Frank J. Albers

Causes of Hemodialysis Access Failure

Complications of hemodialysis access remain significant problems in the population receiving renal replacement therapy. The causes of access loss must be recognized before appropriate interventions can be designed. The native primary arteriovenous fistula is the access of choice because of its good survival characteristics and low rate of complications. Unfortunately, a substantial number of patients have vasculature insufficient to create and maintain this access. Once a primary fistula is established, thrombosis is the leading cause of failure: its causes can be divided into early (less than 6 weeks) and late complications. In patients unable to have fistulas, arteriovenous conduits of expanded polytetrafluoroethylene (ePTFE) are now the prostheses of choice. Again thrombosis is the leading cause of this access loss but there is also a substantial rate of failure from infection, pseudoaneurysms, perigraft hematomas, and simple attrition of the prosthesis. Thrombosis of ePTFE grafts is usually associated with anatomic stenosis at the venous anastomosis, within the graft itself, or in the central venous system. Graft thromboses cannot always be attributed to anatomic lesions: in these circumstances, thrombosis has been attributed to low-flow states. It is possible that the normal balance between endothelial procoagulant and anticoagulant forces are disrupted within the arteriovenous conduit. Recurrent venipuncture, hemodialysis therapy itself, or pathophysiological forces inherent in the access may all favor hemostasis. Infection also causes significant hemodialysis access morbidity. The causative organism is usually Staphylococcus aureus but several other pathogens have been reported. Ideally, all prostheses should be removed when infected, but this approach must be tempered by the reality of limited hemodialysis access sites. There is no consensus as to the best therapeutic approach to access infection.

Clinical and Pathologic Features of Familial Focal Segmental Glomerulosclerosis

The occurrence of focal segmental glomerulosclerosis (FSGS) in a familial pattern has been rarely reported previously. Over the last 10 years we have treated 31 patients among eight families with familial FSGS. The diagnosis was confirmed by renal biopsy in 18 cases, and each family had at least two members in whom the diagnosis was confirmed histologically. Both males and females were affected, as were both blacks and whites. The mean age at presentation was 28 years, with a range of 8 to 56 years. The mean serum creatinine at presentation was 3.7 mg/dL. Twenty-five of the 31 patients progressed to end-stage renal disease; and treatment with prednisone did not appear to retard the progression to end-stage renal disease. Seven patients received a cadaveric renal transplant and none of them showed evidence of recurrence of disease in the graft. The pattern of inheritance in two families appeared to be autosomal dominant; in the other families the pattern of inheritance was less clear and may have been autosomal recessive, although a familial exposure to an unidentified environmental toxin cannot be excluded. Histologic examination of the renal tissue revealed a variety of changes previously described as occurring in FSGS. We conclude that FSGS may occur in a familial pattern that carries a poor prognosis. Further studies of these families may shed light on the pathogenesis of sporadic FSGS.

Functional expression of human 5-HT1A receptors and differential coupling to second messengers in CHO cells

SummaryThe signal transduction linkages of the cloned human 5-HT1A receptor as expressed stably in CHO cells were studied. A transfected clonal cell line which expresses 900 ± 36 fmol 5-HT1A receptor/mg protein (designated CHO-5-HT1A/WT-27) responded to 5-HT and/or 8-OH-DPAT by coupling to several second messenger pathways. The 5-HT1A receptor inhibited, but did not stimulate, membrane adenylyl cyclase activity and whole cell cAMP accumulation in a dose-dependent manner (for 5-HT, IC50 = 146 ± 27 and 55 ± 12 nM, respectively). Activation of the receptor was associated with other signal transduction linkages: (i) a 40–50% increase in hydrolysis of inositol phosphates (for 5-HT, EC50 = 1.33 ± 0.15 μM for 5-HT), (ii) a transient elevation of cytosolic Ca2+ levels (apparent at 1–100 μM 5-HT) which was not affected by chelation of extracellular Ca2+ by EGTA, and (iii) an augmentation of [3H]-arachidonic acid release pharmacologically with the calcium ionophore A23187 or by activation of endogenous thrombin or P2 purinergic receptors (for 5-HT, EC50 = 1.22 ± 0.17 μM). This pathway may be an amplification mechanism for signaling in anatomic regions with high concentrations of several neuro-transmitters, hormones or autacoids, such as at neuronal junctions or near areas of platelet aggregation. All linkages were sensitive to pertussistoxinpre-treatment (IC50≈0.5–0.6 ng/ml × 4.5 h for all pathways), suggesting the involvement of Gi protein(s) in these signal transduction pathways. Coupling to varied signal transduction pathways in a single cell system may be a common feature of receptors which classically inhibit adenylyl cyclase such as the 5-HT1A receptor.

Clinical Characteristics of Atherosclerotic Renovascular Disease

In addition to its role in secondary hypertension, ischemic renal disease is becoming recognized as a significant cause of renal insufficiency. The prevalence and natural history of this disease remain unknown due to difficulty in identification of the process. There are several scenarios that may help alert the clinician to the presence of atherosclerotic renovascular disease. In hypertensive patients, poorly controlled blood pressure on several medications or rapid acceleration of hypertension can suggest renovascular disease. In addition, high-grade retinopathy or abdominal bruits seem to be associated with this condition: bruits have the highest positive predictive value of the clinical signs. Renal artery stenosis also may be related to rapidly progressive renal failure. The classic association is renal failure after use of angiotensin-converting enzyme inhibitors; however, acute renal failure induced through any sudden therapeutic decrease in blood pressure may imply the presence of renal artery stenosis. Unexplained azotemia in the elderly patient also has been associated with renovascular disease. It is possible that the majority of patients with renal artery stenosis are those with a clinically silent process. Advanced age, peripheral atherosclerotic vascular disease, and coronary artery disease may all have a high association with stenosis of one or both renal arteries. It is nevertheless unknown whether a radiographically detected lesion implies current or future clinical complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Considerations in Heodialysis Access Infection

Hemoaccess infections remain a substantial cause of morbidity in patients on hemodialysis, especially with the increasing reliance on prosthetic devices as the average age of the hemodialysis population increases. Access manipulation, either through needle puncture or secondary surgical procedures, is the primary etiology of infection. Other conditions such as access location, patient hygiene, and intravenous drug use can cause contamination. Local evidence of inflammation or infection, especially pain and purulence, are the most reliable signs of infection; however, the access can be infected and there may be minimal systemic symptoms. Medical therapy must be directed primarily against Staphylococcus aureus, with vancomycin being used most frequently. There are distinct conditions in which infection with gram-negative bacilli is also common. A coordinated effort between medical management and surgical intervention is essential to optimize therapy. Several situations, such as loss of vascular integrity or infection at anastomosis sites, mandate full excision of the graft. However, the access or at least the access site, can be preserved through creative surgical intervention along with aggressive medical treatment. Approaches to the diagnosis and treatment of infection in autologous arteriovenous fistulae, polytetrafluoroethylene arteriovenous conduits, and cuffed dual-lumen venous hemodialysis catheters are discussed.

Survival in Renal Vascular Disease

Renal artery stenosis (RAS) is a relatively uncommon but important potentially reversible cause of renal failure. Little is known about the natural history of ischemic renal disease secondary to RAS. In previous reports, these researchers examined the incidence and risk factors associated with RAS. The study presented here investigates the long-term follow-up of these patients, specifically the effect of RAS on 4-yr, all-cause mortality in a group of 1235 patients undergoing diagnostic cardiac catheterization and abdominal aortography. A total of 1235 consecutive patients undergoing cardiac catheterization also underwent an abdominal flush aortogram. Significant RAS was considered present if one or more renal artery had 50% or greater narrowing in luminal diameter. Four-year unadjusted survival for patients with RAS was 65% compared with 86% for patients undergoing catheterization without significant RAS. Factors associated with decreased 4-yr survival included increased age, increased serum creatinine, presence of RAS, peripheral vascular disease, congestive heart failure, diabetes, hypertension, and reduced ejection fraction. Using the Cox proportional hazards model, the factors associated with decreased 4-yr survival were the presence of significant RAS, reduced ejection fraction, elevated serum creatinine, and symptoms of congestive heart failure. These observations indicate that the presence of significant RAS is a strong independent predictor of 4-yr survival in this patient population.