Nephropathy associated with sickle cell anemia: an autologous immune complex nephritis. I. Studies on nature of glomerular-bound antibody and antigen identification in a patient with sickle cell disease and immune deposit glomerulonephritis.

The nature of the glomerular-bound antibody and the putative antigen was investigated in one of the patients with sickle cell disease and immune deposit membranoproliferative glomerulonephritis by immunohistologic and glomerular antibody elution. Renal proximal tubular epithelial antigen was localized in association with immunoglobulins G (IgG), M (IgM), Clq fraction of the first component of complement (Clq) and the third component of complement (C3) in a granular pattern along the glomerular basement membrane of the patient's kidney. IgG and IgM were eluted from glomeruli. These immunoglobulins fixed to the proximal tubules of normal human kidney by direct immunofluorescence. This localization was abolished by absorption of the eluted immunoglobulins with renal tubular epithelial (RTE) antigen. The IgG eluted from the glomeruli blocked the fixation of rabbit anti-RTE antigen to normal proximal tubular brush border. These studies suggest that the nephritis in this patient was due to deposition of complexes or RTE antigen and specific antibody. An autologous immune complex nephritis may develop in some patients with sickle cell anemia secondary to RTE antigen released possibly after renal ischemia or some other phenomenon causing renal tubular damage.     

Felty's syndrome: Effect of lithium on granulopoiesis

The effect of lithium carbonate upon granulopoiesis was studied in eight patients with Felty's syndrome. Absolute granulocyte counts increased in all patients receiving 900 mg lithium carbonate daily for six weeks. Increased urinary and serum granulocyte colony-stimulating activity was observed in all patients during lithium therapy. A causal relationship between increases in colony-stimulating activity and increased granulocytes is postulated.     

Familial leukemia and aplastic anemia associated with monosomy 7

A kindred is described in which eight of 14 patients in one generation had acute nonlymphocytic leukemia or aplastic anemia either alone or terminating in acute nonlymphocytic leukemia. The proband and two siblings in one branch of this kindred presented with aplastic anemia, whereas acute nonlymphocytic leukemia was the presenting feature in the other two branches. Karyotypic evolution from a normal karyotype to monosomy 7 was demonstrated in the proband, and group C monosomy was seen in two other patients. The proband's serum sample inhibited in vitro growth of normal bone marrow colonies. The occurrence of hematologic disease in this kindred appears to be the result of a maternally transmitted trait, and persons younger than 30 years of age appear to have the highest risk of hematologic disease.     

Analysis of 5 year experience of home dialysis as a treatment modality for patients with end-stage renal failure

We are reporting a detailed analysis of our 5 year experience with 78 home hemodialysis patients whose mean age was 39 years. All but 4 of 46 patients who had hypertension during the course of their dialysis were controlled by fluid removal and antihypertensive medications. Only two of eight patients who had positive hepatitis B antigen had clinical evidence of hepatitis. Persistent ascites was found in eight patients; four of these patients responded to either transplantation or intensive hemodialysis. Peripheral neuropathy was progressive in four diabetic patients but remained stable in nine other patients with neuropathy. Roentgenographic evidence of bone disease was found in 67.1 per cent of patients, and 21 per cent of them had fractures. The cumulative survival for the 78 patients was 95.9, 87.6, 68.7 and 53.4 per cent at 0.5, 1, 2, and 3 years, respectively. The major causes of death were cardiovascular, infectious complications and voluntary termination of dialysis. This analysis of our experience in home dialysis has allowed prospective planning in an attempt to improve both the survival and quality of life of home hemodialysis patients. The need for intensive and continuous socioeconomic and psychologic evaluation is discussed.     

Complications of assisted ventilation. A prospective study of 354 consecutive episodes

Three hundred fourteen consecutive patients were studied prospectively during 354 episodes of assisted ventilation in a 5 month period. These patients ranged in age from 15 to 95 years, and ventilatory support was required for from 1 hour to 54 days. Over-all survival was 64 per cent. Eighteen complications were studied prospectively, of which three (intubation of the right mainstem bronchus, endotracheal tube malfunction and alveolar hypoventilation) were associated with decreased survival. Four hundred individual complications or potential complications were observed. Intubation of the right mainstem bronchus was associated with alveolar hyperventilation, atelectasis and/or tension pneumothorax in a significant number of cases (all, P < 0.001). The onset of pneumonia, pneumothorax, atelectasis, gastric distention and ventilator malfunction all were observed during assisted ventilation, but none was associated with increased mortality. Careful attention to the recognition and prevention of complications, especially those associated with endotracheal intubation, is mandatory in all patients treated with assisted ventilation.     

Clinical and physiologic studies of two siblings with prekallikrein (Fletcher factor) deficiency.

Two siblings with hereditary Fletcher factor (prekallikrein) deficiency were studied for alterations of fibrinolysis, platelet function, skin inflammatory responses, permeability factor (PF/dil) formation and leukocyte chemotaxis. In vivo stimulation of fibrinolytic activity was normal; the bleeding time and platelet functions (adhesivity, aggregation, release reaction) were also normal. Both immediate (wheal-flare reaction to histamine, bradykinin, prostaglandin E1, physical agents) and delayed sensitivity skin test reactions were within normal limits. Migration of subjects' leukocytes to attractants in skin windows and in Boyden-type chambers was the same as that of control leukocytes. Serum complement components were essentially normal. One subject's leukocytes showed normal tissue factor production on stimulation by endotoxin, although prekallikrein deficiency did impair the endotoxin-stimulated generation of serum procoagulant activity. PF/dil caused increased vessel permeability in human skin; in vitro generation of PF/dil required both the Hageman factor and prekallikrein. The Fletcher factor-deficient subjects responded in a normal manner to PF/dil. Based on the Fletcher factor-coagulation assay, the biologic half-disappearance time of prekallikrein (after the transfusion of normal plasma in one of the subjects) was estimated at 35 hours. Therefore, these studies suggest that severe prekallikrein (Fletcher factor) deficiency in man is not associated with any clinically significant impairment in hemostasis, fibrinolysis, inflammatory responses or leukocyte function.     

Carpal tunnel syndrome as the initial manifestation of tuberculosis.

Two patients presenting with carpal tunnel syndrome as the initial manifestations of tuberculosis were seen during a recent four month period at a larg city-county hospital. Although the clinical picture of the carpal tunnel syndrome was typical, a definite diagnosis could not be made until the time of surgery because of the many other causes of the carpal tunnel syndrome. A review of the experience with musculoskeletal tuberculosis and carpal tunnel syndrome at our hospital indicates that although this combination is not common, it is one of the treatable causes of the carpal tunnel syndrome. A review of the literature substantiates this impression.     

Hypercalcemia of acute renal failure: Clinical significance and pathogenesis

Hypocalcemia is a frequent accompaniment of acute renal failure, but paradoxically hypercalcemia also has been described in association with acute renal failure. In this paper we describe two patients who provide some insights into both the potential clinical importance and mechanism of the hypercalcemia associated with acute renal failure. The clinical significance is emphasized by the presence of diffuse metastatic calcification observed at postmortem examination in one patient. In both patients the increase in serum calcium concentration was not coincident with a decrease in serum phosphorus concentration; when measured in one patient, serum levels of parathyroid hormone were undetectable. These findings, along with the consistent association with rhabdomyolosis, support the proposal that the hypercalcemia of acute renal failure is caused by dissolution of dystrophic calcifications In traumatized muscle and may lead to severe metastatic calcifications.     

Bronchoconstriction and pulmonary hypertension during abortion induced by 15-methyl-prostaglandin F2alpha.

Patients have experienced severe breathlessness during second trimester abortion initiated by the intramuscular injection of 15-methyl-prostaglandin F2alpha (15-me-PGF2alpha). In four healthy women given 400 mug of 15-me-PGF2alpha to induce abortion, pulmonary function tests showed reductions in arterial oxygen tension, maximum expired air flow and vital capacity. Residual lung volume and the slope of phase III of the closing volume curves increased.     

Infectious risk factors in the immunosuppressed host

A survey of 194 renal transplant recipients was undertaken to clarify factors of importance in the genesis of infections in the immunosuppressed host. The need for high dose prednisone therapy and the occurrence of hyperglycemia were significantly greater in patients with fatal and nonfatal post-transplant infections than in patients without such infection. Being over 40 years of age at the time of transplantation and the presence of leukopenia were occasionally significantly associated with infectious death after transplantation. Renal failure was associated with infectious death in some transplant recipients; this association likely reflected the use of high dose immunosuppressive agents to treat refractory rejection. Hypogammaglobulinemia, azathioprine therapy (at the dosage level studied) and the sex and race of the recipient, the type of underlying renal disease, nephrectomy, splenectomy and thymectomy were not associated with post-transplant infectious death.There was a marked diminution in infection and infectious death after 1965. We postulate that this decline was due to two factors: (1) the accumulation of extensive experience with post-transplant infections leading to a more aggressive diagnostic and therapeutic approach in recent transplant recipients with infection, and (2) a decrease in the use of high dose prednisone therapy and of the occurrence of hyperglycemia in recent transplant recipients. The more frequent use of related donor kidneys and the introduction of antilymphocyte globulin permitted less use of high dose prednisone therapy in transplant recipients after 1965.     

Primary cutaneous inoculation drug-resistant tuberculosis

A laboratory technician with a previously negative tuberculin reaction punctured her thumb with a needle containing drug-resistant tuberculous organisms while performing guinea pig inoculation. Diagnosis was established 8 weeks after the initial injury by culture of the excised tissue. Complete resolution of the tuberculous process was accomplished with surgery and chemotherapy. The patient never had a positive tuberculin reaction, and this presumably was due to early chemotherapy.     

Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome.

Most patients with extreme obesity do not exhibit alveolar hypoventilation, but an intriguing minority do. The mechanism(s) of this phenomenon remain unknown. A disorder in ventilatory control has been suggested as a major factor in the pathogenesis of the obesity-hypoventilation syndrome. Accordingly, hypoxic and hypercapnic ventilatory drives were measured in 10 patients with the typical symptoms of the syndrome: obesity, hypersomnolence, hypercapnia, hypoxemia, polycythemia and cor pulmonale. Hypoxic ventilatory drive, measured as the shape parameter A, averaged 21.9 +/- 5.35, approximately one-sixth that in normal controls, A = 126 +/- 8.6 (P less than 0.01). The ventilatory response to hypercapnia also was markedly reduced, the slope of the response averaging 0.51 +/- 0.005, or about one-third the normal value of 1.83 +/- 0.13 (P less than 0.01). This decreased responsiveness in hypoxic and hypercapnic ventilatory drive was consistent throughout the group. The depression in ventilatory drive found in the obesity-hypoventilation syndrome may be causally related to the alveolar hypoventilation manifested by these patients.     

Arterial calcification and pathology in uremic patients undergoing dialysis.

Arterial samples obtained from uremic patients were compared with those obtained from nonuremic control subjects. Arteries from the uremic patients showed fibrous or fibroelastic intimai thickening, calcification of the internal elastic lamella, medial ground substance and medial elastic fibers, and disruption and reduplication of the internal elastic lamella. Lipid deposition was seen infrequently. The calcium concentrations of the arteries of the patients were greater than those of the control subjects. Correlations were found between the degree of intimai thickening and the duration of renal disease, and between arterial calcification and both the duration of hypertension and the duration of renal disease. In the control subjects, positive exponential correlations were found between age and arterial calcium concentrations, but at any age the calcium concentration was greater in the aorta than in the other arteries.This study has demonstrated that pathologic changes are extremely common in the arteries of uremic patients, that calcification is an integral part of this disease process and that, despite hyperlipidemia, lipid deposition is not an initiating factor. The changes seen probably represent an acceleration of the normal arterial aging process. This study has also shown that the disease seen may be, in part, related to the duration of uremia and to the duration of hypertension. It is likely that the arterial disease seen in uremia is a result of a summation of the many atherogenic risk factors present in these patients.     

Immune complexes in primary biliary cirrhosis: Higher prevalence of circulating immune complexes in patients with associated autoimmune features

A longitudinal study, examining the levels of immune complexes serially for three years, in serum from 88 patients with primary biliary cirrhosis was performed by the Raji cell radioimmunoassay. Studies of the association of autoimmune features in primary biliary cirrhosis and the effect of D-penicillamine therapy in relation to the levels of complexes were carried out. Twenty-two patients (25 percent) were found to have autoimmune features, such as Sjögren's syndrome, rheumatoid-like arthritis, scleroderma, Raynaud's disease, and Hashimoto's thyroiditis. In this subset of patients with primary biliary cirrhosis, a significantly higher prevalence (86 percent) of circulating immune complexes was detected compared with those patients showing no autoimmune features (60 percent). In addition, patients with associated autoimmune features had higher mean levels of immune complexes (259.7 μg AHG eq/ml) compared with those without autoimmune features (202.1 μg AHG eq/ml). The mean levels of complement C4, reflecting activation of classic complement pathway, were significantly lower in patients with elevated immune complexes and associated autoimmune features. The mean level of immune complexes in 13 patients receiving D-penicillamine, in contrast to the placebo group, decreased at one year but subsequently was greater than the initial level. Patients who had normal levels of immune complexes and received penicillamine therapy continued to have complex levels within the normal range for up to three years of follow-up study, but patients receiving placebo showed significantly elevated levels at subsequent intervals. Thus, levels of immune complexes in primary biliary cirrhosis may reflect the association with autoimmune features.     

Hyperlipidemia in adult, pediatric and diabetic renal transplant recipients.

Serum cholesterol and triglyceride concentrations were measured and lipoprotein electrophoreses were performed on serum samples from 175 adult, 19 pediatric and 11 diabetic transplant recipients and from 102 healthy volunteer subjects. Serum lipids were also measured in 14 patients prior to and for 40 weeks following transplantation. p]The mean serum cholesterol and triglyceride concentrations were greater in all three groups of transplant recipients than in the healthy volunteer subjects but there were no differences in serum lipids between any two of the transplant recipient groups. Sixty-one per cent (125) of the patients had hyperlipidemia. Lipoprotein electrophoreses demonstrated that the hyperlipoproteinemia was heterogeneous, 26 per cent (46) of the patients had type IV hyperlipoproteinemla, 23 per cent (39) type 11b and 11 per cent (19) type 11 A. Serum lipid concentrations in patients receiving alternate-day corticosterold therapy were not different from those receiving daily corticosterold therapy. Positive correlations were found between serum triglyceride concentrations and the daily prednlsone dosage, relative body weight, serum creatinine and blood glucose concentrations. No correlation was found between prednlsone dosage and the latter three variables. A positive correlation was also found between serum triglycerides and relative body weight in the healthy volunteer subjects, but for any given body weight serum triglycerides were significantly greater in the transplant recipients. Transplant recipients with hypercholesterolemla were receiving a larger prednisone dosage than those with normal serum cholesterol levels. Serum cholesterol and triglyceride levels became abnormal within eight weeks of transplantation and remained abnormal throughout the remaining 32 weeks during which these patients were followed. Correlations were found between serum cholesterol and triglyceride levels and the cumulative dose of prednisone during this 40 week period.It is concluded that hyperllpidemla is very common in renal transplant recipients, is a mixture of types 11 A, 11B and IV hyperlipoprotelnemla, is equally prevalent in diabetic, pediatric and adult transplant recipients and is not diminished by the use of alternateday cortlcosteroids. Prednisone dosage, obesity and the degree of Impairment of graft function appear to be responsible for hypertriglycerldemia; prednlsone dosage appears to be responsible for hypercholesterolemla. Serum lipid abnormalities develop within eight weeks of transplantation and can be related to the cumulative dose of prednisone in the early post-transplant period.     

Anticytoplasmic antibodies in antinuclear antibody-negative lupus erythematosus. Correlation with clinical course

A patient with clinical manifestations of systemic lupus erythematosus (SLE) and without antinuclear antibodies was found to have anticytoplasmic antibodies. These anticytoplasmic antibodies were directed against ribosomal ribonucleoprotein, and the titer of anticytoplasmic and anti-ribosomal ribonucleoprotein antibodies correlated with the clinical course of the patient's illness. The importance of detecting anticytoplasmic antibodies and their role in producing disease in patients with SLE is discussed.     

Hereditary angioedema and "familial" lupus erythematosus in identical twin boys

Complement system proteins, C4 metabolism and serologic markers of systemic lupus erythematosus were studied in identical male twins with chronic discoid lupus erythematosus and hereditary angioedema. Systemic lupus erythematosus was confirmed in their mother at age 22 during the twins' gestation. She also manifested symptoms suggesting hereditary angioedema. Low C1&;#x0304; inhibitor (C1&;#x0304; INH) and C4 have been documented since age 13 in both twins. At this time, metabolic studies disclosed a combined C4 fractional hypercatabolism (0.96 to 1.02/day) and decreased synthesis (3.0 to 3.15 mg /kg/day). Normal C1&;#x0304; inhibitor and C4 concentrations are present in their healthy father and maternal grandparents, indicating that the C1&;#x0304; inhibitor deficiency in the twins was inherited as an autosomal codominant from their mother in whom a spontaneous mutation had occurred. Positive antinuclear antibody, increased antibody to denatured deoxyribonucleic acid and immunoglobulin deposits in normal skin in both twins are evidence of systemic lupus erythematosus. In addition, a chronic biologic false-positive serology is present in one twin. We postulate that the association of hereditary angioedema and “familial” systemic lupus erythematosus is a biologically relevant phenomenon. It is proposed that the secondary C4 deficiency predisposed the patient to the development of systemic lupus erythematosus in some presently unknown manner.     

Miliary tuberculosis

The clinical pattern of miliary tuberculosis has changed strikingly in the past two decades, with a decreased frequency, an increased incidence of undiagnosed cases and an increase in the mean age of affected patients. The clinical presentation is not specific; however, headache and abdominal pain are strongly suggestive of meningeal and peritoneal involvement. Skin testing, chest roentgenograms and specimens from extrapulmonic sources are all helpful in establishing a diagnosis. The potential role of brush biopsy and of percutaneous needle lung biopsy in the diagnosis of miliary tuberculosis is presented. Hematologic and hepatic abnormalities are common and diverse but nonspecific, whereas body cavity fluids, when involved with tuberculosis, have changes highly suggestive of this diagnosis. An overview of the supportive measures available in the acutely ill patient and the present drug armamentarium for tuberculosis are discussed.     

Effect of contraceptive steroids on arginine- stimulated glucagon and insulin secretion in women. II. Carbohydrate and lipid physiology in insulin-dependent diabetics.

The effect of contraceptive steroids on aminogenic glucagon secretion was studied in six insulin-dependent diabetic women. After 2 wk treatment with combined mestranol (80 mug) plus norethindrone (1 mg) daily, the mean peak plasma glucagon response to arginine infusion was suppressed to one-fourth of control levels. This was associated with a small but significant decrease in mean basal plasma cholesterol concentrations. There were no changes in basal plasma triglyceride, free fatty acid, glucose, insulin, or alpha-amino nitrogen concentrations or in daily insulin requirements during mestranol plus norethindrone treatment. These results confirm previous reports of no consistent changes in the insulin requirements of insulin-dependent diabetic women using contraceptive steroids and suggest that these women may not experience dramatic changes in their lipid metabolism during contraceptive therapy.     

Macrocytic anemia, thrombocytosis and nonlobulated megakaryocytes: the 5q-syndrome, a distinct entity.

The clinical, hematologic and histologic characteristics of six patients with refractory anemia with deletion of the long arm of chromosome No. 5 are described. These patients had a distinct hematologic picture with macrocytic anemia of mild to moderate severity, normal to low leukocyte count and increased platelet count. The long arm of chromosome No. 5 was deleted in the majority of bone marrow metaphases. The main cause of anemia was underproduction with decreased erythroid precursors in the bone marrow and no increase in peripheral blood reticulocytes. Two of five patients responded transiently to the administration of androgens. In vitro evaluation of the bone marrow growth pattern in semisolid agar culture system was performed in three patients and was found to be normal and distinct from that in patients with preleukemia. In a follow up of up to five years, no patient had changed hematologically and in none had leukemia developed. The 5q-syndrome is a distinct hematologic entity and probably more common than hitherto realized. This diagnosis may have therapeutic and prognostic implications.