Vitamin C supplementation in kidney failure: effect on uraemic symptoms.

BACKGROUND: Vitamin C (ascorbate) deficiency and symptoms consistent with deficiency (fatigue, myalgia, dyspnoea, gingivitis, cardiovascular instability and depression) are common in patients with renal failure. This study aimed to determine if supplementation with ascorbate in patients with severe renal failure improved symptoms or cardiovascular stability, or was associated with adverse effects. METHODS: The study was a 3-month, double-blind, randomized trial of ascorbic acid 250 mg or matching placebo given thrice weekly. Subjects were clinically stable and either received conventional dialysis or had an estimated glomerular filtration rate of <20 mL/min. Symptoms were measured using the Kidney Dialysis Quality of Life-Short Form (KDQOL-SF™) symptom subscale, and the study was 80% powered to detect a change of 10 in the KDQOL-SF™. RESULTS: Ninety-nine subjects were randomized, and ascorbate deficiency was present in 40% at baseline. Mean symptom scores at follow-up were similar in the two groups (P-value=0.19). There was a trend to slightly worse nausea scores in the ascorbate group after controlling for the level of baseline nausea (P=0.09), and there was no impact on cardiovascular stability. Compliance appeared adequate at 91%, and deficiency was corrected in most (85%) of the subjects in the active treatment group. CONCLUSIONS: This study indicates that ascorbate supplementation does not improve symptoms or cardiovascular stability in those with severe renal impairment, but is associated with a trend towards worse nausea.

Clinical evaluation of plasma insulin and C-peptide levels with 3 different high-flux dialyzers in diabetic patients on hemodialysis.

AIM: Changes in plasma immunoreactive insulin (IRI) and connecting-peptide immunoreactivity (CPR) concentrations during hemodialysis (HD) were evaluated in diabetic HD patients with 3 different high-flux membranes. The removal properties of the membranes were compared. METHOD: In this prospective controlled study, 15 stable diabetic patients on HD were randomly selected for 6 HD sessions with 3 different membranes: polysulfone (PS), cellulose triacetate (CTA), and polymethylmethacrylate (PMMA). Blood samples were obtained from the blood tubing at the arterial (A) site at the beginning and end of the sixth HD session. At 60 minutes after dialysis initiation, blood samples were obtained from both the A and venous (V) sites of the dialyzer to investigate the clearance and removal properties of the membranes. RESULTS: The plasma IRI and CPR levels decreased significantly at each time point with all 3 membranes. IRI clearance with the PS membrane was significantly higher than that with the CTA and PMMA membranes. No difference was observed in the IRI reduction rate between the 3 membranes. CPR clearance and reduction rate with the PMMA membrane were lower than with the PS and CTA membranes. No significant difference was observed in serum creatinine clearance and reduction rates between the 3 membranes; however, serum urea nitrogen clearance was significantly lower with the PMMA membrane compared with the PS and CTA membranes. A significantly high beta2-microglobulin clearance and reduction rate was achieved in the order PS > CTA > PMMA. CONCLUSION: Plasma IRI and CPR are cleared by HD; their clearance rates differ with the dialyzer membranes. Plasma IRI clearance with the PS membrane is higher than that with the CTA and PMMA membranes.

Transdermal estradiol for the management of refractory uremic bleeding.

PURPOSE: The efficacy and thrombogenicity of transdermal estradiol in the management of refractory uremic bleeding in adults are examined. SUMMARY: Platelet dysfunction from chronic kidney disease may induce uremic bleeding. This type of bleeding may involve the skin, oral and nasal mucosa, gingivae, respiratory system, and gastrointestinal or urinary tract. While the mainstay of treatment for uremic bleeding primarily involves dialysis and use of prohemostatic agents such as desmopressin and erythropoiesis-stimulating agents, certain patients may experience bleeding refractory to these interventions. In this clinical scenario, a weak conditional recommendation (grade 2C) supporting transdermal estradiol as a therapy of last resort exists. Limited data suggest that transdermal estradiol may reduce bleeding time and transfusion requirements in dialysis patients with recurrent episodes of hematochezia, gastrointestinal telangiectasia, and hematomas. The management of uremic bleeding will require long-term therapy, and case reports have documented the safe use of transdermal estradiol for up to 25 months. Oral conjugated estrogens increase the risk of deep vein thrombosis in women; however, the transdermal route of administration has been associated with a lower incidence of venous thromboembolism and stroke relative to oral estrogen and, in some studies, its associated risk of thrombosis is not significantly different when compared with placebo. CONCLUSION: Patients who are refractory to routine interventions for uremic bleeding may benefit from transdermal estrogen despite the limited data. Extended therapy with low-dose transdermal estrogen (≤50 µg daily) may provide a hemostatic benefit that outweighs thrombotic risk.

Emerging drugs for hyperphosphatemia.

Cardiovascular mortality is the leading cause of death in the uremic patient. Hyperphosphatemia is considered an independent risk factor associated with cardiovascular morbidity and mortality in dialysis patients. As phosphate control is not efficient with diet or dialysis, phosphate binders are commonly prescribed in patients with chronic renal failure. Aluminum salts, the first phosphate binders, even if effective, have several side effects due to their deposition in CNS, bone and hematopoietic cells. Calcium-containing phosphate binders, used in the last 15 years, increase total body calcium load and may exacerbate metastatic calcification, thus, increasing the risk of cardiovascular mortality. Recently two new compounds non-aluminum and non-calcium phosphate binders, sevelamer hydrochloride and lanthanum carbonate, have been introduced. Sevelamer, besides the effect on phosphate, has been associated with reduction of coronary and aortic calcification and with other pleiotropic effects especially on lipid metabolism. Lanthanum carbonate has similar phosphate control to calcium-based binders with less incidence of hypercalcemia but long-term clinical studies are needed for testing long-term exposure. Recently the authors found in dialysis patients, that salivary phosphorus correlated with serum phosphorus. Therefore, they supposed that the use of salivary phosphate binders could reduce its absorption and represent a chance for reducing the serum phosphate concentration in uremic patients.

Itch Management: Systemic Agents.

Itch is a global clinical problem and finding effective treatment remains a therapeutic challenge because of the complex pathophysiology of itch. The key component of treating itch should be directed at the underlying etiologies when possible. However, without eradication of the underlying diseases, treatment is often palliative at best. Treatment with systemic therapies can vary according to the etiology of the chronic itch. The aim of this article is to review the major systemic anti-itch agents and give a summary on the possible systemic treatments for different types of itch.

Effects of erythropoietin and vitamin E-modified membrane on plasma oxidative stress markers and anemia of hemodialyzed patients.

BACKGROUND: Oxidant stress has a pathogenic role in uremic anemia, possibly interfering with erythropoietin (EPO) function and red blood cell (RBC) survival. Therefore, it is expected that antioxidant therapy might exert a beneficial effect on these parameters. METHODS: To test this hypothesis, we investigated some oxidant stress indices, anemia levels, and RBC survival in 47 hemodialysis (HD) patients randomly assigned to three groups. Patients in groups A (n = l8) and B (n = 20) were on dialysis therapy using conventional cellulosic and synthetic membranes and were administered high and low doses of recombinant human EPO (rHuEPO), respectively. Patients in group C (n = 9) were dialyzed with vitamin E-modified membranes (CL-Es) and investigated in a two-step prospective study. In step Cl, patients were administered rHuEPO doses similar to those of group A. In step C2, rHuEPO doses were reduced to those of group B. As oxidant stress markers, we determined in plasma the susceptibility of lipids to undergo iron-catalyzed oxidation (reactive oxygen molecules [ROMs] test) and malondialdehyde-4-hydroxynonenal (MDA-4HNE), alpha-tocopherol (alpha-T), total thiol (-SH), and total antioxidant activity. RBC survival was measured using the chromium 51 T/2 technique in 22 patients. RESULTS: Results show that: (1) high rHuEPO doses (groups A and C1) were associated with decreased ROM production, low alpha-T levels, and slightly increased -SH levels compared with corresponding groups on low rHuEPO doses (groups B and C2); (2) treatment with CL-Es (group C) increased plasma alpha-T and decreased -SH levels; these data were associated with decreased indices of lipid peroxidation, particularly MDA-4HNE 1evels, only in patients administered low rHuEPO doses; (3) alpha-T concentration influenced RBC survival, which was remarkably decreased in HD patients; patients treated with CL-Es showed a better degree of anemia correction; and (4) alpha-T level correlated negatively with -SH level and seemed to be independent of the extent of peroxidation and oxidizability of plasma lipids. CONCLUSION: Both EPO and CL-E can influence plasma antioxidants and, to an extent, lipid peroxidation processes. However, this study shows that even in patients treated with low rHuEPO doses, RBC survival close to normal and sufficient correction of anemia are achieved only when appropriate alpha-T levels are reached.

Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis.

Five patients who suffered catastrophic colonic necrosis are presented. All patients were uremic and received sodium polystyrene (Kayexalate) in sorbitol enemas for the treatment of hyperkalemia shortly before the development of signs and symptoms of colonic necrosis. In all specimens extensive ischemic necrosis was present, and Kayexalate crystals were noted in the intestinal lumen. Four of the five patients eventually died. To further investigate the occurrence of colonic necrosis after the administration of Kayexalate in sorbitol enemas, a series of experiments were performed in rats. Two groups of Sprague-Dawley rats were studied. One group was made uremic by performance of bilateral nephrectomy. The other group underwent sham operation. Enemas of saline, Kayexalate alone, sorbitol alone, or Kayexalate in sorbitol were administered. In nonuremic rats, transmural necrosis was noted in seven of 10 rats receiving sorbitol enemas and in six of 10 rats receiving Kayexalate in sorbitol enemas. No significant pathologic changes were noted in the rats receiving other enemas. In uremic rats, extensive transmural necrosis was noted in all rats receiving enemas of sorbitol or Kayexalate in sorbitol. All of these 19 rats died within the period of observation compared with no deaths in 18 rats that received enemas without sorbitol (p less than 0.001).

Kayexalate (sodium polystyrene sulphonate) in sorbitol associated with intestinal necrosis in uremic patients.

BACKGROUND: Kayexalate (sodium polystyrene sulphonate) in sorbitol is commonly used to treat hyperkalemia in patients with renal insufficiency. Isolated case reports and one recent large series have documented intestinal necrosis following administration of kayexalate in sorbitol. METHODS: Two patients with luminal kayexalate crystals associated with intestinal pathology were first identified in the pathology department, and clinicopathological correlation was carried out. RESULTS: Both patients were seriously ill, had prior cardiac surgery and were in renal failure (uremic). Examination of autopsy and colonic resection showed luminal kayexalate crystals associated with underlying mucosal necrosis, submucosal edema and transmural inflammation. CONCLUSION: Although occurring in complex clinical settings, the pathological findings provide additional evidence that kayexalate in sorbitol may be associated with intestinal necrosis and inflammation in uremic patients and that this may be a clinically and pathologically under-recognized iatrogenic bowel injury.

Intestinal necrosis following Calcium Resonium-sorbitol administration in a premature uraemic infant.

Sodium polystyrene sulphonate (Resonium A) in sorbitol given as an enema or orally to treat hyperkalaemia has been described to induce intestinal necrosis in uraemic patients. We report a case of a premature infant with acute renal insufficiency who developed focal transmural necrosis and perforation of the small intestine after 10 days of administration of calcium polystyrene sulphonatum (Calcium Resonium) in sorbitol by enema and by nasogastric tube. On histological examination of the resected part of the small intestine, numerous strongly basophilic angular crystals of resonium were found in the lumen, in the necrotic wall, as well as in the organized exudate on the peritoneal surface. The crystals showed a strong direct Schiff positivity without preoxidation. They were also stained using PAS, Giemsa, Ziehl-Neelsen, Schmorl, and Gram method. In contrast, the crystals were Congo red and Alcian blue (pH 2.5) negative and non-birefringent. The direct Schiff positivity without preoxidation is virtually pathognomonic for resin crystals in routinely processed tissues. The same crystals were observed in the lumen of the small intestine and in peritoneal adhesions at autopsy. Thus our case provides additional evidence that Resonium A/Calcium Resonium in sorbitol administered as an enema or orally can lead to intestinal necrosis in uraemic patients.

New approaches to the removal of protein-bound toxins from blood plasma of uremic patients.

The article is devoted to the theoretical aspects of the development of the effective method for the removal of protein-bound uremic toxins. It is shown that the methods of flow and differential scanning microcalorimetry are sufficient enough for the evaluation of the degree of ligand loading of human serum albumin with protein-bound uremic toxins. The molecules of albumin isolated from blood plasma of the patients being kept on chronic dialysis are demonstrating significant alterations of conformation and complex-forming properties, the correction of which by conventional methods of extracorporeal detoxification (exhaustive dialysis, treatment on synthetic SCN carbons) are practically ineffective. Deliganding of uremic albumin may be successfully performed on conventional carbon haemosorbents upon preliminary separation of blood plasma and its dilution with acetate buffer 1:1 at pH = 5.08. Treatment of the whole blood of patients onto new mass-fractal deliganding carbon, i.e., hemosorbents of HSGD trademark. These HSGD haemosorbents quite effectively could be used for restoration of main parameters of uremic HAS molecules conformation and ligand-binding activity simultaneously with hemodialysis upon the protection by locally performed citrate anticoagulation as an easier and cheaper method for the removal of protein-bound uremic toxins.

Sorbent membrane dialysis in uremia.

The inclusion of activated charcoal within hemodialysis membranes offers potentially improved plasma clearance of creatinine and middle molecules. However, the carbon becomes saturated with continued use and beyond 1 h removal of solutes is by dialysis alone. Two independently conducted crossover studies, to assess the efficacy of sorbent membrane dialysis (SMD) in the treatment of uremia, found predialysis urea levels increased by approximately 15%, creatinine by 10-15%, and inorganic phosphate levels by 10-18% on SMD compared to conventional hemodialysis. One study also observed "middle molecule' (peak "b') levels elevated. No differences were observable in the clinical status of patients. The results suggest that the charcoal content of the SMD device is too small to effect any advantages over conventional dialysis.

Intravenous calcitriol lowers serum calcium concentrations in uraemic patients with severe hyperparathyroidism and hypercalcaemia.

We studied the effects of intravenous calcitriol in four persistently hypercalcaemic patients established on haemodialysis. All had marked hyperparathyroidism and had been previously shown to be intolerant to vitamin D by mouth. Calcitriol was administered at the end of each dialysis session in doses of 0.5-2.5 micrograms for 2 months and continued for 7 and 8 months in two patients. A significant decrease in serum calcium was observed after 2 weeks, which was maintained throughout treatment despite increasing the dose of calcitriol. This was associated with a decrease in serum concentrations of iPTH (28% of the initial value at 4 weeks), suggesting a shift in the set-point for PTH secretion. During longer-term treatment, serum calcium values increased, but lower concentrations of iPTH were maintained. We conclude that an increment in serum calcium is not a prerequisite for the suppressive action of calcitriol on parathyroid secretion and that the presence of hypercalcaemia does not preclude its use. Longer-term studies on a larger number of patients are required to assess the therapeutic potential of intravenous calcitriol in hypercalcaemic patients.

Colestimide can be used as a phosphate binder to treat uraemia in end-stage renal disease patients.

Colestimide is a potent therapeutic compound used widely for treatment of hypercholesterolaemia, and it was discovered coincidentally that it can be used to lower the serum phosphate concentration in cases of secondary hyperparathyroidism with refractory hyperphosphataemia. Colestimide is useful for treating hyperphosphataemia in end-stage renal disease (ESRD) patients undergoing haemodialysis. Twenty-eight patients who were being treated for hyperphosphataemia with 3.5+/-1.1 g/day calcium carbonate were enrolled in the study. Colestimide was added to their prescription for 4 weeks at a mean dosage of 2.3 g/day. The serum phosphate concentration decreased significantly from 6.1+/-1.1 mg/dl before treatment to 5.3+/-1.1 mg/dl at 4 weeks (P<0.0001). The calcium-phosphate product also decreased significantly from 59.6+/-11.3 mg/dl(2) before treatment to 50.5+/-12.0 mg/dl(2) (P<0.0001). The serum total cholesterol significantly (P<0.001) decreased at 1 week and remained constant until the end of treatment. Colestimide is a cationic polymer with chloride as the counterion. Its chemical structure resembles that of sevelamer hydrochloride, which is already being used clinically as a phosphate binder. This suggests that colestimide uses the same mechanism as sevelamer hydrochloride to treat hyperphosphataemia. The present results demonstrate that colestimide can function as a Ca-free, aluminium-free, non-absorbable, phosphate binder in ESRD patients. In addition, colestimide can reduce the serum phosphate concentration in combination with calcium carbonate.

Use of combined hemodialysis/hemoperfusion in chronic uremia.

The capacity of charcoal to absorb endogenous and exogenous toxins is well established. It removes substances of higher molecular weight than standard dialysis membranes. The regular use of charcoal hemoperfusion as an adjunct to hemodialysis in chronic uremia is a real prospect capable of improving the patient's clinical and laboratory condition and/or reducing the weekly time of treatment. In line with our previous experience, 5 consenting informed patients on regular dialysis treatment from 9 to 35 months (residual creatinine clearance 0-1.8 ml/min, mean diuresis 350 ml) were treated without interruption for 5-8 months according to a schedule including two combined hemodialysis/hemoperfusion procedures instead of the previous three hemodialysis sessions. Patients were on adequate dialysis and their clinical, metabolic and laboratory conditions were stable. In the hemodialysis/hemoperfusion procedure a cartridge containing 150 g of methacrylate-coated activated charcoal with high biocompatibility was inserted in the dialysis circuit in series with a flat plate or hollow fiber dialyzer. Clinical, laboratory and metabolic conditions remained unchanged in all patients despite the one third reduction in dialysis hours per week. The tolerance of treatment was good: platelets, white cells and fibrinogen were unaffected. The marked reduction in weekly time of treatment led to a more satisfactory personal and social rehabilitation, enabling more patients to be treated with the same facilities.

Why hemodialysis patients are in a prooxidant state? What could be done to correct the pro/antioxidant imbalance.

Oxidative stress which results from an imbalance between reactive oxygen species production and antioxidant defense mechanisms is now well recognized in hemodialysis (HD) patients and could be involved in dialysis-related pathologies such as accelerated atherosclerosis, amyloidosis and anemia. In order to evaluate the rationale for preventive intervention against oxidative damage during HD, we review the factors that are implied and may be responsible for the imbalance between pro- and antioxidative mechanisms. The inflammatory state mainly due to hemobioincompatibility of the dialysis system plays a critical role in the production of free oxygen radical species contributing by this way to worsen the prooxidant status of uremic patients. Two factors largely contribute to the stimulation of the NADPH oxidase: hemoreactivity of the membrane and trace amounts of endotoxins. The antioxidant system is severely impaired in uremic patients and gradually altered with the degree of renal failure. HD could further impair this antioxidant system mainly by losses of (a) hydrophilic unbound small-molecular-weight substances such as vitamin C, (b) trace elements and (c) enzyme-regulatory compounds. Two main axes may be proposed in order to prevent and/or to decrease oxidative stress in HD patients. One consists in improving the hemocompatibility of the dialysis system mainly by using a dialyzer with low hemoreactivity and ultrapure, sterile, nonpyrogenic dialysate. The other consists in supplementing the deficiency patients with antioxidants. This could be achieved by oral or perdialytic supplementation. Vitamin E could be bound on dialyzer membrane. Alternatively, hemolipodialysis consists in loading HD patients with vitamin C or E via an ancillary circuit made of vitamin E-rich liposomes. The presence of liposomes could also facilitate the removal of hydrophobic prooxidative substances.

Histidine for treatment of uraemic anaemia.

A group of 28 uraemic patients on dialysis treatment were given daily supplements of histidine by mouth. Plasma amino-acid concentration, plasma iron, serum transferrin, packed cell volume, and reticulocyte count were all measured before and after two months of histidine supplementation. The treatment raised the plasma histidine concentration and at the same time there was a rise in transferrin and iron levels and packed cell volume. Reticulocyte counts fell after two months of histidine supplementation.