Hematocrit and prohepcidin: causation or simply association?
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Antimicrobial Cationic Peptides↗
Biomedical subjects
Francesco Locatelli
Publications and source records attributed to Francesco Locatelli.
Predictors of outcome in Henoch-Schönlein nephritis in children and adults.
BACKGROUND: Factors predictive of renal outcome were investigated in 219 cases of biopsy-proven Henoch-Schönlein purpura nephritis (HSPN); 83 children and 136 adults enrolled in a national study were followed up for up to 27 years (median, 4.5 years). METHODS: The criterion for defining disease progression was time elapsed until doubling of baseline creatinine level and until dialysis therapy. Age, sex, data at onset (renal function, proteinuria, hematuria, hypertension, and crescents), and data during follow-up (proteinuria and therapy) were tested as covariates. RESULTS: Multivariate Cox regression analysis indicated the following parameters as independent prognostic predictors: age (adults versus children, relative risk, 3.57; 95% confidence interval, 1.18 to 10.79; P = 0.024 for creatinine level doubling; relative risk, 14.89; 95% confidence interval, 1.72 to 129.07; P = 0.014 for dialysis therapy), sex (females versus males, relative risk, 5.71; 95% confidence interval, 1.67 to 19.55; P = 0.006 for creatinine level doubling; relative risk, 26.03; 95% confidence interval, 2.64 to 256.73; P = 0.005 for dialysis therapy), and mean proteinuria during follow-up (for each 1 g/d of protein increase, relative risk, 1.77; 95% confidence interval, 1.35 to 2.32; P < 0.001 for creatinine level doubling; relative risk, 1.73; 95% confidence interval, 1.18 to 2.52; P = 0.005 for dialysis therapy). Information for mean proteinuria levels during follow-up increased the sensitivity at logistic regression to 62.5%, with dialysis therapy as the end point. No data detected at diagnosis, including renal function impairment, proteinuria, hypertension, and crescentic nephritis (involving > 50% of glomeruli in only 2.6%), were significantly related to functional decline at multivariate Cox. CONCLUSION: This analysis indicates that, even more than when decreased renal function, severe proteinuria, hypertension, or crescents are present at onset, the risk for progression of HSPN (greater in adults and females) was associated with increasing mean proteinuria levels during follow-up.
Adolescent↗
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.
Hemodiafiltration↗
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.
Hemodiafiltration↗
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.
Albuminuria↗
Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients.
BACKGROUND: Chronic kidney disease patients who are resistant to erythropoietin (EPO) treatment may suffer from malnutrition and/or inflammation. METHODS: In a cross-sectional study of haemodialysis patients, we investigated the relationship between the natural logarithm of the weekly EPO dose normalized for post-dialysis body weight and outcome measures of nutrition and/or inflammation [BMI, albumin and C reactive protein (CRP)] by means of multiple linear regression analysis. On the basis of the decile distribution of weekly EPO doses, we also evaluated four groups of patients: untreated, hyper-responders, normo-responders and hypo-responders. RESULTS: Six hundred and seventy-seven adult haemodialysis patients were recruited from five Italian centres. BMI and albumin were lower in the hypo-responders than in the other groups (21.3+/-3.8 vs 24.4+/-4.7 kg/m(2), P<0.001; and 3.8+/-0.6 vs 4.1+/-0.4 g/dl, P<0.001), whereas the median CRP level was higher (1.9 vs 0.8 mg/dl, P = 0.004). The median weekly EPO dose ranged from 30 IU/kg/week in the hyper-responsive group to 263 IU/kg/week in the hypo-responsive group. Transferrin saturation linearly decreased from the hyper- to hypo-responsive group (37+/-15 to 25+/-10%, P = 0.003), without any differences in transferrin levels. Ferritin levels were lower in the hypo-responsive than in the other patients (median 318 vs 445 ng/ml, P = 0.01). At multiple linear regression analysis, haemoglobin, BMI, albumin, CRP and serum iron levels were independently associated with the natural logarithm of the weekly EPO dose (R(2) = 0.22). CONCLUSIONS: Our findings support a clear association between EPO responsiveness and nutritional and inflammation variables in haemodialysis patients; iron deficiency is still a major cause of hypo-responsiveness.
Aged↗
Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up report from the Research on Adverse Drug Events and Reports (RADAR) Project.
Since its introduction in 1988, recombinant human erythropoietin (epoetin) has been standard treatment for patients with anemia due to chronic kidney disease. From 1998 to 2004, nearly 200 epoetin-treated persons with chronic kidney disease developed antibodies to epoetin, resulting in pure red cell aplasia (PRCA). The majority of these patients received Eprex, an epoetin alfa product marketed exclusively outside the United States. Herein, we report on the long-term outcome of these individuals. For 170 chronic kidney disease patients who developed epoetin-associated PRCA and had 3 months or more follow-up information available, case reports from the Food and Drug Administration and epoetin manufacturers were reviewed for information on clinical characteristics of the patients, immunosuppressive treatments, epoetin responsiveness, and hematologic recovery. Overall, 64% of the PRCA patients received immunosuppressive therapy, including 19 who also underwent a renal transplantation. Thirty-seven percent experienced a hematologic recovery, with higher hematologic recovery rates among PRCA patients who received immunosuppressive therapy (57% vs 2%, P < .001). Among 34 patients who received epoetin after the onset of PRCA, 56% regained epoetin responsiveness. The highest rates of epoetin responsiveness were observed among persons whose antierythropoietin antibodies were undetectable when epoetin was administered (89%). Among chronic kidney disease patients with epoetin-associated PRCA, epoetin discontinuation and immunosuppressive therapy or renal transplantation is necessary for hematologic recovery. Reinitiation of epoetin therapy among individuals could be considered if antierythropoietin antibodies are undetectable.
Autoantibodies↗
Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial.
Elevated arterial pressure enhances the risk for cardiovascular (CV) events in patients with diabetic nephropathy. The optimal BP and the component of the elevated BP that affect the risk have not been defined. A post hoc analysis was performed to assess the impact of achieved systolic, diastolic, and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial (IDNT) and had a baseline serum creatinine above the normal range, up to 266 micromol/L (3.0 mg/dL), 24-h urine protein >900 mg/d, and at least 6 mo of follow-up. Patients were randomized to irbesartan, amlodipine, or placebo, with other antihypertensive agents to a BP goal of < or =135/85 mmHg. Progressively lower achieved systolic BP (SBP) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure (CHF) but not myocardial infarctions (MI). A SBP below this threshold was associated with increased risk for CV deaths and CHF events. Achieved diastolic BP <85 mmHg was associated with a trend to increase in all-cause mortality, significant increase in MI, but decreased risk for strokes. Increased pulse pressure predicted increased all-cause mortality, CV mortality, MI, and CHF. It is concluded that achieved SBP approaching 120 mmHg and diastolic BP of 85 mmHg are associated with the best protection against CV events in these patients. BP < or =120/85 may be associated with an increase in CV events.
Antihypertensive Agents↗
Pathochemical toxicity of perfluorocarbon-5070, a liquid test performance fluid previously used in dialyzer manufacturing, confirmed in animal experiment.
In the light of clustered deaths in late 2001 associated with hemodialysis (HD), this article analyzes the pathochemical toxicity of the perfluorocarbon-5070 (PF-5070), a liquid used as test performance fluid for detecting capillary leaks during dialyzer manufacturing. Residual PF-5070 in some Athane dialyzers of the involved brands was infused in the injured patients during hemodialysis. The clinical presentation was in contrast with other previously described severe reactions to HD. Foam material was discovered in the right ventricle and caval vein of the patients who underwent postmortem examination. Deaths were attributed to gas embolism without the external causes identified. To explore the pathochemical toxicity of the inert liquid PF-5070, an animal model was developed. In a rabbit model, single slug intravenous injections as bolus of increasing doses of PF-5070 were performed. In a first set of experiments, three groups of three rabbits were administered increasing doses of PF-5070 at 4, 40, or 160 microl/kg. After intravenous injection, the animals were observed for clinical signs of adverse effects and underwent autopsy after death. Doses were normalized to animal body weight to allow comparison with supposed patient exposure. Five of nine rabbits died soon after PF-5070 dosing: One rabbit died within 4 h in the 4 microl/kg group, one rabbit died within 30 min in the 40 microl/kg group, and three rabbits died within 30 min in the 160 mul/kg group. In a second set of experiments, six rabbits were injected with a lethal dose of PF-5070 to analyze clinical symptoms and pathophysiology. All rabbits died on the day of dosing and displayed neurologic disorders (paralysis, nystagmus, rigidity, convulsions), then breathing abnormalities (rapid breathing, salivation, dark mucous membrane), and fatal collapse. Autopsy of rabbits showed evidence of gas retention in the lung tissue and gas bubbles in the right cardiac cavities. Histologic findings included alveolar hemorrhage with pulmonary edema, cerebellum, and cortex patchy areas of infarction. Single-dose intravenous administration of PF-5070 reproduced in a rabbit model the pathophysiologic effects observed in the hemodialysis patients. Severity of the symptoms observed in the animals was dose-dependent. Clinical and pathologic findings can be explained by the capacity of perfluorocarbon to emulsify blood at body temperature, to increase partial pressure in the pulmonary capillary bed, and to form bubbles in the pulmonary capillary circulation, thus blocking lung and visceral perfusion. Such experimental findings indicate the toxicity of PF-5070 administered intravenously and make the pathochemical toxicity link with the hemodialysis-related deaths caused by the presence of residues of PF-5070 in the Althane dialyzers. We conclude, in light of this outbreak and the subsequent investigations, that liquid PF-5070 is a highly toxic compound when administered intravenously because of its emulsifying properties. The use of PF-5070 or any liquid fluorocarbon compounds in medical devices with blood contact and particularly in the dialyzer manufacturing should be considered with caution.
Animals↗
Anemia and heart failure in chronic kidney disease.
Cardiovascular disease is mainly responsible for the poor long-term survival observed in chronic kidney disease (CKD) patients on dialytic treatment. Anemia is an early complication of CKD and, by inducing important cardiovascular alterations, first of all left ventricular hypertrophy, it does not only impair quality of life, but has also been shown to be an independent risk factor for adverse cardiovascular outcomes in CKD patients. Clinical studies, although with discordant results, have shown that cardiovascular benefits, mainly in terms of left ventricular hypertrophy regression, may be achieved by a partial correction of hemoglobin levels, however, it still is unclear whether starting anemia correction in a very early phase of CKD or aiming for complete normalization of hemoglobin levels higher than the targets recommended by current guidelines may provide further cardiovascular advantages. Results of ongoing, large-scale, prospective, randomized, clinical trials therefore are awaited with much interest to clarify better which practices of anemia correction may provide the best results on the improvement of cardiovascular status and thus of long-term survival of patients with renal disease.
Age Distribution↗
Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy.
BACKGROUND: Little is known of the effects of blood pressure reduction by specific classes of antihypertensive drugs on the association between proteinuria reduction and progression of kidney insufficiency and development of end-stage kidney disease in patients with overt diabetic nephropathy in type 2 diabetes mellitus. METHODS: Associations between baseline proteinuria and proteinuria reduction by either irbesartan, amlodipine, or control for similar decrements in blood pressure and the cumulative incidence of renal end points were examined using the Kaplan-Meier method in patients enrolled in the Irbesartan Diabetic Nephropathy Trial. RESULTS: Risk for kidney failure doubled for each doubling of baseline proteinuria level (hazard ratio, 2.04; 95% confidence interval, 1.87 to 2.22; P < 0.001). For each halving of proteinuria level between baseline and 12 months with treatment, risk for kidney failure was reduced by more than half (hazard ratio, 0.44; 95% confidence interval, 0.40 to 0.49; P < 0.001). For the same proportional change in proteinuria, the reduction in risk for kidney failure was significantly greater for irbesartan compared with amlodipine ( P = 0.048), but not control ( P = 0.245). Proteinuria reduction in the first 12 months of therapy with irbesartan is associated with 36% of the total renoprotective effect observed. CONCLUSION: Baseline proteinuria is an important risk factor for kidney failure and provides a means to identify patients at greatest risk. Halving proteinuria halves the kidney risk. Proteinuria reduction using an angiotensin receptor-blocking agent, such as irbesartan, should be regarded as an important therapeutic goal in renoprotective strategies.
Adult↗
Comparison of hemodialysis, hemodiafiltration, and hemofiltration: systematic review or systematic error?
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Chi-Square Distribution↗
Inflammation and resistance to treatment with recombinant human erythropoietin.
Despite an increase in the use and average dose of recombinant human EPO (rh-EPO) over the last 15 years, a substantial percentage of patients still do not achieve hemoglobin targets recommended by international guidelines. The definition of rh-EPO resistance has been introduced to identify those patients in whom the target hemoglobin level is not attained despite a greater-than-usual dose of erythropoietin-stimulating agent (ESA). In recent years, increasing attention has been paid to the relationship between dialysis, increased inflammatory stimulus, malnutrition, and ESA response. About 35% to 65% of hemodialysis patients show signs of inflammation that could be a cause of anemia through the suppression of bone marrow erythropoiesis by a number of cytokines. A large proportion of chronic kidney disease patients also have protein-energy malnutrition and wasting; low serum albumin levels, together with other more specific nutritional markers, are predictors of rh-EPO response. A diminished nutritional state could then be a feature of patients who are resistant to ESA treatment, with malnutrition probably being a consequence of a chronic inflammatory state. Starting from the hypothesis that anemia, partially attributable to a reduced response to ESA, could be the link among malnutrition, inflammation, and the poor outcome of chronic kidney disease patients, we designed a multicenter observational study, the Malnutrition-Inflammation-Resistance-Treatment Outcome Study (MIRTOS), aimed at evaluating the impact and possible causes of resistance to ESA in a large sample of hemodialysis patients. We hope the results of MIRTOS will represent a step forward toward a better understanding of the factors influencing the response to ESA in hemodialysis patients.
Anemia↗
Once weekly treatment with epoetin-beta.
Studies have shown that both intravenous (i.v.) and subcutaneous (s.c.) administration of epoetin-beta therapy are effective and well tolerated in the treatment of renal anaemia; however, the s.c. route provides enhanced efficacy with a lower dose compared with the i.v. route and it is more cost-effective. Epoetin dosing frequency is an important issue for health care professionals and patients. Recent studies have shown that epoetin-beta administered once weekly and once every 2 weeks can maintain stable target haemoglobin and haematocrit levels in dialysis patients. Such reduced dosing frequencies may improve patient satisfaction and compliance with treatment, and encourage patients to self-administer. Furthermore, less frequent dosing administration would be associated with economic benefits in terms of reduced nursing time in the clinic or out-patient setting. Where this is clinical practice, fewer injections and visits to the clinic should also improve patients' quality of life. A range of effective dosing regimens with epoetin-beta administered via either pre-filled syringes, multidose vials or injector pens allows physicians to tailor treatment to an individual patient's preference.
Anemia↗
Haemodialysis with on-line monitoring equipment: tools or toys?
BACKGROUND: On-line monitoring of chemical/physical signals during haemodialysis (HD) and bio-feedback represents the first step towards a 'physiological' HD system incorporating adaptive and logic controls in order to achieve pre-set treatment targets. METHODS: Discussions took place to achieve a consensus on key points relating to on-line monitoring and bio-feedback, focusing on the clinical applications. RESULTS: The relative blood volume (BV) reduction during HD can be monitored by optic devices detecting the variations in concentration of haemoglobin/haematocrit. BV changes result from an equilibrium between ultrafiltration and the refilling capacity. However, BV reduction has little power in predicting intra-HD hypotensive episodes, while the combination of the patient-dialysate sodium gradient, the relative BV reduction between the 20th and 40th minute of HD, the irregularity of the profile of BV reduction over time and the heart rate decrease from the start to the 20th minute of HD predict intra-HD hypotension with a sensitivity of 82%, a specificity of 73% and an accuracy of 80%. A bio-feedback system drives the relative BV reduction according to desired values by instantaneously changing the ultrafiltration rate and the dialysate conductivity. This system has proved to reduce the incidence of intra-HD hypotension episodes significantly. Ionic dialysance and the patient's plasma conductivity can be calculated easily from on-line inlet and outlet dialysate conductivity measurements at two different steps of dialysate conductivity. Ionic dialysance is equivalent to urea clearance corrected for recirculation and is a tool for continuously monitoring the dialysis efficiency and detecting early problems with the delivery of the prescribed dose of dialysis. Given the strict and linear relationship between conductivity and sodium content, the conductivity values replace the sodium concentration values and this permits the development of a conductivity kinetic model, by means of which sodium balance can be achieved at each dialysis session. The conductivity kinetic model has been demonstrated to improve intra-HD cardiovascular stability in hypotension-prone patients significantly. Ionic dialysance is also a useful tool to monitor vascular access function, as it can be used to obtain serial measurements of vascular access blood flow. On-line urea monitors provide detailed information on intra-HD urea kinetics and delivered dialysis dose, but they are not in widespread use because of the costs related to the disposable materials (e.g. urease cartridge). The body temperature monitor measures the blood temperature at the arterial and venous lines of the extra-corporeal circuit and, thanks to a bio-feedback system, is able to modulate the dialysate temperature in order to influence the patient's core body temperature, which can be kept at constant values. This is associated with improved intra-HD cardiovascular stability. The module can also be used to quantify total recirculation. CONCLUSIONS: On-line monitoring devices and bio-feedback systems have evolved from toys for research use to tools for routine clinical application, particularly in patients with clinical complications. Conductivity monitoring appears the most versatile tool, as it permits quantification of delivered dialysis dose, achievement of sodium balance and surveillance of vascular access function, potentially at each dialysis session and without extra cost.
Biofeedback, Psychology↗
Mini-peritoneal equilibration test: A simple and fast method to assess free water and small solute transport across the peritoneal membrane.
BACKGROUND: Loss of ultrafiltration (UF) of peritoneal membrane is one of the most important causes of peritoneal dialysis failure. UF is determined by osmotic forces acting mainly across small pores (UFSP) and ultrasmall pores or free water transport. At present, only semiquantitative estimates or complicated computer simulations are available to assess free water transport. The aim of this study was to assess free water transport during a 3.86% peritoneal equilibration test lasting 1 hour. In this condition, sodium transport is mainly due to convection, allowing the estimate of ultrafiltration of small pores and then of free water transport (total UF - UFSP). METHODS: In 52 peritoneal dialysis patients we performed a 3.86% peritoneal equilibration test (4 hours) and a 3.86% mini-peritoneal equilibration test (1 hour) and compared UF and small solute transports obtained with the two methods. RESULTS: During the 3.86% mini-peritoneal equilibration test, UFSP and free water transport were 279 +/- 142 mL and 215 +/- 86 mL, respectively; free water transport well correlated to total UF during the 3.86% peritoneal equilibration test (r= 0.67). The groups of peritoneal transporters, categorized according to glucose dialysate ratio (D/D(0)) and to creatinine/plasma ratio (D/P(Creat)), were in good agreement for the two peritoneal equilibration tests (weighted kappa 0.62 and 0.61, respectively). CONCLUSION: The 3.86% mini-peritoneal equilibration test is a simple and fast method to assess free water transport. It also gives information about total UF and small solute transports and it is in good agreement with the 3.86% peritoneal equilibration test.
Adult↗
Relationship between urea clearance and ionic dialysance determined using a single-step conductivity profile.
BACKGROUND: On-line determination of ionic dialysance (ID) has been used to measure the clearance of small solutes like urea. However, attempts to determine the in vivo relationship between ID and urea clearance have led to discordant findings. The aim of this study was to determine the relationship between the mean values of repeated instantaneous determinations of ID throughout a dialysis session ((m)ID), obtained using a single-step inlet dialysate conductivity profile, and the mean values of urea clearance corrected for access recirculation (K(eu1)), total recirculation (access plus cardiopulmonary recirculation, K(eu2)), and the entire postdialysis urea rebound (K(wb)). METHODS: Eighty-two anuric patients on chronic thrice-weekly hemodialysis were studied using an Integra machine equipped with the Diascan module for the automatic determination of ID. The mean values of repeated ID measurements made at 30-minute intervals were compared with K(eu1) (available for only 31 patients), K(eu2), and K(wb). RESULTS: The results in all 82 patients were: (m)ID = 176 +/- 23 mL/min; K(eu2) = 181 +/- 25 mL/min; K(wb) = 159 +/- 22 mL/min. The mean (m)ID/K(wb) and (m)ID/K(eu2) ratios were, respectively, 1.11 +/- 0.06 and 0.98 +/- 0.06. The results in the 31 patients for whom K(eu1) values were available were: (m)ID = 179 +/- 24 mL/min and K(eu1) = 200 +/- 27 mL/min; the mean (m)ID/K(eu1) ratio was 0.90 +/- 0.05. CONCLUSION: The mean value of repeated ID determinations obtained using a single-step conductivity profile underestimates urea clearance corrected for access recirculation, and may be considered an adequate estimate of urea clearance corrected for total recirculation.
Anuria↗