Keith N. Drummond

Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes

BACKGROUND Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that block the renin-angiotensin system. METHODS We conducted a multicenter, controlled trial involving 285 normotensive patients with type 1 diabetes and normoalbuminuria and who were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. The retinopathy end point was a progression on a retinopathy severity scale of two steps or more. Intention-to-treat analysis was performed with the use of linear regression and logistic-regression models. RESULTS A total of 90% and 82% of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year period did not differ significantly between the placebo group (0.016 units) and the enalapril group (0.005, P=0.38) or the losartan group (0.026, P=0.26), nor were there significant treatment benefits for other biopsy-assessed renal structural variables. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group; the incidence was higher with losartan (17%, P=0.01 by the log-rank test) but not with enalapril (4%, P=0.96 by the log-rank test). As compared with placebo, the odds of retinopathy progression by two steps or more was reduced by 65% with enalapril (odds ratio, 0.35; 95% confidence interval [CI], 0.14 to 0.85) and by 70% with losartan (odds ratio, 0.30; 95% CI, 0.12 to 0.73), independently of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo. CONCLUSIONS Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy. (ClinicalTrials.gov number, NCT00143949.)

Hemolytic Uremic Syndrome in Families

The occurrence of the hemolytic uremic syndrome in three siblings prompted us to study this illness in families. Two groups of patients could be identified when 83 siblings with the syndrome in 41 families were examined. Siblings whose onset occurred within a short time of each other had a relatively good prognosis (19 per cent mortality); those whose onset was more than a year apart had a poorer prognosis (68 per cent mortality). We speculate that an environmental agent may have caused the syndrome in the first group, and that genetic factors may have been important in the second.

Tryptophan Metabolism in Man

The amino acid tryptophan is unique because it contains the indole nucleus and because it is metabolized in man through several different biochemical pathways to a number of specific products. It is the precursor of serotonin and 5-hydroxyindoleacetic acid. In addition, after cleavage of the indole ring, it may be metabolized by way of the kynurenine pathway to 3-hydroxyanthranilic acid and ultimately to nicotinamide. In mammalian liver the benzene ring is oxidized and metabolized through a number of intermediate reactions to glutarate, acetate, and carbon dioxide (1, 2). Tryptophan is also the precursor of indolic acids, such as 3-indoleacetic acid. In man this compound is formed both by tissue enzymes and by bacteria in the gut (3). In the intestinal tract, bacteria that contain tryptophanase (4) reductively cleave the side chain of tryptophan and form indole, which is absorbed, conjugated in the liver, and excreted as indican (sulfated potassium ester of indoxyl). In addition to the various reactions involving the indole ring or side chain, tryptophan, like other amino acids, is incorporated into protein. These pathways are schematically shown in Figure 1. The many different enzyme systems and important cofactors, such as pyridoxal phosphate, that take part in these reactions have been ably reviewed (5-7) and will not be discussed here. In the investigation of tryptophan metabolism in man, a number of variables must be considered. These include not only these enzymes and cofactors, but

The blue diaper syndrome: Familial hypercalcemia with nephrocalcinosis and indicanuria: A new familial disease, with definition of the metabolic abnormality☆

Abstract A new familial disease is described in which hypercalcemia and nephrocalcinosis are associated with a defect in the intestinal transport of tryptophan. Bacterial degradation of the tryptophan leads to excessive indole production and thus to indicanuria which, on oxidation to indigo blue, causes a peculiar bluish discoloration of the diaper. Possible pathogenetic interrelationships between the disturbances in calcium homeostasis and defective transport of the amino acid tryptophan are considered.

Thyroid antigen-antibody nephritis.

Abstract A patient with autoimmune thyroiditis developed nephrosis. Light, immunofluorescence, and electron microscopic examination of renal biopsy tissue demonstrated epimembranous nephropathy. Thyroglobulin and thyroid microsomal antigen were demonstrable in her glomeruli by indirect immunofluorescence microscopy.

A controlled prospective study of cyclophosphamide in relapsing, corticosteroid-responsive, minimal-lesion nephrotic syndrome in childhood

This prospective controlled study was designed to investigate whether cyclophosphamide reduces the recurrence rate in relapsing, corticosteroid-responsive, minimal-lesion nephrotic syndrome (MLNS) in childhood. Patients were treated with either prednisone alone (Group 1) or prednisone and cyclophosphamide (Group 2) for four months. Duration of follow-up was 25 months. Relapse icidence was 90.9 per cent in Group 1 and 16.7 per cent in Group 2 (p

The hemolytic-uremic syndrome is a syndrome.

The article in this weeks issue of the Journal by Koster and his colleagues raises important questions not only about the pathogenesis of the hemolytic-uremic syndrome but, perhaps more importantl...

Anaphylactoid purpura nephritis: Clinicopathological correlations

Although it has been recognized for many years that progressive glomerulonephritis is one of the most serious features of anaphylactoid purpura, clinicopathological correlations of the nephritis have not been made. We have grouped our patients with anaphylactoid purpura according to a clinical classification and have correlated this with histologic and immunofluorescent microscopic findings seen on renal biopsy. The degree of nephritis bore no relation to the severity of the extrarenal manifestation. Significant nephritis may often have its onset after other manifestations of the syndrome have disappeared. Our patients with severe nephritis accompanied by nephrotic syndrome have done well. This may be due to treatment with azathioprine and prednisone.

Treponemal Antigens in Congenital and Acquired Syphilitic Nephritis: Demonstration by Immunofluorescence Studies

Two patients, a 4-month-old infant girl with congenital syphilis and a 45-year-old man with secondary syphilis, had the nephrotic syndrome with glomerulonephritis. Immunoglobulins and treponemal antigenic material were seen in the glomeruli of both patients by immunofluorescence microscopic studies of renal tissue. Electron micrographs showed subepithelial electron dense deposits along the glomerular basement membrane. This confirms earlier suggestions that the renal injury is of an immune-complex type.

The glomerulopathy of congenital syphilis--an immune deposit disease.

R E N A L D l S r A S E is an uncommon complication of congenital syphilis. Although the clinical and laboratory features have been documented, ~-6 there are few reports on the histology of the kidney ~, 4, 6 and only one description of immunopathologic studies of renal tissue. The renM lesion has been considered to result from the invasion of the kidney by spirochetes z or to be secondary to hypersensitivity reaction, s Immune complex deposition has been implicated in the pathogenesis of the nephrotic syndrome associated with secondary syphilis in adults2, ~0 This paper describes the renal immunopathologic and light microscopic findings in a male infant with the nephrotic syndrome due to congenital syphilis. A patient presented at 10 weeks of age with the clinical and laboratory features of the nephrotic syndrome. In addition he had a mucopurulent discharge from both nostrils and a perianal rash; the skin of the palms was peeling. He had an active chorioretinitis