Keith E. Holley

A Controlled Trial of Fish Oil in IgA Nephropathy

BACKGROUND The n-3 fatty acids in fish oil affect eicosanoid and cytokine production and therefore have the potential to alter renal hemodynamics and inflammation. The effects of fish oil could prevent immunologic renal injury in patients with IgA nephropathy. METHODS In a multicenter, placebo-controlled, randomized trial we tested the efficacy of fish oil in patients with IgA nephropathy who had persistent proteinuria. The daily dose of fish oil was 12 g; the placebo was a similar dose of olive oil. Serum creatinine concentrations, elevated in 68 percent of the patients at base line, and creatinine clearance were measured for two years. The primary end point was an increase of 50 percent or more in the serum creatinine concentration at the end of the study. RESULTS Fifty-five patients were assigned to receive fish oil, and 51 to receive placebo. According to Kaplan-Meier estimation, 3 patients (6 percent) in the fish-oil group and 14 (33 percent) in the placebo group had increases of 50 percent or more in their serum creatinine concentrations during treatment (P = 0.002). The annual median changes in the serum creatinine concentrations were 0.03 mg per deciliter (2.7 mumol per liter) in the fish-oil group and 0.14 mg per deciliter (12.4 mumol per liter) in the placebo group. Proteinuria was slightly reduced and hypertension was controlled to a comparable degree in both groups. The cumulative percentage of patients who died or had end-stage renal disease was 40 percent in the placebo group after four years and 10 percent in the fish-oil group (P = 0.006). No patient discontinued fish-oil treatment because of adverse effects. CONCLUSIONS In patients with IgA nephropathy, treatment with fish oil for two years retards the rate at which renal function is lost.

Epidemiology of adult polycystic kidney disease, Olmsted county, Minnesota: 1935-1980

Between January 1, 1935 and December 31, 1980, adult polycystic kidney disease (APKD) was diagnosed in 40 residents of Olmsted County, Minnesota, resulting in an age- and sex-adjusted annual incidence rate of 1.38/100,000 person-years. In addition, 16 cases were detected at autopsy, increasing the rate to 2.06. It is estimated that 16 additional cases would have been discovered had all deaths come to autopsy, resulting in a rate of 2.75, or approximately twice the incidence rate of cases diagnosed during life. Because of improvements in medical care and diagnostic techniques, APKD has been diagnosed earlier and more frequently in the recent decades. This, along with therapeutic advances, explains the improvement in kidney and patient survival for the patients diagnosed during 1956-1980, as compared to those diagnosed during 1935-1955. Normotension at diagnosis tended to be associated with better kidney and/or patient survival. Cardiovascular disease was the leading cause of death.

Treatment of Diffuse Proliferative Lupus Nephritis with Prednisone and Combined Prednisone and Cyclophosphamide

To evaluate the effectiveness of cyclophosphamide in the treatment of lupus nephritis, we designed a prospective study of patients with diffuse proliferative lupus nephritis. Twenty-six patients received prednisone (average dose, 40 mg per day) and 24 combined prednisone (average dose, 29 mg per day) and cyclophosphamide (average dose, 107 mg per day) for six months. Thereafter, all patients received maintenance doses of prednisone. Most of the patients improved (84 per cent) after six months of initial treatment with either program. Early progression of disease, ending mainly in end-stage renal disease, was equally frequent in the two treatment groups in patients with already advanced disease. In a four-year follow-up study there was a higher incidence (P approximately 0.04) and average rate (P approximately 0.02) of clinical recurrence of nephritis in the group initially given only steroid than in the group initially given both drugs. However, the proportion of patients alive after four years with stable or improved renal function was similar in the two treatment groups.

Laboratory investigation of deaths due to anaphylaxis

To establish a useful laboratory protocol to investigate possible cases of fatal anaphylaxis, we measured mast-cell-derived tryptase levels and allergen-specific immunoglobulin E (IgE) antibody levels in sera obtained prior to or within 24 h after death from 19 anaphylaxis victims. Elevated serum tryptase levels (range = 12 ng/mL to 150 micrograms/mL) were found in nine of nine Hymenoptera sting fatalities, six of eight food-induced fatalities, and two of two reactions to diagnostic therapeutic agents. Tryptase levels were normal (less than 10 ng/mL) in 57 sequential sera obtained postmortem from six control patients. Tryptase could not be measured in pleural or pericardial fluids for technical reasons. Serum IgE antibodies were elevated in five of the nine Hymenoptera sting fatalities and in eight of the eight fatal food reactions; assays were unavailable for the two diagnostic/therapeutic agents. If elevated, the victims serum IgE antibodies to food could be used to identify allergens in uneaten portions of foods consumed shortly before the anaphylactic event. IgE antibodies were moderately stable during storage in a variety of anticoagulants at room temperature for up to 11 weeks. Elevated mast-cell-derived tryptase levels in postmortem sera reflect antemortem mast cell activation and may be used as a marker for fatal anaphylaxis. If assays are available for IgE antibodies to relevant allergens, such assays provide evidence for antemortem sensitization; these assays may be modified to identify allergens in foods consumed by victims of food-induced anaphylaxis.

Membranoproliferative glomerulonephritis. A prospective clinical trial of platelet-inhibitor therapy

Forty patients with Type I membranoproliferative glomerulonephritis were treated for one year with dipyridamole, 225 mg per day, and aspirin, 975 mg per day, in a prospective, randomized, double-blind, placebo-controlled study. At the base line, the half-life of 51Cr-labeled platelets was reduced in 12 of 17 patients. The platelet half-life became longer and renal function stabilized in the treated group, as compared with the placebo group, suggesting a relation between platelet consumption and the glomerulopathy. The glomerular filtration rate, determined by iothalamate clearance, was better maintained in the treated group (average decrease, 1.3 ml per minute per 1.73 m2 of body-surface area per 12 months) than in the placebo group (average decrease, 19.6). Fewer patients in the treated group than in the placebo group had progression to end-stage renal disease (3 of 21 after 62 months as compared with 9 of 19 after 33 months). The data suggest that dipyridamole and aspirin slowed the deterioration of renal function and the development of end-stage renal disease.

The progression of vesicoureteral reflux nephropathy

The relations among renal function, proteinuria, and glomerular lesions were studied in 54 patients with reflux nephropathy. The clinical course to end-stage renal disease was not appreciably altered by late surgical correction of the reflux, occurrence of urinary tract infection, or hypertension. All patients with progressive renal disease had significant proteinuria. Mesangial glomerular lesions can occur in the absence of proteinuria detectable by routine analysis, whereas lesions similar to those seen in idiopathic focal sclerosing glomerulopathy were present in the renal biopsies from proteinuric patients. Deposition of immunoproteins was limited to glomeruli undergoing sclerosis. Similarly, electron-dense deposits were confined to areas of mesangial alterations. Our results suggest that mesangial alterations occur early in the course of reflux nephropathy and may lead to the development of focal sclerosis. At later stages, counterproductive mechanisms of adaptation to the loss of viable nephrons might result in an acceleration of the clinical course to renal failure.

Long-term follow-up and response to chemotherapy in patients with light-chain deposition disease

Nineteen patients with light-chain deposition disease (LCDD) were studied retrospectively. This report presents data on long-term patient and renal survival and the response to intermittent administration of melphalan and prednisone. Immunoelectrophoresis or immunofixation demonstrated a monoclonal protein in the serum of 78% and in the urine of 84% of the patients; 16% had no demonstrable monoclonal protein in serum or urine. The median age at presentation was 51 years (range, 37 to 77 years). Twelve (63%) of the patients had a monoclonal protein of undetermined significance without evidence of myeloma. The typical glomerular lesion was a diffuse mesangial nodular lesion that was positive for periodic acid-Schiff (PAS) stain with acute and chronic tubulointerstitial changes. Fifteen patients had kappa light-chain deposition and four had lambda light-chain deposition. Five-year actuarial patient survival and survival free of end-stage renal disease were 70% and 37%, respectively. Seventeen patients received melphalan and prednisone, and one patient received chlorambucil and prednisone. All of the patients had some impairment of renal function at presentation, and 58% had a serum creatinine concentration greater than 354 mumol/L (4.0 mg/dL). There was either stabilization or improvement in renal function after chemotherapy in five of eight patients who had a serum creatinine concentration less than 354 mumol/L (4.0 mg/dL) at the initiation of therapy. Of the 11 patients with a high serum creatinine concentration (greater than 354 mumol/dL [4.0 mg/dL]), 82% progressed to end-stage renal disease despite therapy. Follow-up urine protein studies demonstrated at least a 50% decrease in urine protein excretion in five of 15 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Irreproducibility of the Activity and Chronicity Indices Limits Their Utility in the Management of Lupus Nephritis

Histological indices of renal pathology in lupus nephritis have been proposed as prognostic signs and as a method to quantitate therapeutic response. We tested the reproducibility of the activity (AI) and chronicity indices (CI) in the renal biopsies from 83 patients with lupus nephritis, enrolled in a controlled therapeutic trial. The AI/CI were calculated separately by four renal pathologists using published criteria. Pair-wise Spearmans rank correlation coefficient was used to examine the relationship among the scores of the four raters, and their degree of reproducibility was evaluated using the coefficient of reliability. The mean CI scores ranged from 2.84 to 4.61, and the mean AI ranged from 9.64 to 12.89. The correlation among the different pathologists scores ranged from 0.44 to 0.63 for the AI and 0.60 to 0.76 for the CI. One pathologist (M.M.S.) rated the biopsies twice, and the correlation between the two ratings was 0.58 for the AI and 0.74 for the CI. Thus, the AI and CI calculated by different pathologists and the temporally separate observations of a single observer were only moderately correlated. The reproducibility of a single rating was low, showing a reliability coefficient of 0.48 for the AI and 0.57 for the CI. The low reliability coefficient suggests that the variability among pathologists was the result of interpretative differences. We conclude that the AI/CI are too subjective to be used as therapeutic guides or as prognosticators.

Diffuse Glomerulonephritis Associated with Infected Ventriculoatrial Shunt

Abstract Of six patients with diffuse glomerulonephritis and associated infected ventriculoatrial shunt, three had improved renal function after removal of the infected shunt, and three died from Central-nervous-system disease. The renal disease probably resulted from an immunologic response to the staphylococcal infection rather than from direct bacterial embolization of the kidney.

Treatment of Lupus Nephritis with Prednisone and Combined Prednisone and Azathioprine

Abstract The relative effectiveness of high-dose prednisone (group A) was compared with the same regimen plus azathioprine (group B) for the treatment of lupus nephritis of mild or moderate severit...