Preoperative estimated glomerular filtration rate and the risk of major adverse cardiovascular and cerebrovascular events in non-cardiac surgery.

BACKGROUND: Chronic kidney disease is an independent predictor of perioperative cardiovascular morbidity and mortality. We analysed the preoperative estimated glomerular filtration rate (eGFR) as a risk factor for perioperative major adverse cardiovascular and cerebrovascular events (MACCE) in non-cardiac surgery. METHODS: In a post hoc analysis of the ANESCARDIOCAT database, patients were classified into six stages of eGFR calculated with the abbreviated Modification of Diet in Renal Disease Study and the Chronic Kidney Disease Epidemiology Collaboration equations: >90 (1), 60-89.9 (2), 45-59.9 (3a), 30-44.9 (3b), 15-29.9 (4), and <15 (5) ml min(-1) 1.73 m(-2). We analysed differences in MACCE, length of hospital stay, and all-cause mortality between eGFR stages. RESULTS: The eGFR was available in 2323 patients. Perioperative MACCE occurred in 4.5% of patients and cardiac-related mortality was 0.5%. Five hundred and forty-three (23.4%) patients had an eGFR of <60 ml min(-1) 1.73 m(-2) and 127 (5.4%) had an eGFR below 45 ml min(-1) 1.73 m(-2). Logistic regression analysis showed that MACCE increased with eGFR impairment (P<0.001), with a marked increase from stage 3b onwards (odds ratio 1.8 vs 3.9 in 3a and 3b, respectively, P=0.047). All-cause mortality was not related to eGFR (P=0.071), but increased substantially between stages 3b and 4. The length of stay correlated with eGFR (P<0.001). CONCLUSIONS: Perioperative MACCE increase with declining eGFR, primarily when <45 ml min(-1) 1.73 m(-2). We recommend the use of preoperative eGFR for cardiovascular risk assessment.

Dietary and pharmacological control of calcium and phosphate metabolism in dialysis patients.

Chronic kidney disease-mineral and bone disorder is a new term defining a complex syndrome which underlines the need of a systemic approach to disturbances of calcium and phosphate metabolism in patients with renal failure. In recent years, the availability of new phosphorus binders and the appearance of new selective vitamin D receptor activators and calcimimetics have increased our current armamentarium and have changed previous paradigms. All these drugs can be used in combination, acting in distinct yet complementary pathways, with a resultant improvement in their individual clinical profile and reduction in secondary effects, while enhancing the achievement of clinical guideline targets. On the other hand, we should be aware that treatment costs are increasing and most of our knowledge is opinion-based. In this article, we shall consider rational recommendations on the control of calcium, phosphorus and parathyroid hormone while awaiting new evidence. We shall also briefly review some important related issues such as vascular calcification, adynamic bone disease, osteoporosis and the need of parathyroidectomy. Future guidelines may modify current recommendations, but we believe that the lack of an absolute evidence is not equivalent to the lack of awareness of the important problem which chronic kidney disease-mineral and bone disorder represents.

Efficacy of cinacalcet administered with the first meal after dialysis: the SENSOR Study.

BACKGROUND: Cinacalcet, a novel calcimimetic, simultaneously lowers parathyroid hormone (PTH), phosphorus (P), calcium (Ca) and Ca x P in patients who are on dialysis with secondary hyperparathyroidism (sHPT) associated with CKD. Previous studies have required cinacalcet to be administered during the dialysis session and at the same time on non-dialysis days. The aim of the SENSOR study was to demonstrate that cinacalcet given in a more clinically practical manner with the first major meal after dialysis is noninferior to cinacalcet given with food during the dialysis session. METHODS: In this open-label study dialysis patients with poorly controlled sHPT (intact PTH (iPTH) (3) 300 pg/ml) were randomized to receive cinacalcet either daily with their post-dialysis meal (n = 337) or with food during the dialysis session (n = 336). The primary endpoint was the proportions of patients with mean iPTH pound 300 pg/ml ( pound 31.8 pmol/l) at Weeks 11 and 13 of a 21-week treatment period. Secondary endpoints included the proportion of patients with Ca x P < 55 mg2/dl2 (< 4.44 mmol2/l2) at Weeks 11 and 13 and patients who discontinued the study due to nausea or vomiting. RESULTS: Comparable proportions of patients in the cinacalcet "during dialysis" and "post-dialysis meal" groups had a mean iPTH pound 300 pg/ml (54 vs. 57%, respectively, 95% confidence interval (CI) difference -4, +10%) and Ca x P < 55 mg2/dl2 (78 vs. 73%, respectively, 95% CI difference -11, +2%) at Weeks 11 and 13. The groups were also comparable at Week 21. Cinacalcet was well tolerated, with < 3% of patients in both groups discontinuing due to nausea or vomiting. A combined post-hoc analysis of both groups showed the incidence of nausea and vomiting was lower if cinacalcet was administered during the evening. CONCLUSIONS: Administering cinacalcet with the first main meal after dialysis was as effective as administration with food during the dialysis session. Cinacalcet was well tolerated. The incidence of gastrointestinal adverse events appeared to be lower when cinacalcet was administered in the evening.

[Unawareness of the K/DOQI guidelines for bone and mineral metabolism in predialysis chronic kidney disease: results of the OSERCE Spanish multicenter-study survey]. / Desconocimiento de las guías K/DOQI sobre la alteración del metabolismo óseo-mineral asociada a la enfermedad renal crónica no en diálisis: resultados de la encuesta en el estudio multicéntrico español OSERCE.

Since its publication in 2003, the K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease (CKD) have become a worldwide reference. The aim of this study was to analyze the observance to these guidelines in patients with a glomerular filtration rate < 60 ml/min/1,73m2 not yet included in dialysis in a Spanish multicenter cohort. A questionnaire by investigator/centre was completed by 32 different nephrologists participating in the OSERCE study and representing the overall Spanish public health net. We observed that biochemical parameters were measured less frequently than recommended, except in CKD stage 3. The therapeutic goals for intact PTH were not properly reported by 59 % of the consulted nephrologists for stages 3 and 4, whereas only 22% did not report them properly for stage 5. The goals for phosphorus were not adequately reported in 50 % of cases (stages 3 y 4) and 60 % (stage 5). For calcium, these values were 70 %, 73.3 % and 65.5 % for stages 3, 4 and 5, respectively. A corrected plasma calcium between 9.5 and 10.2 mg/dl is still considered adequate for 31%. As much as 87% nephrologists stated that they did not sistematically measure calcidiol plasma levels. In general, these results demonstrate that there is a great degree of unawareness of K/DOQITM predialysis guidelines. Thus, their poor implementation is probably not only due to the lower availability of approved therapeutic agents, the difficult achievement of goals or the disbelief on current recommendations. It would be desirable that forthcoming guidelines such as the KDIGO could also consider the need of educational efforts for CKD-Mineral and Bone Disorder.

[Tables estimating glomerular filtration rate from plasma creatinine]. / Tablas para la estimación del filtrado glomerular a partir de la creatinina plasmática.

Chronic kidney disease (CKD) and its related complications have become an important health and social problem. Very expensive resources are required in end-stage renal disease, and both complications of CKD as well as the important associated cardiovascular risk demand for interventions long before renal substitution therapies are needed. Thus, early diagnosis of CKD is currently considered of paramount importance, and it is based essentially upon the estimation of the glomerular filtration rate by formulae such as the abbreviated equation of the MDRD study. Nevertheless, in spite of international published recommendations, an automatic calculation to estimate the glomerular filtration rate (GFR) from serum creatinine is not reported by most laboratories yet and the need for creatinine assay standardisation is far from being implemented. Thus, we have designed some tables to show the creatinine value corresponding to different GFR for ages between 20 and 90 y/o, at 5 years intervals and in both sexes with both the MDRD-4 and MDRD-IDMS equations (Modification of Diet in Renal Disease-Isotope Dilution Mass Spectrometry). Moreover, we have created a global table including an estimation of GFR from plasma creatinine, age and sex by the MDRD-IDMS formula, the recommended for those laboratories which measure serum creatinine with assays aligned to the reference method. These tables aim to increase the awareness of the different assays for serum creatinine and to facilitate the diagnosis of CKD converting serum creatinine into GFR. This action should allow not only the early detection but also the possibility to establish the appropriate medical actions recommended after CKD detection.

Etelcalcetide: injectable calcimimetic for the treatment of secondary hyperparathyroidism in hemodialysis-dependent patients.

Chronic kidney disease is associated with mineral and bone disorders that are now considered as a syndrome. One of the major complications of this syndrome is secondary hyperparathyroidism (SHPT). SHPT increases bone turnover and the risk of fracture. SHPT is also associated with cardiovascular calcification and high mortality risk. The classical medical therapies of SHPT lack long-term efficacy and have undesirable effects on serum calcium and phosphate levels. Surgical parathyroidectomy is a radical therapeutic solution potentially exposing patients to a permanent state of hypoparathyroidism among other complications. Oral cinacalcet revolutionized the treatment of SHPT because of its great efficacy; however, more than one-third of patients do not respond appropriately to cinacalcet, mostly because of intolerance and lack of compliance. Intravenous etelcalcetide improves medical adherence and reduces pill burden. It is 10-15% superior than cinacalcet in controlling parathyroid hormone, but also leads to more frequent episodes of hypocalcemia.

Integral pharmacological management of bone mineral disorders in chronic kidney disease (part II): from treatment of phosphate imbalance to control of PTH and prevention of progression of cardiovascular calcification.

INTRODUCTION: Chronic kidney disease-mineral and bone disorders (CKD-MBD) are associated with costly complications and dismal hard-outcomes. AREAS COVERED: In two comprehensive articles we review contemporary and future pharmacological options for treatment of phosphate (P) imbalance (part 1) and hyperparathyroidism (this part 2), taking into account CKD-accelerated cardiovascular calcification (CVC) processes. EXPERT OPINION: Improvements in CKD-MBD require an integral approach, addressing all three components of the CKD-MBD triad. Here, initial guidance to control hyperparathyroidism is provided, taking into account the presence/absence of CVC. We include also measures for patients at risk of adynamic bone disease or suffering from calciphylaxis. Many epidemiological studies (relating to vitamin D) and thorough analyses of recent randomized clinical trials (of cinacalcet) point towards benefits of attempting to improve biochemical parameters while trying to, at least, avoid progression of CVC by more rational use of intestinal P-binders and low-dose vitamin D derivatives and/or calcimimetics. This approach does not seem to be far away from significantly improving hard-outcomes, at least in the dialysis population. The availability of new drugs and the performance of randomized clinical trials should ultimately lead to define earlier, clearer, and more cost-effective patient stratification and biochemical targets with consequent significant clinical improvements.

Integral pharmacological management of bone mineral disorders in chronic kidney disease (part I): from treatment of phosphate imbalance to control of PTH and prevention of progression of cardiovascular calcification.

INTRODUCTION: Chronic kidney disease-mineral and bone disorders (CKD-MBD), involving a triad of laboratory and bone abnormalities, and tissue calcifications, are associated with dismal hard-outcomes. AREAS COVERED: In two comprehensive articles, we review contemporary and future pharmacological options for treatment of phosphate (P) imbalance (this part 1) and hyperparathyroidism (part 2), taking into account CKD-accelerated atheromatosis/atherosclerosis and/or cardiovascular calcification (CVC) processes. EXPERT OPINION: Improvements in CKD-MBD require an integral approach, addressing all three components of the CKD-MBD triad. Individualization of treatment with P-binders and combinations of anti-parathyroid agents may improve biochemical control with lower incidence of undesirable effects. Isolated biochemical parameters do not accurately reflect calcium or P load or bone activity and do not stratify high cardiovascular risk patients with CKD. Initial guidance is provided on reasonable therapeutic strategies which consider the presence of CVC. This part reflects that although there is not an absolute evidence, many studies point to the need to improve P imbalance while trying to, at least, avoid progression of CVC by restriction of Ca-based P-binders if economically feasible. The availability of new drugs (i.e. inhibitors of intestinal transporters), and studies including early CKD should ultimately lead to clearer and more cost/effective clinical targets for CKD-MBD.

[New therapy strategies in secondary hyperparathyroidism on dialysis (I): new concepts, new treatments]. / Nuevas estrategias terapéuticas para el hiperparatiroicismo secundario en diálisis (I): nuevos conceptos, nuevos tratamientos.

Secondary hyperparathyroidism (SHP) is still an early and frequent complication of chronic renal disease (CRD). Currently, CRD is an independent cardiovascular risk factor, and calcium-phosphorus metabolism is one of the modifiable related factors. In this first article, we summarize the recent SHP treatment paradigm shift in dialysis patients, derived from the better knowledge and understanding of vascular calcification. We analyze the most recent guidelines (K/DOQI), and describe the general implications of hyperphosphatemia, as well as our therapeutic approach with phosphorus-binders. Since sevelamer additionally presents some pleiotropic effects and it attenuates the progression of vascular calcification, we consider it in the first-line of treatment despite it is not yet demonstrated a survival benefit. We also minimize the use of elemental calcium to a maximum of 1000 to 1500 mg/day. Lanthanum carbonate may well be an important therapeutic agent in the near future, especially if security concerns related to metal accumulation are overcome. Ferric citrate, colestilan and nicotinamide may soon play a role. All these drugs, isolated or in combination, are important in the treatment of SHP since a great deal of its success and the avoidance of some dialysis-related complications depend on an efficient phosphorus control.

[New therapeutic strategies in secondary hyperparathyroidism on dialysis (II): vitamin D analogues and calcium-mimetics]. / Nuevas estrategias terapéuticas para el hiperparatiroidismo secundario en diálisis (11): análogos de la vitamina D y calcimiméticos.

Secondary hyperparathyroidism (SHP) is a frequent complication of dialysis patients. In this second article we will analyze the new vitamin D analogs, capable of decreasing parathyroid hormone (PTH) levels with a lower effect on intestinal calcium and phosphorus absorption. Among other advantages described in the experimental setting, paricalcitol shows a survival benefit in dialysis patients as compared to calcitriol, at least in retrospective studies, and thus it became our first-line vitamin D derivative. Calcimimetics are unique since they decrease PTH levels without increasing serum calcium and phosphorus. Actually, calcium and phosphorus decrease in a significant number of patients. These drugs will soon be authorized in Spain, and we describe the better achievement of K/DOQI guidelines as well as other beneficial effects observed in the experimental animal with them. Finally, we mention the potential benefit of mild metabolic acidosis, the use of bisphosphonates, the role of bone morphogenetic protein BMP-7, and the use of teriparatide. The future treatment of SHP will probably require the independent management of calcium, phosphorus, vitamin D and PTH. Thus, low-dose combined treatments with selective drugs may prove more effective than sequential therapies.

[Sterile maggots as adjuvant procedure for local treatment in a patient with proximal calciphylaxis]. / Larvas estériles como coadyuvantes al tratamiento local en una paciente con calcifilaxis proximal.

Proximal calciphylaxis with skin ulcerations has a very poor survival and infection is the main cause of the high mortality rate. We present the case of a diabetic obese hemodialysis woman diagnosed of severe calciphylaxis with extensive ulcers in the abdomen and left thigh. After a first ineffective debridement attempt, systemic medical treatment was associated with daily wet cures with enzymatic ointments and maggot therapy resulting in spectacular granulation and healing of these ulcers. We want to underline the great properties of sterile maggots to selectively dissolve necrotic tissue, to disinfect the wound and to stimulate healing. Thus, sterile-maggot debridement may constitute a very good adjuvant treatment even in proximal ulcers of calciphylaxis, preventing systemic infection.

Comparison of two parathyroid hormone assays for the rat: the new immunoradiometric and the older competitive binding assay.

A competitive binding assay for parathyroid hormone (PTH INS) has been used since 1986 to measure PTH in rats. During the past year an immunoradiometric assay for the measurement of PTH (PTH IRMA) in the rat was developed. The purpose of the present study was to compare results obtained with the PTH INS and IRMA and to provide a framework for comparison for investigators who have used the PTH INS in previous studies. A total of 99 rats were studied; 27 rats had normal renal function, and 72 rats had surgically induced renal failure. In the azotemic rats, the magnitude of hyperparathyroidism was varied by changing the calcium and phosphorus composition of the diet. The correlation between the two PTH assays in the 99 rats was r = 0.98, p < 0.001. For the 27 rats with normal renal function, the correlation even within the narrow range of normal PTH values was significant, r = 0.71, p < 0.001. In the 72 azotemic rats, in which the highest INS PTH value was approximately 17 times normal, the correlation between the two PTH assays was r = 0.98, p < 0.001. The PTH IRMA provides distinct advantages, such as extended standard range, shortened incubation time, increased sensitivity, and technical simplicity, but our results indicate that the PTH INS provided an accurate measurement of PTH. Furthermore, our results should provide investigators who have used the PTH INS in previous studies with a framework for comparison with studies in which the PTH IRMA was used.

Dynamics of skeletal resistance to parathyroid hormone in the rat: effect of renal failure and dietary phosphorus.

UNLABELLED: Secondary hyperparathyroidism develops in renal failure and is generally ascribed to factors directly affecting parathyroid hormone (PTH) production and/or secretion. These include hypocalcemia, phosphorus retention, and a calcitriol deficiency. However, not often emphasized is that skeletal resistance to PTH is an important factor. Our study evaluated: (1) the relative effects of uremia and dietary phosphorus on the skeletal resistance to PTH; and (2) how, during a PTH infusion, the dynamics of skeletal resistance to PTH were affected by renal failure. Renal failure was surgically induced and, based on serum creatinine, rats were divided into normal, moderate renal failure, and advanced renal failure. In each group, three diets with the same calcium (0.6%) but different phosphorus contents were used: high (1.2%, HPD); moderate (0.6%, MPD); and low (0.2%, LPD) phosphorus. The study diet was given for 14-16 days followed by a 48 h infusion of rat PTH(1-34) (0.11 microg/100 g per hour), a dose five times greater than the normal replacement dose. During the PTH infusion, rats received a calcium-free, low phosphorus (0.2%) diet. In both moderate and advanced renal failure, the PTH level was greatest in the HPD group (p < 0.05) and, despite normal serum calcium values, PTH was greater in the MPD than the LPD group (p < 0.05). Despite phosphorus restriction and normal serum calcium and calcitriol levels in the azotemic LPD groups, the PTH level was greater (p < 0.05) in the LPD group with advanced rather than moderate renal failure. During PTH infusion, the increase in serum calcium was progressively less (p < 0.05) in all groups as renal function declined. Furthermore, despite normal and similar serum phosphorus values at the end of PTH infusion, the serum calcium concentration was less (p < 0.05) in the HPD group than the other two groups and similar in the LPD and MPD groups. IN CONCLUSION: (1) uremia and phosphorus each had separate and major effects on skeletal resistance to PTH; (2) skeletal resistance to PTH was an important cause of secondary hyperparathyroidism, even in moderate renal failure; (3) during PTH infusion, the dynamics of skeletal resistance to PTH changed because all groups received a low phosphorus diet, and the adaptation to a new steady state was delayed by the degree of renal failure and the previous dietary phosphorus burden; and (4) normal serum phosphorus may not be indicative of body phosphorus stores during states of disequilibrium.

Low-dose cyclosporine and mycophenolate mofetil in renal allograft recipients with suboptimal renal function.

BACKGROUND: Cyclosporine (CsA) nephrotoxicity can be identified by functional changes and chronic renal damage. CsA-associated renal fibrosis has been related to the overproduction of transforming growth factor (TGF)-beta1, a fibrogenic cytokine. Mycophenolate mofetil (MMF) may allow CsA dose reduction without increasing the risk of rejection. METHODS: We studied the impact of CsA dose reduction in association with MMF on renal function and TGF-beta1, production in 16 long-term renal allograft recipients with suspected CsA nephrotoxicity. Two grams/day of MMF were introduced, and CsA dose was reduced to reach whole-blood levels between 40 and 60 ng/ml within 1 month. CsA dose and levels, renal function parameters, and platelet-poor plasma TGF-beta1 levels were evaluated before and 6 months thereafter. RESULTS: MMF allowed a decrease in both the mean dose of CsA (3.8+/-1.35 vs. 2.2+/-0.73 mg/kg/day; P<0.01) and CsA levels (148+/-36 vs. 53+/-19 ng/ml; P<0.001). The reduction of CsA was associated with a decrement of serum creatinine levels (210+/-46 vs. 172+/-41 micromol/L; P<0.001) and an increase in both the glomerular filtration rate (32.9+/-12 vs. 39.1+/-14 ml/min/1.73 m2; P<0.02) and renal plasma flow (195+/-79 to 218.6+/-74.02 ml/min/1.73 m2; P<0.02). There was a reduction in plasma TGF-beta1 levels (4.6+/-4.2 vs. 2.0+/-1.4 ng/ml; P=0.003) and CsA levels correlated with TGF-beta1 (r=0.536, P=0.002). No rejection episodes occurred, and an improvement in both systolic (149+/-13 vs. 137+/-12 mmHg; P<0.01) and diastolic blood pressure (89+/-14 vs. 83+/-10 mmHg; P<0.04) were observed. CONCLUSIONS: These short-term results show that MMF introduction allows a CsA dose reduction, which improves renal function, reduces TGF-beta1 production, and improves the control of hypertension, without increasing the incidence of acute rejection.

Protocol renal allograft biopsies and the design of clinical trials aimed to prevent or treat chronic allograft nephropathy.

BACKGROUND: The minimum sample size to perform a clinical trial aimed to modify the natural history of chronic allograft nephropathy (CAN) is very large. Since the presence of chronic tubulointerstitial damage in renal protocol biopsy specimens is an independent predictor of late outcome, we evaluated whether protocol biopsies could facilitate the design of trials aimed to prevent or treat CAN. METHODS: Two hundred eighty-two protocol biopsy specimens were obtained 3 months after transplantation in 280 patients with serum creatinine levels <300 micromol/L, proteinuria <1000 mg/day, and stable function. The specimens were evaluated according to the Banff criteria. RESULTS: Graft survival depended on the presence of CAN and renal transplant vasculopathy (RTV). Thus, biopsy specimens were classified as: (a) no CAN (n=174); (b) CAN without RTV (n=87); and (c) CAN with RTV (n=21). Graft survival at 10 years was 95%, 82%, and 41%, respectively (P=0.001). Total serum cholesterol before transplantation was 4.5+/-1.1, 4.6+/-1.1, and 5.3+/-1.6 mmol/L, respectively (P=0.009) and it was the only predictor of RTV. Power analysis (beta=20%, alpha=5%) was done to evaluate whether protocol biopsies can facilitate the design of clinical trials aimed either to prevent or treat CAN. We showed that the most feasible approach would be to use the presence of CAN as the primary efficacy end point in a prevention trial. To demonstrate a 50% reduction in the incidence of CAN at 3 months, 570 patients would be required. CONCLUSIONS: Protocol biopsies may allow a reduction of sample size and especially the time of follow-up in a trial aimed to prevent CAN.

Changes in serum osteocalcin levels in the follow-up of kidney transplantation.

Serum osteocalcin, total alkaline phosphatase, intact parathyroid hormone (PTH), creatinine, calcium, and phosphate were determined in 23 kidney cadaveric allograft recipients, immediately before and 0.5, 1, 3 and 6 months after surgery. Immunosuppressive treatment was based on low doses of corticosteroids and cyclosporin combined with antilymphoblast globulin. The decrease in serum creatinine was accompanied by falling PTH concentrations. Serum osteocalcin levels were higher than normal before kidney transplantation and diminished at 0.5 and 1 month after surgery. Significant increases in serum osteocalcin concentrations were observed 3 and 6 months after kidney transplantation with a significant correlation with alkaline phosphatase levels. The increase in serum osteocalcin levels observed in our transplanted patients is not related with a parallel increase in serum creatinine levels nor with an increment in PTH levels; it seems to reflect an increase in the osteoblastic activity, which is not altered by steroid therapy.

A practical approach to the molecular biology of kidney diseases: from basic science to bed side.

Nowadays, the term "Molecular Biology" (MB) is generally a pplied to the biochemical processes that involve genes and the expression of proteins for which specific genes code. In recent years, astonishing advances have occurred in this field. Currently, there are many important powerful techniques allowing scientists to study the molecular mechanisms involved in many human genetic diseases. Furthermore, it is important to underline that the possibilities are not limited to the diagnosis and study of these genetic diseases. Indeed, by studying gene expression, MB also allows the molecular study of many acquired diseases such as viral hepatitis and cancer.Therefore, these major advances in the knowledge of gene biology are facilitating the arrival of a new era of gene therapy. This article will describe the most important techniques currently used in MB. Firstly, techniques involved in recombinant DNA technology will be discussed and these will include the study of DNA and the possibility of identifying the expression of abnormal genes, e.g. to identify individuals for paternity. Secondly, a description of techniques designed to study the expression of genes and their regulation will follow and they involve the study of RNA. Thirdly, the impact of genetic molecular studies as tools for medical diagnosis will be discussed and analysed. Finally, a discussion concerning the rational basis for gene therapy and its future perspectives is included. In this article, we have focused on technical or diagnostic aspects ofMolecular Biology. Although Ethics are also an interesting issue to deal with, theseissues are far beyond the scope of this review.

[Antilymphocyte serum, cyclosporine and corticoids, versus OKT3, cyclosporine, and corticoids in kidney transplantation]. / Sérum anti-lymphocyte, ciclosporine et corticoïdes, versus OKT3, ciclosporine et corticoïdes en transplantation rénale.

UNLABELLED: The use of the antilymphoblast globulin (ALG) or OKT3 associated with cyclosporine (CyA) and steroids has been useful in kidney cadaveric transplantation. 101 patients who received their first cadaveric renal transplant were randomized according to the immunosuppression used. Group A (n = 53): horse ALG 15 mg/kg just before transplant surgery; ALG 12 mg/kg on the first day after transplant followed by 4 doses of 10 mg/kg on alternate days; Cya p.o 8 mg/kg/d; prednisone 0.25 mg/kg/d. Group B (n = 48): OKT3 5 mg just before transplant followed by 4 doses of 5 mg/d.; CyA and prednisone were administered using the same schedule as group A. RESULTS: the incidence of rejection during the first 3 months was: group A: 13 percent, group B: 17 percent (NS). The probability of being free of acute rejection (Kaplan-Meier) 24 months after transplant was 89 percent in group A and 79 percent in group B (NS). The day of onset of the first acute rejection episode was 25 +/- 20 days after transplant in group A, and 17 +/- 10 day in group B (NS). Incidence of tubular necrosis: group A 21 percent, group B 19 percent (NS).

Clinical Uses of 1,25-dihydroxy-19-nor-vitamin D(2) (Paricalcitol).

The activation of vitamin D receptors (VDR) - (including activation by 25-hydroxyvitamin D) - seems to have not only mineral-metabolism beneficial effects but also important extra-skeletal actions. Paricalcitol is a synthetic vitamin D2 agonist of the VDR approved for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD). As a result of its selectivity, paricalcitol provides a wider therapeutic window for PTH suppression, minimizing deleterious effects of high serum calcium and/or phosphate concentrations. Paricalcitol also shares, and sometimes improves pleiotropic vitamin-D related systemic effects. For instance, paricalcitol has been repeatedly shown to decrease calcium and phosphate deposition in vessels and to decrease the expression of osteogenic factors preventing the active transformation of smooth muscle vascular cells into osteoblast-like cells in experimental models. In patients, paricalcitol has been associated with improved survival of dialysis patients and it may improve residual albuminuria in diabetic patients. Consequently, paricalcitol may enhance the standard of care in these high-risk patients. Although it seems reasonable to use these potential advantages to guide the individual and integral management of the complex CKD-mineral and bone disorder, it is necessary to recognize that many of these observations have not been proven nor confirmed in prospective clinical trials.

Role of vitamin D receptor activators in peritoneal dialysis.

Chronic kidney disease (CKD), including patients on peritoneal dialysis (PD), is linked to an important increase in mortality risk. Within the new systemic term CKD-MBD, alterations in vitamin D metabolism are also included. Many adverse events have been associated with vitamin D deficiency or lack of vitamin D receptor (VDR) activation both in the general population and CKD patients, and these associations seem to be maintained in PD patients. Particularities of PD in vitamin D metabolism, calcium balance, low PTH levels and the high prevalence of adynamic bone disease are discussed. We also review the associations of clinical or survival benefits with vitamin D supplementation, VDR or selective VDR activation, although they are low-graded and most of them obtained from HD databases. Nevertheless, we think that the combined approach to secondary hyperparathyroidism seems also to be appropriate in PD patients, and vitamin D (native plus VDR or selective VDR activation) seem an important part of the required integral approach. The later may provide additional benefits but definitive prove is still lacking.