The use of drug-eluting stents in the management of transplant renal artery stenosis.

Transplant renal artery stenosis (TRAS) is a common occurrence following kidney transplantation with an incidence rate ranging from 6% to 23%. A single-center retrospective study was conducted to examine the use of drug-eluting stents (DES) in eligible patients with hemodynamically significant TRAS. Between March 2008 and January 2011, 12 patients were diagnosed with TRAS with reference vessel diameter measuring <5 mm and underwent endovascular intervention (EVI) with DES placement. TRAS was detected within the first year posttransplantation in a majority of these patients (83%) and manifested as hypertension (100%), allograft dysfunction (100%) and edema (58%). Procedural success rate was 100%. Patients were followed for a mean period of 16 ± 10 months. Blood pressure improved from a mean of 156/82 to 138/73 mmHg at the end of the follow-up period. In 11/12 patients, serum creatinine improved from 3.1 ± 1.3 mg/dL to 2.3 ± 0.5 mg/dL at the end of the follow-up period. TRAS of early onset is readily amenable to EVI with stent placement resulting in improvement in blood pressure control and allograft function.

Uterine leiomyoma causing urinary obstruction of the transplanted kidney.

Obstruction of the ureter as a cause of acute or chronic kidney injury in the transplanted kidney is unusual beyond the perioperative period. We present a case of ureteric obstruction, infection and septicemia caused by a large uterine leiomyoma in a patient 8 years post transplantation. Initial treatment comprised of intravenous fluid and antibiotics followed by urgent drainage of the collecting system. Subsequent hysterectomy resolved the obstruction with resolution of renal failure. In young female kidney transplant recipients, gynecologic causes, although rare, need to be considered as possible etiologies of urinary obstruction and renal dysfunction.

Alpha 2 adrenergic agonists stimulate Na+-H+ antiport activity in the rabbit renal proximal tubule.

The role of adrenergic agents in augmenting proximal tubular salt and water flux, was studied in a preparation of freshly isolated rabbit renal proximal tubular cells in suspension. Norepinephrine (NE, 10(-5) M) increased sodium influx (JNa) 60 +/- 5% above control value. The alpha adrenergic antagonist, phentolamine (10(-5) M), inhibited the NE-induced enhanced JNa by 90 +/- 2%, while the beta adrenergic antagonist, propranolol, had a minimal inhibitory effect (10 +/- 2%). The alpha adrenergic subtype was further defined. Yohimbine (10(-5) M), an alpha2 adrenergic antagonist but not prazosin (10(-5) M), an alpha1 adrenergic antagonist completely blocked the NE induced increase in JNa. Clonidine, a partial alpha2 adrenergic agonist, increased JNa by 58 +/- 2% comparable to that observed with NE (10(-5) M). Yohimbine, but not prazosin, inhibited the clonidine-induced increase in JNa, confirming that alpha2 adrenergic receptors were involved. Additional alpha2 adrenergic agents, notably p-amino clonidine and alpha-methyl-norepinephrine, imparted a similar increase in JNa. The clonidine-induced increase in JNa could be completely blocked by the amiloride analogue, ethylisopropyl amiloride (EIPA, 10(-5) M). The transport pathway blocked by EIPA was partially inhibited by Li and cis H+, but stimulated by trans H+, consistent with Na+-H+ antiport. Radioligand binding studies using [3H]prazosin (alpha1 adrenergic antagonist) and [3H]rauwolscine (alpha2 adrenergic antagonist) were performed to complement the flux studies. Binding of [3H]prazosin to the cells was negligible. In contrast, [3H]rauwolscine showed saturable binding to a single class of sites, with Bmax 1678 +/- 143 binding sites/cell and KD 5.4 +/- 1.4 nM. In summary, in the isolated rabbit renal proximal tubular cell preparation, alpha2 adrenergic receptors are the predominant expression of alpha adreno-receptors, and in the absence of organic Na+-cotransported solutes, alpha2 adrenergic agonists enhance 22Na influx into the cell by stimulating the brush border membrane Na+-H+ exchange pathway.

Epstein-Barr virus infection of renal proximal tubule cells: possible role in chronic interstitial nephritis.

Chronic interstitial nephritis frequently accompanies renal diseases of different etiologies. Far less common is the entity of primary interstitial nephritis wherein the glomerular and vascular structures of the kidney are not the primary focus of the disease process. Using in situ hybridization and the polymerase chain reaction, we detected DNA from the Epstein-Barr Virus (EBV) exclusively in renal tissue of patients with the idiopathic variety of chronic interstitial nephritis. The EBV genome, but not that of cytomegalovirus or adenovirus, was detected primarily in renal proximal tubule cells. Furthermore, the CD21 antigen, which serves as the receptor for EBV in B lymphocytes, was detected by immunocytochemistry primarily on proximal tubule cells and was markedly upregulated in the EBV-infected tissue. Western blot analysis of primary cultures of normal proximal tubule cells identified a 140-kDa protein, confirming the expression of the CD21 antigen. Colocalization experiments using proximal and distal tubule markers confirmed that EBV DNA and the CD21 antigen are found primarily in proximal tubule cells. EBV infection of renal proximal tubular cells may participate in evoking a cellular immune response that results in a damaged renal interstitium.

Osmolar regulation of endothelin signaling in rat renal medullary interstitial cells.

We tested the hypothesis that endothelin (ET) responsiveness in the renal medulla is modulated by ambient osmolarity. Cultured renal medullary interstitial cells (RMICs) were incubated from 3 to 24 h in isosmolar culture medium (300 mOsm/kg H2O) or media rendered hyperosmolar (600 mOsm/kg H2O) by the addition of urea. Under hyperosmolar conditions, the peak of ET-evoked Ca2+ transient was blunted by 45-58% (P < 0.02) and PGE2 accumulation decreased from 16- to 2-fold above basal values (P < 0.001). To explore whether hyperosmolar conditions blunt intracellular signaling via modulation of receptor number or expression, kinetics of ET binding and Northern blot analysis of ETA receptor mRNA was performed. Under hyperosmolar conditions, ETA receptor density was reduced by 84% versus isosmolar conditions (238 +/- 12 vs. 1450 +/- 184 fmol/mg) (P < 0.01). In contrast to the ligand binding studies, ETA receptor mRNA was increased by 58% (P < 0.05) in cells grown under hyperosmolar versus isosmolar media. These observations indicate that in the hyperosmolar setting, ET-evoked intracellular signaling is blunted in RMICs due to ET receptor downregulation. Since ETA receptor mRNA is increased under hyperosmolar conditions, we conclude that ET receptor downregulation is the consequence of either decreased translation of message, increased degradation of receptor peptide, or increased internalization of specific receptor sites.

Sirolimus-associated diffuse alveolar hemorrhage in a renal transplant recipient on long-term anticoagulation.

Sirolimus (rapamycin, rapamune) is an effective immunosuppressant that has been widely used in solid organ transplantation. Recently, two disconcerting side effects, namely pulmonary toxicity, usually in the form of interstitial pneumonitis, and the onset of nephrotic range proteinuria, have been recognized. We report the case of a renal transplant recipient who had been on chronic anticoagulation therapy for a mechanical aortic valve, and who developed pulmonary distress necessitating emergent intubation 18 days after starting sirolimus therapy. Open lung biopsy showed diffuse alveolar hemorrhage with fibrin deposits in the alveolar spaces and small bronchi. Urine protein/creatinine ratio at that time was 16.7. Upon discontinuation of sirolimus, alveolar hemorrhage and nephrotic range proteinuria resolved. We suggest that extra vigilance be paid in individuals who are on chronic anticoagulation and who are started on sirolimus.

Methodological and statistical issues of quality of life (QoL) and economic evaluation in cancer clinical trials: report of a workshop.

In recent years, quality of life (QoL) and economic evaluations have become increasingly important as additional outcome measures in cancer clinical trials. However, both fields of research are relatively new and in need of finding solutions to a substantial number of specific methodological problems. This paper reports on the proceedings of a symposium aimed at summarising and discussing some of the most contentious methodological and statistical issues in QoL and economic evaluations. In addition, possible solutions are indicated and the most pertinent areas of research are identified. Issues specific to QoL evaluations that are addressed include clinically meaningful changes in QoL scores; how to analyse QoL data and to handle missing and censored data and integration of length of life and QoL outcomes. Issues specific to economic evaluations are the advantages and disadvantages of various outcome measures; statistical methods to analyse economic data and choice of decision criteria and analytical perspective. How to perform QoL and economic evaluations in large and simple trials and whether the gap between QoL and utility measures can be bridged are also discussed.

Pauci-immune rapidly progressive glomerulonephritis after nephrectomy in a renal donor.

Idiopathic rapidly progressive glomerulonephritis (RPGN) is a clinicopathologic syndrome in which glomerular damage is accompanied by a rapid and progressive decline in renal function, usually resulting in irreversible renal failure in weeks or months. We report the occurrence of pauci-immune RPGN, more specifically microscopic polyarteritis nodosa (PAN), in a 60-year-old woman 15 months after donor nephrectomy, and 3 months after documentation of intact, residual renal function. The transplanted kidney continues to function well in the recipient, 6 years posttransplantation, and 4.5 years beyond destruction of the donor's contralateral kidney by RPGN. The donor underwent cadaveric renal transplantation after 2 years on dialysis, and at the 3-year mark has intact renal function. These intriguing observations strongly argue that host environmental factors, rather than intrarenal factors, play a major causative role in the pathogenesis of RPGN.

Combined medical surgical therapy for pulmonary mucormycosis in a diabetic renal allograft recipient.

Mucormycosis is a rare opportunistic infection that complicates chronic debilitating diseases and immunosuppressed solid-organ transplant recipients. We present a case of life-threatening pulmonary mucormycosis in a diabetic renal allograft recipient who survived with reasonable renal function. Early recognition of this entity and prompt use of bronchoalveolar lavage (BAL) are critical to the outcome. Antifungal therapy combined with early surgical excision of infected, necrotic tissue appears to be the preferred course of action. Judicious withholding of immunosuppressants until fungemia cleared did not jeopardize allograft function.

Does admission to a medical department improve patient life expectancy?

Doubts about the effectiveness of medical care in improving patient health have been raised by epidemiological studies and by studies of geographical variation and inappropriate use of health care. To investigate this problem, the life expectancy gain (LEG) from consecutive admissions to a department of internal medicine during a six-week period was assessed by two expert panels, each consisting of an internist, a surgeon, and a general practitioner. The mean LEG for all admissions was 2.25 years (n = 422). Sixty-one percent had a LEG of 0.10 years or less, while 5% had a LEG of more than 9.98 years. In a probabilistic sensitivity analysis, the mean LEG remained greater than zero under assumptions of overestimated positive LEG and underestimated negative LEG. We conclude that the life expectancy of the majority of the patients was not influenced by the admission, but that a minority had substantial gains, resulting in a high overall mean LEG.

Human T-cell lymphotropic virus testing of blood donors in Norway: a cost-effect model.

BACKGROUND: Human T-cell lymphotropic virus type I and II (HTLV-I and II) are human retroviruses that can be transmitted by transfusion of whole blood. An HTLV-I infection is associated with adult T-cell leukaemia (ATL) and with tropical spastic paraparesis (TSP). Antibody tests from 5.5 million European blood donors have shown that the HTLV prevalence is low, ranging from 0 to 0.02%. This paper examines costs and effects associated with the intervention of testing all new blood donors for HTLV. METHODS: A mathematical model was used to calculate the number of cases prevented by the intervention. For a given prevalence of HTLV in the blood donor population, the model calculates the number of recipients infected by transfusion, and the number of partners and offspring that will in turn be infected. The model then calculates the number of subjects with disease due to HTLV-I infection and the number of deaths from disease. From these numbers the measures of cost and effect are calculated. RESULTS: Testing all new blood donors for HTLV is calculated to cost US$ 9.2 million per life saved, or US$ 420,000 per quality adjusted life year gained by the intervention, when the HTLV prevalence among donors is 1 per 100,000. When the prevalence among donors is 10 per 100,000 the intervention will cost US$ 0.9 million per life saved, or US$ 41,000 per quality adjusted life year gained. The same analysis shows that testing blood donors for human immunodeficiency virus (HIV) saves money when the HIV prevalence among donors is above 0.7 per 100,000. CONCLUSION: For Norway, studies suggest a willingness to pay to save a statistical life of approximately US$ 1.2 million. The costs fall under this value when the number of infected persons is > or = 8 per 100,000 donors. The results are uncertain because of the uncertainty in HTLV infection and disease parameters.

Progesterone-evoked increases in sperm [Ca2+]i correlate with the egg penetrating ability of sperm from fertile but not infertile men.

OBJECTIVES: To investigate the relationship between sperm capacitation and intracellular calcium ([Ca2+]i) and to correlate these findings with routine semen parameters and sperm fertilizing ability. DESIGN: Baseline and P-evoked increases in [Ca2+]i of fresh versus capacitated human sperm were measured for known fertile donors and infertile men and compared with the results of semen analysis and in vitro penetration of zona-free hamster eggs. SETTING: Andrology laboratory in a university hospital. PATIENTS: Infertile men undergoing semen analysis. INTERVENTIONS: Capacitation of spermatozoa and exposure of sperm to P (1 microgram/mL). MAIN OUTCOME MEASURES: [Ca2+]i as measured using fura-2, percent zone-free hamster eggs penetrated, and number of penetrating sperm per egg. RESULTS: Steady state [Ca2+]i increased from 74 +/- 32 nM to 166 +/- 97 nM after capacitation, as did P-evoked peak and plateau [Ca2+]i. Deletion of calcium from the assay buffer with ethylene-bis (oxy-ethylenenitriolo) tetraacetic acid abrogated the P-evoked increments. RU486, a P receptor antagonist; reduced the P-evoked response in a dose-dependent manner. Progesterone-evoked calcium responses of sperm varied between different ejaculates of the same fertile donor and correlated with their egg penetrating ability. Sperm from infertile men with abnormal morphology exhibited lower egg penetrating ability and lower mean peak P-evoked [Ca2+]i than morphologically normal sperm. However, free intracellular calcium parameters correlated only weakly with penetrating ability for individual infertile men. CONCLUSION: Progesterone-evoked increases in [Ca2+]i in motile capacitated spermatozoa cannot be used to discriminate between dysfunctional spermatozoa and those capable of penetrating eggs.

Insulin lispro therapy in pregnancies complicated by type 1 diabetes mellitus.

OBJECTIVE: To compare the efficacy and safety of preprandial administration of rapid-acting lispro analogue with regular short-acting insulin to pregnant women with type 1 diabetes. STUDY DESIGN: Open randomised multicentre study. Women were treated with multiple insulin injections aiming at normoglycaemia. Blood glucose was determined six times daily, HbA(1c) every 4 weeks. Diurnal profiles of blood glucose were analysed at gestational week 14 and during the study period at weeks 21, 28 and 34. PARTICIPANTS: 33 pregnant women with type 1 DM were randomised to treatment with lispro insulin (n=16) or regular insulin (n=17). RESULTS: Blood glucose was significantly lower (P<0.01) after breakfast in the lispro group, while there were no significant group differences in glycemic control during the rest of the day. Severe hypoglycaemia occurred in two patients in the regular group but biochemical hypoglycaemia (blood glucose <3.0 mmol/l) was more frequent in the lispro than in the regular group (5.5 vs. 3.9%, respectively). HbA(1c) values at inclusion were 6.5 and 6.6% in the lispro and regular group respectively. HbA(1c) values declined during the study period and were similar in both groups. There was no perinatal mortality. Complications during pregnancy, route of delivery and foetal outcome did not differ between the groups. Retinopathy progressed in both groups, one patient in the regular group developed proliferative retinopathy. CONCLUSION: The results suggest that it is possible to achieve at least as adequate glycemic control with lispro as with regular insulin therapy in type 1 diabetic pregnancies.

Therapeutic options in the treatment of multiple myeloma: pharmacoeconomic and quality-of-life considerations.

A review of current treatment options in multiple myeloma is presented, including data on health-related quality of life and pharmacoeconomics. For induction chemotherapy, no combination of cytostatic drugs has been shown to be consistently superior to the simple cyclic oral treatment with melphalan and prednisone that has been available for 30 years. The total resource consumption and direct costs per patient treated with melphalan and prednisone is approximately $US10,000 (1995 values). As median survival is prolonged from less than a year in untreated patients to 30 to 36 months, this treatment must be considered cost effective. Interferon-alpha has a modest effect on progression-free and overall survival when added to chemotherapy regimens. However, the high cost and toxicity of this drug results in an unfavourable cost-utility ratio, estimated to be between $US50,000 to $US100,000 per quality-adjusted life-year gained. Clinical trials suggest that high dose chemotherapy followed by autologous stem cell support administered to patients who have achieved disease stabilisation or objective response to conventional induction chemotherapy, prolongs median survival by about 1.5 years. Preliminary cost-utility analyses suggest a cost per life-year gained of $US30,000 to $US40,000. Further potential improvements of this therapeutic modality are under way. Several bisphosphonates have been tested for the ability to prevent the skeletal complications of multiple myeloma. Monthly infusions of pamidronate have been shown in 1 randomised trial to significantly reduce the rate of skeletal complications. Unfortunately, the rapid and widespread acceptance of this therapy seems to preclude further prospective, placebo-controlled trials with cost-utility evaluation.

Cost-utility analysis of melphalan plus prednisone with or without interferon-alpha 2b in newly diagnosed multiple myeloma. Results from a randomised controlled trial.

This study evaluated the cost utility of adding interferon-alpha 2b to conventional treatment in patients with multiple myeloma. It also provides a methodology for transforming complex quality-of-life profiles into a single index value on the conventional 0 to 1 quality-adjusted life-year scale (QALY). From 1990 to 1992, 583 patients with newly diagnosed, symptomatic multiple myeloma were enrolled in a randomised, multicentre, phase III study to evaluate the addition of interferon-alpha 2b to treatment with melphalan and prednisone. Addition of interferon-alpha 2b yielded a 12% increase in median survival time, at the expense of a slight reduction in quality of life during the first year of treatment. The gain in survival time was not large enough to reach statistical significance. Patients receiving interferon-alpha 2b also had a 5- to 6-month prolongation of the plateau phase. Cost per QALY gained by adding interferon-alpha 2b was conservatively estimated at $US110,000. Potentially better cost effectiveness may be found in different treatment regimens or in certain patient subgroups.

Methods for quality adjustment of life years.

Several valuation techniques are in use for quality adjusting life years in cost utility analysis. The paper gives an overview of the variability in results. A close inspection of a number of instruments with respect to their theme, instructions, decision framing and the phrasing of questions make many of the observed differences in results understandable. When judging the validity of the different techniques, three points should be kept in mind. One is that statements about validity should be made with respect to concrete versions rather than broad categories like 'the rating scale', 'time trade-off' etc. Another point is that a valuation technique that is valid in clinical decision analysis may not be valid in health program evaluation, and vice versa. The third point is that quality weights for life years are empirically more meaningful, in the sense that they are more amenable to empirical testing, if they are interpreted simply as preference weights rather than measures of amounts of well life in the utilitarian tradition. Time trade-off with a moderate time horizon is recommended in clinical decision analysis, while a combination of time trade-off and a variant of person trade-off is recommended in health program evaluation.

Maximizing health benefits vs egalitarianism: an Australian survey of health issues.

Economists have often treated the objective of health services as being the maximization of the QALYs gained, irrespective of how the gains are distributed. In a cross section of Australians such a policy of distributive neutrality received: (a) very little support when health benefits to young people compete with health benefits to the elderly; (b) only moderate support when those who can become a little better compete with those who can become much better; (c) only moderate support when smokers compete with non smokers; (d) some support when young children compete with newborns; and (e) wide spread support when parents of dependent children compete with people without children. Overall, the views of the study population were strongly egalitarian. A policy of health benefit maximization received very limited support when the consequence is a loss of equity and access to services for the elderly and for people with a limited potential for improving their health.

Reducing sick leave costs by shortening waiting periods for elective surgery.

Some sick leave of patients waiting for elective surgery could be avoided if these patients were treated with less delay. One way of achieving this is to give priority to patients on sick leave. Problems of fairness that such a policy would raise might be solved by assuring that part of the production gains stemming from avoided sick leave were used to increase treatment capacity to benefit all patients, including those not on sick leave. Another way to reduce sick leave due to waiting time is to increase supply temporarily and reduce treatment backlog without changing priorities among patient groups. If treatment thresholds are unaffected, such a temporary increase in supply will relieve all later patients of some of their waiting and render a production gain that may exceed marginal costs. If treatment thresholds are lowered as a result of waiting time's being reduced, there will still be production gains in patients benefiting by the temporary increase in supply, but in this situation the gains may cover only part of marginal costs.

The person-trade-off approach to valuing health care programs.

The person-trade-off technique is a way of estimating the social values of different health care interventions. Basically it consists in asking people how many outcomes of one kind they consider equivalent in social value to X outcomes of another kind. The paper outlines a number of the author's previous studies using the technique. The studies suggest that while the technique is theoretically appealing for resource-allocation purposes, it is in practice quite demanding. It needs to be applied in fairly large groups of subjects to keep random measurement error at an acceptable level. Possible framing effects include the effects of argument presentation and the choice of start points in numerical exercises. To control for these effects, it seems important to take subjects through a multistep procedure, in which they are induced to carefully consider the various arguments that might be relevant in each exercise and to reconsider initial responses in the light of their implications. The investigator must also think through which decision context he or she wishes to study and make his or her choice of context very clear when reporting the results. In spite of these problems, the person-trade-off technique deserves greater attention in the field of cost-utility analysis.