Developing a tool for noninvasive monitoring of renal allografts

Renal transplantation has emerged as the therapy of choice for many patients with end-stage renal disease. One of the major goals is to tailor immunosuppressive therapy to the individual needs of every patient at every time point post transplant, balancing the risk for rejection and over-immunosuppression. Such individualized treatment will require assays that can detect harmful processes in the allograft early and that can be measured repeatedly. In this review, advantages and disadvantages of current assays to monitor renal allografts noninvasively and how proteomic technology might contribute to the development of novel biomarkers to improve patient management will be discussed.     

Principles of Drug Therapy in Patients with Renal Disease

Patients with reduced renal function commonly require drug therapy for various associated conditions. Most drugs are fully or partially excreted by the kidney; therefore, drug dosage regimens often need to be adjusted in order to provide safe yet effective treatment for patients with renal disease. In addition, certain therapeutic agents have potential nephrotoxicity and pharmacologic actions that may jeopardize already compromised renal function. Understanding of drug pharmacology, the therapeutic dose and the speed of drug elimination in a given patient will lead to correct assessment of the drug regimen.     

Possibility of using TFX (thymus factor X) in the treatment of systemic lupus erythematosus

A case of a 32-year female patient with the systemic lupus erythematosus is presented. The patient was treated with prednisone in a daily dose of 40-60 mg. Due to the exacerbations of the symptoms and advanced renal disorders, the patient was given TFX together with corticotherapy. Thymus factor X is an extract of real thymus of immunorecorrective properties. It specifically acts on the lymphatic system, especially disordered mechanisms of both cellular and humoral immunity. Thymus factor X was given in the dose of 10 mg (one ampoule) i.m. for the three first months followed by one ampoule every three days for the next three months. The patient is given one ampoule of TFX once a week since the 6th months of therapy. Diminishment of the symptoms was observed. The patient is in remission since a one-year follow-up period. It was also possible to reduce the dose of prednisone to 15 mg a day. The patient is controlled every 3 months. Partial normalization of renal functioning and immunological mechanisms are seen. A decrease in antinuclear antibodies and immunoglobulins, normalization in complement components, an increase in T-cells percentage and conversion of the delayed skin reaction are noted. The authors conclude that TFX may be helpful in the treatment of the autoimmunological diseases, including the systemic lupus erythematosus.     

Vaccine therapy for renal cell carcinoma

Several potential vaccines have been evaluated for the treatment of patients with renal cell carcinoma (RCC). They include dendritic cells pulsed with tumor lysate, a dendritic cell-tumor cell hybrid, irradiated tumor cells admixed with adjuvants, and a heat shock protein-peptide complex. Promising results have been obtained in several early clinical trials, but issues of tumor immunosuppression and lack of identified tumor-associated antigens must be addressed before vaccine therapy can be applied successfully in advanced RCC. In this patient population, vaccine therapy will likely be required in combination with other forms of immunotherapy, such as interleukin-2 and thalidomide. In contrast, vaccine therapy alone may be sufficient for high-risk patients in the adjuvant setting.     

A cervical ligamentum flavum cyst in an 82-year-old woman presenting with spinal cord compression: a case report and review of the literature

Introduction

Legionnaires' disease is recognized as a multi-systemic illness. Afflicted patients may have pulmonary, renal, gastrointestinal tract and central nervous system complications. However, renal insufficiency is uncommon. The spectrum of renal involvement may range from a mild and transient elevation of serum creatinine levels to anuric renal failure requiring dialysis and may be linked to several causes. In our present case report, we would like to draw attention to the importance of the pathological documentation of acute renal failure by reporting a case of a patient with acute tubulointerstitial nephritis complicating Legionnaires' disease.

Case presentation

A 55-year-old Caucasian man was admitted to our hospital for community-acquired pneumonia complicated by acute renal failure. Legionella pneumophila serogroup type 1 was diagnosed. Although the patient's respiratory illness responded to intravenous erythromycin and ofloxacin therapy, his renal failure worsened, he became anuric, and hemodialysis was started. A renal biopsy was performed, which revealed severe tubulointerstitial nephritis. After initiation of steroid therapy, his renal function improved dramatically.

Conclusions

This case highlights the importance of kidney biopsies in cases where acute renal failure is a complicating factor in Legionnaires' disease. If the presence of acute tubulointerstitial nephritis can be confirmed, it will likely respond favorably to steroidal treatment and thus irreversible renal damage and chronic renal failure will be avoided.     

Simulation model for planning renal services in a district health authority.

OBJECTIVE--To investigate the use of a computer simulation model in planning and budgeting for renal replacement services. SETTING--Regional renal unit. RESULTS--The simulation provided projections that accurately reflected the actual numbers of people maintained on different forms of renal replacement therapy in previous years. Projections up to the end of the century showed that with no change in the demand for the service the total number of people on the renal replacement programme would increase by 40%. Increasing the uptake of new patients from 40 per million to 55 per million would mean an increase of 66% in patient numbers over the same period. Similarly, at present day prices the cost of providing the service would rise by 31% with no change in demand and by twice this with the greater uptake of new patients. Increasing the number of transplant operations was shown to offer little prospect of a reduction in these costs. CONCLUSION--The simulation program could be used by individual renal units to evaluate different treatment policies and to budget for resource use. Even at current demand levels resource requirements for renal replacement therapy will continue to grow until after the end of the century.     

利妥昔单抗维持治疗弥漫大B 细胞淋巴瘤的初步研究

目的:对弥漫大B细胞淋巴瘤患者进行利妥昔单抗维持治疗(Maintenance Rituximab,MR)的安全性及疗效的研究和探讨.方法:38例患者诱导治疗结束后根据患者及家属意见和经济条件分为MR组和观察组.每组19例.诱导治疗阶段两组患者均接受6～8个疗程R-CHOP(每3周)或R-EPOCH方案治疗.维持阶段,利妥昔单抗在诱导治疗完成后4-8周开始,375mg/m2,每3个月1次共2年(8次)或直至疾病复发、进展、死亡.维持前均经影像学检查证实无复发.结果与结论:MR对R-EPOCH或R-CHOP的诱导治疗后达到CRu/CR初治DLBCL病人,有很好的近期疗效,能提高其DFS率,但OS率无改善,而且其毒副反应小,可以耐受.     

Renal replacement therapy review: past, present and future

Support of renal function in modern times encompasses a wide array of methods and clinical scenarios, from the ambulatory patient to the critically ill. The ability to safely and routinely deliver ongoing organ support in the outpatient setting has until recently separated renal replacement therapy from other organ support. Renal replacement therapy (RRT) can be applied intermittently or continuously using extracorporeal (hemodialysis) or paracorporeal (peritoneal dialysis) methods. The purpose of this article is to familiarize the reader with the history, physiology, mode, dose, equipment and future of renal replacement therapy and not to detail the technical methods employed for blood purification.     

Use of Renal Replacement Therapy May Influence Graft Outcomes following Liver Transplantation for Acute Liver Failure: A Propensity-Score Matched Population-Based Retrospective Cohort Study

Introduction

Acute kidney injury is associated with a poor prognosis in acute liver failure but little is known of outcomes in patients undergoing transplantation for acute liver failure who require renal replacement therapy.

Methods

A retrospective analysis of the United Kingdom Transplant Registry was performed (1 January 2001–31 December 2011) with patient and graft survival determined using Kaplan-Meier methods. Cox proportional hazards models were used together with propensity-score based full matching on renal replacement therapy use.

Results

Three-year patient and graft survival for patients receiving renal replacement therapy were 77.7% and 72.6% compared with 85.1% and 79.4% for those not requiring renal replacement therapy (P<0.001 and P = 0.009 respectively, n = 725). In a Cox proportional hazards model, renal replacement therapy was a predictor of both patient death (hazard ratio (HR) 1.59, 95% CI 1.01–2.50, P = 0.044) but not graft loss (HR 1.39, 95% CI 0.92–2.10, P = 0.114). In groups fully matched on baseline covariates, those not receiving renal replacement therapy with a serum creatinine greater than 175μmol/L had a significantly worse risk of graft failure than those receiving renal replacement therapy.

Conclusion

In patients being transplanted for acute liver failure, use of renal replacement therapy is a strong predictor of patient death and graft loss. Those not receiving renal replacement therapy with an elevated serum creatinine may be at greater risk of early graft failure than those receiving renal replacement therapy. A low threshold for instituting renal replacement therapy may therefore be beneficial.     

Continuous ambulatory peritoneal dialysis: experience with 22 unselected patients with renal failure.

The present study describes our experience with CAPD in an unselected group of patients presenting with endstage renal failure. Twenty-three consecutive patients were offered CAPD, in-center, and home hemodialysis. Twenty-two patients selected CAPD, including 14 patients more than 60 years of age, four patients with diabetes, and one with multiple myeloma. CAPD training was performed in an out-of-hospital office facility. One patient returned to hemodialysis following the development of resistant Pseudomonas peritonitis, two patients died of a myocardial infarction, and one patient died with a GI bleed. The other 18 patients are doing well. Assessment of 17 patients maintained on therapy for four months or more revealed that the patients are less depressed, less organic, and have fewer physical symptoms than previously reported for a comparable group of patients maintained on hemodialysis for a similar period of time. In conclusion, CAPD can be successfully employed, at least for the initial months of therapy, to treat the vast majority of patients with endstage renal disease. CAPD training and follow-up care can be provided in an out-of-hospital office facility.     

Does route of administration affect the outcome of TNF antagonist therapy?

The tumor necrosis factor (TNF) antagonists are parenterally administered biologic response modifiers indicated for the management of rheumatoid arthritis. Although infliximab, etanercept, and adalimumab are all members of this class, they differ in route of administration and dosing regimen. In the USA and in Europe, infliximab, in combination with oral methotrexate, is administered intravenously, initially at a dose of 3 mg/kg at weeks 0, 2, and 6, then every 8 weeks thereafter. The US Food and Drug Administration (FDA) has further approved that the dosage can be increased to 10 mg/kg and the doses can be given as often as every 4 weeks to optimize patient outcome (information based on the US package insert dated June 2002). Etanercept and adalimumab are given subcutaneously and can be self-injected. The FDA-approved dose of etanercept is 25 mg twice weekly, and of adalimumab is 40 mg every 2 weeks with methotrexate, or 40 mg alone. Medication adherence, possibly the most important factor in maintaining the benefits of anti-TNF therapy, is influenced by the interaction between the patient and his or her healthcare team, the patient's attitude toward the disease and medication regimen, and the choice of therapy.     

Breast reconstruction with postmastectomy radiation therapy: current issues

Two recent trials have demonstrated superior locoregional control, disease-free survival, and overall survival in node-positive breast cancer patients with the addition of postmastectomy radiation therapy to mastectomy and chemotherapy. Based on these results, there has been an increased use of postmastectomy in patients with early-stage breast cancer. The inability to determine which patients will require postmastectomy radiation therapy has increased the complexity of planning for immediate breast reconstruction. There are two potential problems with performing an immediate breast reconstruction in a patient who will require postmastectomy radiation therapy. One problem is that postmastectomy radiation therapy can adversely affect the aesthetic outcome of an immediate breast reconstruction. Several studies have evaluated the outcomes of breast reconstructions that were performed before radiation therapy and have revealed a high incidence of complications and poor aesthetic outcomes. Furthermore, these studies have found that often an additional flap is required to restore breast shape and symmetry. The other potential problem is that an immediate breast reconstruction can interfere with the delivery of postmastectomy radiation therapy. During planning for immediate breast reconstruction, it is imperative to carefully review the stage of disease and the likelihood the patient will require postmastectomy radiation therapy. Unfortunately, the ability to detect and predict the presence or extent of axillary lymph node involvement is limited, and the need for postmastectomy radiation therapy is usually not known until after mastectomy. In all cases of decision making regarding possible postoperative radiation therapy and whether or not to perform immediate breast reconstruction, the situation should be discussed at a multidisciplinary conference or addressed among the various medical, surgical, and radiation teams, with active participation by the patient. Immediate breast reconstruction probably should be avoided in patients known to require postmastectomy radiation therapy and delayed until it is certain the therapy will be needed in patients who may require the therapy.     

Therapy of lupus nephritis: lessons learned from clinical research and daily care of patients

Despite numerous randomized clinical trials over the last three decades for identifying the optimal treatment option for lupus nephritis, renal involvement still significantly impacts the survival and quality of life of patients with lupus and the search for the ideal immunosuppressive regimen is far from complete. The purpose of this review is to summarize the major recent achievements in the field. More specifically, the following topics will be discussed: intravenous cyclophosphamide versus mycophenolate mofetil (MMF) for induction; azathioprine versus MMF for maintenance; targeted therapies. The review will address clues for optimal global care, such as the need for complete initial evaluation, the importance of patient education, the unmasking of non-compliance to therapy, the reason for an early treatment switch in non-responding patients, the need for prolonged immunosuppression, optimal renal protection, and prevention of cardiovascular disease and other comorbidities.     

Beta(2)-microglobulin removal by extracorporeal renal replacement therapies

There is increasing evidence that end-stage renal disease patients with lower beta(2)-microglobulin plasma levels and patients on convective renal replacement therapy are at lower mortality risk. Therefore, an enhanced beta(2)-microglobulin removal by renal replacement procedures has to be regarded as a contribution to a more adequate dialysis therapy. In contrast to high-flux dialysis, low-flux hemodialysis is not qualified to eliminate substantial amounts of beta(2)-microglobulin. In hemodialysis using modern high-flux dialysis membranes, a beta(2)-microglobulin removal similar to that obtained in hemofiltration or hemodiafiltration can be achieved. Several of these high-flux membranes are protein-leaking, making them suitable only for hemodialysis due to a high albumin loss when used in more convective therapy procedures. On-line hemodiafiltration infusing large substitution fluid volumes represents the most efficient and innovative renal replacement therapy form. To maximize beta(2)-microglobulin removal, modifications of this procedure have been proposed. These modifications ensure safer operating conditions, such as mixed hemodiafiltration, or control albumin loss at maximum purification from beta(2)-microglobulin, such as mid-dilution hemodiafiltration, push/pull hemodiafiltration or programmed filtration. Whether these innovative hemodiafiltration options will become accepted in clinical routine use needs to be proven in future.     

First successful case of in vitro fertilization-embryo transfer with venom immunotherapy for hymenoptera sting allergy

BACKGROUND: To describe immune and endocrine responses in severe hymenoptera hypersensitivity requiring venom immunotherapy (VIT) during in vitro fertilization (IVF). CASE PRESENTATION: A 39-year old patient was referred for history of multiple miscarriage and a history of insect sting allergy. Four years earlier, she began subcutaneous injection of 100 mcg mixed vespid hymenoptera venom/venom protein every 5-6 weeks. The patient had one livebirth and three first trimester miscarriages. Allergy treatment was maintained for all pregnancies ending in miscarriage, although allergy therapy was discontinued for the pregnancy that resulted in delivery. At our institution ovulation induction incorporated venom immunotherapy (VIT) during IVF, with a reduced VIT dose when pregnancy was first identified. Serum IgE was monitored with estradiol during ovulation induction and early pregnancy. Response to controlled ovarian hyperstimulation was favorable while VIT was continued, with retrieval of 12 oocytes. Serum RAST (yellow jacket) IgE levels fluctuated in a nonlinear fashion (range 36-54%) during gonadotropin therapy and declined after hCG administration. A healthy female infant was delivered at 35 weeks gestation. The patient experienced no untoward effects from any medications during therapy. CONCLUSION: Our case confirms the safety of VIT in pregnancy, and demonstrates RAST IgE can remain <60% during IVF. With proper monitoring, VIT during IVF can be safe and appropriate for selected patients and does not appear to adversely affect blastocyst implantation, early embryo development or perinatal outcome. Further studies will be needed to develop VIT guidelines specifically applicable to IVF.     

Renal excretion of fluoride in renal failure and after renal transplantation.

We have compared the renal excretion of fluoride in a variety of patients with chronic renal failure maintained with and without protein restriction before and during regular dialysis treatment and after transplantation. The patients tended to continue to excrete normal dietary loads of fluoride quite well until renal function was seriously reduced. From a regression of function on excretion the mean level of creatinine clearance when a normal dietary load of fluoride 0.0526 plus or minus 0.019 mmol/2 h (1.0 plus or minus 0.36 mg/24h) has a 90% chance of being excreted lies around 16 ml/min, a level when most patients with renal failure will be symptomatic. Acute loading of such patients with additional fluoride in the form of sodium fluoride from 40 mg to 60 mg/day showed a twofold to threefold increase of serum fluoride concentrations, slight increases in urinary fluoride excretion, and heavy tissue absorption, suggesting that prior fluoride loading of the skeleton had not taken place. These effects contrasted with those in one patient with normal renal function and with those in one patient with skeletal saturation due to prolonged loading. After renal transplantation fluoride excretion increased but reached normal levels within three months of satisfactory function, suggesting that fluoride loading in renal failure and during regular dialysis therapy had not been excessive.     

Continuous renal replacement therapy in children post-hematopoietic stem cell transplantation: the present and the future

Allogeneic hematopoietic stem cell transplantation (HSCT) use has expanded markedly to treat different disorders like hematologic malignancies, immunodeficiency, and inborn errors of metabolism. However, it is commonly associated with complications that limit the benefit of this therapy. Acute renal failure occurs commonly after HSCT and results in increased risk of mortality. In many instances, children post-HSCT develop acute renal insufficiency in the context of other organ failure, necessitating intensive care unit admission for management. Recently, continuous renal replacement therapy (CRRT) has emerged as the favored modality of renal replacement therapy in the care of critically ill children who are hemodynamically unstable. Currently, CRRT is being utilized more often in the care of critically ill post- HSCT children to treat renal failure or to prevent fluid overload (FO). FO > 20% has been shown in many studies to be an independent risk of mortality in critically ill children and therefore, many clinicians will initiate this therapy due to FO even without overt renal failure. CRRT may be beneficial in disease processes as acute lung injury due to removal of fluid. CRRT results in improved oxygenation in post-HSCT children with acute lung injury and this improvement is sustained for at least 48 hours after initiation of this therapy. Survival in post-HSCT children requiring this therapy ranges from 17% to 45%, however, long term survival is still poor. This review will discuss current practice of CRRT in children post-HSCT, as well as future directions.     

Advising Patients on the Use of Complementary and Alternative Medicine

Complementary and alternative medicine (CAM) is an area of great public interest and activity, both nationally and worldwide. Many alternative medical practices have existed for hundreds, even thousands of years. Patients and professionals are turning to CAM for a variety of reasons. Most have tried conventional medicine for a particular (usually chronic) medical condition and have found the results inadequate. Some are concerned over the side effects of conventional therapies. Some are seeking out a more “holistic” orientation in health care where they can address body, mind, and spirit. A continuing challenge will be how to address CAM services that are based on time, practitioner–patient interactions, and self-care, using modern standards of evidence, education, licensing, and reimbursement. For most CAM therapies, there is insufficient research to say definitively that it works and CAM research is especially limited in the area of cancer. Given that situation, the questions (but not answers) facing the medical practitioner are clear-cut. Should the practitioner await the definitive results of formal Phase III randomized clinical trials, or should the practitioner rely on limited data, seeking out evidence that makes physiological sense and small trials that seem to offer some benefit to the patient? When and at what point do you discourage, permit, or recommend an available alternative therapy? The answers are not simple. There may be differences of opinion and values among the patient, the practitioner, and the organizations that pay for a therapy. CAM areas should be approached with every patient who enters the office recognizing that there are precautions to consider when patients are using, or plan to use, such therapies. This paper presents a broad survey of what complementary and alternative medicine is from the perspectives of both the public as user and the conventional medical practitioner, as well as provides examples of issues pertinent to understanding and evaluating research in CAM. The past is back and the future will involve integration of modern and ancient ways.     

Why Therapeutic Response May Not Prolong the Life of a Cancer Patient: Selection for Oncogenic Resistance

Most cancers do not respond to chemotherapy. Disappointedly, even objective clinical responses to anticancer therapy often do not translate into improvements in overall survival. To explain the response-survival paradox, it has been pointed out that effective therapy is ineffective against cancer stem cells, which replenish the tumor (causing relapse). In contrast, I discuss that, according to this scenario, patient survival will be prolonged at least by the duration of remission. Furthermore, stem-cell-based relapses will be sensitive to the initial therapy, and in theory cancer could be controlled indefinitely. To explain the paradox, I discuss that effective therapy selects for resistance among proliferating cancer cells. Importantly, mechanisms of resistance can be divided into non-oncogenic (e.g., drug transporters and mutation in drug-targets) and oncogenic (apoptosis and cell cycle dysregulation). The latter is associated with highly aggressive cancer phenotype and, therefore, there is no increase in overall survival. I further suggest that (a) therapeutic response is a prerequisite for successful therapy, (b) resistance can be exploited for therapeutic advantage, (c) each response can be translated into increased survival, and (e) in slow growing tumors, cancer can be stopped without tumor shrinkage. Therapy will control cancer if it can selectively suppress proliferating cancer cells and will improve survival as long as acquired resistance can be exploited.     

Intravenously Given Methylprednisolone in Refractory Asthma

A study was designed to compare the time course response of two high-dose methylprednisolone regimens in adult refractory corticosteroid-dependent asthmatics: Group A received 125 mg intravenously every six hours for three days; group B received 125 mg every six hours for ten days. Sixteen patients during 22 hospital stays were randomly assigned to one of the two groups. Forced vital capacity (FVC), forced expired volume in one second (FEV₁) and forced expiratory flow between 25 percent and 75 percent of vital capacity (FEF_25%-75%) improved significantly over the ten days in both groups (P<.005) in all patients. No differences in baseline two-, four-, seven- or ten-day spirometric values were noted between groups (P>.2).In most steroid-dependent asthmatic patients, three days'' therapy with 125 mg every six hours of methylprednisolone given intravenously resulted in obvious and sustained ventilatory improvement. Close observation with spirometric and clinical evaluation is then necessary to detect the occasional patient in whom relapse will occur and longer periods of high-dose steroid therapy will be needed.