Proteolysis breaks tolerance toward intact α345(IV) collagen, eliciting novel anti-glomerular basement membrane autoantibodies specific for α345NC1 hexamers.

Goodpasture disease is an autoimmune kidney disease mediated by autoantibodies against noncollagenous domain 1 (NC1) monomers of α3(IV) collagen that bind to the glomerular basement membrane (GBM), usually causing rapidly progressive glomerulonephritis (GN). We identified a novel type of human IgG4-restricted anti-GBM autoantibodies associated with mild nonprogressive GN, which specifically targeted α345NC1 hexamers but not α3NC1 monomers. The mechanisms eliciting these anti-GBM autoantibodies were investigated in mouse models recapitulating this phenotype. Wild-type and FcγRIIB(-/-) mice immunized with autologous murine GBM NC1 hexamers produced mouse IgG1-restricted autoantibodies specific for α345NC1 hexamers, which bound to the GBM in vivo but did not cause GN. In these mice, intact collagen IV from murine GBM was not immunogenic. However, in Col4a3(-/-) Alport mice, both intact collagen IV and NC1 hexamers from murine GBM elicited IgG Abs specific for α345NC1 hexamers, which were not subclass restricted. As heterologous Ag in COL4A3-humanized mice, murine GBM NC1 hexamers elicited mouse IgG1, IgG2a, and IgG2b autoantibodies specific for α345NC1 hexamers and induced anti-GBM Ab GN. These findings indicate that tolerance toward autologous intact α345(IV) collagen is established in hosts expressing this Ag, even though autoreactive B cells specific for α345NC1 hexamers are not purged from their repertoire. Proteolysis selectively breaches this tolerance by generating autoimmunogenic α345NC1 hexamers. This provides a mechanism eliciting autoantibodies specific for α345NC1 hexamers, which are restricted to noninflammatory IgG subclasses and are nonnephritogenic. In Alport syndrome, lack of tolerance toward α345(IV) collagen promotes production of alloantibodies to α345NC1 hexamers, including proinflammatory IgG subclasses that mediate posttransplant anti-GBM nephritis.

Focal segmental glomerulosclerosis in kidney resected for renal cell carcinoma.

A diagnosis of renal dysfunction is usually made on the basis of clinical, biochemical, radiologic, and renal tissue analysis. Accurate diagnosis often requires a renal biopsy, but that procedure is contraindicated in certain clinical circumstances, particularly in patients who have only one kidney. We describe a patient who previously had undergone left nephrectomy for a renal clear cell carcinoma, in whom the diagnosis of focal segmental glomerulosclerosis was made on retrospective analysis of remnant renal tissue from the patient's nephrectomy specimen.

Characteristics of 100 consecutive patients presenting with orthostatic hypotension.

OBJECTIVE: To elucidate the demographic and clinical characteristics of a consecutive series of patients who presented for evaluation of orthostatic hypotension. PATIENTS AND METHODS: From January 1, 1997, through September 30, 2001, we assessed retrospectively the demographic and clinical characteristics, antihypertensive medication use, and blood pressure variability in 100 consecutive patients with orthostatic hypotension who underwent 24-hour ambulatory blood pressure monitoring (OH group) and in a convenience sample of 100 age-matched patients who underwent 24-hour ambulatory blood pressure monitoring for evaluation of hypertension (HTN group). RESULTS: The OH group had a mean +/- SD age of 71.6 +/- 9.4 years, and 42% were women. The most common symptoms were light-headedness and weakness. Comorbid conditions included neurologic diseases (38%), preexisting hypertension (36%), hyperlipidemia (31%), cardiac arrhythmias and coronary artery disease (45%), and neoplasm (28%). During ambulatory blood pressure monitoring, postprandial decreases in blood pressure were noted in 83% of the OH group, supine or sleep hypertension in 84%, and noncompensatory heart rate variability in 75%. Findings on autonomic testing were abnormal in 99% of patients, serum creatinine value was increased in 30%, proteinuria was present in 27%, and left ventricular hypertrophy was present in 20%. CONCLUSIONS: Orthostatic hypotension is present in a heterogeneous group of disease states, is usually symptomatic, and is often associated with an abnormal blood pressure profile of reversal of circadian pattern, postprandial hypotension, and noncompensatory heart rate variability. Consequent target organ (kidney) damage can be as frequent as in patients who undergo 24-hour ambulatory blood pressure monitoring for evaluation of hypertension.

Erythema multiforme associated with candesartan cilexetil.

Candesartan cilexetil is an angiotensin II receptor antagonist that is widely used in the treatment of hypertension. It is generally well tolerated and rarely has adverse effects. We report the case of a 50-year-old man with a 3-year history of hypertension that was difficult to manage because of intolerance to multiple medications. Treatment with candesartan cilexetil was initiated, and blood pressure control improved markedly. Five weeks later, the patient presented with a 2 x 3-cm ulcerative plaque covered with a fibrinous exudate on the right upper lip. Findings from a biopsy of the upper lip were diagnostic for erythema multiforme. Treatment with candesartan cilexetil was discontinued, and the lesions resolved completely within a few weeks. To our knowledge, this is the first report of erythema multiforme induced by the antihypertensive medication candesartan cilexetil.

Bisalbuminemia in chronic kidney disease.

Hereditary and acquired bisalbuminemia, in which the serum contains an albumin variant differing from albumin A by single amino-acid substitutions, have been reported in different races or ethnic groups and in association with various pathologic states. The importance of this rare condition in the pathophysiology of established diseases is uncertain. We evaluated a 68-year-old woman with chronic kidney disease who presented with worsened serum creatinine concentration despite lack of dietary or medical changes. Serum protein electrophoresis was performed with an automated rapid electrophoresis system. Bisalbuminemia was noted as an incidental finding on serum protein electrophoresis. The serum creatinine level stabilized with dietary protein restriction and a beta-blocking agent/diuretic combination for blood pressure control. Although the possibility that some physiologic or pharmacologic substances may not bind to abnormal albumin variants as well as they bind to normal albumin should not be discounted, the finding of bisalbuminemia did not influence the diagnosis, management, course, or prognosis of chronic kidney disease. The role of persistent bisalbuminemia in renal disease is uncertain.