Charles R. Nolan

Eosinophiluria - A new method of detection and definition of the clinical spectrum

Eosinophiluria is considered a useful marker of drug-induced acute interstitial nephritis. However, recognition of eosinophiluria by Wrights staining is technically difficult, and the spectrum of disorders causing eosinophiluria is not completely defined. We have adapted Hansels stain for the examination of urinary sediment. Whereas there was a variable uptake of Wrights stain by eosinophils in the urine, such eosinophils were readily recognized with Hansels stain by the presence of bright red granules. The prevalence of eosinophiluria in acute interstitial nephritis was 10 of 11 patients, in acute tubular necrosis none of 30, in acute pyelonephritis none of 10, in acute cystitis 1 of 15, in postinfectious glomerulonephritis 1 of 6, in rapidly progressive glomerulonephritis 4 of 10, and in acute prostatitis 6 of 10. Eosinophiluria in acute interstitial nephritis was demonstrated by Hansels stain in 10 of 11 patients but by Wrights stain in only 2 of 11 patients. We conclude that Hansels stain substantially improves the recognition of eosinophiluria as compared with Wrights stain. Eosinophiluria is useful in distinguishing acute interstitial nephritis from acute tubular necrosis. The clinical spectrum of eosinophiluria also includes rapidly progressive glomerulonephritis, acute prostatitis, and occasionally, acute cystitis or postinfectious glomerulonephritis.

Calcium Acetate Control of Serum Phosphorus in Hemodialysis Patients

Calcium acetate has many characteristics of an ideal phosphorus binder. It is a readily soluble salt that avidly binds phosphorus in vitro at pH 5 and above. One-dose/one-meal balance studies show it to be more potent than calcium carbonate or calcium citrate. We studied chronic (3-month) phosphorus binding with calcium acetate in 91 hyperphosphatemic dialysis patients at four different centers. All phosphorus binders were stopped for 2 weeks. Calcium acetate at an initial dose of 8.11 mmol (325 mg Ca2+) per meal was then used as the only phosphorus binder. Dose was adjusted to attempt control of predialysis phosphorus level less than 1.78 mmol/L (5.5 mg/100 mL). Final calcium acetate dose was 14.6 mmol (586 mg) Ca2+ per meal. Sixteen patients developed mild transient hypercalcemia (mean, 2.84 mmol/L [11.4 mg/dL]. Initial phosphorus values in mmol/L (mg/dL) were 2.39 (7.4); at 1 month, 1.91 (5.9); and at 3 months, 1.68 (5.2). Initial calcium values in mmol/L (mg/dL) were 2.22 (8.9); at 1 month, 2.37 (9.5); and at 3 months, 2.42 (9.7). Initial aluminum values in mumol/L (micrograms/L) were 2.99 (80.7); and at 3 months were 2.54 (68.4). Initial C-terminal parathyroid hormone (C-PTH) values in ng/mL were 14.6; at 1 month, 11.9; and at 3 months, 13.2. Sixty-nine patients then entered a double-blind study. Phosphorus binders were stopped for 1 week. Calcium acetate (at a dose established in a prior study) or placebo was then administered for 2 weeks. Next, patients were crossed to the opposite regimen for 2 weeks. Initial phosphorus was 2.36 mmol/L (7.3 mg/100 mL) and calcium 2.22 mmol/L (8.9 mg/100 mL).(ABSTRACT TRUNCATED AT 250 WORDS)

Strategies for Improving Long-Term Survival in Patients with ESRD

In 2003, more than 320,000 people in the United States were receiving dialysis for ESRD, with predicted increases to 650,000 by 2010 and 2 million by 2030. Mortality from cardiovascular disease (CVD) in patients with ESRD is 10 to 30 times higher than in the general population. The exact mechanism of accelerated CVD in patients with kidney disease is unknown. Treatment costs for ESRD are in excess of

Calcium salts in the treatment of hyperphosphatemia in hemodialysis patients.

14 billion annually (6.4% of Medicare budget). Strategies to improve long-term outcomes include aggressive risk factor modification, minimization of dialysis complications, and kidney transplantation. Because abnormalities of mineral metabolism contribute to mortality risk, phosphate binder therapy is fundamental. More expensive non-calcium-containing phosphate binders such as sevelamer have been recommended to reduce cardiovascular calcification. However, the lack of outcome data and the

Role of the eosinophil in chronic vascular rejection of renal allografts

2 to

How should hyperphosphatemia be managed in dialysis patients

3 billion annual cost make it difficult to justify widespread utilization of newer binders as first-line therapy. Conversely, kidney transplantation is known to improve survival in ESRD. Progression of atherosclerosis and CVD in patients with renal failure is largely due to loss of renal function per se, and provision of a functioning kidney through renal transplantation halts the progression of CVD and dramatically reduces mortality. Despite this fact, many patients lose Medicare funding for immunosuppressive therapy 3 yr posttransplantation. To achieve the goal of prevention of cardiovascular mortality in patients with ESRD, it clearly would be more prudent, efficacious, and cost-effective to use Medicare prescription drug dollars to provide full coverage for life-long immunosuppressive drug therapy after renal transplantation.

Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-Blind, Randomized Trial

Purpose of reviewHyperphosphatemia in patients with end-stage renal disease leads to secondary hyperparathyroidism and renal osteodystrophy, and is independently associated with mortality risk. How hyperphosphatemia increases mortality risk is unknown but it may promote cardiovascular calcification. It is recommended that dialysis patients be treated to maintain normal serum phosphorus. Although calcium-based phosphate binders are cost-effective, their long-term safety has been questioned because of their postulated role in progression of cardiovascular calcification. In this regard, sevelamer hydrochloride has been recommended as an alternative phosphate binder. In this review, we will examine these issues and provide rational guidelines for the use of calcium-based phosphate binders. Recent findingsResults from the calcium acetate Renagel evaluation study indicate that calcium acetate is more effective than sevelamer in controlling serum phosphorus and calcium x phosphorus product in hemodialysis patients. However, in the Treat-to-Goal study dialysis patients treated with sevelamer had less progression of coronary and aortic calcification than patients treated with calcium-containing binders. The mechanism underlying the slower rate of progression of cardiovascular calcification in sevelamer-treated patients remains uncertain but may relate to decreased calcium loading or to dramatic reductions in LDL cholesterol. SummaryAt present, evidence incriminating calcium-containing phosphate binders in the progression of cardiovascular calcification in end-stage renal disease remains largely circumstantial. As calcium acetate is more efficacious and cost-effective than sevelamer, it remains an accepted first-line drug. Treatment with sevelamer hydrochloride should be considered for patients with persistent hypercalcemia during calcium-based binder therapy despite appropriate adjustment of vitamin D therapy.

Lack of mortality benefit with sevelamer

Obiliterative arteriopathy in chronic renal allograft rejection is caused by intimal smooth muscle proliferation accompanied by infiltration of lymphocytes, monocytes, and eosinophils. We investigated the role of the eosinophil in chronic rejection. Twenty-four allograft nephrectomies were examined for the presence of eosinophils on hematoxylin-eosin-stained sections and using epifluorescence on Fisher-Giemsa-stained sections. Among 15 cases with chronic rejection, eosinophils were detected in 14 cases (93%) with epifluorescence compared with only six cases (40%) with hematoxylin-eosin staining (P = 0.005). With epifluorescence, eosinophils were identified in the intimal, adventitial, and tubulointerstitial compartments in 73%, 80%, and 87% of cases, respectively. To examine the pathogenic relevance of the eosinophils in the vessel wall, we investigated the effect of eosinophil-conditioned medium on DNA synthesis in cultured vascular smooth muscle cells. Autofluorescent eosinophils were isolated from atopic human donors using a fluorescence-activated cell sorter. Supernatant was collected from eosinophils (1 x 10(6)/mL) cultured overnight in medium with 0.5% fetal bovine serum. Incorporation of 3H-thymidine into DNA was measured in rat and human vascular smooth muscle cells treated for 24 hours with eosinophil-conditioned medium at 1:20, 1:10, 1:5, and 1:2 dilutions. Eosinophil-conditioned medium had a significant dose-dependent stimulatory effect on DNA synthesis in both cell lines. Our results indicate that eosinophil involvement in chronic renal allograft rejection is more common than previously recognized. The stimulatory effect of eosinophil-conditioned medium on vascular smooth muscle cell DNA synthesis suggests that eosinophils may be involved in the pathogenesis of the obliterative arteriopathy characteristically seen in chronic vascular rejection of renal allografts.

Treatment of hyperphosphatemia in hemodialysis patients : The Calcium Acetate Renagel Evaluation (CARE Study)

The level to which serum phosphorus (P) is controlled has not improved substantially despite the widespread availability of effective and low-priced phosphate binders. This is due in part to the ubiquitous presence of phosphorous in the diet of dialysis patients. Equally important seems to be a lack of physician appreciation for the significant adverse effects posed to our patients by hyperphosphatemia. It is now clear, however, that elevated serum phosphorus levels are associated with an increased mortality rate. Abnormalities in mineral metabolism are increasingly recognized as cardiovascular risk factors unique to patients with chronic kidney disease (CKD) and awareness of this fact must form the basis for management decisions regarding hyperphosphatemia. Although the precise mechanisms underlying the relationship between serum P and mortality remain under investigation, a growingbodyof evidence supports an association between serum P and the development and progression of vascular calcification. Giachelli et al. (1) showed that human vascular smooth muscle cells alter their phenotype in the presence of modest increases in phosphorus and begin to express bone-related proteins, ultimately resulting in calcium-phosphate deposition. This phosphorus-related in vitro phenomenon has also been reported in the MGP null mouse model of vascular calcification and recently in a study examining the inferior epigastric arteries of dialysis patients at the time of renal transplant (2). The development of vascular calcification, whether intimal (in association with atherosclerotic plaque) or medial, clearly exerts negative effects on cardiovascular structure and function. London et al. (3) showed that the presence of calcified vessels increases arterial wall stiffness and left ventricular mass. Increased aortic stiffness as measured by aortic pulse wave velocity is a potent predictorofmortality inbothdialysis patients and the general population (4). In a recent very large retrospective cohort analysis, Klassen et al. (5) reported that each 10mmHg increase in pulse pressure, an indirect measureof arterial stiffness, increases thehazard ratio for 1-year mortality by 12%. Moreover, Blacher et al. (6) reported that the presence and extent of calcified vessels as assessed by ultrasound is an independent predictor of mortality in dialysis patients. What should we set as the target phosphorus? In a recent analysis of 40,000 hemodialysis patients, Chertow et al. (7) reported a significant increase inmortality when serum P rose above 5 mg/dl. This finding, together with data showing that better control of serum phosphorus is associated with long-term survival on hemodialysis (8), supports the recommendation that serum P be maintained in the normal range. This new goal has tremendous implications when discussing the risks and benefits of the current treatment paradigm for hyperphosphatemia.

Forty-five year follow-up after uninephrectomy

BACKGROUND 1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation. STUDY DESIGN Final 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double-dummy, multicenter, phase 3 trial. SETTING & PARTICIPANTS 543 de novo kidney recipients randomly assigned to LCPT (n=268) or IR-Tac (n=275); 507 (93.4%) completed the 24-month study. INTERVENTION LCPT tablets once daily at 0.17 mg/kg/d or IR-Tac twice daily at 0.1 mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11 ng/mL; thereafter, 4-11 ng/mL). The intervention was 24 months; the study was double blinded for the entirety. OUTCOMES & MEASUREMENTS Treatment failure (death, transplant failure, biopsy-proven acute rejection, or loss to follow up) within 24 months. Safety end points included adverse events, serious adverse events, new-onset diabetes, kidney function, opportunistic infections, and malignancies. Pharmacokinetic measures included total daily dose (TDD) of study drugs and tacrolimus trough levels. RESULTS 24-month treatment failure was LCPT, 23.1%; IR-Tac, 27.3% (treatment difference, -4.14% [95% CI, -11.38% to +3.17%], well below the +10% noninferiority criterion defined for the primary 12-month end point). Subgroup analyses showed fewer treatment failures for LCPT versus IR-Tac among black, older, and female recipients. Safety was similar between groups. From month 1, TDD was lower for LCPT; the difference increased over time. At month 24, mean TDD for LCPT was 24% lower than for the IR-Tac group (P<0.001), but troughs were similar (means at 24 months: LCPT, 5.47 ± 0.17 ng/mL; IR-Tac, 5.8 ± 0.30 ng/mL; P=0.4). LIMITATIONS Trial participant eligibility criteria may limit the generalizability of results to the global population of de novo kidney transplant recipients. CONCLUSIONS Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of IR-Tac. Lower TDD reflects LCPTs improved bioavailability and absorption.