Israel Medical Association Journal

Background: Advanced glycation end products, formed by the non-enzymatic glycation of proteins with reducing sugars, are thought to play a pathogenetic role in the vascular complications of diabetes, uremia and atherosclerosis. β2-microglobulin is a major constituent of amyloid fibrils in dialysis-related amyloidosis. AGE[1]-modified β2m[2] has been found in amyloid deposits of long-term hemodialysis patients. AGE-modified β2m has also been shown to enhance chemotaxis and increase tumor necrosis factor-alpha and interleukin-1 beta secretion by circulating and tissue monocytes/macrophages.

Objectives: To investigate the effect of AGE-modified β2m and AGE-human serum albumin on TNF-α[3] and IL-1β[4] secretion by human peritoneal macrophages derived from patients on continuous ambulatory peritoneal dialysis.

Methods: Human PMØ[5] were isolated from peritoneal dialysis effluent of stable CAPD[6] patients and were incubated for 24 hours with AGE-modified β2m, β2m, AGE-HSA[7], HSA or lipopolysaccharide. TNF-α or IL-1β secretion was measured by enzyme-linked immunosorbent assay in cell-free culture supernatants.

Results: Both AGE-modified β2m and AGE-HSA significantly increased TNF-α and IL-1β secretion by human PMØ in a dose-dependent manner (50–200 μg/ml). In contrast, β2m or HSA had no such stimulatory effect on TNF-α secretion but had a small significant increase in IL-1β secretion.

Conclusions: AGE-modified β2m promotes in vitro TNF-α and IL-1β secretion by human PMØ of CAPD patients. Activation of these macrophages by AGE-modified β2m may be a contributory factor to the morphologic changes and altered permeability of the peritoneal membrane in long-term CAPD. 

Objectives: To investigate the effect of low calcium dialysis on post-dialysis hypertension in view of an evident link between serum calcium and blood pressure in both normal renal function and chronic renal failure patients.

Methods: We evaluated 19 chronic hemodialysis patients in whom both post-dialysis hypertension and PDHCa[1] were observed. We investigated changes in serum total calcium, ionized calcium, intact parathormone levels and arterial blood pressure in response to 4 weeks low calcium dialysis as a treatment for PDHCa.

Results: When PDHT[2] patients were treated with low calcium dialysis, post-dialysis blood pressure was significantly decreased compared to pre-dialysis values (155.3 ± 9.7/82.2 ± 7.9 mmHg pre-dialysis vs. 134.1 ± 20.8/80 ± 8.6 mmHg post-dialysis, P = 0.001). Additionally, post-dialysis blood pressure was significantly lower than post-dialysis blood pressure prior to the low calcium dialysis treatment (176.1 ± 15/86 ± 10.8 mmHg post-standard dialysis, 134.1 ± 20.8/80 ± 8.6 mmHg after low calcium dialysis, P = 0.001). A decline in post-dialysis serum calcium (2.34 ± 0.2 vs. 2.86 ± 0.12 mmol/L, P = 0.04) and ionized calcium (1.17 ± 0.12 vs. 1.3 ± 0.06 mmol/L, P = 0.03) compared to pre-dialysis levels was also achieved by this treatment, with no significant changes in iPTH[3] levels.

Conclusions: These data suggest a role for low calcium dialysis in treating acute serum calcium elevation and post-dialysis hypertension in patients receiving maintenance hemodialysis.

Background: Hyperhomocysteinemia is a well-recognized risk factor for accelerated atherosclerosis in hemodialysis patients.

Objectives: To examine the effects of two doses of vitamins B6 and B12 and folic acid on homocysteine levels in hemodialysis patients and assess the functional impact of the methylenetetrahydrofolate reductase genotype on the response to treatment.

Methods: In a randomized prospective study, we assessed the effects of folic acid and two doses of B-vitamins in 50 hemodialysis patients with hyperhomocysteinemia. Patients were divided into two groups: 26 patients (group A) who received 25 mg of vitamin B₆ daily and one monthly injection of 200 µg vitamin B12, and 24 patients (group B) who received 100 mg of vitamin B6 daily and one monthly injection of 1,000 µg vitamin B12. In addition, both groups received 15 mg folic acid daily. Patients were evaluated for homocysteine levels as well as for coagulation and a thorough lipid profile. Baseline Hcy[1] levels were determined after at least 4 weeks washout from all folic acid and B-vitamins that were given. MFTHR[2] alleles were analyzed, as were activated protein C resistance, von Willebrand factor and lupus anticoagulant.

Results: Basal plasma Hcy levels were significantly elevated in hemodialysis patients compared with normal subjects (33.8 ± 4.3 vs. 4.5 to 14.0 mmol/L). Following treatment, Hcy levels were significantly reduced to 21.2 ± 1.6 in group A and 18.6 ± 1.4 mmol/L in group B (P < 0.01). There was no difference in Hcy reduction following the administration of either high or low dosage of vitamins B6 and B12 utilized in the present study. There was no correlation between Hcy levels or thrombophilia and high incidence of thrombotic episodes in hemodialysis patients. Genotypic evaluation of MTHFR revealed that the presence of homozygous thermolabile MTHFR (n = 5) was associated with higher Hcy levels and better response to treatment (Hcy levels decreased by 58%, from 46.2 ± 14.6 to 19.48 ± 4.1 mmol/L following treatment). In patients with heterozygous thermolabile MTHFR (n = 25), Hcy levels decreased by 34%, from 31.2 ± 3.7 to 18.1 ± 1.1 mmol/L following treatment. The efficacy of high and low doses of B-vitamins on the reduction of homocysteine levels was comparable.

Conclusions: Treatment with B-vitamins in combination with folic acid significantly decreased homocysteine levels in hemodialysis patients, independently of the tested doses. In addition, mutations in MTHFR were associated with elevated plasma levels of Hcy. Neither vascular access nor.

Background: The ischemic “steal” syndrome complicates angio-access in a growing number of hemodialysed patients. Until now, operative attempts (fistula ligation or banding) to treat this problem have met with only limited success.

Objective: To assess the results of DRIL (distal revascularization-interval ligation) procedure in treating the “steal” syndrome.

Methods: A retrospective review (1996–2002) was conducted of all 11 patients who underwent the DRIL[1] procedure in two tertiary care hemodialysis units.

Results: Two patients were excluded because of inadequate medical documentation. All of the nine patients remaining suffered from overt atherosclerotic disease, six had diabetic nephropathy and four were smokers. The arterio-venous access, which led to the “steal” syndrome, was proximally located in all (antecubital in 8, thigh area in 1). “Steal” symptoms included hand pain, paraesthesia, neurologic deficits and gangrenous ulcers. DRIL was technically successful in all patients. There were no perioperative deaths. Immediate and complete relief of pain was achieved in eight of the nine patients. One patient with gangrene later required a transmetacarpal amputation. No patient required hand amputation. During follow-up (range 1–26 months) hemodialysis was continued uninterruptedly using the problematic AVA[2] in all patients. Thrombosis occurred in the AVA in only two patients after the DRIL procedure at 9 and 24 months postoperatively, respectively. Three patient deaths were unrelated to the DRIL.

Conclusions: In selected patients the DRIL procedure is a safe and effective way to treat the “steal” syndrome. AVA patency is not compromised by this operation. Preoperative angiography, before and after manual compression of the AVA, is crucial for the proper selection of patients who will benefit most from the DRIL procedure.

Background: In lipid oxidation kinetics studies, prevalent cardiovascular disease has been associated with shortened lag phase, the length of time preceding the onset of oxidation.

Objectives: To examine, in vitro, copper-induced lipid oxidation kinetics in unfractionated serum from hemodialysis patients and to determine differences in kinetic parameters between patients with and without a history of CVD[1].

Methods: Of the 76 patients enrolled in a study of oxidative stress in hemodialysis (44/76 with prevalent CVD, 53/76 males), 9 males with a history of myocardial infarction were selected and matched for age, diabetes and smoking status with 9 males from the non-CVD group. The kinetics of lipid oxidation was studied. Blood chemistry determinations including serum lipids, lipoproteins, hemostatic factors and serum malondialdehyde were obtained. Variables were compared using the t-test for independent samples with history of MI[2] entered as the categorical variable.

Results: Tmax, the oxidation kinetic parameter defined as the time at which the rate of absorbing product accumulation was maximal, was significantly shorter in dialysis patients with a history of MI than in those without (115.2 ± 38.5 vs. 162.7 ± 48.9 minutes, P = 0.04). Further, Tmax and MDA[3] were negatively correlated to one another (r = -0.47, P = 0.04). Odds ratios indicate that each 1 minute increase in Tmax was associated with a 3% decrease in odds that a subject had a history of MI.

Conclusions: These findings indicate the presence of increased oxidative stress in hemodialysis patients with a history of MI.

Background: Lower limb critical ischemia is a major problem in dialysed patients.

Objective: To evaluate the results of revascularization procedures, amputations and prosthetic rehabilitation in dialysed amputees.

Methods: Major amputation was carried out in 48 patients (4.5% of the dialysis population), and 24 patients entered the rehabilitation program. Widespread arterial calcification was common and led to falsely elevated ankle-brachial pressure indices in 9 of 14 limbs. Eight patients underwent revascularization. Subsequent major amputation was carried out 4 ± 4.5 months after the revascularization (above knee in 5 patients and below knee in 3). Of the 16 patients who underwent primary amputation, only 2 were above-knee amputees. Seven patients with toe or metatarsal amputation went on to a major amputation 1.8 ± 1.2 months after the distal amputation.

Results: No differences were found between diabetic and non-diabetic patients regarding the number of revascularization operations performed, the level of major amputation, or overall survival. Prosthetic rehabilitation was considered successful in 12 patients, partially successful in 8, and failed in 4 patients. Patient survival time was shortest in those patients with failed rehabilitation. A younger age confirmed favorable rehabilitation results, while long-standing diabetics and bilateral amputees were poor rehabilitation candidates. Patients who underwent primary amputation had more successful rehabilitation. A comparison between 24 dialysed amputees and 138 non-uremic amputees revealed similar rehabilitation results, although hospitalization time was longer in the dialysed patients.

Conclusions: Early definitive therapy is essential when dealing with critical ischemia. After diagnostic angiography, proximal revascularization should be performed where feasible. Primary amputation is indicated in patients with extensive foot infection or gangrene. Prosthetic rehabilitation is warranted in most dialysed amputees.
 

Background: The role of continuous renal replacement therapy in patients with acute renal failure is well recognized. CRRT[1] has also become an important modality of treatment in various acute situations without renal failure.

Objectives: To describe our experience with CRRT in acutely ill infants and children without renal failure.

Methods: We analyzed all infants and children who underwent CRRT during the years 1998-2000 in the pediatric intensive care unit and we focus our report on those who were treated for non-renal indications.

Results: Fourteen children underwent 16 sessions of CRRT. The indications for CRRT were non-renal in 7 patients (age range 8 days to 16 years, median = 6.5). Three children were comatose from maple syrup urine disease, three were in intractable circulatory failure secondary to septic shock or systemic inflammatory response, and one had sepsis with persistent lactic acidosis and hypernatremia. Three children underwent continuous hemodiafiltration and four had continuous hemofiltration. The mean length of the procedure was 35 ± 24 hours. All patients responded to treatment within a short period (2–4 hours). No significant complications were observed. Two patients experienced mild hypothermia (34°C), one had transient hypotension and one had an occlusion of the cannula requiring replacement.

Conclusion: Our findings suggest that CRRT is a safe and simple procedure with a potential major therapeutic value for treating acute non-renal diseases in the intensive care setting.

Background: Hepatitis C virus is the major cause of acute and chronic hepatitis in patients with end-stage renal disease receiving replacement therapy.

Objectives: To define the prevalence of HCV RNA in a population of patients on dialysis in Israel, to determine the relative risk of acquiring HCV infection while treated by hemodialysis or chronic ambulatory peritoneal dialysis, and to define the HCV genotypes in this population.

Methods: During 1995 we studied 162 dialysis patients. Information was obtained regarding the mode of dialysis, years of treatment, number of blood transfusions, and results of serological testing for HCV, hepatitis B virus, and human immunodeficiency virus. Anti-HCV antibodies were tested by a third-generation microparticle enzyme immunoassay. HCV RNA was determined by polymerase chain reaction. HCV genotyping was performed by a hybridization assay.

Results: HCV RNA was detected in 18% of the HD group and 7% of the CAPD group. The number of HCV RNA-positive patients was significantly higher in the HD than the CAPD group (P < 0.05). HCV RNA-positive HD patients were treated longer than the HCV RNA-negative patients (P < 0.02).

Conclusions: Third-generation immunoassay proved to be highly sensitive (94%) and specific (91%) in identifying HCV RNA positivity. Several HCV subtypes were detected, lb being the most frequent. Identification and isolation of infected HCV patients may minimize its spread in dialysis units and prevent cross-infection.