Pietro Pozzoni

Renal Replacement Therapy in Patients with Diabetes and End-Stage Renal Disease

The number of patients who have diabetes and ESRD and are being admitted to renal replacement treatment (RRT) is increasing dramatically worldwide, and in many countries, diabetes has become the single most frequent cause of ESRD. Although the prognosis of patients who have diabetes and are receiving RRT has greatly improved, survival and medical rehabilitation rates continue to be significantly worse than those of nondiabetic patients, mainly because of preexisting severely compromised cardiovascular conditions. The most common RRT modality in patients with diabetes is still hemodialysis, but it gives rise to a number of clinical problems, in particular difficulties in the management of the vascular access and high frequency of intradialytic hypotension. However, patients who have diabetes and are on peritoneal dialysis have to face a progressive increase in peritoneal permeability, loss of ultrafiltration, and peritoneal fibrosis, all phenomena being accelerated in patients with diabetes and ultimately leading to an increased technique failure. The results of observational studies and national registries, although conflicting, suggest that these two dialytic modalities are somehow comparable in terms of outcomes, whereas accumulating evidence shows that both survival and medical rehabilitation of patients with diabetes are significantly better after renal transplantation, which should be the first-choice option for patients who have diabetes and reach ESRD but unfortunately still accounts for only a limited proportion of RRT treatments in these patients.

Renal Manifestations in the Metabolic Syndrome

The metabolic syndrome, which is characterized by obesity, serum lipid profile alterations, hypertension, and fasting hyperglycemia, is very common in developed countries, and its prevalence is likely to increase. Chronic kidney disease (CKD) also has become a significant public health problem because it affects a considerable proportion of the adult population and is a major risk factor for cardiovascular disease and premature death. Although it is widely known that the metabolic syndrome is a major risk factor for the development of type 2 diabetes and cardiovascular disease, its precise relationship with the risk for renal impairment only recently has been clarified: Patients with the metabolic syndrome are at significantly higher risk for microalbuminuria and/or CKD, and the level of risk is related to the number of components of the syndrome itself. Although it is difficult to discriminate the detrimental renal effects of the metabolic syndrome from those of hypertension and impaired glucose metabolism, its other aspects (particularly obesity) may favor independently the development of renal abnormalities and may be considered new modifiable risk factors for CKD. These observations provide a rationale for intervention studies that aim to verify whether treating the many components of the metabolic syndrome can effectively prevent the development and progression of renal damage.

International Study of Health Care Organization and Financing for renal replacement therapy in Italy: an evolving reality

The Italian national health system funds universal health care through general taxation, but health services are provided by local institutions. This study examines the epidemiology, provision, and funding of renal replacement therapy (RRT) in Italy. In 2001, prevalence and incidence of RRT in Italy were 0.083% and 0.014%, respectively. A 1999 donation law markedly increased renal transplantation rates. Italy spends 8.3% of its GDP on health care; 1.8% is for end-stage renal disease (ESRD) patients, who represent 0.083% of the general population. The reorganization of the NHS requires attention from the health community so that economic and geographic health disparities are not exacerbated.

Anemia and Cardiovascular Risk: The Lesson of the CREATE Trial

Anemia has received increasing attention as an independent cardiovascular risk factor in patients with chronic kidney disease (CKD); a number of studies have highlighted its clear relationship with CKD mortality, because its impact on cardiac function leads to the development of left ventricular hypertrophy. However, despite the association between higher hemoglobin levels and better outcomes, a number of clinical studies have failed to demonstrate that fully correcting anemia has a positive effect on morbidity and mortality in patients with CKD. The Cardiovascular Reduction Early Anemia Treatment Epoetin beta (CREATE) study was designed from the hypothesis that, as anemia develops early in the course of CKD and nearly at the same time as cardiovascular disease, its earlier correction may provide better protection against the development of cardiovascular abnormalities. This randomized, multicenter, open-label, parallel-group trial involved 603 patients who had moderate anemia (hemoglobin 11 to 12.5 g/dl) and stage 3 to 4 CKD (estimated GFR 15 to 35 ml/min) and were randomly assigned to attain complete or partial anemia correction. The final results are due to be published within a few months, but the preliminary analyses do not show that complete anemia correction leads to any cardiovascular advantage, although the cardiovascular event rate was half that expected, possibly as a result of patient selection, trial effect, and improved medical care. The baseline findings also indicated that the burden of cardiovascular disease already is very high even in relatively early stages of CKD.

Effectiveness of sodium and conductivity kinetic models in predicting end-dialysis plasma water sodium concentration: preliminary results of a single-center experience.

The attainment of a neutral sodium balance represents a major objective in hemodialysis patients. It requires that at the end of each dialysis session, total body water volume (Vf) and total plasma water sodium concentration (Napwf) are constant. Whereas to achieve a constant Vf it is sufficient that ultrafiltration equals the interdialytic increase in body weight, it is impossible to predict the value of Napwf and calculate the dialysate sodium concentration needed to obtain it without making use of kinetic mathematical models. The effectiveness of both sodium and conductivity kinetic models in predicting Napwf has already been validated in previous clinical studies. However, applying the sodium kinetic model appears to be poorly feasible in the everyday clinical practice, due to the need for blood samples at the start of each dialysis session for the determination of predialysis plasma water sodium concentration. The conductivity kinetic model appears to be more easily applicable, because no blood samples or laboratory tests are needed to determine plasma water conductivity (Cpw) and ionic dialysance (ID), used in place of plasma water sodium concentration and sodium dialysance, respectively. We applied the 2 models in 69 chronic hemodialysis patients using the Diascan Module® for the automatic determination of Cpw and ID, and using the latter as an estimate of sodium dialysance in the sodium kinetic model. The conductivity kinetic model was shown to be more accurate and precise in predicting Napwf as compared with the sodium kinetic model. Both accuracy and imprecision of the 2 models were not significantly affected by the method used to estimate total body water volume. These findings confirm the conductivity kinetic model as being an effective and easily applicable instrument for the achievement of a neutral sodium balance in chronic hemodialysis patients.

Recombinant human epoetin beta in the treatment of renal anemia

Cardiovascular disease is the leading cause of the poor long-term survival of patients with chronic kidney disease (CKD). Anemia complicating CKD not only impairs patients’ quality of life, but is also an independent risk factor for adverse cardiovascular outcomes. The availability of recombinant human erythropoietin (rHuEPO) has greatly changed the management of anemia in CKD patients. Besides improving hemoglobin levels, rHuEPO therapy has been demonstrated to significantly improve quality of life and decrease morbidity and mortality in patients with CKD. Epoetin beta, together with epoetin alfa and darbepoetin alfa, is one of the erythropoiesis-stimulating agents now available on the market. Different studies have shown that epoetin beta once-weekly administration to hemodialysis patients is as effective as three-times-weekly administration in maintaining hemoglobin levels at equivalent weekly doses. This raises the possibility of reducing the frequency of administration of rHuEPO therapy, thus increasing the alternatives available for tailoring anemia therapy to patients needs, and at the same time reducing nursing times and treatment costs. This is expected to potentially enhance patient compliance, thus helping more patients achieve their target hemoglobin levels.

The relevance of convection in clinical practice: A critical review of the literature

Convective treatments (high‐flux hemodialysis (HD), hemodiafiltration and hemofiltration) are characterized by enhanced removal of middle and large molecular weight solutes compared with conventional low‐flux HD. As these molecules are claimed to play an important role in the genesis of many complications of chronic HD, the availability of these techniques represented an intriguing innovation and a possible means to improve the still poor prognosis of HD patients. Here we will critically review the most important published studies comparing convective treatments with low‐flux HD on chronic morbidity, preservation of residual renal function, and long‐term survival.

Effect of anaemia on left ventricular hypertrophy in end-stage renal disease

Cardiovascular disease (CVD) is highly prevalent among end-stage renal disease (ESRD) patients and is the main reason for their high mortality and morbidity rates. The large proportion of patients starting renal replacement therapy who also have CVD, suggests that pathogenetic factors leading to cardiac dysfunction begin in the early stages of chronic kidney disease (CKD). Anaemia may be an important pathogenetic factor responsible for cardiovascular abnormalities, in particular left ventricular hypertrophy (LVH), which significantly worsens the prognosis of CKD patients. This would account for the association between anaemia and both hospitalisation and mortality rates in such patients and leads to the expectation that correction of anaemia will improve cardiovascular status and long-term prognosis. A partial regression of LVH after a partial correction of anaemia has been observed in several studies, but it is still unclear whether normalizing haemoglobin concentrations produces additional cardiac advantages. Indeed, no significant differences between partial and complete correction of anaemia in inducing regression of established LVH have been demonstrated so far, but further investigation is needed. Furthermore, normalization of anaemia improves quality of life and physical function of selected categories of patients. Also keeping in mind the potential risks of haemoglobin normalization in haemodialysis patients with severe heart disease and grafts, individualising the target haemoglobin concentration to the characteristics of the patients is probably one of the winning strategies in the modern management of renal anaemia.

Hematocrit and Prohepcidin: Causation or Simply Association?

associations but unable to demonstrate cause-effect relationships. Although support was provided by the results of previous experimental studies [3] , a cross-sectional correlation is not suffi cient to indicate whether hematocrit stimulates hepcidin production by the liver: in the absence of the time factor, it is unfortunately impossible to speculate which comes ‘fi rst’ and which ‘afterwards’. For the same reason, it is not surprising that no relationship was found between prohepcidin and ferritin levels, since the cross-sectional design of the study could not avoid the potentially confounding effect of iron supplementation, which is known to be one of the factors stimulating hepcidin expression. As the patients with the lowest ferritin levels are probably those receiving the highest iron dose, the cross-sectional design may have masked possible positive correlations between hepcidin, ferritin and iron supplements, thus leading to the erroneous conclusion that they were not interrelated. In future trials, possible correlations between hepcidin and ferritin should be studied in patients not receiving iron supplementation. In conclusion, the results of this preliminary study by Hsu et al. [1] deserve particular attention because they present the fi rst results of a clear and direct relationship between plasma prohepcidin and hematocrit levels in chronic HD patients. However, these fi ndings require further evaluation in order to clarify whether the altered hepcidin expression is pathogenetically related to renal anemia or simply an epiphenomenon. Longitudinal cohort studies in which prohepcidin levels are followed up Starting from the observation that patients with chronic hemodialysis (HD) and chronic anemia may share the same laboratory fi ndings (i.e. low transferrin saturation and high ferritin levels), Hsu et al. [1] investigated the relationship between plasma levels of prohepcidin, the inactive prohormone of hepcidin, and various indices of the iron status, infl ammation and erythropoietin treatment in 71 prevalent HD patients. Since hepcidin, a liver-derived peptide stimulated by infl ammatory cytokines [2] , acts as a negative regulator of intestinal iron absorption and iron release from macrophages, it is believed to represent the molecular link between chronic infl ammation and anemia, and may also play a role in anemic patients with high ferritin levels on chronic HD. The study failed to demonstrate any relationship between indices of the iron status and serum prohepcidin concentrations in the HD patients, but hematocrit levels proved to be independently and positively correlated with plasma prohepcidin levels also at multivariate analysis. Based on these results, the authors suggested that hematocrit levels may have a benefi cial effect on the regulation of prohepcidin production, i.e. they postulated a causal link between hematocrit and prohepcidin levels. The results of the study are intriguing, because they offer the fi rst evidence of a relationship between hepcidin expression and the degree of anemia in the setting of end-stage renal disease. However, the conclusions drawn by the authors require some caution. The study was indeed designed as a cross-sectional study, known to highlight the existence of Published online: February 10, 2006

A Critical Assessment of Uremia Research

There are considerably fewer randomized controlled trials investigating hemodialysis (HD) than other fields of internal medicine, and no significant improvements have been observed over time. Only the National Cooperative Dialysis Study and the HEMO trial were based on hard endpoints such as morbidity and mortality, but neither considered on-line hemodiafiltration or super-flux membranes, which are thought to provide a number of advantages in terms of the cardiovascular condition of uremic patients. However, results of well-designed clinical trials showing that increasing convection may improve the clinical outcome of HD patients are still lacking. The need for maximizing removal of uremic toxins calls for more frequent HD sessions, but this may be affected by many organizational problems. Therefore, well-designed, long-term clinical trials are urgently needed to investigate which currently available therapeutic instruments can improve the clinical outcome of uremic patients.