Analytical solution of phosphate kinetics for hemodialysis.

Chronic kidney diseases imply an ongoing need to remove toxins, with hemodialysis as the preferred treatment modality. We derive analytical expressions for phosphate clearance during dialysis, the single pass (SP) model corresponding to a standard clinical hemodialysis and the multi pass (MP) model, where dialysate is recycled and therefore makes a smaller clinical setting possible such as a transportable dialysis suitcase. For both cases we show that the convective contribution to the dialysate is negligible for the phosphate kinetics and derive simpler expressions. The SP and MP models are calibrated to clinical data of ten patients showing consistency between the models and provide estimates of the kinetic parameters. Immediately after dialysis a rebound effect is observed. We derive a simple formula describing this effect which is valid both posterior to SP or MP dialysis. The analytical formulas provide explanations to observations of previous clinical studies.

Effect of far infrared therapy on arteriovenous fistula maturation, survival and stenosis in hemodialysis patients, a randomized, controlled clinical trial: the FAITH on fistula trial.

BACKGROUND: An arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis treatment. After creation many of the AVFs will never mature or if functioning will need an intervention within 1 year due to an AVF stenosis. Studies investigating possible therapies that improves the AVF maturation and survival are scarce. Far infrared therapy (FIR) has shown promising results. In minor single centre and industry supported trials FIR has shown improved AVF maturation and survival. There is a need of a randomized multicentre controlled trial to examine the effect of FIR on the AVF maturation and survival and to explore the possible AVF protective mechanism induced by the FIR treatment. METHODS: This investigator initiated, randomized, controlled, open-labeled, multicenter clinical trial will examine the effect of FIR on AVF maturation in patients with a newly created AVF (incident) and AVF patency rate after 1 year of treatment in patients with an existing AVF (prevalent) compared to a control group. The intervention group will receive FIR to the skin above their AVF three times a week for 1 year. The control group will be observed without any treatment. The primary outcome for incident AVFs is the time from surgically creation of the AVF to successful cannulation. The primary outcome for the prevalent AVFs is the difference in number of AVFs without intervention and still functioning in the treatment and control group after 12 months. Furthermore, the acute changes in inflammatory and vasodilating factors during FIR will be explored. Arterial stiffness as a marker of long term AVF patency will also be examined. DISCUSSION: FIR is a promising new treatment modality that may potentially lead to improved AVF maturation and survival. This randomized controlled open-labelled trial will investigate the effect of FIR and its possible mechanisms. TRIAL REGISTRATION: Clinicaltrialsgov NCT04011072 (7th of July 2019).

Vitamin D, surface electromyography and physical function in uraemic patients.

BACKGROUND: Muscle function is impaired in uraemic patients and several causes have been proposed. Deficiency of 25-hydroxyvitamin D (25-OHD), which affects muscle function in non-uraemic patients, may very well also be associated with the myopathy found in these patients. The aim of this study was to investigate the association between 25-OHD and muscle function as well as physical function in chronic kidney disease (CKD) and peritoneal dialysis (PD) patients. METHODS: In this cross-sectional study, 21 adult patients with CKD stage 3-5 and 21 patients treated with PD were included. Standard biochemistry parameters were measured including 25-OHD, 1,25-dihydroxycholecalciferol (1,25-OHD) and parathyroid hormone analysis. Muscle function was determined by 30-second surface electromyography (sEMG) recordings of a right thigh muscle (vastus lateralis) and a second left finger muscle (second dorsal interosseous) under voluntary contractions. Physical function was determined using a 30-second Chair Stand Test and the Short Form 36 quality of life questionnaire. Clinical characteristics were collected from the patient records. RESULTS: Moderate vitamin 25-OHD deficiency (<40 nmol/l) was measured in 52% of patients with CKD and in 71% of the patients on PD. Severe deficiency (<15 nmol/l) was measured in 14% of patients on PD. There were no significant differences between the CKD and PD patients in terms of sEMG results. 25-OHD was not correlated to any results from the tests of sEMG or physical function. However, a higher sEMG frequency and signal root mean square (RMS) were positively associated with a higher Chair Stand Test score. Time to maximum sEMG frequency was negatively correlated to the Chair Stand Test score (p < 0.05), and positively correlated to the level of comorbidity (p < 0.05). sEMG signal peak-peak amplitude, frequency and RMS were positively correlated to the quality of life scales Physical Function, Role Physical, General Health, Vitality, Social Function, Mental Health, and Physical Component Scale (p < 0.001). CONCLUSIONS: 25-OHD deficiency was prevalent in uraemic patients in the present study. Muscle function as determined using sEMG and the Chair Stand Test was not associated with 25-OHD. The results may be biased by the limited variation in 25-OHD and masked by effects of several other variables in this very sick population.

Mortality due to bleeding, myocardial infarction and stroke in dialysis patients.

Essentials Mortality due to bleeding vs. arterial thrombosis in dialysis patients is unknown. We compared death causes of 201 918 dialysis patients with the general population. Dialysis was associated with increased mortality risks of bleeding and arterial thrombosis. Clinicians should be aware of the increased bleeding and thrombosis risks. SUMMARY: Background Dialysis has been associated with both bleeding and thrombotic events. However, there is limited information on bleeding as a cause of death versus arterial thrombosis as a cause of death. Objectives To investigate the occurrence of bleeding, myocardial infarction and stroke as causes of death in the dialysis population as compared with the general population. Methods We included 201 918 patients from 11 countries providing data to the ERA-EDTA Registry who started dialysis treatment between 1994 and 2011, and followed them for 3 years. Age-standardized and sex-standardized mortality rate ratios for bleeding, myocardial infarction and stroke as causes of death were calculated in dialysis patients as compared with the European general population. Associations between potential risk factors and these causes of death in dialysis patients were investigated by calculating hazard ratios (HRs) with 95% confidence intervals (CIs) by the use of Cox proportional-hazards regression. Results As compared with the general population, the age-standardized and sex-standardized mortality rate ratios in dialysis patients were 12.8 (95% CI 11.9-13.7) for bleeding as a cause of death (6.2 per 1000 person-years among dialysis patients versus 0.3 per 1000 person-years in the general population), 13.4 (95% CI 13.0-13.9) for myocardial infarction (22.5 versus 0.9 per 1000 person-years), and 12.4 (95% CI 11.9-12.9) for stroke (14.3 versus 0.7 per 1000 person-years). Conclusion Dialysis patients have highly increased risks of death caused by bleeding and arterial thrombosis as compared with the general population. Clinicians should be aware of the increased mortality risks caused by these conditions.

Algorithm for optimal dialysis access timing.

BACKGROUND: Acute initiation of dialysis is associated with increased morbidity due to access and uremia complications. It is frequent despite early referral and regular out-patient control. We studied factors associated with end-stage renal disease (ESRD) progression in order to optimize the timing of dialysis access (DA). METHODS: In a retrospective longitudinal study (Study 1), the biochemical and clinical course of 255 dialysis and 64 predialysis patients was registered to determine factors associated with dialysis-free survival (DFS). On the basis of these results an algorithm was developed to predict timely DA, defined as >6 weeks and <26 weeks before dialysis initiation, with too late placement weighted twice as harmful as too early. The algorithm was validated in a prospective study (Study 2) of 150 dialysis and 28 predialysis patients. RESULTS: Acute dialysis was associated with increased 90-day hospitalization (17.9 vs. 9.0 days) and mortality (14% vs. 6%). P-creatinine and p-urea were poor indicators of DFS. At any level of p-creatinine, DFS was shorter with lower creatinine clearance and vice versa. Patients with systemic renal disease had a significantly shorter DFS than primary renal disease, due to faster GFR loss and earlier dialysis initiation. Short DFS was seen with hypoalbuminemia and cachexia; these patients were recommended early DA. The following algorithm was used to time DA (units: 1iM and ml/min/1.73 m2): P-Creatinine - 50 x GFR + (100 if Systemic Renal Disease) >200. Use of the algorithm was associated with earlier dialysis placement and a fall in acute dialysis requirements from 50% to 23%. The incidence of too early DA was unchanged (7% vs. 9%), and was due to algorithm non-application. The algorithm failed to predict imminent dialysis in 10% of cases, primarily due to acute exacerbation of stable uremia. Dialysis initiation was advanced by approximately one month. CONCLUSIONS: A predialysis program based on early dialysis planning and GFR-based DA timing may reduce the requirement for acute dialysis initiation and patient morbidity and mortality, at the cost of slightly earlier dialysis initiation.

Consistent absorption of cyclosporine from a microemulsion formulation assessed in stable renal transplant recipients over a one-year study period.

To evaluate the pharmacokinetic properties of the new microemulsion formulation of cyclosporine (Sandimmun Neoral), a double-blind, prospective study in stable renal transplant recipients was performed. The patients were randomized on a 4:1 basis either to receive Sandimmun Neoral (n = 45) or continue on regular Sandimmun (n = 12). Before randomization, a steady-state pharmacokinetic profile study was performed in all patients while they were still on regular Sandimmun. Pharmacokinetic assessments were then performed after 8 and 12 weeks and after 1 year. A milligram-to-milligram dose conversion was shown to be adequate to maintain the patients within a predefined target therapeutic window. Changes in pharmacokinetic parameters after conversion to Sandimmun Neoral were consistent with an increased rate and extent of cyclosporine absorption from the Neoral formulation. This was reflected by a shorter time to reach peak concentration and also by a mean increase in peak concentration by 67%, and an overall mean increase in drug exposure (area under the curve) by 34%. These findings were also confirmed 1 year after conversion. Furthermore, significantly reduced intraindividual variability in pharmacokinetic parameters was found, as well as improvements in the correlation between trough concentrations and area under the curve after conversion to Sandimmun Neoral. In conclusion, our results indicate an improved and consistent absorption of cyclosporine from the Neoral formulation, which should make clinical management easier and safer.

Albumin-induced changes in the electrocardiographic QRS complex.

The amplitude of the QRS wave of the electrocardiogram was correlated with conventional serum electrolyte concentrations in 94 nonhypertensive and 53 hypertensive patients. There was a highly significant correlation of QRS amplitude with serum albumin level in both groups. There was also significant correlation with serum calcium level in the nonhypertensive group, but this significance disappeared after correction for albumin. Changes in the serum albumin level during the hospital admission of the nonhypertensive patients were positively correlated with changes in QRS amplitude. Albumin infusion into 13 healthy persons resulted in significantly increased QRS amplitude, which was related to changes in serum albumin concentration. These results suggest that changes in serum protein concentration cause changes in QRS amplitude, possibly as a result of increased conductivity.

Parathyroid hormone during maintenance dialysis: influence of low calcium dialysate, plasma albumin and age.

UNLABELLED: Intact PTH measurements between 1989-96 in a 116-patient (63 HD, 53 PD) dialysis unit were reviewed to evaluate the determinants of PTH. Prophylactic treatment included calcium carbonate and maximal alphacalcidol therapy. A forward stepwise multiple regression analysis showed that duration of dialysis, phosphate, albumin and chronic glomerulonephritis were independently positively correlated with PTH, and that ionized calcium, parathyroidectomy, age, diabetic nephropathy and systemic disease were independently negatively correlated. During the first five years of dialysis PTH rose from 124 ng/L (SD range 33-462) to 160 (63-402)* in HD patients but fell from 119 ng/L (33-423) to 88 (31-251)** in PD patients despite the less intensive treatment. PTH fell with increasing age (40-50 years 173 ng/L (52-575); > 60 years 100 (31-316)**) and hypoalbuminemia (< 400 micromol/L 68 ng/L (22-209); > 550 pmol/1138 (41-457)**). PD patients were generally older and increasingly malnourished; after correcting for these factors, no influence of dialysis modality on PTH could be seen. Low-calcium dialysate (1.25 mmol/L) was introduced for both dialysis groups in 1994. Consequent to this, aluminium consumption was virtually eliminated and consumption of alphacalcidol increased. PTH fell from 161 to 128 ng/L in HD patients but rose from 119 to 135 ng/L in PD patients. The incidence of parathyroidectomy fell from 4.3%/year to 1.5%/year*. CONCLUSION: Malnourishment and increasing age reduce PTH secretion and are important determinants of hyperparathyroidism during maintenance dialysis. Adynamic bone disease is common in PD patients and associated with low PTH levels, and may be a consequence of malnourishment and involutional changes. The introduction of low-calcium dialysate reduced the incidence of parathyroidectomy. Control of hyperparathyroidism improved in HD but not PD patients.

Aluminum concentrations in serum, dialysate, urine and bone among patients undergoing continuous ambulatory peritoneal dialysis (CAPD).

Aluminum (Al) concentration in serum, urine, and dialysate was estimated in 21 patients undergoing continuous ambulatory peritoneal dialysis (CAPD). In 12 of the patients bone Al concentration was measured as well. Mean serum Al level was 32.4 +/- 21.0 micrograms/l. The Al concentrations in the dialysate and urine were 9.1 +/- 4.1 micrograms/l and 52.5 +/- 47.3 micrograms/l, respectively. Bone Al concentration was 21.0 +/- 14.9 ppm and correlated significantly with concentrations of Al in serum (p less than 0.01) and dialysate (p less than 0.01). A mass transfer (MT) from the patients to the dialysate was observed in all patients (-44.0 +/- 28.8 micrograms/24 h). There was a highly significant correlation between peritoneal Al MT and serum Al (p less than 0.001), actual Al consumption (p less than 0.05) and bone Al concentration (p less than 0.005) supporting the existence of an overflow phenomenon. Despite very low Al levels in the dialysate, patients are at risk of elevated Al levels in the serum, dialysate, urine and bone because of consumption of Al-containing phosphate binders.

Vitamin D and vitamin-D-binding protein kinetics in patients treated with continuous ambulatory peritoneal dialysis (CAPD).

Serum and dialysate levels of 25-hydroxycholecalciferol (25-OHD3), 1,25 dihydroxycholecalciferol (1,25-(OH)2D3), and vitamin-D-binding protein (DBP) were measured in 14 patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Serum levels of 25-OHD3 and DBP were within normal range (29.1 +/- 22.9 nmol/L and 5.9 +/- 1.1 mumol/L, respectively). Serum levels of 1,25-(OH)2D3 were subnormal in all (less than 16 pmol/L) but one. In 5 patients, dialysate concentrations of 25-OHD3 were 2.3 +/- 0.9 nmol/L, the rest had levels less than 1.0 nmol/L. Small quantities of 1,25-(OH)2D3 were found in the dialysate effluents. DBP could be detected in the dialysate in all patients (0.24 +/- 0.06 mumol/L). Mass transfer (MT) of 25-OHD3 and DBP were respectively -10.4 +/- 8.3 nmol/24 h and -1.46 +/- 0.46 0.46 mumol/24 h. Peritoneal clearances of 25-OHD3 and DBP were low (0.40 +/- 0.37 mL/min and 0.18 +/- 0.06 mL/min, respectively. We conclude that CAPD leads to losses of 25-OHD3 and DBP. However, the peritoneal loss of DBP is well compensated and does not result in serum deficiency. Serum 25-OHD3 levels did not correlate with time on CAPD.

Bone histology in CAPD patients: a comparison with hemodialysis and conservatively treated chronic uremics.

Thirteen patients treated with CAPD, 22 patients maintained on hemodialysis (HD) using aluminium-free water and matched for duration of treatment and 15 conservatively treated uremic patients (CONS) were evaluated by iliac bone biopsy to analyse the influence of CAPD on bone histomorphometry. CAPD patients were significantly (p less than 0.05) older (63.1 +/- 14.0, HD 52.7 +/- 13.3, CONS 53.3 +/- 11.7). Compared to HD the results were as follows: CAPD patients required significantly less aluminium to control hyperphosphatemia (0.16 vs. 0.49 g, p less than 0.005). They had a significantly lower incidence of symptomatic bone disease (p less than 0.05). Histomorphometry showed significantly lower osteoid volume (4.3 + 2.8% vs. 8.6 + 5.5%, p less than 0.05) and aluminium labelling intensity (0.15 vs. 1.0, p less than 0.05). Apart from bone mass indices, other histomorphometric variables showed an insignificantly more favourable trend in CAPD patients compared to HD. CONS patients had a significantly lower bone formation rate than CAPD (p less than 0.05), but otherwise no histomorphometric differences were observed. We conclude that CAPD patients require less aluminium therapy, have a lower risk of aluminium bone contamination, and may have a lower risk of developing uremic osteodystrophy.

[Hyperlipidemia in nephrotic syndrome]. / Hyperlipidaemi ved nefrotisk syndrom.

Hyperlipidemia is common in patients with the nephrotic syndrome. The main cause is probably increased hepatic lipogenesis, a non-specific reaction to falling oncotic pressure secondary to hypoalbuminemia. Cardiovascular morbidity and mortality are increased in patients with the nephrotic syndrome, with the exception of patients with minimal change disease. It is not clear whether this is caused by the hypercholesterolemia or secondary to uremia or medical treatment. Experiments suggest that hypercholesterolemia may cause glomerulosclerosis, a common complication of the nephrotic syndrome. The hypercholesterolemia of the nephrotic syndrome can now be treated effectively with HMG coenzyme A reductase inhibitors.

[Analysis of phenprocoumon dose regulation based on measurement of coagulation factors II, VII and X]. / Analyse af fenprocoumon-dosisregulering baseret på måling af koagulationsfaktorer 2, 7, og 10.

One hundred anticoagulation treatment records were reviewed retrospectively using stepwise regression analysis to determine the influence of phenprocoumaron on the levels of coagulation factors 2, 7 and 10 (KF) measured relative to normal. The phenprocoumaron dose was expressed relative to the correct maintenance dose determined from the entire record ("overdose", OD measured in mg). Phenprocoumaron treatment influenced the KF over two days, approximately 50% on each day, the total change being -0.03 x OD. Continuous incorrect dosage resulted in KF change, equilibrating at a new level after about four weeks at -0.47 x OD. Similarly, continuous correct dosage in patients with a non-therapeutic FK resulted in equilibration within the therapeutic range after four weeks. For long-term treatment, the dosage was likely to be inaccurate under the following circumstances: 1) if the KF was outside the therapeutic range and moving away from it; 2) if the KF was inside the therapeutic range and the change was greater than 0.05. Algorithms for calculation of phenprocoumaron therapy are presented.

Senescence rates in patients with end-stage renal disease: a critical appraisal of the Gompertz model.

The most frequently used model to describe the exponential increase in mortality rate over age is the Gompertz equation. Logarithmically transformed, the equation conforms to a straight line, of which the slope has been interpreted as the rate of senescence. Earlier, we proposed the derivative function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end-stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional kidney transplant have mortality rates comparable to the general population. Therefore, we calculated the age-specific mortality rates for European patients on dialysis (n=274 221; follow-up=594 767 person-years), for European patients with a functioning kidney transplant (n=61 286; follow-up=345 024 person-years), and for the general European population. We found higher mortality rates, but a smaller slope of logarithmic mortality curve for patients on dialysis compared with both patients with a functioning kidney transplant and the general population (P<0.001). A classical interpretation of the Gompertz model would imply that the rate of senescence in patients on dialysis is lower than in patients with a functioning transplant and lower than in the general population. In contrast, the derivative function of the Gompertz equation yielded the highest senescence rates for patients on dialysis, whereas the rate was similar in patients with a functioning transplant and the general population. We conclude that the rate of senescence is better described by the derivative function of the Gompertz equation.

A high peritoneal large pore fluid flux causes hypoalbuminaemia and is a risk factor for death in peritoneal dialysis patients.

BACKGROUND: Hypoalbuminaemia is common in peritoneal dialysis (PD) patients and has an associated high mortality. An excess morbidity and mortality has previously been found in patients with high peritoneal transport. A high peritoneal large pore fluid flux (Jv(L)) results in increased peritoneal loss of protein that possibly contributes to patient morbidity. Alternatively, hypoalbuminaemia and high transport status could be just a marker of capillary pathology associated with atherosclerotic comorbidity. METHODS: Peritoneal dialysis capacity computer modelling of peritoneal transport, based on Rippe's three-pore model, was performed to measure Jv(L) in 155 incident PD patients 2-4 weeks after PD initiation. Patient clinical and biochemical status was determined -6, -3, -1, 1 and 6 months after PD initiation, and every 6 months thereafter. Jv(L) was redetermined in prevalent patients 2 and 4 years after PD initiation. RESULTS: Jv(L) was 0.106+/-0.056 ml/min/1.73 m(2) (median 0.094, interquartile range 0.068-0.128). It was correlated to age*** (*P<0.05; **P<0.01; ***P<0.001) (20-30 years 0.079+/-0.04; 70 years 0.121+/-0.071), but not to gender. No correlation to diabetic or preexisting renal replacement therapy was seen, but patients with atherosclerosis had higher Jv(L) (0.123+/-0.06 vs 0.100+/-0.056*) as had patients with other systemic disease (0.121+/-0.68 vs 0.100+/-0.051*). Jv(L) was positively correlated to area parameter (r = 0.41***), and negatively correlated to plasma albumin (-0.36***). Patients were divided into three equal groups: group 1, Jv(L) <0.075 ml/min/1.73 m(2); group 2, 0.075-0.11; group 3: >0.11. There was no difference between the groups in p-albumin prior to PD. Immediately after PD start, differences between the three groups appeared (1 month p-albumin: (micromol/l) group 1, 548+/-83; group 2, 533+/-86; group 3, 497+/-78**), and persisted for up to 6 years. No significant change in Jv(L) was seen at 2 and 4 years. Patients with significant albuminuria also had hypoalbuminaemia (<1 g/day: 546+/-81 mumol/l; >2 g/day: 503+/-54 micromol/l). Intermittent PD ameliorated the effect of Jv(L) on albumin losses and clearance. Mortality was increased significantly with raised Jv(L), independently of age (2 year mortality: group 1, 10%, group 3, 32%*). There was no overall effect on technique survival, but hypoalbuminaemic group 3 patients had a higher failure rate. CONCLUSION: Jv(L) is related to hypoalbuminaemia and mortality after PD initiation. A high Jv(L) seems to be a marker of preexisting vascular pathology, and to cause hypoalbuminaemia after PD initiation. It is suggested that peritoneal albumin loss can have an identical pathogenic effect as urinary albumin loss, by causing an iatrogenic "nephrotic" syndrome.

Hyperfiltration, creatinine clearance and chronic graft loss.

Chronic graft loss (CGL) may be caused by immunological- or hyperfiltration-mediated tissue destruction. If the hyperfiltration theory is correct, grafts from female donors given to heavy recipients, and having a relatively poor initial function, should suffer an accelerated rate of loss of function. 590 renal transplantations surviving more than 1 yr, including 171 cases of (CGL), were reviewed to identify causes of CGL. No overall influence of recipient or donor sex was found, but female donation resulted in lower acute graft loss and higher CGL. Warm ischemia affected CGL marginally, but cold ischemia < 12 h (excluding living donors) reduced CGL (35 vs. 53% at 10 yr, p < 0.05) and delayed function increased CGL (38% vs. 56% p < 0.001). Patients with a high urea production had high CGL (43% vs. 77%, p < 0.02). No overall effect of recipient weight was found; however 7 patients weighing > 90 kg all had CGL within 10 yr. Creatinine clearance was increasingly correlated to recipient weight (r = 0.23 at 1 yr, 0.38 at 10 yr, p < 0.001). For all years, change in creatinine clearance correlated with change in weight (p < 0.001). The most important factor predicting CGL was creatinine clearance, (> 80 ml/min: 6% at 10 yr; 20-40 ml/min 53%). However, at any level of creatinine clearance, patients with late CGL had a slower loss of renal function. Rate of change of renal function was proportional to creatinine clearance, but only for grafts surviving > 6 yr. Creatinine clearance rose between 3 mths and 2 yr; this rise indicated a good prognosis, was related to recipient weight and weight increase, and was reduced in older donors and cyclosporine treated patients. For patients with low clearance (< 60 ml/min), the increased CGL seen in patients with previous rejection episodes could be explained by their consequent lower clearance, but above this level, rejection episodes had an independent deleterious effect. These findings are compatible with hyperfiltration being the major cause of CGL after 6 yr. Before this immunological factors dominate. Good quality grafts respond to the increased protein load of heavy recipients with an increased GFR. Thus at any time, graft GFR is a function of protein-induced hyperfiltration, immunological graft destruction and hyperfiltration-mediated damage. Hyperfiltration-mediated renal damage is not a problem if the creatinine clearance is greater than 60 ml/min.

The effect of acute rejection on long-term renal graft survival is mainly related to initial renal damage.

It has been suggested that poor long-term prognosis of acute rejection is due to hyperfiltration-mediated injury secondary to the initial renal damage, rather than to ongoing immunological mechanisms. A total of 953 renal transplant recipients was reviewed to examine the effect of acute rejection episodes on graft function and survival; 40% had no rejections, 45% one, 12% two and 3% three. Rejection episodes adversely affected short- and long-term prognosis (5-year survival for no rejections, 62%; one, 34%; two, 26%; three, 19%, P < 0.001) and creatinine clearance at one year (cl 1) (none, 56.7 ml/ min; one, 51.1; two, 52.9; three, 35.2, P < 0.01). This was mainly due to increased graft loss, but patient survival was also reduced (5-year survival for no rejections, 77%; one, 76%; two, 63%; three, 53%, P < 0.05). There was no overall effect of rejection number, independently of cl 1. However, subgroup analysis showed a detrimental effect of rejection number on grafts with high residual function, i.e. cl 1 > 60 ml/min (5-year graft survival none and one, 87%; two and three, 71%, P < 0.01). Late initial rejection episodes adversely affected prognosis (5-year survival 1-7 days, 34%; 8-60, 31%; 60-300, 21%, P < 0.05) and residual graft function (cl 1 1-7 days, 56.2 ml/min; 8-60, 48.7; 60-300, 44.6, P < 0.01). In conclusion, the poor long-term prognostic effect of rejection episodes is mainly, but not entirely, related to initial graft destruction. Late (> 2 months after transplantation) initial rejection is an important independent risk factor for graft loss.

Treatment of refractory cancer-associated hypercalcemia with aminohydroxypropylidene diphosphonate.

The case history is presented of a 45-year-old woman who was receiving chemotherapy for a pulmonary adenocarcinoma and who developed severe symptomatic hypercalcemia. Despite intensive treatment with fluids, loop diuretics, prednisone, calcitonin and repeated doses of mithramycin, she remained hypercalcemic. She was then treated with aminohydroxypropylidene diphosphonate (APD) with consequent rapid normalization of the serum calcium and disappearance of symptoms. We conclude that APD is a valuable supplement to the treatment of malignant hypercalcemia in that it may be effective when traditional therapies have failed.