De novo once-monthly darbepoetin alpha treatment for the anemia of chronic kidney disease using a computerized algorithmic approach.

BACKGROUND: Anemia of chronic kidney disease (CKD) has been traditionally treated by erythropoiesis-stimulating agents (ESAs) and/or iron following manual determination of dose. We hypothesized that once-monthly (QM) algorithmically dosed darbepoetin α (DA) and iron administration would successfully treat anemia of CKD in ESA-naïve CKD subjects. METHODS: QM DA and iron doses were determined via a computerized program targeting a hemoglobin (Hb) of 10.5 - 12.5 g/dl in anemic, ESA-naïve, CKD Stages 3 - 5 subjects. Six consecutive QM doses were administered. Hb, ferritin, and transferrin saturation were recorded. Data are presented as means ± standard deviation. RESULTS: Anemia was identified in 133 subjects, with a mean follow-up of 188 days. DA doses and Hb were significantly greater at Months 3 and 6 compared to baseline (p < 0.05); DA doses were 109 ± 68 µg and 118 ± 91, respectively, at Months 3 and 6. Hemoglobin levels were correspondingly 11.3 ± 1.1 g/dl and 11.3 ± 1.0. 78% of patients achieved the target Hb by 6 months of therapy. The elevation of Hb was greater in non-proteinuric than proteinuric subjects at 6 months of treatment (11.6 ± 0.8 g/dl vs. 11.0 ± 1.1; p < 0.05), despite lower DA dose (96 ± 76 µg vs. 139 ± 98; p < 0.05). CONCLUSION: Successful treatment of the anemia of CKD by QM DA based upon a computerized dosing program was achieved by 6 months in 78% of ESA-naïve, CKD subjects.

Excretion and metabolism of catecholamines by the isolated perfused rat kidney.

The excretion and metabolism of labeled epinephrine and norepinephrine by the isolated, perfused rat kidney were studied. The excretion of both catecholamines significantly exceeded the amount filtered, thus providing direct evidence of net tubular secretion. Renal clearance of epinephrine was significantly greater than that of norepinephrine. Tubular secretion was a linear function of the concentration of unbound catecholamine in the medium with no demonstrable tubular maximum at the concentrations studied. The isolated kidney removed catecholamines from the medium by metabolism as well as excretion in the urine. O-Methylation was the major metabolic route and O-methylated metabolites were rapidly excreted and concentrated in urine. Preferential excretion and metabolism of epinephrine were confirmed in double-label experiments in which [14C]epinephrine and [3H]norepinephrine were perfused together. The ratio of 14C:3H in urine exceeded that in perfusion medium for total radioactivity as well as for catecholamines and O-methylated amines. The present study thus provides direct evidence for (a) net tubular secretion of epinephrine and norepinephrine with a direct relationship between secretion and medium concentration; (b) significant renal metabolism of both epinephrine and norepinephrine with O-methylation as the major metabolic route; and (c) preferential excretion and metabolism of epinephrine.

Potassium transport by the isolated perfused kidney.

Rat kidneys perfused outside of the body with an artificial medium are able to increase their fractional excretion of potassium in response to a rising concentration of potassium in the medium but never show net secretion of potassium. By contrast, isolated perfused kidneys from chronically potassium-loaded rats regularly secrete potassium in excess of the amount filtered. Ouabain completely blocks the secretion of potassium by these isolated kidneys, suggesting that Na-K-ATPase mediates potassium secretion by potassium-adapted rats. Neither sodium deprivation, pretreatment with deoxycorticosterone, nor pretreatment with methylprednisolone prepared the kidney to secrete potassium, despite stimulation of Na-K-ATPase activity in cortex or outer medulla. Potassium loading was the only maneuver tested that increased the activity of Na-Katpase in the inner medulla (white papilla) and also produced potassium secretion by the isolated kidney. Surgical ablation of the papilla abolished the net secretion of potassium normally seen in perfused kidneys of potassium-adapted rats, thus underlining the importance of the papilla in the process of potassium adaptation.

The native arteriovenous fistula in 2007. Surveillance and monitoring.

In the past 5 years, some clinical trials have questioned the value of surveillance in managing vascular accesses. Although prolongation of access life span is an important end point, reduction of thrombotic events reduces patient risks resulting from loss of access patency. Most of the available evidence suggests that detection of stenosis and prevention of thrombosis is valuable. When a test indicates the likely presence of a stenosis, then venography or fistulography should be used to definitively establish the presence and degree of the stenosis. In most but not all cases, angioplasty should be performed if the stenosis is greater than 50% by diameter. The value of routine use of any surveillance technique for detecting anatomic stenosis alone, without concomitant functional assessment by measurement of access flow, venous pressure, recirculation or other physiologic parameters, has not been established. Stenotic lesions should not be repaired merely because they are present. If such correction is performed, then intraprocedural or periprocedural measurement of access flow (QA) or intra-access pressure should be conducted to demonstrate a functional improvement with a successful percutaneous transluminal angioplasty.

The native arteriovenous fistula in 2007. Research needs.

Several research questions are open in the field of vascular access for hemodialysis. The present paper reviews both prognostic issues, such as the identification of factors for patient stratification before access insertion, and intervention questions, such as comparison of the advantages and disadvantages of different surgical solutions, the effects of different medications on vascular pathology, the different cannulation practices to prevent vessel wall lesions and technologies for early diagnosis of access dysfunction. Given that the quality of the available literature in nephrology is often suboptimal, nephrologists need to pay special attention to methodology issues before embarking on expensive multicenter studies.

The continuous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis: results of a phase II study.

AIM: This study was designed to assess the potential of the continuous erythropoietin receptor activator (C.E.R.A.) to correct anemia at extended administration intervals in erythropoiesis-stimulating agent-naive patients with chronic kidney disease (CKD) not on dialysis and to determine its optimal starting dose. METHODS: Patients were assigned to subcutaneous C.E.R.A. at 3 doses: 0.15, 0.30 and 0.60 microg/kg/wk. During the first 6 weeks, dose adjustments for efficacy were not permitted in order to assess dose response. Within each of the 3 dose groups, patients were randomized to receive C.E.R.A. QW, Q2W or Q3W; the total dose during the first 6 weeks was the same for a particular dose group across the frequency subgroups. During the next 12 weeks, dose was adjusted according to predefined hemoglobin (Hb) criteria. The primary efficacy parameter was change in Hb over 6 weeks, estimated from regression analysis between baseline and the point at which the patient received a dose change or blood transfusion. It therefore provided an estimate of Hb increase based on starting dose. Other endpoints included Hb response rate (proportion of patients with a Hb increase > 1.0 g/dl on 2 consecutive occasions). A 1-year extension period investigated long term tolerability and efficacy. RESULTS: A dose-dependent relationship was noted in the mean change in Hb from baseline over 6 weeks (p < 0.0001), independent of administration schedule (p = 0.9201). There was also a significant relationship between Hb change and median serum C.E.R.A. concentration (p < 0.0001). Erythropoietic responses were sustained in all groups with mean changes from baseline in Hb > 1.2 g/dl observed at doses > or = 0.30 microg/kg/wk. Hb response rate increased with increasing dose: 67, 72 and 90% with C.E.R.A. 0.15, 0.30 and 0.60 microg/kg/wk, respectively. Generally, the median Hb response time was faster with increasing dose (89, 43 and 31 days, respectively). Response was unrelated to administration frequency. Stable Hb concentrations were maintained throughout the 1-year extension period. C.E.R.A. was generally well tolerated, and the most common adverse events were hypertension, urinary tract infection and renal failure. CONCLUSIONS: C.E.R.A. corrected anemia and maintained sustained and stable control of Hb over 1 year. These results suggest that 0.60 microg/kg subcutaneous C.E.R.A. given twice monthly is a suitable starting dose for further investigation in Phase III studies in patients with CKD not on dialysis.

Characteristics of enzyme-linked immunosorbent assay for detection of IgG antibodies specific to Сhlamydia trachomatis heat shock protein (HSP-60)

The goal of this work was to study sensitivity and specificity of the developed ELISA set for the identification of IgG antibodies against Chlamydia trachomatis HSP-60 (using biotinylated tyramine-based signal amplification system). The study was conducted using a panel of characterized sera, as well as two reference ELISA sets of similar purpose. According to the results of ELISA informative value parameters, the ELISA we have developed showed the highest specificity and sensitivity parameters (no false negative or false positive results were registered). In 4 out of 15 intralaboratory panel serum samples initially identified as negative, anti-HSP-60 IgG-antibodies test result in reference ELISA sets upon dilution changed from negative to positive. The nature of titration curves of false negative sera and commercial monoclonal antibodies А57-В9 against C. trachomatis HSP-60 after incubation for 24 h was indicative of the presence of anti-idiotypic antibodies in these samples. Upon sera dilution, idiotypic-anti-idiotypic complexes dissociated, which caused the change of test result. High informative value of the developed ELISA set for identification of IgG antibodies against C. trachomatis HSP-60 has been proven. Anti-idiotypic antibodies possessing C. trachomatis anti-HSP-60 activity and being one of the causes of false negative results of the relevant ELISA-based tests have been identified in blood sera of individuals infected with chlamydial genitourinary infection agents.

Resolving the paradigm crisis in intravenous iron and erythropoietin management.

Despite the proven benefits of intravenous (i.v.) iron therapy in anemia management, it remains underutilized in the hemodialysis population. Although overall i.v. iron usage continues to increase slowly, monthly usage statistics compiled by the US Renal Data System suggest that clinicians are not implementing continued dosing regimens following repletion of iron stores. Continued therapy with i.v. iron represents a key opportunity to improve patient outcomes and increase the efficiency of anemia treatment. Regular administration of low doses of i.v. iron prevents the recurrence of iron deficiency, enhances response to recombinant human erythropoietin therapy, minimizes fluctuation of hemoglobin levels, hematocrit levels, and iron stores, and may reduce overall costs of care. This article reviews the importance of i.v. iron dosing on a regular basis in the hemodialysis patient with iron-deficiency anemia and explores reasons why some clinicians may still be reluctant to employ these protocols in the hemodialysis setting.

Prostaglandin E and hypercalcemia in breast carcinoma: only a tumor marker? A need for perspective.

Prostaglandin E concentrations were measured in a patiet with breast carcinoma, hypercalcemia, undetectable parathyroid hormone (PTH) and no evidence of bone metastases. Catheterization of the drainage bed of her tumor documented production of E series prostaglandins. Treatment with the largest recommended doses of indomethacin for 10 days failed to lower her plasma prostaglandin E (PGE) concentrations or to correct the hypercalcemia, but it normalized urinary excretion of PGE. Subsequent chemotherapy reduced prostaglandin concentrations toward normal values concomitant with a reduction of clinically estimated tumor burden. During this period of time, serum calcium concentrations had no consistent relationship to the plasma PGE levels. We suggest that PGE merely reflected the tumor burden of this patient and did not directly contribute to the genesis of her hypercalcemia. The pertinent literature relating PGE and hypercalcemia is reviewed.

Effect of plasma proteins and buffer in flushing solutions on rat kidney preservation by cold storage.

The isolated rat kidney perfused at 37 C was used to evaluate the effect of adding plasma proteins to, and varying osmolality of, cold-storage flushing solutions with or without buffering. Addition of albumin improved immediate poststorage kidney function (glomerular filtration rate [GFR], fractional sodium reabsorption, and fractional protein clearance) of all flushing solutions tested after 6 hr and 24 hr of storage. At 6 hr, these improvements also correlated with less weight gain. Flushing solutions containing citrate and sulfate produced significantly better return of function after 24 hr of cold storage than Krebs' or Collins'-derived solutions. Osmolality was unimportant with solutions containing citrate. Collins' solution with reduced MgSO4 yielded better poststorage function than conventional solution. An all-citrate isotonic solution buffered with 15 mmol THAM preserved poststorage function at 48 hr better than a similarly buffered solution containing both citrate and sulfate. Loss of dry weight during storage and subsequent perfusion appeared to correlate, in these experiments, with loss of poststorage function. The isolated rat kidney provides discrimination among various flushing solutions. The technique might be useful in the assay of additional variables that might affect the quality of kidney preservation.

Effect of delayed graft function and ALG on the circaseptan (about 7-day) rhythm of human renal allograft rejection.

Postimplantation records of 157 kidney transplant recipients with first rejection episodes within 50 days of surgery were studied. Of these 36 had living-related and 121 cadaver donors. Recipients of cadaver donor kidneys were divided into four subgroups: with and without postoperative acute renal failure (ARF), and with and without approximately two weeks of immunosuppression by antilymphoblast globulin (ALG) added to conventional therapy. All recipients with immediate function without ALG showed evidence of periodicity in probability of occurrence of rejection that was highly significant for a 7-day period beginning at the time of surgery. The remaining groups showed less significant periodicity or no significant periodicity beginning at the time of surgery, but they did show a highly significant circaseptan rhythm of rejection episodes beginning with cessation of ALG treatment or with onset of diuresis following ARF in the absence of ALG. It is suggested that clinical manifestation of the immunologic attack of recipient upon graft has an intrinsic development period of about 7 days beginning with implantation. However, initiation of the first period may be blocked by ALG or by low renal blood flow during ARF.

Use of the isolated perfused kidney model to assess the acute pharmacologic effects of cyclosporine and its vehicle, cremophor EL.

"Nephrotoxicity" secondary to cyclosporine and its clinically used vehicle, Cremophor EL, was examined in the isolated perfused rat kidney model. This model allows the serial determination of renal hemodynamic and tubular functional studies over a 3-hr duration using a normothermic, low hematocrit (13-15%) perfusion system. Initial studies indicated that the addition of small quantities of Cremophor EL resulted in marked renal vasoconstriction with decreased renal blood flow and deterioration in renal tubular function. These effects were highly significant and were of the same magnitude whether or not cyclosporine was present in the system. Cyclosporine was therefore examined after being dissolved in another vehicle, methanol. A 10% (v/v) amount of plasma was necessary in the perfusate to prevent significant adsorption of cyclosporine to the perfusion apparatus. Cyclosporine at concentrations below 100 ng/ml resulted in minor changes in renal hemodynamics. Beginning at 100 ng/ml glomerular filtration rate dropped significantly and renal vascular resistance increased three-fold. Fractional excretion of sodium significantly increased and the urine:plasma inulin ratio significantly decreased. We conclude that the clinically used drug vehicle, Cremophor EL, has significantly adverse effects on renal hemodynamics and tubular function. In addition, CsA causes similar renal toxicity in a dose-dependent fashion. Simultaneous administration of these two nephrotoxic agents could contribute to the high incidence of acute renal failure seen after transplantation. These observations suggest that an alternate vehicle with less renal toxicity might significantly decrease the incidence of this clinical problem.

Diagnostic and prognostic significance of an increase in fractional protein clearance ratio before and during rejection of renal transplant.

We measured prospectively changes in fractional protein clearance ratio (CPr/CCr) in 21 live-related (LR) and 41 cadaver donor (CD) renal transplants before and during onset of first rejections. Fifty-three recipients manifested a rejection within the first post-transplant month. Fractional protein clearance increased in all patients during rejection. An increase in CPr/CCr prior to other evidence of impending rejection, and therefore clinically useful, required at least a 10-day rejection-free interval dated from onset of diuresis (whether diuresis was immediate or delayed by acute tubular necrosis (ATN)). Twenty-three of 25 nonantilymphocyte globulin (ALG)-treated CD transplants manifested clinical and laboratory signs of the first rejection episode prior to the 10th day of diuresis compared with 5 of 21 LR and none of 16 ALG-treated CD transplants. Persistence of elevated CPr/CCr despite treatment forecast graft loss (11 of 13), whereas a decrease in this ratio was associated with ultimate reversal of the rejection process.

Effect of cyclosporine and delayed graft function on posttransplantation erythropoiesis.

The effect of delayed graft function and immunosuppressive drugs on posttransplant erythropoiesis was studied prospectively in 18 living-related (LR) and 84 cadaver-donor (CD) recipients. Eight of 18 LR and 20 of 84 CD recipients received antilymphoblast globulin (ALG) in addition to azathioprine and prednisone. Sixty-four CD recipients received cyclosporine (CsA) with prednisone. In the absence of rejection reticulocytosis began 6.7 +/- 0.2 days following graft implantation in azathioprine-only-treated LR recipients. This was lengthened by ALG to 9.4 +/- 0.3 and 9.9 +/- 0.7 days in LR and CD recipients, respectively, whose grafts functioned immediately. Delayed graft function prolonged onset of reticulocytosis to 15.9 +/- 0.9 days in ALG-treated but not in CsA-treated recipients (5.8 +/- 0.4 days). The shortest latency was noted in CsA-treated recipients (4.9 +/- 0.5 days) with immediately functioning grafts. The earlier onset of reticulocytosis of CsA-treated recipients was followed by statistically significant blunting of peak reticulocytosis, which correlated with a slower rate of correction of anemia (delta Hct = 0.19/day) compared with non-CsA-treated recipients (delta Hct = 0.34/day). Early rejection was associated with abrogation of reticulocytosis and correction of anemia without regard to immunosuppressive regimen) until rejection was reversed. Erythropoietin (EPO) was measured sequentially in 5 patients with immediate function. In 4 of 5 cases changes in EPO preceded those in reticulocytosis. EPO rose from a mean of 13 mU/ml pretransplant to a peak of 50 within 3 weeks and decreased to 18 mU/ml within 6 weeks of graft implantation. At six months posttransplant, normalized reticulocyte counts were only 55% higher (1.75 vs. 1.13%) but hematocrit had increased from 26 +/- 1% to 42 +/- 1%. Hematocrit varied inversely with serum creatinine, which was highest in CsA-treated patients with initial delayed graft function. We conclude that correction of anemia posttransplantation is driven by EPO but other factors may also be important, that neither ATN nor ALG-therapy have clinically important effects on erythropoiesis, and that CsA reduced "effective" erythropoiesis and influences correction of anemia--particularly if delayed graft function complicates the initial course posttransplantation.

A comparison of the effects of cyclosporine versus antilymphocyte globulin on delayed graft function in cadaver renal transplant recipients.

There has been concern that cyclosporine's nephrotoxicity increases the incidence of delayed graft function (DGF), prolongs periods of oliguria, and reduces graft survival. In order to further study whether CsA should be used in DGF, we conducted a randomized prospective trial of the effect of CsA versus antilymphocyte globulin on the effects of DGF. Between 12/22/85 and 3/11/88, all patients with DGF after an initial 12-24 hr of CsA were randomized to either daily Minnesota ALG and prednisone or lower-dose CsA (10 mg/kg/day) and prednisone. Resolution of DGF was defined as a lack of dialysis dependency and a 25% fall in the serum creatinine (CR). If DGF was not resolved by 2 weeks, transplant renal biopsies were performed to assess the presence of occult rejection. CsA (10 mg/kg/day) was initiated in the ALG group only after resolution of the DGF. Of the 45 patients who recovered graft function, 19 received ALG and 26 received CsA. CsA significantly prolonged the duration of DGF (ALG 9.74 days, CsA 13.69 days, P = 0.035) but did not result in a prolongation of hospitalization. No difference in CR was found between the two groups at 1 month, 3 months, 6 months, or 12 months. Mean CR at 12 months was 1.98 mg/dl for ALG versus 1.96 mg/dl for CsA. Overall graft survival did not differ in the CsA and ALG groups (P = 0.33). CsA does slightly increase the duration of DGF as compared with ALG but has no effect on one-year serum CR or one-year graft survival. Since there appeared to be no harmful long-term effects of the slight lengthening of DGF, a lower-dose of CsA protocol with biopsy surveillance for occult rejection can be used in patients with DGF.

Defining a renal anemia management period.

Estimates of the prevalence of anemia during chronic renal insufficiency (CRI) vary depending on how anemia is defined. An analysis of patients beginning dialysis in the United States found that 67% had a hematocrit of less than 30% and 51% had a hematocrit of less than 28%. The anemia of CRI, therefore, appears to be prevalent even as it is underrecognized and undertreated-despite the widespread realization that there is much to be gained by treatment with recombinant human erythropoietin, with little risk of accelerating the progression of kidney disease. It is difficult to separate the effects of anemia in CRI from those of other comorbid conditions, but it is clear that anemia is a strong predictor of mortality and cardiac morbidity. Correction of anemia would be expected to negate the contribution of anemia to the mortality and cardiac morbidity associated with CRI. While this hypothesis is well-validated in hemodialysis patients, data in the population with CRI are preliminary but encouraging. Recent small prospective studies have established that treatment of anemia with recombinant human erythropoietin can reverse some degree of the cardiac morphological changes seen in CRI. While awaiting the results of large long-term clinical trials, the concept of the renal anemia management period (RAMP) draws attention and focus to the need for proactive and aggressive treatment of anemia among patients with CRI. The RAMP is defined as the period of time after the onset of CRI during which anemia develops, requiring diagnosis and treatment. Treatment of anemia during the RAMP has the potential to ameliorate, or even prevent, significant future morbidity in patients with CRI.

A study of parenteral iron regimens in hemodialysis patients.

The administration of parenteral iron dextran to hemodialysis patients is typically intermittent. We sought to determine the most appropriate intervals for sampling iron parameters during intermittent need-based and continuous maintenance regimens and to quantify differences in efficacy between such regimens during long-term therapy. After a single course of 10 consecutive 100-mg iron doses administered to 14 patients on 16 occasions, transferrin saturation (TSAT) and ferritin were unreliable indices of iron status for the next 2 and 6 weeks, respectively. TSAT and ferritin levels at 1 week were virtually identical to those at 2 weeks after the administration of a single 50-mg or 100-mg iron dextran dose to 16 other patients. Twelve patients on maintenance iron therapy (25 to 100 mg/wk; TSAT, 30% to 50%) had a statistically significant decrease in the amount of recombinant human erythropoietin (rHuEPO) needed to maintain hemoglobin (Hb) levels between 10 and 11 g/dL compared with 12 patients receiving intermittent need-based dosing, an effect that persisted from week 16 to week 72 of the study. Maintenance iron was feasible even in a third group of eight patients targeted to sustain an Hb level of 14 g/dL. In both iron maintenance groups, iron indices could be measured at weekly intervals, and ferritin levels did not progressively increase over time. Continuous maintenance iron dextran used to maintain TSATs of 30% to 50% significantly reduced rHuEPO requirements and resulted in no adverse side effects in chronic hemodialysis patients. After weekly maintenance 25- to 100-mg iron dextran doses, iron indices can be measured after 1 week; a delay of 2 weeks is not necessary.

Physiological and pharmacodynamic considerations for route of EPO administration.

Three intertwined issues--effectiveness, dosage, and route of administration--dominate discussion about recombinant human erythropoietin (rHuEPO). The major biological effect of rHuEPO is to regulate the number of committed erythroid precursors and to cause them to mature into erythrocytes. The constant presence of rHuEPO is critical to the sustenance, multiplication, and differentiation of committed erythroid progenitors that otherwise undergo apoptosis and die before they reach maturity. The route for rHuEPO administration influences the plasma concentration-time profiles. The erythropoietic response is not dependent on the peak concentration of rHuEPO achieved but on the duration of time that rHuEPO levels are maintained above a critical concentration. High levels immediately after intravenous doses are unnecessary to either induce or to sustain erythropoiesis. During the period of relative rHuEPO deficiency that invariably follows intravenous administration, committed but still rHuEPO-dependent cells undergo apoptosis and die in the bone marrow. The subcutaneous route sustains rHuEPO levels above basal levels in the interdialytic period, prevents death of rHuEPO-dependent cells, and results in more efficient and more sustained erythropoiesis. Areas under active investigation include modifications of the parent hormone and novel delivery systems that decrease elimination and maximize the residence time of rHuEPO in the circulation.

The relationship between dialysis graft pressure and stenosis.

RATIONALE AND OBJECTIVES: Pressure measurements during dialysis have been used to screen for venous outlet stenosis, but the relationship between the degree of stenosis and pressure has not been defined. METHODS: To determine this relationship, failing or failed dialysis grafts (n = 34) were studied with angiography and pressure measurements from the segment of the graft near the arterial anastomosis. RESULTS: By linear regression, the relationship between the highest grade stenosis in or central to the graft and pressure was as follows: percent stenosis = 55 systolic graft pressure/systolic blood pressure+13 (r = 0.75). CONCLUSIONS: There is a positive correlation between the severity of stenosis and graft pressure, confirming the use of this measurement in screening for stenosis. It is hypothesized that this relationship is the result of progressive elimination of the normal pressure drop between the artery and arterial limb of the graft as the degree of stenosis increases.

Increased absolute calcium binding to albumin in hypoalbuminaemia.

The amount of calcium bound to protein was measured in 30 patients with differing diseases and varying degrees of hypoalbuminaemia. Total serum calcium increased directly with both serum albumin and ultrafilterable calcium concentrations. The estimated amount of calcium bound per gram of albumin varied inversely with the albumin concentration, decreasing from 2.1 to 1.0 mg calcium/g albumin as albumin concentration increased from 1.7 to 3.1 g/dl. Circulating parathyroid hormone (PTH) concentrations varied inversely with measured ultrafilterable calcium concentrations. The frequency of raised PTH concentrations decreased as serum albumin increased. Use of a conventional correction factor for albumin binding (0.88 mg calcium bound per gram of albumin) to calculate corrected total calcium led to major errors in estimating ultrafilterable calcium in these patients. The PTH concentrations in turn correlated with the degree of deviation between estimated and measured ultrafilterable calcium concentrations. Ionised calcium was low in seven of ten additional hypoalbuminaemic patients studied whereas correction of total calcium for albumin indicated normocalcaemia in all. Thus correction of total calcium in patients with hypoalbuminaemia by formulae which use a fixed binding ration of calcium to albumin may give an erroneous impression of normocalcaemia. The increase in calcium binding ratio during hypoalbuminaemia needs to be considered during assessment of calcium status in these patients.