Tejas V. Patel

Serum Amyloid P Inhibits Fibrosis Through FcγR-Dependent Monocyte-Macrophage Regulation in Vivo

The fibrosis that occus in kidney after tissue injury can be inhibited by serum amyloid protein, which stimulates the cytokine interleukin 10. Suppressing Fibrosis When it comes to repairing damaged tissues or organs, there can be too much of a good thing. Although sometimes the body’s natural repair processes lead to complete restoration of normal tissue after an injury, at other times these processes continue unrestrained, leading to the replacement of normal tissue with fibrous scars—potentially causing organ failure and death. Such fibrosis is a common underlying feature of a wide variety of diseases, including cirrhosis of the liver, cardiovascular disease, rheumatoid arthritis, and progressive kidney disease. Even though fibroproliferative diseases are a leading cause of death in Western societies, there are currently no therapies that target fibrosis directly. Now, Duffield and colleagues describe a potential antifibrotic therapy for fibrosis of the kidney. The body’s repair processes are triggered by a range of harmful events, such as physical trauma, infections, toxin-induced damage, or an inadequate supply of blood. Tissue repair progresses through several stages, including an inflammatory response with an influx of white blood cells like monocytes, apoptosis and necrosis, the activation of wound-healing myofibroblasts, and the deposition and remodeling of extracellular matrix. When this matrix expands in an apparently uncontrolled manner, fibrous scars—consisting primarily of collagen—are formed. Compounds that inhibit the formation of these scars would be welcome tools for treating fibroproliferative diseases. Duffield’s group sought to determine whether serum amyloid P (SAP)—a protein previously shown to inhibit fibrosis in the lung and heart—might also suppress fibrosis in the kidney. SAP can bind ligands on the surface of apoptotic cells as well as Fcγ receptors on certain immune cells, and binding of SAP to the apoptotic cell ligands induces Fcγ receptor–dependent phagocytosis. These observations suggest that SAP might localize to sites of injury, aiding in the removal of wounded tissue. Duffield’s team showed that administration of human SAP to mice with experimentally induced kidney injury markedly decreased fibrosis. The SAP was recruited to the injured kidney where it was associated with dead cells. In the lung and heart, SAP appears to act by inhibiting fibrocytes, which directly produce collagen matrix. In the kidney, however, fibrocytes do not participate in fibrosis. Instead, the researchers determined, kidney fibrosis in mice depends on inflammatory monocytes and macrophages. SAP binds to and suppresses these cells, an effect that depends on expression of the anti-inflammatory cytokine IL-10 and regulated binding to Fcγ receptors, which are expressed on monocytes and macrophages. Given that a form of human SAP is now being tested in a phase 1 clinical trial in healthy volunteers, we may soon know whether it suppresses fibrotic disease in humans. New therapies that target chronic inflammation with fibrosis are urgently required. Increasing evidence points to innate activation of inflammatory cells in driving chronic organ fibrosis. Serum amyloid P is a naturally circulating soluble pattern recognition receptor, a member of the family of pentraxin proteins. It links danger-associated molecular pattern recognition to Fcγ receptor–mediated phagocytosis. Here we show that fibrosis progression in the mouse kidney is significantly inhibited by therapeutic administration of human serum amyloid P, regulated by activating Fcγ receptors, and dependent on inflammatory monocytes and macrophages, but not fibrocytes. Human serum amyloid P–mediated inhibition of mouse kidney fibrosis correlated with specific binding of human serum amyloid P to cell debris and with subsequent suppression of inflammatory monocytes and kidney macrophages in vitro and in vivo, and was dependent on regulated binding to activating Fcγ receptors and interleukin-10 expression. These studies uncover previously unidentified roles for Fcγ receptors in sterile inflammation and highlight serum amyloid P as a potential antifibrotic therapy through local generation of interleukin-10.

A Preeclampsia-like Syndrome Characterized by Reversible Hypertension and Proteinuria Induced by the Multitargeted Kinase Inhibitors Sunitinib and Sorafenib

The oral multitargeted kinase inhibitors (MTKI) sunitinib (SU11248, Sutent; Pfizer, New York) and sorafenib (BAY 43-9006, Nexavar; Bayer Pharmaceuticals, West Haven, CT, and Onyx Pharmaceuticals, Emeryville, CA) are increasingly used to treat malignant solid tumors. These small-molecule agents inhibit signaling through receptor tyrosine kinases such as vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, and c-KIT, among others (1). In the kidney, glomerular podocytes express VEGF and glomerular endothelial cells express VEGF receptors. Podocyte-specific deletion of a single VEGF allele causes proteinuria and capillary endotheliosis in rodents, and disrupted glomerular VEGF signaling is strongly implicated in the pathogenesis of human preeclampsia (2–4).

Safety of Ferumoxytol in Patients With Anemia and CKD

BACKGROUND Iron deficiency anemia is a common complication in patients with chronic kidney disease (CKD). Currently available intravenous (IV) iron replacement therapies have either inconvenient regimens of administration or adverse event profiles that limit their utility in the outpatient setting. Ferumoxytol is a novel, semisynthetic, carbohydrate-coated, superparamagnetic iron oxide nanoparticle that is administered IV as an injection. The main objective of this study was to assess the safety of ferumoxytol for the treatment of patients with CKD stages 1 to 5 and 5D. STUDY DESIGN Phase 3, randomized, double-blind, placebo-controlled, crossover, multicenter study of a single 510-mg dose of ferumoxytol versus saline as placebo. SETTING & PARTICIPANTS 750 patients with CKD stages 1 to 5 and 5D. INTERVENTION An IV injection of either 17 mL of ferumoxytol or saline placebo over 17 seconds on day 0 and the alternate agent on day 7. OUTCOMES & MEASUREMENTS Descriptive comparison of adverse events, laboratory tests, and vital signs. RESULTS Of 750 randomly assigned patients with CKD, 60% were not on dialysis therapy. 713 patients received ferumoxytol, and 711 received placebo. There were 420 adverse events reported; 242 in 152 patients (21.3%) with ferumoxytol and 178 in 119 patients (16.7%) with placebo. The incidence of related adverse events was 5.2% with ferumoxytol and 4.5% with placebo. The most common related adverse events after each treatment included symptoms related to the injection/infusion site, dizziness, pruritus, headache, fatigue, and nausea. Serious adverse events occurred in 21 patients (2.9%) after ferumoxytol and 13 patients (1.8%) after placebo. Serious related adverse events were observed in 1 patient (0.1%) after each treatment. There was no meaningful decrease in blood pressure after administration of ferumoxytol or placebo. LIMITATIONS Follow-up was 7 days after each study treatment. CONCLUSIONS Ferumoxytol is well tolerated and has a safety profile similar to placebo in anemic patients with CKD stages 1 to 5 and 5D.

Kidney Pathological Changes in Metabolic Syndrome: A Cross- sectional Study

BACKGROUND The worldwide prevalence of metabolic syndrome is increasing and has been associated with chronic kidney disease. Kidney pathological findings in patients with metabolic syndrome have not been well described, as was explored in this study. STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS We retrospectively screened clinical information for 146 patients who underwent elective nephrectomy for renal cell carcinoma between January 2005 and March 2007 at Brigham and Womens Hospital, Boston, MA. Twelve patients with metabolic syndrome were identified. Twelve age- and sex-matched patients who did not have any of the criteria for metabolic syndrome were used as controls. PREDICTOR Presence of metabolic syndrome defined by using Adult Treatment Panel III criteria. OUTCOMES Histological characteristics in each group, decrease in kidney function at 1-year follow-up. MEASUREMENTS Two pathologists blinded to the clinical diagnosis independently evaluated nephrectomy specimens using Banff criteria to objectively assess histological characteristics. RESULTS Baseline characteristics were similar between the 2 groups. On histopathologic examination, patients with metabolic syndrome compared with controls had a greater prevalence of tubular atrophy (P = 0.006), interstitial fibrosis (P = 0.001), and arterial sclerosis (P = 0.001), suggesting microvascular disease. Patients with metabolic syndrome had greater global (P = 0.04) and segmental glomerulosclerosis (P = 0.05). Glomerular volume and cross-sectional surface area were not different. The combined end point of tubular atrophy greater than 5%, interstitial fibrosis greater than 5%, and presence of arterial sclerosis was more prevalent in patients with metabolic syndrome (P = 0.003; odds ratio, 33; confidence interval, 2.9 to 374.3) than controls. After 1 year, estimated glomerular filtration rate was significantly lower in patients with metabolic syndrome compared with controls (P = 0.03). LIMITATIONS Small sample size, retrospective design. CONCLUSIONS We report a high prevalence of microvascular disease in patients with metabolic syndrome. There was a steeper decrease in kidney function over time in patients with metabolic syndrome, suggesting limited renal reserve. Aggressive screening and management may be warranted in patients with metabolic syndrome to protect kidney function.

Association of anemia and erythropoiesis stimulating agents with inflammatory biomarkers in chronic kidney disease

Inflammatory cytokines are important predictors of cardiovascular mortality especially in patients with chronic kidney disease. Here we explored the relationship of anemia and epoetin treatment to inflammatory cytokine levels in patients with chronic kidney disease. One hundred non-dialysis patients with chronic kidney disease over 18 years of age were evenly split into anemic and non-anemic cohorts. Of the 50 anemic patients, 23 were receiving erythropoiesis stimulating agents treatments. Levels of tumor necrosis factor (TNF)-alpha were found to be significantly higher and serum albumin was significantly lower with trends towards higher interleukin (IL)-6 and IL-8 in anemic compared to non-anemic patients. Further analysis by multiple logistic regression found that anemic patients treated with erythropoiesis stimulating agents had significantly higher odds for the upper two quartiles for IL-6, IL-8 and TNF-alpha compared to non-anemic patients. Our study found that the anemia of chronic kidney disease was associated with up regulation of TNF-alpha, and possibly IL-6 and IL-8 along with increased levels of these proinflammatory cytokines in patients treated with epoetin.

Role of vitamin D in chronic kidney disease.

Decline in renal function is related directly to cardiovascular mortality. However, traditional risk factors do not fully account for the high mortality in these patients. Activated vitamin D, a hormone produced by the proximal convoluted tubule of the kidney, appears to have beneficial effects beyond suppressing parathyroid hormone (PTH). However, activated vitamin D also can cause hypercalcemia and hyperphosphatemia in chronic kidney disease. Newer agents such as vitamin D receptor activators (eg, paricalcitol) suppress PTH with reduced risk of hypercalcemia and hyperphosphatemia. Recent evidence from animal and preliminary human studies supports an association between vitamin D receptor activators and reduced risk of cardiovascular disease deaths, irrespective of PTH levels. New pathways of vitamin D regulation also have been discovered, involving fibroblast growth factor-23 and klotho. Although considerable work has been performed to advance our understanding of the effects of vitamin D in health and chronic kidney disease, more investigations and randomized trials need to be performed to elucidate the mechanistic underpinnings of these effects.

A forgotten cause of kidney injury in chronic myelomonocytic leukemia.

Kidney failure is a known complication of hematologic malignancy. Common causes include direct parenchymal infiltration by leukemic cells, intrarenal leukostasis, tumor lysis syndrome, Fanconi syndrome, cryoglobulinemia, paraprotein deposition disease, obstruction, and chemotherapy-induced tubular or vascular toxicity. 1 Although these causes of kidney injury are well characterized, other less common causes of malignancy-associated kidney disease exist. These may be poorly recognized because they have been less frequently reported. We present a patient with chronic myelomonocytic leukemia (CMML) who developed an unusual kidney complication of his malignancy. The cause of his decreased kidney function was diagnosed only after performing kidney biopsy.

Endothelial activation markers in anemic non-dialysis chronic kidney disease patients.

Background/Aims: Anemia in chronic kidney disease is an independent predictor of cardiovascular disease (CVD). We explored the relationship between anemia and markers of inflammation and endothelial activation in non-dialysis chronic kidney disease (ND-CKD) patients to understand this mechanism. Methods: Cross-sectional analysis was performed on 30 adult ND-CKD patients for markers of inflammation and endothelial activation using a multiplexed immunoassay. Data were analyzed according to the anemic status defined by the modified World Health Organization criteria. Results: Seventeen patients were classified as anemic. Baseline characteristics by anemic status were similar except that anemic patients were older (p = 0.006), had lower estimated glomerular filtration rate (eGFR; p = 0.01) and higher prevalence of CVD (p = 0.02). Compared to non-anemic patients, log-transformed values of fibrinogen (p = 0.012); von Willebrand factor (vWF, p = 0.008), vascular cell adhesion molecule-1 (VCAM-1, p = 0.025) and C-reactive protein (p = 0.043) were elevated in anemic patients. Serum ferritin (p = 0.93) and serum albumin (p = 0.06) were not different. Age and eGFR-adjusted logistic regression analysis showed that anemic patients had increased odds for a composite of higher median values of fibrinogen, vWF and VCAM-1 (p = 0.01, odds ratio 8.1, 95% CI 1.08–111.0). Conclusion: We report the association of anemia with elevated markers of endothelial activation in ND-CKD patients. Longitudinal studies are needed to confirm our findings.

The Case ∣ Progressive hypertension and proteinuria on anti-angiogenic therapy

A 76-year-old woman with type II diabetes and hypertension was diagnosed with gastrointestinal stromal tumor. At the time of diagnosis, she was on insulin glargine 10 U daily and atenolol 50 mg daily. She had a blood pressure (BP) of 104/58 mm Hg, serum creatinine (SCr) of 1.2 mg per 100 ml, and no proteinuria. For treatment of the gastrointestinal stromal tumor, she was started on imatinib mesylate. Sixteen months into this therapy, the tumor progressed. At that point, she had a BP of 130/78 mm Hg, weight of 53.4 kg, SCr of 1.2 mg per 100 ml, and still no proteinuria. Imatinib was replaced with sunitinib 37.5 mg daily (Sutent). Over the next 20 weeks, her BP gradually rose to 166/76 mm Hg. A total of 30 weeks after initiation of sunitinib, her BP was 142/49 mm Hg, weight was 59.2 kg, SCr was 2.4 mg per 100 ml, and protein/creatinine ratio was 7.2 (g/g). When she was first seen in the renal clinic 3 months later, her BP was 156/69 mm Hg, weight was 59.4 kg, jugular venous pressure was 6 cm, cardiopulmonary examination was unremarkable, renal artery bruits were not appreciated, but 1+ pitting pedal edema was present. Urinalysis showed 3+ protein with a bland sediment. SCr was 1.8 mg per 100 ml and urine protein/creatinine was 10.4 (g/g) (Figure 1). Serum complement and protein electrophoreses were normal; ANA, cryoglobulin, and rheumatoid factor were negative; and there was no evidence of microangiopathic hemolysis. Figure 1 Development and resolution of proteinuria during sunitinib treatment

Cardiovascular complications in diabetic kidney disease.

Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD). Due to an explosion in the incidence and the prevalence of Type 2 DM, the burden of CKD is expected to increase proportionately. Both DM and CKD are associated with a high incidence of cardiovascular (CV) morbidity and mortality, and it is important to understand the unique nature of CV disease in patients with the combination of these two conditions. In this report, we review the traditional and nontraditional risk factors that underlie the high risk of CV disease in this population, with a particular focus on vascular calcification, mineral metabolism, and therapeutic paradigms for the treatment of cardiovascular disease in this unique and high‐risk population.