J. Ashley Jefferson

VEGF Inhibition and Renal Thrombotic Microangiopathy

The glomerular microvasculature is particularly susceptible to injury in thrombotic microangiopathy, but the mechanisms by which this occurs are unclear. We report the cases of six patients who were treated with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in whom glomerular disease characteristic of thrombotic microangiopathy developed. To show that local reduction of VEGF within the kidney is sufficient to trigger the pathogenesis of thrombotic microangiopathy, we used conditional gene targeting to delete VEGF from renal podocytes in adult mice; this resulted in a profound thrombotic glomerular injury. These observations provide evidence that glomerular injury in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy.

Hyperuricemia exacerbates chronic cyclosporine nephropathy

BACKGROUND Hyperuricemia frequently complicates cyclosporine (CSA) therapy. The observation that longstanding hyperuricemia is associated with chronic tubulointerstitial disease and intrarenal vasoconstriction raised the hypothesis that hyperuricemia might contribute to chronic CSA nephropathy. METHODS CSA nephropathy was induced by the administration of CSA (15 mg/kg/day) for 5 and 7 weeks to rats on a low salt diet (CSA group). The effect of hyperuricemia on CSA nephropathy was determined by blocking the hepatic enzyme uricase with oxonic acid (CSA-OA). Control groups included rats treated with vehicle (VEH) and oxonic acid alone (OA). Histological and functional studies were determined at sacrifice. RESULTS CSA treated rats developed mild hyperuricemia with arteriolar hyalinosis, tubular injury and striped interstitial fibrosis. CSA-OA treated rats had higher uric acid levels in association with more severe arteriolar hyalinosis and tubulointerstitial damage. Intrarenal urate crystal deposition was absent in all groups. Both CSA and CSA-OA treated rats had increased renin and decreased NOS1 and NOS3 in their kidneys, and these changes are more evident in CSA-OA treated rats. CONCLUSION An increase in uric acid exacerbates CSA nephropathy in the rat. The mechanism does not involve intrarenal uric acid crystal deposition and appears to involve activation of the renin angiotensin system and inhibition of intrarenal nitric oxide production.

Increased Oxidative Stress Following Acute and Chronic High Altitude Exposure

The generation of reactive oxygen species is typically associated with hyperoxia and ischemia reperfusion. Recent evidence has suggested that increased oxidative stress may occur with hypoxia. We hypothesized that oxidative stress would be increased in subjects exposed to high altitude hypoxia. We studied 28 control subjects living in Lima, Peru (sea level), at baseline and following 48 h exposure to high altitude (4300 m). To assess the effects of chronic altitude exposure, we studied 25 adult males resident in Cerro de Pasco, Peru (altitude 4300 m). We also studied 27 subjects living in Cerro de Pasco who develop excessive erythrocytosis (hematocrit > 65%) and chronic mountain sickness. Acute high altitude exposure led to increased urinary F(2)-isoprostane, 8-iso PGF(2 alpha) (1.31 +/- 0.8 microg/g creatinine versus 2.15 +/- 1.1, p = 0.001) and plasma total glutathione (1.29 +/- 0.10 micromol versus 1.37 +/- 0.09, p = 0.002), with a trend to increased plasma thiobarbituric acid reactive substance (TBARS) (59.7 +/- 36 pmol/mg protein versus 63.8 +/- 27, p = NS). High altitude residents had significantly elevated levels of urinary 8-iso PGF(2 alpha) (1.3 +/- 0.8 microg/g creatinine versus 4.1 +/- 3.4, p = 0.007), plasma TBARS (59.7 +/- 36 pmol/mg protein versus 85 +/- 28, p = 0.008), and plasma total glutathione (1.29 +/- 0.10 micromol versus 1.55 +/- 0.19, p < 0.0001) compared to sea level. High altitude residents with excessive erythrocytosis had higher levels of oxidative stress compared to high altitude residents with normal hematological adaptation. In conclusion, oxidative stress is increased following both acute exposure to high altitude without exercise and with chronic residence at high altitude.

Podocyte Biology for the Bedside

The explosion of podocyte biology during the last decade has radically altered our views on the pathophysiologic process of proteinuria, glomerular disease, and progressive kidney disease. In this review, we highlight some of these landmark findings, but focus on recent advances in the field and implications for translating this biology into therapy for podocyte diseases.

Therapy of membranous nephropathy associated with malignancy and secondary causes

Membranous nephropathy (MN) most commonly is idiopathic, but secondary causes are common in children and in older adults. The most common secondary causes of MN in industrialized countries include malignancy and systemic lupus erythematosis. Infectious causes (hepatitis B, quartan malaria, schistosomiasis) remain the most common etiologies in endemic areas. In this article we describe the clinical approach to patients with MN associated with malignancy and other common secondary causes. Treatment of secondary MN generally targets the primary disease rather than the renal lesion.

High Altitude Renal Syndrome (HARS)

More than 140 million people live permanently at high altitude (>2400 m) under hypoxic conditions that challenge basic physiology. Here we present a short historical review of the populating of these regions and of evidence for genetic adaptations and environmental factors (such as exposure to cobalt) that may influence the phenotypic responses. We also review some of the common renal physiologic responses focusing on clinical manifestations. The frequent presentation of systemic hypertension and microalbuminuria with relatively preserved GFR coupled with the presence of polycythemia and hyperuricemia suggests a new clinical syndrome we term high altitude renal syndrome (HARS). ACE inhibitors appear effective at reducing proteinuria and lowering hemoglobin levels in these patients.

Podocyte Disorders: Core Curriculum 2011

There are approximately one million glomeruli in each human kidney. Each glomerulus is composed of a tuft of capillary loops supported by the mesangium and enclosed in a pouch-like extension of the renal tubule of the nephron known as Bowman’s capsule. The glomerulus consists of four resident cell types, the mesangial cell, the glomerular endothelial cell, the visceral epithelial cell (podocyte), and the parietal epithelial cell lining Bowman’s basement membrane. Recent experimental and clinical advances have identified the podocyte as the predominant cell of injury in glomerular diseases typified by heavy proteinuria, which is the focus of this article.

Has the circulating permeability factor in primary FSGS been found

A circulating permeability factor has long been implicated in the pathogenesis of primary focal segmental glomerulosclerosis (FSGS). Recent evidence in animal models, and now in several cohorts of patients with primary FSGS, suggest that the soluble urokinase-type plasminogen-activator receptor (suPAR) might fulfill at least a role as biomarker and perhaps even as contributing factor. Although ongoing studies are needed, confirmation of these findings might lead to new diagnostic and therapeutic strategies for this often resistant glomerular disease, as well as a better understanding of podocyte dysfunction.

Renal Function and Proteinuria after Successful Immunosuppressive Therapies in Patients with FSGS

BACKGROUND AND OBJECTIVES In the FSGS Clinical Trial, 22 cyclosporine-treated and 20 mycophenolate/dexamethasone-treated patients experienced a complete or partial remission after 26 weeks, completed 52 weeks of treatment, and were studied through 78 weeks. Herein, changes in the urine protein/creatinine ratio (UP/C) and estimated GFR (eGFR) throughout the entire study period are defined. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS The FSGS Clinical Trial, which was conducted from November 2004 to January 2010, enrolled patients aged 2-40 years, with eGFR ≥40 ml/min per 1.73 m(2) and UP/C >1 mg/mg after ≥4 weeks of corticosteroid therapy. Both groups received lisinopril or losartan throughout the study. UP/C and eGFR were measured at 0, 26, 52, and 78 weeks. RESULTS The median UP/C in the cyclosporine- and mycophenolate/dexamethasone-responsive patients fell by 89.8% and 82.7% at 52 weeks; the fall was largely sustained at 78 weeks (74.7% and 80.3%, respectively). The mean eGFR fell by 19.4% in the cyclosporine group and rose by 7.0% in the mycophenolate mofetil/dexamethasone group at 52 weeks, but subsequently rose by 16.4% and fell by 2.6%, respectively, in the two groups from 52 to 78 weeks. CONCLUSIONS In this subset of responding FSGS patients, the improvement in UP/C after cyclosporine or mycophenolate/dexamethasone treatment was largely sustained for 6 months after therapy. Reduction in eGFR in the cyclosporine group was improved 6 months after cyclosporine was stopped although the levels were lower than baseline in seven patients who entered the study with decreased eGFR.

Diagnosis: Should renal biopsies be performed in the very elderly?

As the population ages, more elderly people are developing kidney disease. Nephrologists are often reluctant to perform renal biopsy in elderly patients, but in many cases, the diagnostic benefits of this procedure outweigh the risks.