Renal replacement therapy in multiple myeloma and systemic amyloidosis

Renal failure frequently complicates both multiple myeloma and systemic amyloidosis. Renal replacement therapy (RRT) may be poorly tolerated and its role in such patients is not clearly defined. Of fifty patients (26 males and 24 females) referred to a single centre because of renal failure associated with multiple myeloma or systemic amyloidosis 37 progressed to end-stage renal failure and 30 of these patients received RRT. Nine patients have been treated by CAPD, 13 by haemodialysis, and 8 patients have required both forms of dialysis. Overall one year and two year survival rates were 66% and 57% respectively. The median duration on RRT was 7.5 months (range 1-96 months) with a 51% one year, and a 46% two year survival rate. Of 7 patients with amyloidosis who underwent renal transplantation, 3 died within 6 months of transplantation. Undiagnosed cardiac involvement contributed to this early mortality. We conclude that renal replacement therapy is appropriate for some patients with multiple myeloma and systemic amyloidosis who develop endstage renal failure. Careful assessment and selection of patients is necessary prior to renal transplantation.

Comorbidities and current smoking status amongst patients starting renal replacement therapy in England, Wales and Northern Ireland from 2003 to 2008: national and centre-specific analyses

Introduction: The prevalence of comorbidities in incident renal replacement therapy (RRT) patients changes with age and varies between ethnic groups. This study describes these associations and the independent effect of comorbidities on outcomes. Methods: Adult patients starting RRT between 2003 and 2008 in centres reporting to the UK Renal Registry (UKRR) with data on comorbidity (n ¼ 14,909) were included. The UKRR studied the association of comorbidity with patient demographics, treatment modality, haemoglobin, renal function at start of RRT and subsequent listing for kidney transplantation. The relationship between comorbidities and mortality at 90 days and one year after 90 days from start of RRT was explored using Cox regression. Results: Completeness of comorbidity data was 40.0% compared with 54.3% in 2003. Of patients with data, 53.8% had one or more comorbidities. Diabetes mellitus and ischaemic heart disease were the most common conditions seen in 30.1% and 22.7% of patients respectively. Current smoking was recorded for 14.5% of incident RRT patients in the 6-year period. Comorbidities became more common with increasing age in all ethnic groups although the difference between the 65–74 and 75+ age groups was not significant. Within each age group, South Asians and Blacks had lower rates of comorbidity, despite higher rates of diabetes mellitus. In multivariate survival analysis, malignancy and ischaemic/neuropathic ulcers were the strongest independent predictors of poor survival at 1 year after 90 days from the start of RRT. Conclusion: Differences in prevalence of comorbid illnesses in incident RRT patients may reflect variation in access to health care or competing risk prior to commencing treatment. At the same time, smoking rates remained high in this ‘at risk’ population. Further work on this and ways to improve comorbidity reporting should be priorities for 2010–11.

Comorbidities and current smoking status amongst patients starting renal replacement therapy in England, Wales and Northern Ireland: national and centre-specific analyses

Introduction: The prevalence of 13 comorbid conditions and smoking status at the time of starting renal replacement therapy (RRT) in England, Wales and Northern Ireland are described. Methods: Adult patients starting RRT between 2002 and 2007 in centres reporting to the UK Renal Registry (UKRR) and with data on comorbidity (n¼13,293) were included. The association of comorbidity with patient demographics, treatment modality, haemoglobin, renal function at start of RRT and subsequent listing for kidney transplantation were studied. Association between comorbidities and mortality at 90 days and one year after 90 days from start of RRT was explored using Cox regression. Results: Completeness of data on comorbidity returned to the UKRR remained poor. Of patients with data, 52% had one or more comorbidities. Diabetes mellitus and ischaemic heart disease were the most common conditions seen in 28.9% and 22.5% of patients respectively. Comorbidities became more common with increasing age (up to the 65–74 age group), were more common amongst Whites and were associated with a lower likelihood of pre-emptive transplantation, a greater likelihood of starting on haemodialysis (rather than peritoneal dialysis) and a lower likelihood of being listed for kidney transplantation. In multivariable survival analysis, malignancy and ischaemic/neuropathic ulcers were the strongest predictors of poor survival at 1 year after 90 days from start of RRT. Conclusions: The majority of patients had at least one comorbid condition and comorbidity is an important predictor of early mortality on RRT.

Fluid balance, intradialytic hypotension, and outcomes in critically ill patients undergoing renal replacement therapy: a cohort study

Introduction: In this cohort study, we explored the relationship between fluid balance, intradialytic hypotension and outcomes in critically ill patients with acute kidney injury (AKI) who received renal replacement therapy (RRT).

Methods: We analysed prospectively collected registry data on patients older than 16 years who received RRT for at least two days in an intensive care unit at two university-affiliated hospitals. We used multivariable logistic regression to determine the relationship between mean daily fluid balance and intradialytic hypotension, both over seven days following RRT initiation, and the outcomes of hospital mortality and RRT dependence in survivors.

Results: In total, 492 patients were included (299 male (60.8%), mean (standard deviation (SD)) age 62.9 (16.3) years); 251 (51.0%) died in hospital. Independent risk factors for mortality were mean daily fluid balance (odds ratio (OR) 1.36 per 1000 mL positive (95% confidence interval (CI) 1.18 to 1.57), intradialytic hypotension (OR 1.14 per 10% increase in days with intradialytic hypotension (95% CI 1.06 to 1.23)), age (OR 1.15 per five-year increase (95% CI 1.07 to 1.25)), maximum sequential organ failure assessment score on days 1 to 7 (OR 1.21 (95% CI 1.13 to 1.29)), and Charlson comorbidity index (OR 1.28 (95% CI 1.14 to 1.44)); higher baseline creatinine (OR 0.98 per 10 mu mol/L (95% CI 0.97 to 0.996)) was associated with lower risk of death. Of 241 hospital survivors, 61 (25.3%) were RRT dependent at discharge. The only independent risk factor for RRT dependence was pre-existing heart failure (OR 3.13 (95% CI 1.46 to 6.74)). Neither mean daily fluid balance nor intradialytic hypotension was associated with RRT dependence in survivors. Associations between these exposures and mortality were similar in sensitivity analyses accounting for immortal time bias and dichotomising mean daily fluid balance as positive or negative. In the subgroup of patients with data on pre-RRT fluid balance, fluid overload at RRT initiation did not modify the association of mean daily fluid balance with mortality.

Conclusions: In this cohort of patients with AKI requiring RRT, a more positive mean daily fluid balance and intradialytic hypotension were associated with hospital mortality but not with RRT dependence at hospital discharge in survivors.

Clinical potential of gene-directed enzyme prodrug therapy to improve radiation therapy in prostate cancer patients

Despite the advances in prostate cancer diagnosis and treatment, current therapies are not curative in a significant proportion of patients. Gene-directed enzyme prodrug therapy (GDEPT), when combined with radiation therapy, could improve the outcome of treatment for prostate cancer, the second leading cause of cancer death in the western world. GDEPT involves the introduction of a therapeutic transgene, which can be targeted to the tumour cells. A prodrug is administered systemically and is converted to its toxic form only in those cells containing the transgene, resulting in cell kill. This review will discuss the clinical trials which have investigated the potential of GDEPT at various stages of prostate cancer progression. The advantages of using GDEPT in combination with radiotherapy will be examined, as well as some of the recent advances which enhance the potential utility of GDEPT.

Association of functional haem oxygenase-1 gene promoter polymorphism with polycystic kidney disease and IgA nephropathy

Background: Haem oxygenase-1 (HO-1) is a cytoprotective molecule that is reported to have a protective role in a variety of experimental models of renal injury. A functional dinucleotide repeat (GT)n polymorphism, within the HO-1 promoter, regulates HO-1 gene expression; a short number of repeats (S-allele <25) increases transcription. We report the first assessment of the role of this HO-1 gene promoter polymorphism in chronic kidney disease due to autosomal dominant polycystic kidney disease (ADPKD) and IgA nephropathy (IgAN).

Methods: The DNA from 160 patients (99% Caucasian) on renal replacement therapy (RRT) was genotyped. The primary renal disease was ADPKD in 100 patients and biopsy-proven IgAN in 60 patients.

Results: Overall, the mean age at commencement of RRT was not significantly different between patients with and without an S-allele (44.1 years versus 45.0 years, P = 0.64). In patients with ADPKD, the age at commencement of RRT was comparable regardless of the HO-1 genotype (47.7 years versus 46.7 years, P = 0.59). The same was true in patients with IgAN (38.3 years versus 42.2 years, P = 0.28).

Conclusion: This suggests that the functional HO-1 promoter polymorphism does not influence renal survival in CKD due to ADPKD or IgAN.

The finding of reduced estimated glomerular filtration rate is associated with increased mortality in a large UK population

BACKGROUND: CKD as defined by KDIGO/KDOQI has been shown to affect ~ 8.5% of the UK population. The prevalence of CKD in the UK is similar to that in the USA, yet incident dialysis rates are dramatically different. This retrospective cohort study investigates the association between reduced kidney function and mortality in a large UK population. METHODS: All serum creatinine results covering Northern Ireland's 1.7 million population were collected between 1 January 2001 and 31 December 2002. Estimated glomerular filtration rates (eGFR) were calculated for all serum creatinine measurements using four-variable MDRD equation (IDMS aligned). Patients were followed up for both all-cause and cardiovascular mortality data until the end of December 2006. Patients on renal replacement therapy were excluded. Subgroup analysis in the 75 345 subjects enrolled within a parallel primary care study permitted additional survival analysis with adjustment for traditional cardiovascular risk factors. RESULTS: A total of 1 967 827 serum creatinine results from 533 798 patients were collected. During the period of follow-up, 59 980 deaths occurred. In multivariate survival analysis, using eGFR as a time-varying covariate, a graded association between CKD (defined by eGFR) and all-cause mortality was identified. Compared with participants with an eGFR of > 60 mL/min/1.73 m(2), the adjusted hazard ratios (and 95% confidence intervals) for participants with an eGFR of 45-59 mL/min/1.73 m(2) was 1.02 (0.99-1.04), an eGFR of 30-44 mL/min/1.73 m(2) was 1.44 (1.40-1.47), an eGFR of 15-29 mL/min/1.73 m(2) was 2.12 (2.05-2.20) and an eGFR of

Antitumour prodrug development using cytochrome P450 (CYP) mediated activation

An ideal cancer chemotherapeutic prodrug is completely inactive until metabolized by a tumour-specific enzyme, or by an enzyme that is only metabolically competent towards the prodrug under physiological conditions unique to the tumour. Human cancers, including colon, breast, lung, liver, kidney and prostate, are known to express cytochrome P450 (CYP) isoforms including 3A and 1A subfamily members. This raises the possibility that tumour CYP isoforms could be a focus for tumour-specific prodrug activation. Several approaches are reviewed, including identification of prodrugs activated by tumour-specific polymorphic CYPs, use of CYP-gene directed enzyme prodrug therapy and CYPs acting as reductases in hypoxic tumour regions. The last approach is best exemplified by AQ4N, a chemotherapeutic prodrug that is bioreductively activated by CYP3A. This study shows that freshly isolated murine T50/80 mammary carcinoma and RIF-1 fibrosarcoma 4-electron reduces AQ4N to its cytotoxic metabolite, AQ4 (T50/80 K-m = 26.7 mu M, V-max = 0.43 mu M/mg protein/min; RIF-1 K-m = 33.5 mu M, V-max = 0.42 mu M/mg protein/min) via AQM, a mono-N-oxide intermediate (T50/80 K-m = 37.5 mu M; V-max = 1.4 mu M/mg protein/min; RIF-1 K-m = 37.5 mu M; V-max = 1.2 mu M/mg protein/min). The prodrug conversion was dependent on NADPH and inhibited by air or carbon monoxide. Cyp3A mRNA and protein were both present in T50/80 carcinoma grown in vivo (RIF-1 not measured). Exposure of isolated tumour cells to anoxia (2 h) immediately after tumour excision increased cyp3A protein 2-3-fold over a 12 h period, after which time the cyp protein levels returned to the level found under aerobic conditions. Conversely, cyp3A mRNA expression showed an initial 3-fold decrease under both oxic and anoxic conditions; this returned to near basal levels after 8-24 h. These results suggest that cyp3A protein is stabilized in the absence of air, despite a decrease in cyp3A mRNA. Such a 'stabilization factor' may decrease cyp3A protein turnover without affecting the translation efficiency of cyp3A mRNA. Confirmation of the CYP activation of AQ4N bioreduction was shown with human lymphoblastoid cell microsomes transfected with CYP3A4, but not those transfected with CYP2B6 or cytochrome P450 reductase. AQ4N is also reduced to AQ4 in NADPH-fortified human renal cell carcinoma (K-m = 4 mu M, V-max = 3.5 pmol/mg protein/min) and normal kidney (K-m = 4 mu M, V-max = 4.0 pmol/mg protein/min), both previously shown to express CYP3A. Germane to the clinical potential of AQ4N is that although both normal and tumour cells are capable of reducing AQ4N to its cytotoxic species, the process requires low oxygen conditions. Hence, AQ4N metabolism should be restricted to hypoxic tumour cells. The isoform selectivity of AQ4N reduction, in addition to its air sensitivity, indicates that AQ4N haem coordination and subsequent oxygen atom transfer from the active-site-bound AQ4N is the likely mechanism of N-oxide reduction. The apparent increase in CYP3A expression under hypoxia makes this a particularly interesting application of CYPs for tumour-specific prodrug activation.

Advances in microbicide vaginal rings

Vaginal ring devices capable of providing sustained/controlled release of incorporated actives are already marketed for steroidal contraception and estrogen replacement therapy. In recent years, there has been considerable interest in developing similar ring devices for the administration of microbicidal compounds to prevent vaginal HIV transmission. Intended to be worn continuously, such coitally independent micro- bicide rings are being developed to maintain effective vaginal microbicide concentrations over many weeks or months, thereby overcoming issues around timing of product application, user compliance and acceptability associated with more conventional semi-solid formulations. In this article, an overview of vaginal ring technologies is presented, followed by a review of recent advances and issues pertaining to their application for the delivery of HIV microbicides. This article forms part of a special supplement on presentations covering intravaginal rings, based on the symposium “Trends in Microbicide Formulations”, held on 25 and 26 January 2010, Arlington, VA.

Factors influencing patients with stage 5 chronic kidney disease to opt for conservative management: a practitioner research study

Aims and objectives. This study explored decision-making experiences of patients with stage 5 chronic kidney disease when opting for conservative management of their renal failure.

Background. Dialysis is an invasive treatment, and for some older patients, there is an associated treatment burden of dialysis-related symptoms. An alternative choice is conservative management, but little is known about those who make this decision and how they are supported through the process.

Design. Qualitative practitioner research study.

Method. Data were generated from nine patients' naturally occurring clinic consultations with a renal clinical nurse specialist between May 2010 - July 2010. Interviews were transcribed verbatim and findings fed back at three multi-disciplinary meetings to check for relevance and resonance. Common themes were identified and codes applied.

Results. Patients reported age and having to travel three times a week to hospital for dialysis as reasons not to opt for treatment. Others felt well without dialysis not wanting to upset the 'status quo' or to burden loved ones. Most felt equipped to make the decision following explanation and discussion with the clinical nurse specialist in the renal clinic.

Conclusions. Patients opting for conservative management give numerous reasons for this including old age, travel limitations, feeling well without dialysis and not wanting to be a burden, but appear content with their decision. One-to-one discussions with the clinical nurse specialist appear helpful during the decision-making process presenting an opportunity for advancing nursing roles in the chronic kidney disease service.

Relevance to clinical practice. Understanding patients' reasons for refusing dialysis assists in supporting until death. There is an opportunity for developing nursing practice to meet the multi-faceted needs of this group.

High-performance liquid chromatographic determination of 17 beta-estradiol and 17 beta-estradiol-3-acetate solubilities and diffusion coefficients in silicone elastomeric intravaginal rings

A rapid, sensitive reversed-phase high-performance liquid chromatographic method has been developed for the determination of in vitro release of 17 beta-estradiol and its ester prodrug, 17 beta-estradiol-3-acetate, from silicone intravaginal rings. Partial hydrolysis of the acetate under the aqueous conditions provided by the 1% benzalkonium chloride release medium necessitates its conversion to 17 beta-estradiol prior to HPLC analysis. Both steroid peaks have been fully resolved from the benzalkonium chloride peaks by the reported chromatographic method,which employs a C-18 bonded reversed-phase column, an acetonitrile-water (50:50, v/v) mobile phase and a UV detection wavelength of 281 nm. The peak area versus 17 beta-estradiol concentration was found to be linear over the range of 0.0137-1347 mu g ml(-1) The HPLC method has also been used to determine the silicone solubilities and diffusion coefficients of the two related steroids. The almost 100-fold increase in 17 beta-estradiol-3-acetate release from the silicone core-type intravaginal rings compared to 17 beta-estradiol is shown to be due to a 60-fold increase in silicone solubility and a one and a half-fold increase in diffusitivity. The results demonstrate that an effective estrogen replacement therapy dose of 17 beta-estradiol may be administered from a silicone intravaginal reservoir device containing the labile 17 beta-estradiol-3-acetate prodrug. (C) 2000 Elsevier Science B.V. All rights reserved.

Bone mineral density in relation to medical and lifestyle risk factors for osteoporosis in premenopausal, menopausal and postmenopausal women in general practice

Background: Interest in the prevention of osteoporosis is increasing and thus there is a need for an acceptable osteoporosis prevention programme in general practice. AIM. A study was undertaken to identify a cohort of middle-aged women attending a general practice who would be eligible for a longitudinal study looking at bone mineral density, osteoporosis and the effectiveness of hormone replacement therapy. This study aimed to describe the relationship between medical and lifestyle risk factors for osteoporosis and the initial bone density measurements in this group of women. METHOD. A health visitor administered a questionnaire to women aged between 48 and 52 years registered with a Belfast general practice. The main outcome measures were menopausal status, presence of medical and lifestyle risk factors and bone mineral density measurements. RESULTS. A total of 358 women our of 472 (76%) took part in the study which was conducted in 1991 and 1992. A highly significant difference was found between the mean bone mineral density of premenopausal, menopausal and postmenopausal women within the narrow study age range, postmenopausal women having the lowest bone mineral density. A significant relationship was found between body mass index and bone mineral density, a greater bone mineral density being found among women with a higher body mass index. Risk factors such as smoking and sedentary lifestyle were common (reported by approximately one third of respondents) but a poor relationship was found between these two and all the other risk factors and bone mineral density in this age group. CONCLUSION. Risk of osteoporosis cannot be identified by the presence of risk factors in women aged between 48 and 52 years. In terms of a current prevention strategy for general practice it would be better to take a population-based approach except for those women known to be at high risk of osteoporosis: women with early menopause or those who have had an oophorectomy.