The importance of standardization of creatinine in the implementation of guidelines and recommendations for CKD: implications for CKD management programmes.

BACKGROUND: In an attempt to reduce late referral and to improve the care of patients with chronic kidney disease (CKD), different organizations have issued guidelines on when to refer patients to the nephrologist. Most suggest referral of patients with a GFR below 60 ml/min/1.73 m2, and demand referral if the GFR is below 30 ml/min/1.73 m2. It is recommended to use the abbreviated MDRD equation to estimate GFR. This formula is, however, sensitive to the creatinine assay methodology. In addition, the impact of the implementation of such guidelines on the nephrology practice has never been evaluated. This study (i) identifies the true burden of CKD in a population and simulates the effects of a 100% implementation of the guidelines on the nephrology work load, and (ii) evaluates the validity of the estimated GFR using the abbreviated MDRD formula when routinely provided. METHODS: Different laboratories (both hospital and private) in our region were asked to report on all the serum creatinine values performed during the first week of December 2004. If patients had more than one determination, only the lowest serum creatinine value was retained. Patients already known to a nephrology unit were not included. GFR was calculated using the abbreviated MDRD, using the serum creatinine as reported by these laboratories, or after correction to the MDRD-standard using different published equations. RESULTS: 20,108 patients, with a mean age of 53.4+/-16.2 years, 48% females, had at least one serum creatinine determination in the observation period. According to the K/DOQI CKD classification, 20.2, 1.6 and 0.8% of females and 13.3, 1.6 and 0.6% of males were in stage 3, 4 and 5, respectively, when the abbreviated MDRD formula was used with the serum creatinine value as reported by the laboratories. Important differences in classifications were obtained when the different correction formulae for creatinine were applied. According to the current recommendations, this would lead to a mandatory referral of 1650-2400 CKD stage 4 patients per 100 000 inhabitants and a suggested referral of another 4100-15 360 CKD stage 3 patients per 100,000 inhabitants to a nephrology unit. CONCLUSION: Implementation of the current guidelines for referral of CKD patients to nephrologists would lead to an overload of the nephrology care capacities. Large differences in estimated GFRs with different corrections for serum creatinine are observed, resulting in important CKD classification differences. Standardization of serum creatinine assays is mandatory before guidelines, and especially the routine provision of the estimated GFR by the abbreviated MDRD formula, can be implemented in clinical practice.     

DNA probe technology: implications for service planning in Britain

For certain genetic conditions DNA testing identifies carriers and determines the risk status of foetuses, thus helping parents to make more informed prenatal decisions. Data, collected from three genetic centres in England and Wales from August 1986 to July 1990, are used to describe trends in demand for DNA testing, the impact of DNA tests on carrier risk assessment, and the use of DNA tests in relation to pregnancy outcome. Altogether the data include 23,388 subjects and 681 pregnancies in 8738 families divided into five cohorts by year of entry and referral. The most frequent gene disorders referred to the genetic centres are currently being tested or will soon be tested. For these disorders the initial high level of activity has declined and may have reached steady state. Demand for DNA services is high for cystic fibrosis and Duchenne muscular dystrophy, intermediate for Huntington's disease, and low for adult polycystic kidney disease, phenylketonuria and tuberous sclerosis. Based on these findings we suggest that demand for DNA tests will be high in serious, untreatable and slow progressing conditions with early onset; intermediate for conditions affecting intellect and neurological integrity with later onset; and low for treatable, late-onset conditions, or those for which there is evidence of heterogeneity, and variable penetrance. It would be helpful to assess the extent to which this view of demand is confirmed when the new disorders being DNA tested are considered and for the pattern of activity of DNA testing for some types of cancer. Since no DNA centre could offer a fully comprehensive testing service, it is recommended that a structure is created to audit overall activity, assist in policy formulation, and influence supraregional service organisation, in order that the spread of DNA services be planned as effectively as possible. This structure would facilitate monitoring of the evolution of contract specifications agreed by commissioners and providers on a regional basis.     

Effects of methyl isocyanate on rat muscle cells in culture.

Since the Bhopal disaster, in which the causal agent was methyl isocyanate (MIC), exposed people have complained of various disorders including neuromuscular dysfunction. In an attempt to gain some information about the response of muscle tissue to MIC its effects were investigated in cells in culture isolated from muscle of 2 day old rats. After treatment with a range of MIC concentrations (0.025-0.5 microliter/5 ml culture) the total number of nuclei of the two main cell types (fibroblasts and myoblasts) and the number of nuclei in muscle fibres (myotubes) were recorded. At lower doses which had little effect on the total number of nuclei, the formation of muscle fibres--that is, fusion of muscle cells--was prevented as the proportion of nuclei in myotubes was decreased. At higher doses both cell types were killed. This would suggest either an effect on muscle differentiation or a selective toxicity towards myoblasts. The observations were supported by light and electron microscopy.     

PET for evaluation of differential myocardial perfusion dynamics after VEGF gene therapy and laser therapy in end-stage coronary artery disease.

The purpose of this study was to appraise the value of PET in the assessment of the effect of supposedly proangiogenic new therapies such as gene therapy with vascular endothelial growth factor (VEGF) gene and endomyocardial laser therapy. METHODS: Thirty-five patients with end-stage coronary artery disease and class III (Canadian Cardiovascular Society) angina were included. Myocardial ischemia was evaluated with dipyridamole PET scanning and exercise tolerance with bicycle ergometry. Ten patients were treated with naked plasmid DNA encoding for human VEGF165 (VEGF) and 12 patients were treated with laser therapy (direct myocardial revascularization [DMR]) using an electromechanical mapping system. Thirteen patients were treated with standard medical therapy (control). RESULTS: In both active treatment groups, angina was reduced in most subjects, except in 2 VEGF and 5 DMR patients. In the control group, no improvement in anginal classification was found, except in 3 subjects. On the PET scan, solely in the VEGF group, the stress perfusion was significantly improved (from 57 +/- 33 to 81 +/- 55 mL/min/100 g; P = 0.031). Furthermore, in the VEGF group, the number of ischemic segments was reduced from 274 +/- 41 to 234 +/- 48 segments (P = 0.004) but not in the DMR group (from 209 +/- 43 to 215 +/- 52 segments) or in the control group (from 218 +/- 18 to 213 +/- 28 segments). Bicycle exercise duration showed slight nonsignificant changes in the VEGF group (from 3.6 +/- 2.0 to 4.6 +/- 2.1 min), in the DMR group (from 5.1 +/- 1.5 to 4.7 +/- 1.3 min), and in the control group (from 3.3 +/- 1.8 to 3.5 +/- 2.3 min). CONCLUSION: PET showed that intramyocardial gene therapy with the human VEGF165 gene in contrast to laser DMR treatment effectively reduces myocardial ischemia.     

Knowledge of epilepsy among relatives of the epilepsy sufferer.

A 23-item questionnaire was constructed to assess awareness of basic facts about epilepsy. Close family members of the epilepsy sufferer achieved significantly higher scores on the questionnaire than individuals from families without experience of the condition. The questionnaire may be useful in the identification of family members of the epilepsy sufferer whose knowledge of the condition is low and who may require appropriate counselling.     

Intracellular Ca2+ buffers disrupt muscarinic suppression of Ca2+ current and M current in rat sympathetic neurons.

The role of intracellular Ca2+ concentration ([Ca2+]i) in the muscarinic suppression of Ca2+ current and M-type K+ current has been investigated in isolated rat sympathetic neurons using the whole-cell patch-clamp technique and fura-2 fluorescence measurements. Muscarinic stimulation suppressed currents without raising [Ca2+]i. Nonetheless, intracellular bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate (BAPTA) (11-12 mM), a Ca2+ chelator, reduced Ca2(+)-current suppression from 82 to 15%. For the latter, we explain the BAPTA action by a requirement for a certain minimum [Ca2+]i for continued operation of the pathway coupling muscarinic receptors to M-type K+ channels. The pathway coupling muscarinic receptors to Ca channels also showed some dependence on [Ca2+]i, but there may also be a blocking action of BAPTA that is independent of Ca2+ chelation.     

A theory of carcinogenesis based on an analysis of the effects of carcinogens

Carcinogenic stimuli appear to act on target cells (and their daughters) by one or more of three mechanisms. The first is by oxidation of membrane component molecules on the extracellular surfaces of their plasma membranes. The second is by chronic and continuous impingement of electrons on the extracellular surfaces of their plasma membranes and the third is by relocation of predominantly basic molecules to the cytoplasmic surfaces of their plasma membranes. This latter effect in turn causes electrostatic attraction of image charged acidic molecules to the extracellular surfaces to balance the transmembrane charge of the target cells. Each of the above mechanisms results in a condition of increased electronegativity of the extracellular surfaces of plasma membranes of the target cells and their daughters. A theory of transformation is advanced based on the above related modes of action and it is used to explain some previously unexplainable properties of tumors.     

The uptake and costs of guidelines for stroke in a district of southern England.

STUDY OBJECTIVE: To assess the impact of guidelines for stroke management on the utilisation of services by patients and the cost consequences of implementation. DESIGN: Prospective audit. SETTING: District health authority in southern England. PATIENTS: A total of 468 live non-comatose stroke patients registered between November 1991 and May 1993. MAIN OUTCOME MEASURES: A comparison between the three, six month periods for investigations performed and rehabilitation received and their associated costs. RESULTS: The appropriateness of the use of investigations improved over time to between 88 and 92% except for computed tomography (CT) (24%). Younger, more severely impaired patients in a medical bed were more likely to have CT. Overall levels of rehabilitation were low. There was no change in use of physiotherapy (61% to 63%), a significant increase in occupational therapy (26% to 39%) and a non significant change in speech therapy (34% to 25%) over time. Guideline introduction caused a modest 23 Pounds increase in costs per patient in the 2nd six months and 41 Pounds in the 3rd six months but this sum could rise to 430 Pounds per patient if full implementation of the guidelines occurred which is still only around 13% of the costs of nursing care while in hospital. CONCLUSIONS: This 18 month aduit shows only modest changes in practice compared with guidelines, and overall levels of rehabilitation were low. The costs of full implementation seem considerable, but in fact constitute only a small proportion of nursing care costs.     

Evaluating the clinical nurse specialist. A review

This paper reviews evaluative studies on the role of clinical nurse specialists and aims to describe and categorise research according to the methods used. By using the structure, process and outcome framework a clear pattern of research development and evidence emerges. It appears that significant benefits accrue for patients from the contribution of nurse specialists, but more experimental studies with combined methods should now be applied to this area.     

Action of nifedipine of BAY K8644 is dependent on calcium channel state in single smooth muscle cells from rabbit ear artery

The actions of nifedipine or BAY K 8644 were studied on barium currents recorded from single, collagenase- and elastase-dispersed, smooth muscle cells from the rabbit ear artery using the whole-cell configuration of the patch-clamp technique. Nifedipine (3M) caused a reduction in the barium current (I_Ba) evoked by steps to potentials positive of-10mV. This was characterized by a pronounced initial block, an increase in the rate of current decay during the voltage-clamp step, but by no increase in block if pulses were repeated every 600ms. Rapid extracellular application of nifedipine (1M) during the sustained current component (using a new concentration-jump technique) was found to have no effect on I_Ba over 4s at +20mV, but after returning to the holding potential (-60mV) for 10s, sustained I_Ba was subsequently abolished. BAY K 8644 (1M) increased I_Ba at all potentials, and on rapid application during the sustained current component markedly potentiated I_Ba. The results suggest that nifedipine binds with high affinity to the closed, available state of the Ca⁺⁺ channels but they do not suggest binding to the open or inactivated states. The effect of BAY K 8644 is consistent with high affinity binding to the open or inactivated and to the closed, available states.