glomerular volume and the body weight with the glomerular volume regardless of dexamethasone treatment. In conclusion, prenatal exposure to dexamethasone in marmosets does not, in contrast to other mammals studied, result in hypertension or changes in kidney morphology. Our data support the role of body weight as a predictor of elevated glomerular volume and BP development rather than prenatal dexamethasone exposure.

Neuropilin-1 and neuropilin-2 are differentially expressed in human proteinuric nephropathies and cytokine-stimulated proximal tubular cells.

Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) are transmembrane glycoproteins with large extracellular domains that interact with class 3 semaphorins, vascular endothelial growth factor (VEGF) family members, and ligands, such as hepatocyte growth factor, platelet-derived growth factor BB, transforming growth factor-beta1 (TGF-beta1), and fibroblast growth factor2 (FGF2). Neuropilins (NRPs) have been implicated in tumor growth and vascularization, as novel mediators of the primary immune response and in regeneration and repair; however, their role in renal pathophysiology is largely unknown. Here, we report upregulation of tubular and interstitial NRP2 protein expression in patients with focal segmental glomerulosclerosis (FSGS). In an additional cohort of patients with minimal change disease (MCD), membranous nephropathy (MN), and FSGS, elevated NRP2 mRNA expression in kidney biopsies inversely correlated with estimated glomerular filtration rate (eGFR) at the time of biopsy. Furthermore, upregulation of NRP2 mRNA correlated with post-bioptic decline of kidney function. Expression of NRP1 and NRP2 in human proximal tubular cells (PTCs) was differentially affected after stimulation with TGF-beta1, interleukin-1beta (IL-1beta), and oncostatin M (OSM). Although the pro-fibrotic mediators, TGF-beta1 and IL-1beta, induced upregulation of NRP2 expression but downregulation of NRP1 expression, OSM stimulated the expression of both NRP1 and NRP2. Basal and OSM-induced NRP1 mRNA expression, as well as TGF-beta1-induced NRP2 mRNA and protein expression were partially mediated by MEK1/2-ERK1/2 signaling. This is the first report suggesting a differential role of NRP1 and NRP2 in renal fibrogenesis, and TGF-beta1, IL-1beta, and OSM represent the first ligands known to stimulate NRP2 expression in mammalian cells.

Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels.

Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca(2+)-activated K(+) channel (K(Ca)3.1) has been proposed to promote mitogenesis in several cell types and contribute to disease states characterized by excessive proliferation. Here, we hypothesized that K(Ca)3.1 activity is pivotal for renal fibroblast proliferation and that deficiency or pharmacological blockade of K(Ca)3.1 suppresses development of renal fibrosis. We found that mitogenic stimulation up-regulated K(Ca)3.1 in murine renal fibroblasts via a MEK-dependent mechanism and that selective blockade of K(Ca)3.1 functions potently inhibited fibroblast proliferation by G(0)/G(1) arrest. Renal fibrosis induced by unilateral ureteral obstruction (UUO) in mice was paralleled by a robust up-regulation of K(Ca)3.1 in affected kidneys. Mice lacking K(Ca)3.1 (K(Ca)3.1(-/-)) showed a significant reduction in fibrotic marker expression, chronic tubulointerstitial damage, collagen deposition and alphaSMA(+) cells in kidneys after UUO, whereas functional renal parenchyma was better preserved. Pharmacological treatment with the selective K(Ca)3.1 blocker TRAM-34 similarly attenuated progression of UUO-induced renal fibrosis in wild-type mice and rats. In conclusion, our data demonstrate that K(Ca)3.1 is involved in renal fibroblast proliferation and fibrogenesis and suggest that K(Ca)3.1 may represent a therapeutic target for the treatment of fibrotic kidney disease.

The role of FGF-2 in renal fibrogenesis.

Basic fibroblast growth factor (FGF-2) is a pleiotropic cytokine which exerts its effects via four different high affinity receptors (FGFR-1 to -4) which function as protein tyrosine kinases. In the kidney, FGF-2 is expressed in epithelial cells already during fetal development. During later stages, expression of the cytokine can be found in distal tubular epithelial cells, glomerular cells and few interstitial cells. Expression in fibroblasts is robustly upregulated in chronic kidney scarring pointing to an important role in fibrogenesis. Functional studies have demonstrated that FGF-2 exerts mainly proliferative effects on a variety of renal cell types. In regard to fibrogenesis, the expression and induction of proliferation in interstitial fibroblasts may be the most important function. FGF-2 is one of the key factors contributing to autocrine fibroblast proliferation in post-inflammatory matrix synthesis. In addition, FGF-2 facilitates epithelial to mesenchymal transition of tubular epithelial cells contributing early to an increase of matrix producing cells. However, the cytokine does not contribute directly to extracellular matrix synthesis. Still, many aspects of FGF-2 in renal fibrogenesis remains to be evaluated.

Role of basic fibroblast growth factor (FGF-2) in diabetic nephropathy and mechanisms of its induction by hyperglycemia in human renal fibroblasts.

Basic fibroblast growth factor (FGF-2) plays a role in renal fibrogenesis, although its potential implications for tubulointerstitial involvement in diabetic nephropathy are unknown. We evaluated the expression of FGF-2 in kidney biopsies from patients with diabetic nephropathy and studied the mechanisms of its induction in human renal fibroblasts under hyperglycemia. Tubulointerstitial expression of FGF-2 was significantly upregulated in diabetic nephropathy compared with control kidneys with a good correlation to the degree of the injury. Fibroblasts cultivated in high glucose displayed increased FGF-2 mRNA as well as protein synthesis and secretion compared with normal glucose. Proliferation rates under hyperglycemia were significantly higher and could be almost completely inhibited by addition of a neutralizing FGF-2 antibody. Alterations in proliferation were associated with changes in p27(kip1) expression. Hyperglycemia induced the expression of PKC-beta1 and PKC-beta2; however, only inhibition of PKC-beta1 but not PKC-beta2 led to a significant decrease of FGF-2 levels. Relevance of the culture findings and functional association was corroborated by colocalization of FGF-2 and PKC-beta in human diabetic kidneys in vivo. High glucose stimulated fibronectin synthesis and secretion, which could be substantially prevented by inhibition of PKC-beta1 and to a lesser extent by inhibiting the FGF-2. Expression of active phosphorylated form of p38 mitogen-activated protein kinase was upregulated under hyperglycemia; however, its inhibition had no effects on FGF-2 synthesis. Our results implicate a role of FGF-2 in high glucose-altered molecular signaling in pathogenesis of diabetic renal disease.