Plasma vitamin C levels in ESRD patients and occurrence of hypochromic erythrocytes.

INTRODUCTION: The achievement of erythropoiesis in hemodialysis (HD) patients is typically managed with erythropoiesis-stimulating-agents (ESA's) and intravenous iron (IV-iron). Using this treatment strategy, HD patients frequently show an elevated fraction of red blood cells (RBC) with hemoglobin (Hb) content per cell that is below the normal range, called hypochromic RBC. The low Hb content per RBC is the result of the clinical challenge of providing sufficient iron content to the bone marrow during erythropoiesis. Vitamin C supplements have been used to increase Hb levels in HD patients with refractory anemia, which supports the hypothesis that vitamin C mobilizes iron needed for Hb synthesis. METHODS: We conducted a cross-sectional survey in 149 prevalent HD patients of the percent hypochromic RBC, defined as RBC with Hb < 300 ng/uL of packed RBC, in relation to plasma vitamin C levels. We also measured high-sensitivity CRP, (hs-CRP), iron, and ferritin levels. and calculated ESA dose. FINDINGS: High plasma levels of vitamin C were negatively associated with hypochromic RBC (P < 0.003), and high ESA doses were positively associated (P < 0.001). There was no significant association of hs-CRP with percent hypochromic RBC. DISCUSSION: This finding supports the hypothesis that vitamin C mobilizes iron stores, improves iron delivery to the bone marrow, and increase the fraction of RBC with normal Hb content. Further research is warranted on development of protocols for safe and effective use of supplemental vitamin C for management of renal anemia.

Racial differences in estimated GFR decline, ESRD, and mortality in an integrated health system.

BACKGROUND: Current evidence does not clearly identify the contribution of kidney function decline and mortality to racial disparities in end-stage renal disease (ESRD) incidence. We used observed estimated glomerular filtration rate (eGFR) to project the time of onset of kidney failure and examined mortality to better understand these racial disparities. STUDY DESIGN: Retrospective cohort. SETTING & PARTICIPANTS: Adult members of Kaiser Permanente Southern California in 2003-2009 with more than 2 serum creatinine tests and more than 180 days between tests: 526,498 whites, 350,919 Hispanics, 136,923 blacks, and 105,476 Asians. PREDICTOR: Race/ethnicity. OUTCOMES: ESRD (dialysis or transplantation); mortality. MEASUREMENTS: eGFR decline was modeled using linear regression. Kidney failure was projected based on predicted eGFR <15 mL/min/1.73 m² at specified times. Racial differences in projected kidney failure and mortality in those with projected kidney failure were estimated with adjustment for age, sex, and entry eGFR. RESULTS: Blacks had more extreme rates of eGFR decline (1st percentile, -23.6 mL/min/1.73 m² per year), followed by Hispanics (-20.9 mL/min/1.73 m² per year), whites (-20.1 mL/min/1.73 m² per year), and Asians (-17.6 mL/min/1.73 m² per year; P < 0.001). There were 25,065 whites, 11,368 Hispanics, 6,785 blacks, and 3,176 Asians with projected kidney failure during the study period. The ORs for projected kidney failure versus whites during CKD stages 3 and 4 were 1.54 (95% CI, 1.46-1.62) in blacks, 1.49 (95% CI, 1.42-1.56) in Hispanics, and 1.41 (95% CI, 1.32-1.51) in Asians. For those with projected kidney failure, the HRs of death versus whites during CKD stages 3 and 4 were 0.82 (95% CI, 0.77-0.88) in blacks, 0.67 (95% CI, 0.63-0.72) in Hispanics, and 0.58 (95% CI, 0.52-0.65) in Asians. LIMITATIONS: Results may not generalize to the uninsured or subgroups within a race. Projected kidney failure was based on linear trends from clinically obtained eGFR. CONCLUSIONS: We found more extreme rates of eGFR decline in blacks. Projected kidney failure during CKD stages 3 and 4 was high in blacks, Hispanics, and Asians relative to whites. Mortality for those with projected kidney failure was highest in whites. Differences in eGFR decline and mortality contributed to racial disparities in ESRD incidence.

How can we improve the solute and fluid transport prescriptions in hemodialysis to improve patient outcomes?.

Improvements in the dialysis prescription can only be achieved by changes in solute and water transport which provide better control of the metabolic uremic abnormalities that are amenable to dialysis. The key abnormalities identified here are protein catabolites, fluid and electrolyte balance, calcium and phosphorus balance and bone metabolism and acid-base balance. The history of the dialysis prescription is reviewed and changes which might improve the control of these metabolic systems are described. This review concludes there is no support for the recommendation of the routine application of long treatment time and routine use of hemodiafiltration.

A brief review of external mass balance and internal calcium redistribution in dialysis patients--is calcium a uremic toxin?

Recent debates between 2 schools of thought on calcium mass balance in dialysis patients and its relevance to disease--one emphasizing external calcium mass balance, and the other, internal calcium redistribution--have created controversy. Due to decreased ability to excrete calcium and loss of endocrine function by the kidney, patients suffering from chronic kidney disease, particularly when requiring dialysis, demonstrate varying degrees of positive or negative calcium balance, vitamin D deficiency, and secondary hyperparathyroidism. Consequently, patients are prone to bone demineralization, with diminished bone strength, and are thus prone to fractures that substantially worsen morbid outcomes in this population. However, intra- and interdialytic positive calcium mass balance creates complications of a different kind, which include the occurrence of vascular and cardiac disease and reduced survival. This review aims to shed light on the mechanisms of and relationships between external calcium mass balance and internal calcium redistribution and their consequences. It also discusses the potential to improve current regimens by means of diffusive and convective calcium mass transfer for the achievement of neutral calcium mass balance.

Guidelines for vitamin supplements in chronic kidney disease patients: what is the evidence?

Wide discrepancies exist in the use of vitamins in kidney disease, and evidence-based recommendations are sparse. Water-soluble vitamin levels may be inadequate in patients not receiving supplements and this may be associated with increased mortality, which deserves further attention to increase strength of evidence. Supplements should be administered cautiously as renal mechanisms to prevent hypervitaminosis are no longer functional. The most reliable assays for vitamin status examine tissue mechanisms that rely on vitamins as cofactors. Vitamin A levels are generally quite high, vitamin D is low and requires supplementation, and the benefits of vitamin E may be linked to its usage in a modified dialysis membrane. Because of restricted diets that provide limited vitamin intake from food, many renal patients can benefit from a tablet that adds an amount equal to one recommended daily allowance of water-soluble vitamins, but larger amounts are not appropriate or beneficial. Vitamin status is influenced by interaction of many variables, and individual attention to each patient is warranted to achieve optimal vitamin status.

Calcium balance in dialysis is best managed by adjusting dialysate calcium guided by kinetic modeling of the interrelationship between calcium intake, dose of vitamin D analogues and the dialysate calcium concentration.

Calcium mass balance (Ca(MB)) is determined by the difference between Ca absorbed between dialyses (Ca(Abs)) and the Ca removed during dialysis (J(d)Ca(2+)). A mathematical model to quantify (1) Ca(Abs) as a function of Ca intake (Ca(INT)) and the doses of vitamin D analogues, and (2) J(d)Ca(2+) as a function of Ca(2+) dialysance, the mean plasma Ca(2+) ((M)C(pi)Ca(2+)) minus dialysate Ca(2+) (C(di)Ca(2+)), ultrafiltration rate (Q(f)) and treatment time is developed in this paper. The model revealed a basic design flaw in clinical studies of Ca-based as opposed to non-Ca-based binders in that C(di)Ca(2+) must be reduced with the Ca-based binders in order to avoid a positive Ca(MB) relative to the non-Ca-based binders. The model was also used to analyze Ca(MB) in 320 Renal Research Institute hemodialysis patients and showed that all patients irrespective of type of binder were in positive Ca(MB) between dialyses (mean +/- SD 160 +/- 67 mg/day) with current doses of vitamin D analogues prescribed. Calculation of the optimal C(di)Ca(2+) for the 320 Renal Research Institute patients revealed that in virtually all instances, the C(di)Ca(2+) required for neutral Ca(MB), where Ca removal during dialysis was equal to Ca accumulation between dialyses, was less than 2.50 mEq/l and averaged about 2.00 mEq/l. This sharply contradicts the recent KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease - Mineral and Bone Disorder, that suggests a C(di)Ca(2+) of 2.5-3.0 mEq/l. Review of the KDIGO work group discussions shows that this discrepancy stems from the unwarranted work group assumption that intradialytic Ca(MB) is zero. We strongly believe that this guideline for dialysate Ca(2+) is inappropriate and should be modified to more realistically reflect the needs of dialysis patients.

Incidence of end-stage renal disease and death among insured African Americans with chronic kidney disease.

African Americans have the highest incidence of end-stage renal disease (ESRD) in the United States. To understand the basis of this disparity, we examined data from a prepaid, integrated health system for this retrospective cohort study of members who had one or more serum creatinine tests performed over a 9-year period. The cohort included 182,959 adults (8% black) with stage 3 or 4 chronic kidney disease based on their estimated glomerular filtration rate (eGFR). Competing-risk methods were used to determine the incidence of ESRD and death prior to ESRD. At all follow-up times and from any entry eGFR, the cumulative incidence of ESRD was significantly greater in blacks. The age and gender-adjusted hazard ratios for ESRD and death prior to ESRD in blacks compared to non-blacks were 1.83 and 1.15, respectively. Increased survival free of ESRD was found in blacks 70 years and older with eGFR stage 4. The hazard ratio for the combined outcomes of ESRD or death was 1.31 in blacks as compared to non-blacks. Despite equivalent health insurance benefits, blacks with chronic kidney disease were at increased risk for ESRD and death prior to ESRD. Compared to non-blacks, blacks with chronic kidney disease were twice as likely to enter into ESRD as to die prior to ESRD.

Iron and anemia in human biology: a review of mechanisms.

The biology of iron in relation to anemia is best understood by a review of the iron cycle, since the majority of iron for erythropoiesis is provided by iron recovered from senescent erythrocytes. In iron-deficiency anemia, storage iron declines until iron delivery to the bone marrow is insufficient for erythropoiesis. This can be monitored with clinical indicators, beginning with low plasma ferritin, followed by decreased plasma iron and transferrin saturation, and culminating in red blood cells with low-Hb content. When adequate dietary iron is provided, these markers show return to normal, indicating a response to the dietary supplement. Anemia of inflammation (also known as anemia of chronic disease, or ACD) follows a different course, because in this form of anemia storage iron is often abundant but not available for erythropoiesis. The diagnosis of ACD is more difficult than the diagnosis of iron-deficiency anemia, and often the first identified symptom is the failure to show a response to a dietary iron supplement. Confirmation of ACD is best obtained from elevated markers of inflammation. The treatment of ACD, which typically employs erythropoietin (EPO) supplements and intravenous iron (i.v.-iron), is empirical and often falls shorts of therapeutic goals. Dialysis patients show a complex pattern of anemia, which results from inadequate EPO production by the kidney, inflammation, changes in nutrition, and blood losses during treatment. EPO and i.v.-iron are the mainstays of treatment. Patients with heart failure can be anemic, with incidence as high as 50%. The causes are multifactorial; inflammation now appears to be the primary cause of this form of anemia, with contributions from increased plasma volume, effects of drug therapy, and other complications of heart disease. Discerning the mechanisms of anemia for the heart failure patient may aid rational therapy in each case.

Vitamin C deficiency and secondary hyperparathyroidism in chronic haemodialysis patients.

BACKGROUND: Maintenance haemodialysis patients often suffer from secondary hyperparathyroidism and serum parathyroid hormone levels may be influenced by nutritional variables. METHODS: We examined serum bio-intact parathyroid hormone (BiPTH) and plasma vitamin C in 117 chronic haemodialysis patients. Plasma vitamin C was measured by high-performance liquid chromatography with electrochemical detection, on samples collected before start of the dialysis treatment. RESULTS: Plasma vitamin C showed a significant positively skewed distribution, ranging from <2 microM to >300 microM. We found 15% (n = 17) of the patients with severe vitamin C deficiency (<10 microM), 66% (n = 77) in the range 10-80 microM, and 19% (n = 23) with plasma vitamin C >80 microM, the upper limit of normal for non-renal disease population. High plasma vitamin C was associated with lower plasma BiPTH (P = 0.005, one-way analysis of variance), and this association persisted after stepwise multiple regression for other factors known to influence PTH. Low vitamin C levels were also associated with increased serum alkaline phosphatase, a further indicator of the impact of vitamin C status on bone metabolism. Patients who reported dietary vitamin C intake of >or=100 mg/day had lower BiPTH (P = 0.015), consistent with findings from plasma measurements of vitamin C. This novel observation of the interaction between PTH and vitamin C may result from effects of vitamin C on cAMP-linked signalling pathways in bone and parathyroid gland. CONCLUSIONS: This finding does not yet warrant therapeutic intervention with supplemental vitamin C to remedy secondary hyperparathyroidism. However, further research may indicate a key interaction between vitamin C and the parathyroid hormone linked signalling pathways, and may uncover mechanisms of therapeutic importance.

Chemical reactions of vitamin C with intravenous-iron formulations.

BACKGROUND: Intravenous (IV) iron is widely prescribed for patients on haemodialysis, to replace iron losses during treatment. It releases labile iron, which can induce oxidation of vitamin C and trigger oxidant damage. We examined the stability of vitamin C in the presence of IV iron compounds. We further examined in the ability of vitamin C to release iron from these compounds. METHODS: Vitamin C was measured by high-performance liquid chromatography with electrochemical detection. Iron release from iron sucrose (FeSuc) and ferric gluconate (FeGlu) was determined with the ferrozine method. RESULTS: Vitamin C, in human plasma or fetal calf serum, was oxidized in this order of reactivity: FeSuc > FeGlu > blank reaction. FeSuc and FeGlu also oxidized vitamin C when added to freshly obtained whole human blood. During a 4 h incubation in buffer, vitamin C stimulated the release of 60% of the iron content of FeSuc at p 4, with lesser amounts at pH 3, 5 and 6, and 5% release at pH 7. Vitamin C also triggered the release of iron from FeGlu, but less release was observed than with FeSuc. Using ferrozine reagent, no iron release was detected to heparinized human plasma, following addition of 500 microM concentrations of iron compounds. CONCLUSION: Each IV-iron compound can oxidize substantial amounts of vitamin C when added to plasma or whole blood. The interaction of vitamin C is accompanied by release of iron from the particle at mildly acidic pH, which may explain the ability of high-dose vitamin C to mobilize iron from storage sites for erythropoiesis.

Factors for increased morbidity and mortality in uremia: hyperphosphatemia.

Hyperphosphatemia is a metabolic abnormality present in the majority of patients treated by dialysis. Inorganic phosphorus (iP) can be categorized as a true uremic toxin given its known in vivo and in vitro effects and the ability to reduce these effects by normalizing iP levels. However, despite regular and adequate dialysis treatment, the goal of normalization of phosphorus levels rarely is achieved. This article briefly evaluates the significance of hyperphosphatemia in hemodialysis patients, current therapeutic approaches, and describes a new model for evaluating the dialysis prescription for iP balance.

Effective diffusion volume flow rates (Qe) for urea, creatinine, and inorganic phosphorous (Qeu, Qecr, QeiP) during hemodialysis.

In vivo solute clearances can be estimated from dialyzer blood (Qb) and dialysate (Qd) flow rates and a solute- and dialyzer-specific overall permeability membrane area product (KoA). However, these calculations require knowledge of the flow rate of the effective solute distribution volume in the flowing bloodstream (Qe) in order to calculate in vivo clearances and KoAs. We have determined Qe for urea, creatinine, and inorganic phosphorus from changes in concentrations across the blood compartment and mass balance between the blood and dialysate streams. We made four serial measurements over one dialysis in 23 patients and found that Qeu equals the total blood water flow rate, Qecr equals the plasma water flow rate plus 61% of red cell water flow rate, and QeiP is limited to the plasma water flow rate. Equations are derived to calculate Qe for each of these solutes from Qb and hematocrit and in vivo KoAs for each solute were calculated.

Daily dialysis: the long and the short of it.

There is considerable enthusiasm for daily hemodialysis despite the increased time commitment required of patients because of reported improvements in patient well-being, appetite and blood pressure control. To date, this therapy has been largely empirical and has been defined primarily by treatment time (t) and categorized as short daily hemodialysis (SDHD) with t about 2 h and long nocturnal hemodialysis (LNHD) with t 8-9 h. It is the authors' view that studies comparing clinical outcome with SDHD and LNHD to conventional hemodialysis (CHD) must have dialysis dosage well defined if they are to provide generalizable results. There is a broad range and overlap in the magnitude of solute removal in reported studies of SDHD, LNHD and CHD, which is illustrated here through kinetic consideration of four solutes: (1) urea; (2) inorganic phosphorus (iP); (3) beta(2)-microglobulin (beta(2)M) and (4) Na/water. The following observations can be made: (1) Patient subjective reports of increased appetite and protein intake may correlate poorly with kinetic calculation of protein catabolic rate. (2) A model of iP mass balance was developed and indicates that iP removal with CHD is inadequate; current SDHD is also inadequate to highly excessive depending on the dose of dialysis. (3) beta(2)M removal with SDHD is virtually the same as reported for LNHD, reflecting major differences in dialyzer membranes used. (4) The decrease in predialysis overhydration is a predictable function of the number of dialyses per week and may be one of the most important benefits of more frequent dialysis. (5) The standard K(t)/V (stdK(t)/V) provides a uniform method of dose calculation but the therapy prescription should also include consideration of the other solutes evaluated above.

A kinetic model of inorganic phosphorus mass balance in hemodialysis therapy.

BACKGROUND: There is growing evidence that inorganic phosphorus (iP) accumulation in tissues (dTiP/dt) is a risk factor for cardiac death in hemodialysis therapy (HD). The factors controlling iP mass balance in HD are dietary intake (GiP), removal by binders (JbiP) and removal by dialysis (JdiP). If iP accumulation is to be minimized, it will be necessary to regularly monitor and optimize GiP, JbiP and JdiP in individual patients. We have developed a kinetic model (iPKM) designed to monitor these three parameters of iP mass balance in individual patients and report here preliminary evaluation of the model in 23 HD patients. METHODS: GiP was calculated from PCR measured with urea kinetics; JdiP was calculated from the product of dialyzer plasma water clearance (K(pwiP)) and time average plasma iP concentration (TACiP) and treatment time (t); a new iP concentration parameter (nTAC(iP), the TACiP normalized to predialysis CoiP) was devised and shown to be a highly predictable function of the form nTAC(iP) = 1 - alpha(1 - exp[-betaK(pwiP). t/ViP]), where the coefficients alpha and beta are calculated for each patient from 2 measure values for nTAC(iP), K(pwiP).t/ViP early and late in dialysis; we measured 8-10 serial values for nTAC(iP), K(pwiP). t/ViP over a single dialysis in 23 patients; the expression derived for iP mass balance is DeltaTiP = 12(PCR) - [K(pwiP)(t) (N/7)][CoiP(1 - alpha(1 - exp[-beta(Kt/ViP)]))] - k(b).Nb. RESULTS: Calculated nTAC(iP) = 1.01(measured nTAC(iP)), r = 0.98, n = 213; calculated JdiP = 0.66(measured total dialysate iP) + 358, n = 23, r = 0.88, p < 0.001. Evaluation of 10 daily HD patients (DD) and 13 3 times weekly patients with the model predicted the number of binders required very well and showed that the much higher binder requirement observed in these DD patients was due to much higher NPCR (1.3 vs. 0.96). CONCLUSION: These results are very encouraging that it may be possible to monitor the individual effects of diet, dialysis and binders in HD and thus optimize these parameters of iP mass balance and reduce phosphate accumulation in tissues.