Faculty Bibliography

Several studies have found reduced use of recommended medications after myocardial infarction (MI) in patients with impaired kidney function. However, the reasons for such undertreatment are not well understood. A total of 1380 Medicare patients who survived at least 90 d after MI and had prescription drug coverage through Pennsylvania's medication assistance program for the elderly were studied. Filled prescriptions were used to assess use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta blockers, and statins within 90 d of MI. Patients' demographics, comorbidities, and health care utilization before MI also were ascertained. We used logistic regression to test the association between kidney function and postdischarge use of each medication. Overall, 619 (45%) patients filled a prescription for a beta blocker, 675 (49%) received an ACEI or ARB, and 406 (29%) received a statin after discharge but within 90 d after their admission for MI. Reduced kidney function was associated with both lower beta blocker and statin use (P = 0.01 and P = 0.002, respectively), but after multivariate adjustment, these associations disappeared (P = 0.23 and P = 0.62, respectively). Use of ACEI or ARB was nearly half in patients with estimated GFR <30 ml/min compared with patients with better kidney function in univariate and multivariate analyses (P < 0.001). Analyses using serum creatinine measurements rather than estimations of GFR yielded similar results. Differences in other characteristics such as age, rather than kidney function, may be responsible for much or all the reported reduction in use of preventive medications after MI seen in patients with chronic kidney disease.

BACKGROUND:Beta-blockers, statins, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) are standard therapies after myocardial infarction (MI) in the general population. Their use and association with mortality in elderly dialysis patients after MI have not been studied sufficiently. METHODS:Claims records from Medicare and Medicaid patients aged 65 years and older who participated in prescription benefit plans of 2 eastern states were used to identify dialysis patients with MI between 1995 and 2003. Study outcomes were outpatient use of beta-blockers, statins, and ACE inhibitors and/or ARBs within 90 days after MI. We used multivariate logistic regression to assess predictors of such use. Multivariate Cox regression was applied to test for associations between beta-blocker, statin, and ACE-inhibitor and/or ARB use and 1-year mortality. RESULTS:We identified 902 dialysis patients who were hospitalized with MI. Of these, 39.5% died within 90 days and 63.6% died within 1 year after MI. Of 494 patients who were discharged within 21 days or less and survived longer than 90 days, 31.0% were administered an ACE inhibitor and/or ARB; 19.4%, a statin; and 34.2%, a beta-blocker after discharge. Use of ACE inhibitors and/or ARBs was associated with a 30% reduction in 1-year mortality (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.50 to 0.98), whereas statin (HR, 0.97; 95% CI, 0.65 to 1.45) and beta-blocker use (HR, 1.05; 95% CI, 0.78 to 1.43) were not. CONCLUSION/CONCLUSIONS:Elderly dialysis patients have excessively high mortality and low use of standard therapies after MI. Only ACE inhibitors and/or ARBs were associated with a reduced risk for death at 1 year in this population. Whether the high mortality rate in this population is attributable to such low use of preventive cardiovascular medications remains uncertain.

Commercial serological assays for the presence of anti-glomerular basement membrane (GBM) antibodies are thought to be indicative of Goodpasture's syndrome. We report a case in which commercial tests inaccurately suggested that a patient with a pulmonary-renal syndrome had Goodpasture's disease. Additional laboratory testing using recombinant type IV collagen NC1 domain proteins showed that the autoantibodies in question were not directed against the Goodpasture antigen (the alpha3NC1 domain), but against the alpha2NC1 domain of type IV collagen. Our findings represent the first known case of human autoantibodies to the alpha2NC1 domain. Further investigation showed that this patient has decreased alpha3 and alpha5 chain expression in the GBM and defects in type IV collagen, resembling abnormalities in patients with Alport's syndrome.

BACKGROUND:Anti-glomerular basement membrane (GBM) antibodies occasionally occur in Alport patients after renal allograft transplantation. METHODS:We report a patient with Alport's syndrome who lost four transplants each within the first year post transplantation. We searched for the presence of anti-GBM antibodies using recombinant NC1 domains of type IV collagen. Immunoblotting, enzyme linked immunosorbent assay (ELISA), and immunofluorescence were used to detect the presence of antibodies against the glomerular basement membrane. RESULTS:High antibody titers to the alpha3 chain (the Goodpasture antigen) and alpha5 chain of type IV collagen were detected. Review of pathologic specimens showed features of vascular rejection in all specimens. CONCLUSION/CONCLUSIONS:The association of high titer anti-GBM antibodies and vascular rejection may be important. When vascular rejection occurs in Alport patients, the presence of anti-GBM antibodies should be sought. Recombinant anti-GBM assays should be used if standard anti-GBM testing is equivocal.

Theophylline is commonly used in the treatment of bronchospastic lung disease. In addition to gastrointestinal and cardiac dysfunction, hypokalaemia, lactic and ketoacidosis can complicate theophylline overdose. Clinicians frequently fail to identify theophylline's role when complications develop. A case of an 80-year-old man who developed profound metabolic disturbances while hospitalized is presented. The typical causes of these abnormalities were absent, theophylline levels were elevated, and the patient recovered after theophylline was held. Based on our case and review of the literature, we discuss the reasons why theophylline toxicity is under-recognized, and propose mechanisms for the rare metabolic abnormalities identified in this case. A high index of suspicion for theophylline toxicity should be maintained and it should be considered when unexplained acidosis or hypokalaemia occur.

Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-beta superfamily. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development. Here we report that BMP-7 reverses TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-beta1-induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-beta1-induced de novo EMT in a mouse model of chronic renal injury. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-beta1 in the regulation of EMT in health and disease.

There are about 2.5 million glomeruli in the kidneys each consisting of a barrel of glomerular basement membrane surrounded by glomerular endothelial cells on the inside and glomerular epithelial cells with established foot processes (podocytes) on the outside. Defects in this filtration apparatus lead to glomerular vascular leak or proteinuria. The role of vascular endothelial growth factor (VEGF) in the regulation of glomerular vascular permeability is still unclear. Recent studies indicate that patients receiving anti-VEGF antibody therapy may have an increased incidence of proteinuria. In a different setting, pregnancies complicated by preeclampsia are associated with elevated soluble VEGF receptor 1 protein (sFlt-1), endothelial cell dysfunction and proteinuria. These studies suggest that neutralization of physiologic levels of VEGF, a key endothelial survival factor, may lead to proteinuria. In the present study, we evaluated the potential of anti-VEGF neutralizing antibodies and sFlt-1 in the induction of proteinuria. Our studies demonstrate that anti-VEGF antibodies and sFlt-1 cause rapid glomerular endothelial cell detachment and hypertrophy, in association with down-regulation of nephrin, a key epithelial protein in the glomerular filtration apparatus. These studies suggest that down-regulation or neutralization of circulating VEGF may play an important role in the induction of proteinuria in various kidney diseases, some forms of cancer therapy and also in women with preeclampsia.

BACKGROUND:Although the methods for the appropriate management of patients with hyperkalemia are well established, no criteria for hospital admission of patients with this common electrolyte disorder have been promulgated. OBJECTIVES/OBJECTIVE:To examine the current practices regarding hospitalization of patients with hyperkalemia and to consider appropriate criteria for admission. PATIENTS AND METHODS/METHODS:We evaluated a consecutive series of patients hospitalized for hyperkalemia and excluded patients who developed hyperkalemia after admission. For comparison, we selected a series of patients with a similar degree of hyperkalemia who were treated as outpatients. Hyperkalemia was classified as minimal, moderate, or severe. The causes of hyperkalemia were identified, and the therapeutic maneuvers used were ascertained. Although the study did not have the power to determine the relative safety of the 2 therapeutic approaches, we compared the outcomes of the 2 groups of patients. RESULTS:The inpatient group consisted of 11 patients who were admitted for the treatment of hyperkalemia, and we identified 12 patients who received outpatient therapy for hyperkalemia. The patients in the 2 treatment groups were similar with respect to age and the values of serum urea nitrogen, creatinine, and potassium prior to the identification of hyperkalemia. The mean +/-SD potassium concentrations at baseline were 5.4+/-0.7 mmol/L in the inpatients and 5.5+/-0.5 mmol/L in the outpatients. The mean +/-SD potassium concentration in the inpatients was 6.7+/-0.8 mmol/L at the time of hospital admission, compared with 6.7+/-0.5 mmol/L in the outpatients at the time that hyperkalemia occurred. Similar proportions of both groups (6 of 11 inpatients and 7 of 12 outpatients) had moderate or severe hyperkalemia. CONCLUSIONS:Patients admitted to the hospital were clinically indistinguishable from patients treated as outpatients. The justification for the decision to admit patients to the hospital or to treat them as outpatients was often not evident. We suggest criteria for hospitalization, which include severe hyperkalemia (> or =8.0 mmol/L, with changes other than peaked T waves on the electrocardiogram), acute worsening of renal function, and supervening medical problems.