William E. Smoyer

Membranoproliferative Glomerulonephritis Type II (Dense Deposit Disease): An Update

Membranoproliferative glomerulonephritis type II (MPGN II) is a rare disease characterized by the deposition of abnormal electron-dense material within the glomerular basement membrane of the kidney and often within Bruchs membrane in the eye. The diagnosis is made in most patients between the ages of 5 and 15 yr, and within 10 yr, approximately half progress to end-stage renal disease, occasionally with the late comorbidity of visual impairment. The pathophysiologic basis of MPGN II is associated with the uncontrolled systemic activation of the alternative pathway (AP) of the complement cascade. In most patients, loss of complement regulation is caused by C3 nephritic factor, an autoantibody directed against the C3 convertase of the AP, but in some patients, mutations in the factor H gene have been identified. For the latter patients, plasma replacement therapy prevents renal failure, but for the majority of patients, there is no proven effective treatment. The disease recurs in virtually all renal allografts, and a high percentage of these ultimately fail. The development of molecular diagnostic tools and new therapies directed at controlling the AP of the complement cascade either locally in the kidney or at the systemic level may lead to effective treatments for MPGN II.

Management of Childhood Onset Nephrotic Syndrome

The therapeutic approach to childhood nephrotic syndrome is based on a series of studies that began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children in 1967. The characteristics of children presenting with nephrotic syndrome have changed over recent decades with greater frequency of the challenging condition focal segmental glomerulosclerosis and a greater prevalence of obesity and diabetes mellitus, which may be resistant to glucocorticoids in the former and exacerbated by long-term glucocorticoid therapy in the latter 2 conditions. The Childrens Nephrotic Syndrome Consensus Conference was formed to systematically review the published literature and generate a childrens primary nephrotic syndrome guideline for use in educational, therapeutic, and research venues.

Regulation of podocyte structure during the development of nephrotic syndrome.

Abstract Nephrotic syndrome is a common kidney disease seen in both children and adults. The clinical syndrome includes massive proteinuria, hypoalbuminemia, edema, and usually hypercholesterolemia. Development of these clinical changes is closely correlated with profound structural changes in glomerular epithelial cells, or podocytes, which together with the glomerular basement membrane and endothelium comprise the kidney’s blood filtration barrier. Although relatively little is known about the cellular or molecular changes which occur within podocytes during the development of nephrotic syndrome, cytoskeletal proteins very likely play a central role in these changes since they are primarily responsible for the maintenance of cell structure in almost all cells. This review focuses on: (a) the structure and function of podocytes in both the normal state and during nephrotic syndrome and (b) the potential roles of several cytoskeleton-associated proteins identified in podocytes in the development of and/or recovery from the pathophysiological cytoskeletal changes which occur in podocytes during nephrotic syndrome.

Amino acid loss and nitrogen balance in critically ill children with acute renal failure: a prospective comparison between classic hemofiltration and hemofiltration with dialysis.

Hypothesis: Amino acid (AA) loss is not equivalent on continuous venovenous hemofiltration (CVVH) compared with continuous venovenous hemodiafiltration (CVVHD). Amino acid supplementation may be necessary to adjust for a greater clearance on CVVH to maintain nitrogen balance similar to that of CVVHD. Objective: To compare AA losses and nitrogen balance between CVVH and CVVHD in children with acute renal failure. Setting: Pediatric patients in the pediatric intensive care unit of a tertiary referral center. Design: Prospective randomized crossover study in consecutive children who required hemofiltration. Patients: A total of 12 plasma clearance studies for AA and urea, consisting of 24‐hr collections of ultrafiltrate and urine for nitrogen balance, was performed on six patients during CVVH and CVVHD. Patients received total parenteral nutrition (TPN) with caloric intake 20% to 30% above their resting energy expenditure measured by indirect calorimetry and 1.5 g/kg/day protein of TPN. Study conditions were comprised of 2 L/hr/1.73 m2 of dialysate or prefiltered replacement fluid and hemofilter flow rates of 4 mL/kg/min were maintained for all patients. Methods and Main Results: Amino acid clearances were greater on CVVH than CVVHD, except for glutamic acid, where clearance was 6.73 ± 2.31 (SEM) mL/min/1.73 m2 on CVVH and 7.59 ± 2.79 mL/min/1.73 m2 for CVVHD (NS). The clearance difference between the two modalities was 30%. Urea clearance was equivalent (30.1 ± 1.74 mL/min/1.73 m2 and 29.0 ± .97 mL/min/1.73 m2) for CVVH and CVVHD, respectively. Amino acid loss on CVVH and CVVHD was similar (12.50 ± 1.29 g/day/1.73 m2 vs. 11.61 ± 1.86 g/day/1.73 m2, respectively), representing 12% and 11%, respectively, of the daily protein intake. The catabolic state, as measured by urea nitrogen appearance, was high for all patients during the 48‐hr study period with a mean of 291 mg/kg/day during CVVH, and 245 mg/kg/day for CVVHD. Nitrogen balance varied from a negative 12.95 g/day/1.73 m2 to a positive 4.93 g/day/1.73 m2 on CVVH and a negative 7.69 g/day/1.73 m2 to a positive 5.50 g/day/1.73 m2 on CVVHD. Conclusions: Clearance of AA is greater on CVVH than on CVVHD, but no significant difference in AA loss was present between the two therapies. Nitrogen balance often is not met on either therapy when a standard 1.5 g/kg/day protein and a resting energy expenditure of 120% to 130% of calories is delivered by TPN.

Epidemiology and Pathophysiology of Nephrotic Syndrome–Associated Thromboembolic Disease

After infections, thromboembolism is considered by many experts to be the most significant life-threatening complication of nephrotic syndrome. The purpose of this review is to summarize the epidemiology, clinical and molecular pathophysiology, and management of this complication. Children (2.8%) are less likely than adults (26.7%) with nephrotic syndrome to develop thromboembolism. However, infants and children aged >12 years are at much greater risk. Membranous histologic changes increase thromboembolic risk at all ages; in particular, adults with membranous nephropathy have the highest reported risk (37.0%) and children with membranous histology have a rate (25%) that approaches the overall adult rate. There are striking, but variable, pathologic alterations of molecular hemostasis associated with nephrotic syndrome. No clear molecular therapeutic targets have been identified, but most studies show that the major pathologic changes involve antithrombin, fibrinogen, and factors V and VIII. There is inadequate evidence to support routine prophylactic therapy. Therapy includes anticoagulation in all cases, with thrombolysis reserved for those with the most severe thromboembolic disease. Future hemostatic research in nephrotic syndrome should focus on identifying cohorts at highest risk for thrombosis through the use of clinical markers and biomarkers as well as searching for molecular targets to correct the prothrombotic pathophysiology of this disease.

Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: Prevention by lipoic acid treatment

BackgroundA reduction in the number of podocytes and podocyte density has been documented in the kidneys of patients with diabetes mellitus. Additional studies have shown that podocyte injury and loss occurs in both diabetic animals and humans. However, most studies in animals have examined relatively long-term changes in podocyte number and density and have not examined effects early after initiation of diabetes. We hypothesized that streptozotocin diabetes in rats and mice would result in an early reduction in podocyte density and that this reduction would be prevented by antioxidants.MethodsThe number of podocytes per glomerular section and the podocyte density in glomeruli from rats and mice with streptozotocin (STZ)-diabetes mellitus was determined at several time points based on detection of the glomerular podocyte specific antigens, WT-1 and GLEPP1. The effect of insulin administration or treatment with the antioxidant, α-lipoic acid, on podocyte number was assessed.ResultsExperimental diabetes resulted in a rapid decline in apparent podocyte number and podocyte density. A significant reduction in podocytes/glomerular cross-section was found in STZ diabetes in rats at 2 weeks (14%), 6 weeks (18%) and 8 weeks (34%) following STZ injection. Similar declines in apparent podocyte number were found in STZ diabetes in C57BL/6 mice at 2 weeks, but not at 3 days after injection. Treatment with α-lipoic acid substantially prevented podocyte loss in diabetic rats but treatment with insulin had only a modest effect.ConclusionSTZ diabetes results in reduction in apparent podocyte number and in podocyte density within 2 weeks after onset of hyperglycemia. Prevention of these effects with antioxidant therapy suggests that this early reduction in podocyte density is due in part to increased levels of reactive oxygen species as well as hyperglycemia.

Treatment of Henoch-Schönlein Purpura Glomerulonephritis in Children with High-Dose Corticosteroids plus Oral Cyclophosphamide

Background: Henoch-Schönlein Purpura (HSP) is a common childhood vasculitis with manifestations in numerous organ systems, including glomerulonephritis. Patients with more severe HSP-associated glomerulonephritis may develop chronic renal failure. Currently, no widely accepted treatment protocols exist for patients with significant renal involvement. Methods: We retrospectively reviewed the clinical courses of 12 children (mean age 9 years) with HSP glomerulonephritis treated with high-dose corticosteroids plus oral cyclophosphamide. All patients had nephrotic-range proteinuria, and all had significant histopathologic changes on biopsy, including crescentic nephritis in 10 patients. Treatment consisted of either intravenous pulse methylprednisolone or oral prednisone followed by oral cyclophosphamide (2 mg/kg/day) for 12 weeks, along with either daily or alternate-day oral prednisone. Prednisone was tapered following completion of cyclophsophamide. Results: Serum albumin rose significantly after treatment from 2.8 ± (SD) 0.5 to 3.7 ± 0.4 g/dl (p < 0.001), and there was a concurrent reduction in proteinuria, as reflected by decreasing serial protein-to-creatinine ratios: from 6.3 ± 4.4 to 0.8 ± 0.8 (p = 0.002). Renal function remained normal in all patients. Hypertension developed during treatment in 10 patients, all but 1 of whom were normotensive at last follow-up, 35 ± 17 months following biopsy. Conclusions: We conclude that treatment of children with HSP nephritis with high-dose corticosteroids plus oral cyclophosphamide is safe and, as in nephrotic syndrome, appears to significantly reduce proteinuria which is a known risk factor for the development of renal insufficiency in HSP. Further studies with larger numbers of patients should be conducted to confirm this finding.

Epidemiology and Risk Factors for Thromboembolic Complications of Childhood Nephrotic Syndrome: A Midwest Pediatric Nephrology Consortium (MWPNC) Study

OBJECTIVES To identify clinical variables predictive of the risk of thromboembolism (TE), and to confirm the incidence of TE in primary and secondary childhood nephrotic syndrome (NS). STUDY DESIGN A comprehensive chart review identified 326 children with NS from any cause evaluated between 1999 and 2006. These patients had a total of 1472.8 patient-years of follow-up. Comparison statistics, survival analysis, and logistic regression were used to define TE epidemiology and clinical risk factors. RESULTS We found that 9.2% of our cohort had experienced at least 1 TE. The overall incidence was 20.4 patients with TEs/1000 patient-years. The median time to the first TE was 70.5 days after diagnosis of NS. Deep venous thrombosis was the most common TE (76%) and was frequently associated with the use of a central venous catheter (45%). Significant independent predictors of TE included age > or = 12 years at onset of NS (P < .0001), severity of proteinuria (P < .0001), and history of TE preceding diagnosis of NS (P < .0001). Life- or limb-threatening TEs represented 23.7% of the events. CONCLUSIONS Children with NS should be carefully followed for TE, particularly those who are age 12 years or older, have severe proteinuria, or have a previous history of TE.

Hsp27 regulates podocyte cytoskeletal changes in an in vitro model of podocyte process retraction

Nephrotic syndrome (NS) is characterized by structural changes in the actin‐rich foot processes of glomerular podocytes. We previously identified high concentrations of the small heat shock protein hsp27 within podocytes as well as increased glomerular accumulation and phosphorylation of hsp27 in puromycin aminonucleoside (PAN) ‐induced experimental NS. Here we analyzed murine podocytes stably transfected with hsp27 sense, antisense, and vector control constructs using a newly developed in vitro PAN model system. Cell morphology and the microfilament structure of untreated sense and antisense transfectants were altered compared with controls. Vector cell survival, polymerized actin content, cell area, and hsp27 content increased after 1.25 μg/ml PAN treatment and decreased after 5.0 μg/ml treatment. In contrast, sense cells were unaffected by 1.25 μg/ml PAN treatment whereas antisense cells showed decreases or no changes in all parameters. Treatment of sense cells with 5.0 μ g/ml PAN resulted in increased cell survival and cell area whereas antisense cells underwent significant decreases in all parameters. Hsp27 provided dramatic protection against PAN‐induced microfilament disruption in sense > vector > antisense cells. We conclude that hsp27 is able to regulate both the morphological and actin cytoskeletal response of podocytes in an in vitro model of podocyte injury.—Smoyer, W. E., Ransom, R. F. Hsp27 regulates podocyte cytoskeletal changes in an in vitro model of podocyte process retraction. FASEB J. 16, 315–326 (2002)

Management of acute renal failure in the pediatric patient: Hemofiltration versus hemodialysis

Although outcome data for acute renal failure (ARF) in the adult population (analyzed by etiology of ARF, severity of illness, and modality of treatment) are readily available, few similar data exist for the pediatric population. Pediatric survival rate data vary widely, based upon era of analysis, age and size of child, and cause of ARF. Few comparative data are available that address impact by modality chosen to treat ARF. Comparison of 122 children who were treated by hemodialysis (HD; n = 58) versus hemofiltration (HF; n = 64) reveals a combined survival rate of 65%. Survival by modality was higher for HD (83%) than for HF (48%). The major diagnosis treated with HF was sepsis (29/64; 45%), with a survival rate of 31%, whereas the major diagnosis treated with HD (27/58; 46%) was primary renal failure, with a survival rate of 96%. Seventy-one percent of children undergoing HF required pressor support for hypotension, whereas only 24% of those receiving HD needed pressor support (P < 0.01). We conclude that the choice of renal replacement therapy (RRT) modality needs to be determined by the best treatment available. To adequately evaluate therapy measures, further analyses of outcome need to consider those factors that determine choice of RRT and those that affect survival independent of ARF.