Acute tubulointerstitial nephritis attributable to indinavir therapy.

Indinavir sulfate has been reported to cause asymptomatic crystalluria and nephrolithiasis in patients with human immunodeficiency virus (HIV) infection. Patients taking indinavir may present with asymptomatic crystalluria, nephrolithiasis with frank renal colic and obstruction, flank pain in the absence of nephrolithiasis, and dysuria or urgency. Asymptomatic crystalluria has been described as benign. Discontinuation of the drug has not been recommended in the absence of nephrolithiasis. We report two HIV-positive patients receiving indinavir who developed acute interstitial nephritis with foreign body giant cell reaction on renal biopsies. Both patients had asymptomatic crystalluria, although crystals were associated with clumps of white blood cells (WBCs) on urinalysis in one patient. Both cases show that the inflammatory response was significant enough to lead to tubular injury and acute renal impairment. Our findings suggest that asymptomatic crystalluria attributable to indinavir may illicit an inflammatory response with acute renal insufficiency, warranting monitoring of renal function, especially in patients with crystalluria.

True histiocytic lymphoma of the esophagus in an HIV-positive patient: an ultrastructural study.

A 56-year-old white woman, seropositive for human immunodeficiency virus for 18 months without signs of acquired immunodeficiency syndrome, presented with retrosternal pain and progressive dysphagia secondary to an exophytic esophageal mass. Biopsies of the tumor showed a malignant neoplasm composed of pleomorphic, noncohesive cells growing in a diffuse, sheet-like fashion. Immunohistochemically, tumor cells were nonreactive with epithelial, lymphoid, neural, and monocyte/macrophage markers. Despite the noncontributory immunohistochemical findings, ultrastructural study of the tumor cells revealed convincing histiocytic features. Individual cells possessed long, slender filopodial projections, prominent Golgi apparatus, residual bodies, rare lysosomes, and prelysosomes. Immunoglobulin heavy chain and T-cell receptor gamma gene rearrangement studies detected no evidence of a clonal gene rearrangement. The patient responded poorly to chemotherapy and died 5 months after her initial symptom of dysphagia.

Adenosquamous carcinoma of the pancreas.

HYPOTHESIS: Adenosquamous carcinoma of the pancreas is a rare but particularly virulent variant of invasive ductal carcinoma. This review will demonstrate the aggressive biologic activity, histopathologic features, and DNA flow cytometric characteristics of this aggressive lesion. In addition, the outcome is less favorable than in other pancreatic neoplasms, in spite of aggressive surgical and postoperative adjuvant therapy. DESIGN: A retrospective review of 6 patients treated during an 8-year period. SETTING: A major urban university tertiary referral hospital. PATIENTS: There were 6 patients with this unusual tumor seen between 1990 and 1998. There were 4 men and 2 women, all white, with a mean+/-SD age of 63.5+/-14.7 years. Symptoms were similar to those in patients with more common pancreatic malignant neoplasms. RESULTS: Four patients with tumors in the head of the pancreas had pancreatoduodenectomy, and 2 with body and or tail lesions had distal pancreatectomy and splenectomy. Pathologically, all the tumors were poorly differentiated and aneuploid, and 5 of the 6 were locally metastatic. All but 1 patient had postoperative complications, but there were no operative deaths. One half of the patients received postoperative adjuvant chemotherapy and radiation therapy. Only 1 patient is still alive at 9 months after surgery, but has known residual cancer around his portal vein noted during palliative distal pancreatectomy. CONCLUSIONS: Adenosquamous carcinoma of the pancreas is an uncommon variant of exocrine pancreatic neoplasm. It is characterized by an admixture of adenomatous and squamous cell elements and demonstrates aggressive biologic behavior. This series of 6 patients is similar to the 134 cases reported since 1907, in that survival is short despite aggressive surgical therapy. Few patients with this disease live more than 1 year. Aggressive therapy should be tempered by the realization of the uniform poor prognosis associated with this malignant neoplasm.

Adenine phosphoribosyltransferase-deficient mice develop 2,8-dihydroxyadenine nephrolithiasis.

Adenine phosphoribosyltransferase (APRT) deficiency in humans is an autosomal recessive syndrome characterized by the urinary excretion of adenine and the highly insoluble compound 2,8-dihydroxyadenine (DHA) that can produce kidney stones or renal failure. Targeted homologous recombination in embryonic stem cells was used to produce mice that lack APRT. Mice homozygous for a null Aprt allele excrete adenine and DHA crystals in the urine. Renal histopathology showed extensive tubular dilation, inflammation, necrosis, and fibrosis that varied in severity between different mouse backgrounds. Thus, biochemical and histological changes in these mice mimic the human disease and provide a suitable model of human hereditary nephrolithiasis.

Epithelioid hemangioendothelioma of the clitoris: a case report with immunohistochemical and ultrastructural findings.

A 30-year-old woman was referred for evaluation of a small nodule of the clitoris. This was subsequently diagnosed as epithelioid hemangioendothelioma. This rare vascular tumor of intermediate malignancy has not been previously described in the vulva. The patient underwent a modified radical vulvectomy and bilateral inguinal lymph node dissection, and subsequently received photon therapy. She is alive with no evidence of disease 27 months after diagnosis.

Microphleboliths in vascular ectasia of the intestine: a case report.

Vascular ectasia is a well-established cause of obscure gastrointestinal hemorrhage. The primary method of diagnosis is mesenteric arteriography, which demonstrates a pattern of blush or intraluminal extravasation, early venous filling and microvascular distention. The most common location for this lesion is the cecum although small bowel lesions also are recognized. The following is a case of vascular ectasia affecting the jejunum, in which undescribed microphleboliths were found on microscopic examination.

Carcinoid tumor arising in a treated primary germ cell tumor of the mediastinum.

A 33-year-old man had a locally aggressive anterior mediastinal carcinoid tumor, manifested as an enlarging mass refractory to chemotherapy two years after initially successful treatment of a primary germ cell tumor. Ultrastructurally, the tumor contained dense-core endocrine-type secretory granules. Many mediastinal carcinoid tumors have been reported, but we found no examples of such a tumor arising as a sequel to or as a refractory component of a mediastinal germ cell tumor after initially effective therapy.

IgA nephropathy in children: significance of glomerular basement membrane deposition of IgA.

Seventeen children with IgA nephropathy were grouped according to the absence (group I, n = 10) or presence (group II, n = 7) of glomerular basement membrane (GBM) deposition of IgA to determine whether GBM deposition of IgA correlated with laboratory or pathologic data at diagnosis or clinical status at follow-up. Children in group II had significantly (p less than 0.01) more proteinuria at diagnosis than children in group I. The percentage of glomeruli demonstrating crescent formation was significantly (p less than 0.05) higher in group II biopsies. Chronic changes of fibrous crescents, segmental sclerosis, global obsolescence, tubular atrophy, and interstitial fibrosis were also significantly (p less than 0.001) more common in group II biopsies. After a mean follow-up period of 2 years, all children in group II have persistent proteinuria of more than 1 g/24 h, and 3 of 5 have renal insufficiency (2 require dialysis). In contrast, 2 of 9 group I children have proteinuria exceeding 1 g/24 h, and only 1 has renal insufficiency. We conclude that, as compared to children with IgA localized to the mesangium, children with IgA nephropathy and GBM deposition of IgA have a higher urinary protein excretion at the time of diagnosis, more severe histologic alterations including a greater percentage of glomeruli demonstrating crescent formation, more chronic changes of segmental or global sclerosis, tubular atrophy, and interstitial fibrosis. Such children usually have persistent proteinuria and are more likely to develop progressive renal disease.

Effect of prostaglandins on immune complex interaction with glomerular cells in vitro.

Previous studies demonstrated that prostaglandins of the E1 (PGE1) series reduced immune complex (IC) accumulation and inflammation in murine glomeruli in IC glomerulonephritis (GN). This study examines the effect of PGE1 on IC interaction with cultured rabbit glomerular cells and heparan sulfate synthesis by the cells. IC were formed with antigen chemically modified to produce a cationic (CAT) charge or left unmodified (UM). CAT IC binding to cells was greater than UM IC in the absence of PGE1. CAT IC binding to cells was increased by PGE1 while UM IC interaction was not affected. Prolonged exposure of cells to PGE1 enhanced CAT IC binding. Heparan sulfate synthesis by the cells was not affected by the concentrations of PGE1 employed. The findings suggest the benefit provided by PGE1 in murine IC GN may not be due to a direct effect on glomerular cells which reduces glomerular IC accumulation.

Effect of antigen charge on immune complex interaction with glomerular cells in culture.

The effect of antigen charge on immune complex (IC) interaction with glomerular cells was evaluated using cultured rabbit glomerular cells. Rat albumin (Alb) was modified to produce a cationic charge; isoelectric point (pI) 7.4-8.0; anionic charge, pI 4.0-4.2; or left unmodified, pI 6.2-6.4. I125-IC (100 micrograms Alb in complex) was incubated with cells for 44 hr. Cationic Alb IC (CAT IC) interaction was 7 and 10 times greater than unmodified (UM) and anionic (AN) IC, 7596 +/- 613 vs 1016 +/- 176 and 746 +/- 106 pg I125-Alb/micrograms cell protein, mean +/- SE (P less than 0.01). A 10-fold excess of unlabeled CAT Alb decreased CAT IC interaction (6342 +/- 432 vs 1246 +/- 296 pg I125-Alb/micrograms cell protein, P less than 0.01) increased UM IC (981 +/- 186 vs 3994 +/- 394 pg I125-Alb/micrograms cell protein, P less than 0.01), and had no effect on AN IC. A 10-fold excess unlabeled CAT IC increased interaction of both CAT IC (7067 +/- 514 vs 37,416 +/- 3026 pg I125-Alb/micrograms cell protein) and UM IC (994 +/- 123 vs 12,922 +/- 566 pg I125-Alb/micrograms cell protein) but not of AN IC. Incubation of cells with CAT, UM, or AN Alb followed by specific antibody demonstrated increased antibody interaction with cells exposed to CAT Alb (15,212 +/- 676 vs 3866 +/- 406 and 1785 +/- 206 pg I125-IgG/microgram cell protein for UM and AN Alb, respectively).

Angiographic assessment of renal artery pathology: how reliable?

The accuracy of the angiographic interpretation of the histologic type of renal artery stenosis was assessed using a renal pathologist's diagnosis as the "gold standard." The angiograms of 42 renal artery stenoses were interpreted without other information, except age and gender, independently by six angiographers. This assessment indicated that angiography is not an accurate means by which to distinguish between the individual types of fibromuscular disease of the renal artery. However, it is a fairly accurate means by which to distinguish fibromuscular disease in general from atherosclerosis of the renal artery, 207 (82%) correct interpretations of 252. In addition, in the presence of renal artery stenosis, the absence of abdominal aortic atherosclerosis on angiography is an excellent predictor of fibromuscular renal artery disease, 17 (94%) of 18 specimens. Likewise, in the presence of a renal artery stenosis, angiographically demonstrable abdominal aortic atherosclerosis is a fair predictor of atherosclerotic renal artery disease, 16 (76%) of 21 specimens.

Unilateral hypersecretion of aldosterone associated with adrenal hyperplasia as a cause of primary aldosteronism.

In 3 patients with longstanding hypertension and spontaneous or diuretic-induced hypokalemia, the diagnosis of primary aldosteronism was established by the dual criteria of non-suppressible plasma aldosterone level and suppressed plasma renin activity. Preoperative studies of the etiology for the hyperaldosteronism using the postural plasma aldosterone test and adrenal venous steroid measurements gave conflicting results. On the basis of the differential adrenal venous steroid content, which suggested an unilateral adrenal source for the aldosterone hypersecretion, presumed to be adrenal adenoma, each patient was operated upon. In each case the excised adrenal revealed adenomatous or macronodular hyperplasia. Reinvestigation of the patients 3 to 12 months after the adrenalectomy showed that the dynamics of the renin-aldosterone axis was now restored to the normal state even though the patients remained hypertensive. These findings indicate that unilateral hypersecretion of aldosterone associated with adrenal hyperplasia can occur in some patients with primary aldosteronism simulating that due to an aldosteronoma. Such observations also raise questions about the pathogenesis of the adrenal hyperplasia and seem to add further complexity to the evaluation of patients with hyperaldosteronism.

Comparison of the metabolic and toxic effects of 2-chloropropionate and dichloroacetate.

The metabolic and toxic effects of 2-chloropropionate and dichloroacetate, activators of the pyruvate dehydrogenase complex, were compared. In 4-hr fasted mice, the oral LD50 values for 2-chloropropionate and dichloroacetate were 15.4 +/- 0.1 and 32.1 +/- 1.1 mmol/kg, respectively. In suckling rats, both compounds effectively lowered blood lactate and glucose levels and increased blood ketone bodies. Although comparable effects were brought about by both compounds on other metabolites, dichloroacetate caused a greater increase in blood ketone bodies. In a prolonged oral toxicity study using male rats, both compounds decreased growth rate and food consumption and caused neurotoxic effects. Both compounds brought about hind limb weakness, slower nerve conduction velocities and decreased diameter of tibial nerves. 2-Chloropropionate treatment caused testicular abnormalities manifested by testicular maturation arrest and degeneration of germ cells. 2-Chloropropionate-treated rats had significantly lower plasma triacylglycerol levels than control or dichloroacetate-treated rats. In mature rats, total serum ketone bodies were increased by dichloroacetate but not significantly elevated by 2-chloropropionate. Although 2-chloropropionate may lack sufficient safety to warrant chronic use in humans, it is a useful research tool for studying the metabolic effects of activation of the pyruvate dehydrogenase complex. Since 2-chloropropionate is not converted to oxalate and is not as ketogenic as dichloroacetate, 2-chloropropionate may be useful clinically in situations requiring only short-term therapy.

Hyperaldosteronism due to unsuspected adrenal carcinoma: discovery during investigation of hypertension in a young woman.

During investigation for hypertension a 19-year-old black woman was found to have an unsuspected adrenal carcinoma. Hyperaldosteronism was established as the cause of the hypertension by observing suppressed plasma renin activity and nonsuppressible plasma aldosterone concentration. The causal relationship was confirmed by a cure of the hypertension and a return in the responsiveness of the renin-angiotensin-aldosterone axis to normal after removal of the carcinoma. This report emphasizes the value of a comprehensive investigation of hypertension, especially in young patients.

The effect of antimacrophage antiserum on immune complex glomerulonephritis.

The effect of anti-M IgG on acute IC GN was assessed in rabbits. Nephritis was induced in sensitized animals with BSA. Anti-M IgG and the other immunoglobulins given to the various groups were administered by intra-aortic injection at the orifice of the left renal artery to avoid pulmonary sequestration of the antibodies. The animals were nephrectomized on the right to permit unilateral renal perfusion. The immunoglobulins were given to the study groups every 8 hr for 4 days, which corresponded to the period of IC formation and deposition in this model. Renal arteria perfusion with anti-M IgG reduced glomerular cellularity and preserved renal function. The groups given the other immunoglobulins were not afforded the same protection.

Immune complex nephritis in nude mice.

To examine the effect of T lymphocyte deficiency on the course of immune complex nephritis, we studied renal function and structure in Swiss albino nude and non-nude mice following injection of heterologous protein. Four groups of 22 mice each (two nude and two non-nude) received either apoferritin 2 mg or saline daily for 10 weeks. Nude mice were maintained in a gnotobiotic environment. Non-nude mice receiving apoferritin developed proteinuria and had increased cellularity within glomeruli compared to either nude mice receiving apoferritin or to control groups (p less than 0.05). Of 22 non-nude mice receiving apoferritin, 16 had glomerular immune deposits by electron and immunofluorescent microscopy while 9 of 22 counterpart nude mice receiving apoferritin had such deposits. Non-nude mice more commonly showed membraneous deposits. Nude and non-nude mice receiving saline had no glomerular deposits. These preliminary data suggest that T lymphocytes may play a significant role in the development of immune complex nephritis.