Hypercalcemia in renal transplant patients: prevalence and management in Canadian transplant practice.

Hypercalcemia, occurring in up to 25% of patients within 12 months following renal transplantation, and persistent hyperparathyroidism were evaluated following renal transplantation, by retrospective chart review of 1000 adult patients transplanted between January 1, 2003 and January 31, 2008 with at least six months follow-up. Serum calcium, parathyroid hormone, and phosphate levels were recorded at 12, 24, 36, and 48 months. Average follow-up was 766 (535) d (mean (SD); median 668 d). Majority were first transplants (85%); deceased donor 57%. Point prevalence of hypercalcemia (serum Ca(2+) > 2.6 mM) was 16.6% at month 12, 13.6% at month 24, 9.5% at month 36, and 10.1% at month 48. Point prevalence of serum parathyroid hormone (PTH) > 10 pM was 47.6% at month 12, 51.1% at month 24, 43.4% at month 36, and 39.3% at month 48. Estimated glomerular filtration rate (GFR) was maintained throughout and was not different between patients with or without hypercalcemia or elevated PTH. Cinacalcet was prescribed in 12% of patients with hypercalcemia and persistent hyperparathyroidism; parathyroidectomy was performed in 112/1000 patients, 15 post-transplant. Persistent hyperparathyroidism, often accompanied by hypercalcemia, is common following successful renal transplantation, but the lack of clear management suggests the need for further study and development of evidence-based guidelines.

Relative hypoparathyroidism and hypoalbuminemia are associated with hip fracture in hemodialysis patients.

AIMS: Patients with end-stage renal disease treated by hemodialysis are at an increased risk of hip fracture. In the general population, hip fractures are associated with increased morbidity and mortality. The objective of this study was to assess the predictors and outcomes of hip fracture in the hemodialysis population, including quality of life post hip fracture. METHODS: A case-control study from 1999 to 2005 included 29 adult hemodialysis patients with hip fracture and 55 controls, matched on age, gender and number of years on hemodialysis. A logistic regression model was used to derive predictors of hip fracture. The association between time to death post hip fracture and parathyroid hormone was analyzed using a Kaplan-Meier curve. The ability to live independently 1 year after hip fracture was used as a measure of quality of life. RESULTS: Variables associated with hip fracture were a reduction in serum parathyroid hormone by 100 pg/ml (OR = 1.65, 95% CI 1.10, 2.46) and a decrease in serum albumin by 1 g/l (OR = 1.18, 95% CI 1.00, 1.39). 40% of the cases died within the first year post hip fracture. Median survival time in patients with hip fracture and a serum PTH value < 100 pg/ml was 17 days (95% CI 0, 37 days) as compared with 280 days (95% CI 103, 471 days) for those with a PTH value > 100 pg/ml (p < 0.02). Among the patients who survived, 53% were subsequently discharged to a long-term care facility. CONCLUSIONS: Relative hypoparathyroidism and hypoalbuminemia are associated with an increased risk of hip fracture in hemodialysis patients. There is also a significant reduction in quality of life in patients sustaining a hip fracture.

Conversion between bromcresol green- and bromcresol purple-measured albumin in renal disease.

BACKGROUND: Albumin measured by a bromcresol purple dye-binding assay (Alb(BCP)) agrees more closely with the gold standard of immunonephelometry than does bromcresol green (Alb(BCG)) measurement. Both tests are in current clinical use. A method for converting between the two would be useful. METHODS: We measured albumin by bromcresol green and bromcresol purple in 535 patients, 155 of whom had renal disease. We randomly divided data from the patients with renal disease into two equal-sized sets, and used one set to derive, and the remaining set to validate, a regression equation relating the two values. RESULTS: The relationship Alb(BCG)=5.5+Alb(BCP) performed very well in both the renal patient validation set and in the data from 380 unselected in-patients and out-patients. Intraclass correlations for agreement between measured Alb(BCG) and predicted Alb(BCG) was 0.98 in both analyses. CONCLUSIONS: The ability to convert between these measurements will be of use in clinical situations where the absolute value of the serum albumin is important, when data from laboratories using different methodologies must be combined, and in the application of the Modification of Diet in Renal Disease formula to estimate glomerular filtration rate in patients whose albumin has been measured by bromcresol purple.

Interstitial nephritis in patients with inflammatory bowel disease treated with mesalamine.

Mesalamines are slow-release formulations of 5-aminosalicylic acid (5-ASA) and are effective as primary treatment and maintenance therapy in inflammatory bowel disease. Interstitial nephritis is a recognized side effect. We report two cases of biopsy-confirmed interstitial nephritis in patients being treated with 5-ASA. Both had a trial of steroid therapy. One patient had partial recovery of renal function but the other patient was in chronic renal failure and likely was approaching the need for dialysis. Interstitial nephritis is an under-recognized complication of 5-ASA therapy. Early identification and withdrawal of this drug can lead to a partial or complete reversal of renal dysfunction.

Risk of bacteremia from temporary hemodialysis catheters by site of insertion and duration of use: a prospective study.

BACKGROUND: Uncuffed, nontunneled hemodialysis catheters remain the preferred means to gain immediate access to the circulation for hemodialysis. Bacteremia is the primary complication that limits their use. The risk of bacteremia by site of insertion and duration of use has not been well studied. METHODS: Two hundred eighteen consecutive patients who required a temporary hemodialysis catheter were prospectively followed. RESULTS: Catheters were placed at 318 new insertion sites and remained in use for a total of 6235 days. The incidence of bacteremia was 5.4% after three weeks of placement in internal jugular vein and 10.7% after one week in femoral vein [relative risk for bacteremia 3.1 (95% CI, 1.8 to 5.2)]. The incidence of bacteremia was 1.9% one day after the onset of an exit site infection but increased to 13.4% by the second day if the catheter was not removed. Guidewire exchange for malfunction and patient factors did not significantly affect the risk of bacteremia. CONCLUSIONS: Internal jugular catheters may be left in place for up to three weeks without a high risk of bacteremia, but femoral catheters in bed-bound patients should be removed after one week. Catheter exchanges over a guidewire for catheter malfunction do not increase bacteremia rates. Temporary catheters should be removed immediately if an exit site infection occurs.

Albumin-corrected calcium and ionized calcium in stable haemodialysis patients.

BACKGROUND: It is ionized calcium that is physiologically active and under homeostatic control; however, total calcium is more conveniently measured. Formulae for correction of calcium to account for albumin binding have not been validated in a dialysis setting. METHODS: We measured ionized calcium simultaneously with total calcium (t[Ca]), albumin, total protein and pH before dialysis in 50 stable outpatients and convalescent inpatients. RESULTS: Although 92% of patients were taking calcium supplements and 70% taking alphacalcidol, 11 patients (22%) had ionized hypocalcaemia. To facilitate comparison of calculated ionized calcium, measured total calcium (t[Ca]), and 'corrected' calcium (c[Ca]), with the criterion measure of ionized calcium, all measurements were converted to z scores, standardized on the normal range for each variable. Results are expressed as intraclass correlation coefficients (ICC: 0, all differences are due to error; 1, all differences are due to between patient variation). CONCLUSIONS: None of the published formulae greatly improved the test characteristics beyond simply using the total calcium. A correction formula in widespread use (Payne), quoted in reference texts, agreed less well with ionized calcium than did the unadjusted measured calcium. Correction formulae should be abandoned in favour of the use of uncorrected calcium. In cases of doubt, ionized calcium should be directly measured.

Peritoneal membrane transport and hypoalbuminemia: cause or effect?

OBJECTIVE: Peritoneal membrane transport has been associated with serum albumin and clinical outcome. We examined the relationship between serum albumin and peritoneal membrane transport status before and after the initiation of peritoneal dialysis. SETTING: Patients were followed at a tertiary-care regional nephrology program at St. Joseph's Hospital, McMaster University, Hamilton, Ontario, Canada. METHODS: Incident peritoneal dialysis patients between 1 January 1995 and 31 May 1998 were eligible if there was a peritoneal equilibration test within 180 days of starting dialysis, and a serum albumin value measured within 90 days prior to, and 20 to 70 days after initiating dialysis. MAIN OUTCOME MEASURES: Serum albumin, before and after the initiation of dialysis, and the presence of proteinuric renal disease were compared with the peritoneal equilibration test results. RESULTS: Among 67 identified patients, there were 7 high, 27 high-average, 26 low-average, and 7 low transporters and the mean serum albumin values before dialysis were 35.1, 37.4, 37.8, and 40.4 g/L, respectively (p < 0.001). Serum albumin values prior to the initiation of dialysis correlated significantly with the 4-hour D/P creatinine ratio (r = -0.251, p = 0.040). After initiation of dialysis, the correlation was stronger (r= -0.447, p< 0.001). Serum albumin prior to initiation of dialysis was lower for those with proteinuric than nonproteinuric renal disease (36.4 g/L vs 38.8 g/L, p = 0.04). The trend to lower serum albumin in high transporters was seen in patients with both proteinuric and nonproteinuric renal disease. CONCLUSION: The association between higher peritoneal membrane transport and lower serum albumin is present before initiation of dialysis in both proteinuric and nonproteinuric renal disease. The poor outcomes associated with low serum albumin and higher peritoneal membrane transport might be explained by other underlying factors. The contribution of inflammation, malnutrition, and fluid overload requires further study.

To pay or not to pay? A decision and cost-utility analysis of angiotensin-converting-enzyme inhibitor therapy for diabetic nephropathy.

BACKGROUND: Angiotensin-converting-enzyme (ACE) inhibitor therapy can significantly delay the progression of diabetic nephropathy to end-stage renal failure (ESRF). The main obstacle to successful compliance with this therapy is the cost to the patients. The authors performed a cost-utility analysis from the government's perspective to see whether the province or territory should pay for ACE inhibitors for type I diabetic nephropathy on the assumption that cost is a major barrier to compliance with this important therapy. METHODS: A decision analysis tree was created to demonstrate the progression of type I diabetes with macroproteinuria from the point of prescription of ACE inhibitor therapy through to ESRF management, with a 21-year follow-up. Drug compliance, cost of ESRF treatment, utilities and survival data were taken from Canadian sources and used in the cost-utility analysis. One-way and two-way sensitivity analyses were performed to test the robustness of the findings. RESULTS: Compared with a no-payment strategy, provincial payment of ACE inhibitor therapy was found to be highly cost-effective: it resulted in an increase of 0.147 in the number of quality-adjusted life-years (QALYs) and an annual cost savings of $849 per patient. The sensitivity analyses indicated that the cost-effectiveness depends on compliance, effect of benefit and the cost of drug therapy. Changes in the compliance rate from 67% to 51% could result in a swing in cost-effectiveness from a savings of $899 to an expenditure of more than $1 million per additional QALY. A 50% reduction in the cost of ACE inhibitors would result in a cost savings of $299 per additional QALY with compliance rates as low as 58% in the provincial payment strategy. INTERPRETATION: Provincial coverage of ACE inhibitor therapy for type I diabetes with macroproteinuria improves patient outcomes, with a decrease in cost for ESRF services.

Metabolic investigation of recurrent nephrolithiasis: compliance with recommendations.

OBJECTIVES: Nephrolithiasis is a recurrent condition with significant associated morbidity and economic impact. Although urologic intervention addresses symptomatic stone episodes, prevention of recurrences with proven medical therapy is indicated. METHODS: This retrospective study examined 97 patients who presented in 1997 and 1998 with recurrent nephrolithiasis in a large tertiary care center for the presence of an appropriate metabolic investigation as recommended by the National Institutes of Health Consensus Conference. Complete data were abstracted from the hospital and private clinic charts. RESULTS: The average patient age was 50.5 years; 61.9% of patients were men. The mean number of stones per patient was 5.6 (range 2 to 62), with stone analysis performed for 78 patients. Fifty-eight stones (74.4%) were calcium oxalate and/or phosphate, 14 (17.9%) urate, 8 (10.3%) struvite, and 3 (3.8%) cystine. Five patients had two stone types on different occasions. Either lithotripsy or a urologic procedure was required for at least one stone presentation in 89 patients (91.8%). An investigation for stone disease was pending in 54 patients (55.7%). A complete evaluation, satisfying the preset criteria, was performed in 34 patients (35.1%). Six patients who did not undergo evaluation were lost to follow-up. Univariate analysis revealed that referral to a nephrologist (P = 0.001), treatment with medications used for stone disease (P = 0.008), and urate stones (P = 0.005) were associated with a complete investigation. Similarly, these were independently associated with a complete evaluation in regression analysis of 77 complete data sets, with odds ratios of 24.4 (nephrology referral), 4.9 (medication use), and 5.6 (urate stones). CONCLUSIONS: The results of this study demonstrate that a significant proportion of patients with recurrent nephrolithiasis do not undergo appropriate metabolic investigations. Efforts should be made to improve the evaluation of these patients.

Research directions: new clinical frontiers.

One of the greatest remaining challenges facing nephrology research is obtaining data with detail and precision for the three large, yet "forgotten," populations that span the spectrum of kidney disease: patients with chronic renal insufficiency (CRI), peritoneal dialysis patients, and kidney transplant patients. Studies of these populations, particularly the CRI group, are hampered by the relative mobility of these patients, the lack of stringent epidemiologic or clinical definitions, and the tendency to extrapolate data from hemodialysis populations into other clinical settings. This article suggests a two-pronged approach to a research agenda: first, by recognizing the need for better data regarding the natural history of these kidney failure subsets and their comorbidities; and second, by directing greater effort at identifying rational, efficacious, and cost-effective interventions to influence their natural history positively. Specific efforts are suggested in all three populations. For patients with CRI, studies should be directed at (1) identifying high-risk patients; (2) determining methods for making optimal referrals to the nephrologist; (3) identifying and managing CRI, its complications, and its comorbid conditions; and (4) establishing processes for the smooth transition to dialysis. The peritoneal dialysis population will benefit from studies addressing the treatment of anemia and its ability to modify cardiovascular illness and quality of life. Kidney transplant studies should also focus on the identification and management of comorbid conditions, as well as the effects of various interventions on quality of life. Rational evidence-based care of these conditions, which are critically important to patients, their families, and the health care system in general, must await the conduct of well-designed prospective observational and interventional trials.

Preservation of glomerular filtration rate on dialysis when adjusted for patient dropout.

BACKGROUND: Residual renal function (RRF) plays an important role in dialysis patients. Studies in patients on maintenance dialysis suggest that RRF is better preserved in patients receiving peritoneal dialysis (PD) vis-à-vis those receiving hemodialysis (HD). We speculated that regardless of the patient's type of therapy, the estimate obtained for the rate of decline in glomerular filtration rate (GFR) may be biased because of informative censoring associated with patient dropout. Informative censoring occurs when patients who die or transfer to another modality very early have associated with them a lower starting GFR or a higher rate of decline of GFR than patients who either complete the study or who die or transfer much later. If patient dropout is indeed related to the rate of decline in GFR and if this relationship is ignored in the analysis, then the estimate obtained of the rate of decline in GFR may be biased. METHODS: In an attempt to determine if there is a relationship between patient dropout and the decline in GFR, we reanalyzed the CANUSA data by modeling GFR as a nonlinear function of time with the rate of decline being exponential. RESULTS: This article highlights the significance of "informative censoring" when studying the decline of RRF on dialysis. The results show that for the CANUSA cohort, the mean initial GFR was significantly lower, and the rate of decline was significantly higher for patients who died or transferred to HD than for patients who were randomly censored or received a transplant. It is important to emphasize that the impact of informative censoring on previous analyses of the decline of RRF between PD versus HD is presently unclear. If bias caused by informative censoring is the same regardless of what therapy a patient is on, then conclusions from previous studies comparing the decline in GFR between PD and HD would still be valid. However, if the magnitude of the bias differs according to therapy, then additional adjustments would be needed to fairly compare the decline in GFR between PD and HD. Because this analysis is restricted to patients on PD, it would be scientifically incorrect to interpret previous studies solely on the basis of the results from this analysis. CONCLUSION: In any longitudinal study designed to estimate trends in an outcome measured over time, it is important that the analysis of the data takes into account any effect patient dropout may have on the estimated trend. This analysis demonstrates that among PD patients, both the starting GFR and the rate of decline in GFR are associated with patient dropout. Consequently, future studies aimed at estimating the rate of decline in GFR among PD patients should also account for any dependencies between dropout and GFR. Similarly, data analyzing for apparent differences in the rate of decline of GFR between PD and HD should also adjust for possible informative censoring.

Effects of two low-flux cellulose acetate dialysers on plasma lipids and lipoproteins--a cross-over trial.

BACKGROUND: Studies have shown a beneficial effect of high-flux dialysis on lipids, lipoproteins and lipoprotein lipase (Lpl) activity. This has been attributed to improved clearance of Lpl-inhibitory molecules of middle molecular weight, but differences in flux or biocompatibility have not been addressed. We conducted a blinded cross-over trial of two cellulose acetate dialysers (AN140, Althin Medical Inc. and CA210, Baxter Inc.) of similar flux (11 ml/h/mmHg transmembrane pressure) but with different clearances of larger molecules [AN140 sieving coefficient at mol. wt 11,000 Da (beta2-microglobulin) 0.6; CA210 sieving coefficient negligible]. METHODS: Sixteen patients were divided into two groups to receive dialysis with AN140 for 1 week followed by CA210 or vice versa. Before and after the third dialysis with each membrane, plasma lipid and lipoprotein concentrations were measured. Post-dialysis post-heparin lipase activity was measured in six patients. RESULTS: Fifteen patients completed the study. No difference between dialysers was found for apolipoprotein (apo) A1, B or total cholesterol measurements. The rise in triglyceride post-dialysis was attenuated by AN140 (rise 0.05 +/- 0.4 mmol/l vs CA210 0.44 +/- 0.54 mmol/l, P=0.03), while high density lipoprotein (HDL) cholesterol was increased by AN140 (rise 0.18 +/- 0.12 mmol/l vs CA210 0.06 +/- 0.14 mmol/l, P<0.02). ApoE rose with AN140 during dialysis but declined with CA210 (1.10 +/- 1.06 mg/dl and -0.77 +/- 0.63 mg/dl, P=0.002) as did apoCIII (HDL) (AN140 rise 1.33 +/- 2.06 mg/dl; CA210 fall -0.67 +/- 0.73 mg/dl, P=0.001). Lpl activity, measured in six patients, tended to be higher for AN140 (45.3 +/- 10.5 mmol FFA/ml plasma/h vs CA210 (37.2 +/- 7.9 mmol FFA/ml plasma/h) (P=0.16). CONCLUSIONS: We conclude that low-flux dialysis using a cellulose acetate membrane with good clearance of higher molecular weight molecules may be associated with beneficial changes in plasma lipids and lipoproteins.

Increased peritoneal membrane transport is associated with decreased patient and technique survival for continuous peritoneal dialysis patients. The Canada-USA (CANUSA) Peritoneal Dialysis Study Group.

The objective of this study was to evaluate the association of peritoneal membrane transport with technique and patient survival. In the Canada-USA prospective cohort study of adequacy of continuous ambulatory peritoneal dialysis (CAPD), a peritoneal equilibrium test (PET) was performed approximately 1 mo after initiation of dialysis; patients were defined as high (H), high average (HA), low average (LA), and low (L) transporters. The Cox proportional hazards method evaluated the association of technique and patient survival with independent variables (demographic and clinical variables, nutrition, adequacy, and transport status). Among 606 patients evaluated by PET, there were 41 L, 192 LA, 280 HA, and 93 H. The 2-yr technique survival probabilities were 94, 76, 72, and 68% for L, LA, HA, and H, respectively (P = 0.04). The 2-yr patient survival probabilities were 91, 80, 72, and 71% for L, LA, HA, and H, respectively (P = 0.11). The 2-yr probabilities of both patient and technique survival were 86, 61, 52, and 48% for L, LA, HA, and H, respectively (P = 0.006). The relative risk of either technique failure or death, compared to L, was 2.54 for LA, 3.39 for HA, and 4.00 for H. The mean drain volumes (liters) in the PET were 2.53, 2.45, 2.33, and 2.16 for L, LA, HA, and H, respectively (P < 0.001). After 1 mo CAPD treatment, the mean 24-h drain volumes (liters) were 9.38, 8.93, 8.59, and 8.22 for L, LA, HA, and H, respectively (P < 0.001); the mean 24-h peritoneal albumin losses (g) were 3.1, 3.9, 4.3, and 5.6 for L, LA, HA, and H, respectively (P < 0.001). The mean serum albumin values (g/L) were 37.8, 36.2, 33.8, and 32.8 for L, LA, HA, and H, respectively (P < 0.001). Among CAPD patients, higher peritoneal transport is associated with increased risk of either technique failure or death. The decreased drain volume, increased albumin loss, and decreased serum albumin concentration suggest volume overload and malnutrition as mechanisms. Use of nocturnal cycling peritoneal dialysis should be considered in H and HA transporters.

Strategies to improve clinical outcomes in peritoneal dialysis patients: delivered dose and membrane transport.

For patients with end-stage renal disease treated with peritoneal dialysis, prospective cohort studies using multivariate statistical analysis have shown an association between greater urea clearance and a decreased relative risk for death. The recommended weekly Kt/V for urea is 2.0, with the corresponding creatinine clearance (CrCl) of 60 L/1.73 m2. This is considered adequate dialysis but fails to define optimum urea and CrCl targets. The assumption that renal and peritoneal clearances are equivalent has been challenged by circumstantial data and is probably untenable. The relative importance of these clearances requires definition. The suggestion that CrCl is a more important indicator of adequacy of dialysis is confounded by association with renal, rather than peritoneal, clearance and perhaps by the early referral and initiation of dialysis. Recent reports have shown an association between increased peritoneal membrane transport and an increased relative risk for technique failure and/or death. Patients with higher peritoneal transport should have greater clearance of urea and creatinine and better clinical outcomes. Possible explanations for this apparent contradiction include the adverse effects of increased glucose absorption, malnutrition, and fluid overload, the latter caused by decreased ultrafiltration. Available data suggest an important role for the failure of ultrafiltration among patients treated with continuous ambulatory peritoneal dialysis (CAPD). Strategies to improve the clearance of urea and creatinine include the preservation of residual renal function and increased peritoneal clearance. Loss of residual renal function may be delayed by the avoidance of nephrotoxic drugs and angiographic dye. Peritoneal clearance can be enhanced by a combination of increased volume and frequency of peritoneal dialysis cycles. Ultrafiltration failure, but not protein loss, can be addressed with shorter cycles with nocturnal peritoneal dialysis. Development of an alternative to glucose as an osmotic agent is an important strategy.

An evidence-based approach to earlier initiation of dialysis.

The objective was to review evidence addressing the optimal time to initiate dialysis treatment. The database was derived from an evidence-based review of the medical literature and from the Canada-United States peritoneal dialysis study. The publications were divided into (1) those addressing the clinical impact of early versus late referral to a dialysis program; (2) those evaluating the association between residual renal function at initiation of dialysis and the concurrent nutritional status; (3) those evaluating the association between residual renal function at initiation of dialysis and subsequent clinical outcomes, including patient survival. There were five studies evaluating early versus late referral, three cohort design and two case-control design. Late referrals had worse outcomes than early referrals. The former had more serious comorbidity and many had been noncompliant with follow-up. The latter were more likely to have hereditary renal disease. Renal function was slightly worse at initiation among those referred late. Three studies addressed the association between renal function at initiation of dialysis and concurrent nutritional status. Two showed decreased protein intake with diminished glomerular filtration rate (GFR). Poor nutritional status is associated with decreased patient survival among both incident and prevalent dialysis patients. The third study reported excellent patient survival among patients with late initiation of dialysis. These patients had received a supplemented low-protein diet and were not malnourished at initiation of dialysis. Three groups have studied the association between GFR at initiation of dialysis and clinical outcomes. Decreased GFR at initiation of dialysis is associated with a increased probability of hospitalization and death. None of these studies has used the rigorous randomized clinical trial design, and they are therefore subject to bias. Referral time bias, comorbidity, patient compliance, and starting time bias are potential confounders. A randomized clinical trial is required to resolve this important issue. However, there is sufficient evidence to justify initiation of dialysis at a Ccr of 9 to 14 mL/min if there is any clinical or laboratory evidence of malnutrition.