Eugene C. Kovalik

HEPARIN-INDUCED THROMBOCYTOPENIA IN DIALYSIS: Alternative Methods of Anticoagulation for Dialysis-dependent Patients with Heparin-induced Thrombocytopenia

Dialysis patients who are continually exposed to heparin are at risk for heparin‐induced thrombocytopenia (HIT). Heparin‐induced antibodies have been reported to occur in 0–12% of hemodialysis (HD) patients. The diagnosis or suspicion of HIT in this patient population requires careful confirmation of the diagnosis and substitution of heparin with an alternate anticoagulant for dialysis. Alternate agents such as the direct thrombin inhibitors (hirudin and argatroban) are available, but careful dosing and monitoring of the anticoagulant effect are required. Despite careful dosing, hemorrhagic complications have occurred with these agents. Unfortunately there are limited options for treatment of hemorrhagic complications and no specific antidotes are available for the direct thrombin inhibitors. In this report the currently available alternatives to heparin for dialysis, including dosing and monitoring recommendations, are reviewed.

Normalization of hematocrit in hemodialysis patients with cardiac disease does not increase blood pressure.

Since the earliest reports of the use of Epoetin alfa in hemodialysis patients, it has been described that Epoetin alfa may exacerbate preexisting hypertension or induce hypertension in End Stage Renal Disease (ESRD) patients not previously hypertensive. We undertook this study to determine if the correction of anemia in ESRD patients with cardiac disease from a hematocrit of 30 ± 3% to 42 ± 3% with the use of Epoetin alfa would result in increased blood pressure. This study was a substudy of the “Normal hematocrit Study”. Methods Thirty-one patients were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoetin alfa to 42 ± 3% and patients in Group B were maintained with a hematocrit of 30 ± 3% throughout the course of the study. All patients had their blood pressure recorded with a 24 hour ambulatory BP device at study entry and at 28 weeks following randomization when they had achieved their target hematocrit. Pre-dialysis systolic and diastolic BP was also recorded.Results The mean hematocrit increased in Group A from 29.1 ± 2.4% to 40.8 ± 5.2% after 30 weeks. The hematocrit in Group B remained stable at 30 ± 3% throughout the course of the study. There was no difference in mean daytime, mean nighttime or 24 hour systolic or diastolic blood pressure between Groups A and B at either baseline or follow-up. Neither was there a difference in mean pre-dialysis systolic or diastolic BP between Groups A or B at baseline or Follow-up. Four patients in Group A and 4 patients in Group B required an increase in their antihypertensive medication during the course of the study.Conclusion It is possible to increase hematocrit to normal levels in hemodialysis with the administration of Epoetin alfa. The increase in hematocrit from 30 ± 3% to 42 ± 3% is not associated with increased blood pressure.

NORMALIZATION OF HEMATOCRIT IN HEMODIALYSIS PATIENTS DOES NOT AFFECT SILENT ISCHEMIA

Transient ST-segment depression measured on ambulatory ECG monitors has been described as representing silent ischemia. Patients who demonstrate silent ischemia have been reported to show increased mortality compared to patients without silent ischemia. We undertook this study to determine if the correction of anemia in End Stage Renal Disease (ESRD) patients from(± = standard deviation) 30 ± 3 to 42 ± 3 with the use of Epoetin alfa would result in decreased silent ischemia in patients with clinically evident ischemic heart disease or congestive heart failure. Methods: Thirty one ESRD patients with congestive heart failure or patients with clinically-evident ischemic heart disease were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoetin alfa to 42 ± 3% and patients in Group B were maintained with a hematocrit of 30 ± 3% throughout the course of the study. All patients had a 24 hour Holter monitor recording at baseline and at 28 weeks after randomization (when they had reached their target hematocrit). Significant silent ischemia was considered to be present if patients demonstrated at least 60 seconds of ≥ 1 mm ST segment depression. Results: Fifteen patients were randomized to Group A and 16 patients were randomized to Group B. The mean hematocrit increased in group A from 29.1 ± 2.4% to 40.8 ± 5.2% after 30 weeks. The mean hematocrit in Group B remained stable at 30 ± 3% throughout the course of the study. Ten patients demonstrated silent ischemia at baseline. At follow up patients in group A demonstrated a mean of 1.7 ± 4.9 minutes of ischemia compared to 1.1 ± 3.4 minutes in group B. These were not significantly different. A similar number of patients in group A and Group B required adjustments in their anti-anginal medication during the course of the study. Conclusion: It is possible to increase hematocrit to near normal levels in hemodialysis with the administration of exogenous Epoetin alfa. The increase in hematocrit form 30 ± 3% to 42 ± 3% is not associated with a change in the level of silent ischemia these patients demonstrate.

Monoclonal antibodies to antigens abnormally expressed in breast cancer.

We report the production, screening, and characterization of ten murine monoclonal antibodies directed at antigens that are expressed abnormally in human breast tumors. Immunoperoxidase staining of frozen and fixed tissues shows the antigens to be present at low levels on the luminal membrane of normal breast cells and at high levels in the cytoplasm and surface membrane of breast tumor cells. The ten antibodies appear to recognize six different epitopes on the basis of their quantitative differences in reactivity against four antigen preparations, as measured by ELISA. Immunoblots show that eight of the ten antibodies recognize a 300,000 MW molecule from breast tumor preparations; six of these antibodies also react with a second molecule from the same tumor preparations of 280,000 MW. Seven antibodies react with an antigen from milk fat globule membrane of 330,000 MW. It therefore appears that the two molecules from tumor tissue and the one molecule from normal tissue share common epitopes. Selected antibodies were tested for reactivity against 25 primary breast tumors and 14 pairs of primary and metastatic breast tumors. Three antibodies have broad reactivity and stain more than 80% of primary tumors; the three other antibodies identify subsets of those tumors. Results of staining pairs of primary and metastatic lesions show that metastases continue to express antigens of the primary lesion in a high percentage of cells.

Double antibody radioimmunoassay for monitoring metastatic breast cancer

We previously reported the production of a panel of murine monoclonal antibodies which recognize glycoproteins abnormally expressed in human breast tumours. Using two of these antibodies, a double antibody radioimmunoassay was designed to quantify levels of these breast tumour marker glycoproteins in serum. Marker levels greater than 28 units were considered abnormal. Using this criterion, 63% and 75% of patients with breast cancer stages I and II, respectively, and 88% of those with metastatic disease were found to have elevated marker levels. Thirteen percent of patients with non-malignant breast disease also had elevated marker levels. Elevated marker levels were also detected in patients with non breast neoplasms. One hundred and eleven women with metastatic disease were followed. Eighty-two percent of those with progressive disease and 73% of those where disease regressed had 20% changes in marker levels. These changes in marker levels preceded by up to 6 months changes in disease state. From these results we conclude that this assay may be useful for monitoring the course of disease in breast cancer patients.

Can Venous Stenosis Be Prevented

Currently, more than 200,000 people annually are kept alive by maintenance hemodialysis therapy. To provide this form of renal replacement therapy, a reliable means of accessing the vasculature is required. Currently, access needs are met by three methods: the primary arteriovenous fistula (AVF), polytetrafluoroethylene (PTFE) grafts, and tunneled cuffed catheters. Of these three access modalities, only the first two are appropriate for long-term maintenance hemodialysis. Unfortunately, only the primary AVF has shown reliable long-term patency. The Canadian Hemodialysis Morbidity study showed a 71% lower risk of failure of an AVF as compared to PTFE grafts (1). Despite such data, PTFE grafts represent the main access modality of up to 73% of incident hemodialysis patients, although regional variations of 23%–85% exist (2). The preponderance of PTFE grafts and their higher failure rate has led, in part, to the spiraling cost of treating end-stage renal disease patients. Up to 25% of all hospital stays and up to 50% of the first year hemodialysis costs may be attributed to vascular access care (3–5). Due to the failure rate of PTFE grafts, the Dialysis Outcome Quality Initiative guidelines recently published by the National Kidney Foundation recommend that primary AVFs be attempted in at least 50% of all new patients, with the goal that such fistulas will be successful in at least 40% (6). For patients who, for whatever reason, cannot have a primary AVF, strategies must be undertaken to provide maximum graft survival. When grafts fail, the cause of failure is graft thrombosis. The underlying cause of thrombosis usually is stenosis of the venous outflow tract. Although the majority of stenoses occur at the graft vein anastomosis (roughly 45%), up to 34% of lesions can be found in the runoff vessels, particularly the central venous system (7). Intimal hyperplasia appears to be responsible for the stenotic lesions (8). The hyperplasia stems from medial smooth-muscle replication and migration to the intimal area of the vessels, followed by further proliferation and matrix deposition (9, 10). The sequence may be the natural result of the body’s response to injury. Unfortunately, this response is maladaptive for the needs of the hemodialysis patient. Currently, the strategies available to the nephrologist to combat the problem of intimal hyperplasia rely mainly on detecting lesions early and intervening with either angioplasty or surgical revision prior to access failure. Various detection techniques are available such as venous pressure, recirculation, Doppler flow, and online access blood flow monitoring. Unfortunately these techniques do nothing to prevent the underlying physiologic problem. In future, researchers in vascular access therapies must address the problem of intimal proliferation before it can occur. The various stages of the process (smooth-muscle migration, proliferation or extracellular matrix production) serve as targets for therapy. Three areas are of particular interest: pharmacologic prevention of stenosis, graft irradiation to prevent intimal hyperplasia and, finally, genetic therapy aimed at interrupting intimal proliferation. Very little work has been done in the use of drugs to inhibit myointimal proliferation in arteriovenous (AV) grafts. Hakim and Himmelfarb (11) recently reviewed the literature. In new PTFE grafts, dipyridamole has been shown, in small studies, to decrease the rate of thrombosis, whereas aspirin use tends to increase thrombotic events (12). These drugs have no significant effects on previously thrombosed grafts (12). In one small study, ticlodipine also seemed to decrease thrombotic events in AV grafts (13). Fish oil has been used with mixed results (14). These agents are proposed to inhibit venous stenoses by inhibiting both neointimal and fibromuscular hyperplasia in the vein wall by direct action on vessel wall injury, such action being mediated by cytokine-driven pathways. The current proposal is that platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) may be the mediators of this vessel wall injury. Specific antagonists such as dipyridamole may slow or stop this response to injury. Proprietary experimental agents with specific inhibitory action on these cytokines are being actively investigated. The paradoxical effect of aspirin as compared to dipyridamole, according to Hakim and Himmelfarb (11), is likely due to its ability to inhibit both PDGF and bFGF. Aspirin results in an increase of PDGF-induced cell proliferation by inhibiting cyclooxygenase-derived inhibition of smooth-muscle proliferation and stimulating lipoxygenase-mediated proliferation. The use of irradiation to prevent restenosis after angioplasty with or without stent placement in the coronary and peripheral arteries has been under investigation for several years. The technique applied involves the delivery of beta-irradiation via an iridium wire to the angioplasty site. The largest published human trial showed excellent follow-up patency (15). Because the AV graft vein anastomosis accounts for nearly half of the lesions found in thrombosed grafts, this site is amenable to radiotherapy. In an abstract out of Emory University, internal irradiation of the anastomosis after angioplasty yielded encouraging results (16), even though if adAddress correspondence to: Steve J. Schwab, MD, Division of Nephrology, Box 3014, Duke University Medical Center, Durham, NC 27710. Seminars in Dialysis—Vol 12, No 3 (May–June) 1999 pp. 144–145

Hollow‐Fiber versus Parallel‐Plate Dialyzers in Continuous Arteriovenous Hemodialysis

Continuous ar ter iovenous hemodialysis (CAVHD) has gained increasing acceptance over the last decade as a mode of therapy in critical care patients (1,2). The efficiency of solute removal during the procedure is a significant clinical consideration that has been, however, the subject of relatively limited investigation. Many factors likely contribute to the efficiency of solute removal with CAVHD. Dialyzer geometry appears to be one such factor that is both important and relatively unappreciated.

Role of urine and serum protein electrophoresis in evaluation of nephrotic-range proteinuria

The usefulness of routine serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) screening in the evaluation of proteinuria is not known. The data on the clinical utility of these tests in 165 male patients with proteinuria greater than 3 g/d of protein who were screened for the presence of an M-spike are presented. Two hundred fifty-four studies were performed (SPEP, 155; UPEP 99) in these 165 patients. Twenty-four studies (9.8%) were positive for an M-spike (15 serum; 9 urine samples) in 19 patients (11.5%). Fourteen patients (8.5%) had an M-spike in either serum or urine, five patients (3%) in both studies. Two of these 19 patients were diagnosed with myeloma and 1 patient was diagnosed with primary amyloidosis. The other 16 patients were diagnosed with monoclonal gammopathy of unknown significance (MGUS). The group with a positive M-spike was significantly older (mean +/- SEM, 65 +/- 2 years; range, 39 to 78 years v 58 +/- 1 years; range, 25 to 84 years; P = 0.03), had a lower incidence of coexistent diabetes (21.1% v 61.6%; P = 0. 01), and a lower serum albumin level (3.2 v 3.6 g/dL; P = 0.05). Using a multivariable logistic regression model, the presence of an M band was positively correlated with age (odds ratio [OR], 1.056; 95% confidence interval [CI], 1.006 to 1.108) and negatively correlated for serum albumin level (OR, 0.386; 95% CI, 0.184 to 0. 810), hematocrit (OR, 0.923; 95% CI, 0.852 to 1.001), and the presence of diabetes mellitus (OR, 0.128; 95% CI, 0.038 to 0.434). In summary, routine SPEP and UPEP screening in patients with proteinuria greater than 3 g/d of protein detected an M-spike in 11. 5% and myeloma in 1.2% of the patients. The cost per case of myeloma or MGUS discovered was

A Comparison of Percutaneous Transluminal Angioplasty Versus Surgical Correction of Various Access Complications

1,192.

Survival in Renal Vascular Disease

For hemodialysis to be a viable long-term mode of therapy for patients with end-stage renal disease, the ability to repetitively access the circulation via either primary or artificial arteriovenous fistulas is crucial. Unfortunately, recurrent problems with these fistulas have led them to being dubbed the Achilles heel (1) of hemodialysis. When early failures are excluded, autologous (primary or native) arteriovenous fistulas have a greater three-year patency rate than do synthetic fistulas (73% versus 52% [2]). However, less than 25% of patients starting hemodialysis have blood vessels suitable for a primary fistula (3). Most synthetic fistulas today are made of polytetrafluoroethylene (PTFE). The overall complication rate for PTFE grafts is twice as high as that for primary fistulas (2) with six times the thrombosis rate and ten times the infection rate of native grafts (4). The hospitalization cost of fistula related problems, either autologous or PTFE, is estimated to be at least