Umberto Maggiore

Prednisone versus tamoxifen in patients with idiopathic retroperitoneal fibrosis: an open-label randomised controlled trial

BACKGROUND Glucocorticoids are the mainstay of treatment of idiopathic retroperitoneal fibrosis, but they often have substantial toxic effects. Several reports have suggested tamoxifen as an alternative to glucocorticoids. We compared the efficacy of prednisone with that of tamoxifen in maintainance of remission in patients with idiopathic retroperitoneal fibrosis. METHODS In this open-label, randomised controlled trial, we enrolled patients aged 18-85 years with newly diagnosed idiopathic retroperitoneal fibrosis at the Parma Hospital, Parma, Italy, between Oct 1, 2000, and June 30, 2006. After induction therapy with 1 mg/kg daily of prednisone for 1 month, the patients who achieved remission were randomly assigned to receive tapering prednisone (initial dose 0·5 mg/kg daily) for 8 months or tamoxifen (fixed dose 0·5 mg/kg daily) for 8 months. The sequence of randomisation (1:1), blocked in groups of two and four (with block size randomly selected), was generated by the trial statistician with a computer programme. After the end of treatment, the patients were followed up for an additional 18 months. Neither patients nor those giving interventions or analysing the data were masked to group assignment. The two radiologists who assessed CT and MRI scans were masked. The primary endpoint was the relapse rate by the end of treatment (month 8), which was analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00440349. FINDINGS After induction therapy, 36 of the 40 enrolled patients achieved remission and were randomly assigned to treatment (18 per group). One patient (6%) in the prednisone group and seven patients (39%) in the tamoxifen group relapsed by the end of treatment (difference -33% [95% CI -58 to -8, p=0·0408]. The difference in relapse rate between the groups was sustained after the additional 18-month follow-up: the 26-month estimated cumulative relapse probability was 17% with prednisone and 50% with tamoxifen (difference -33% [-62 to -3, p=0·0372]). Cushingoid changes and grade 2 hypercholesterolaemia were more common in the prednisone group than in the tamoxifen group (p=0·0116 and p=0·0408, respectively). INTERPRETATION Prednisone is more effective in prevention of relapses than is tamoxifen in patients with idiopathic retroperitoneal fibrosis. Therefore, prednisone should be considered as first-line treatment for patients with newly diagnosed idiopathic retroperitoneal fibrosis. FUNDING Parma University Hospital.

Effects of a low-salt diet on idiopathic hypercalciuria in calcium-oxalate stone formers: a 3-mo randomized controlled trial

BACKGROUND A direct relation exists between sodium and calcium excretion, but randomized studies evaluating the sustained effect of a low-salt diet on idiopathic hypercalciuria, one of the main risk factors for calcium-oxalate stone formation, are still lacking. OBJECTIVE Our goal was to evaluate the effect of a low-salt diet on urinary calcium excretion in patients affected by idiopathic calcium nephrolithiasis. DESIGN Patients affected by idiopathic calcium stone disease and hypercalciuria (>300 mg Ca/d in men and >250 mg Ca/d in women) were randomly assigned to receive either water therapy alone (control diet) or water therapy and a low-salt diet (low-sodium diet) for 3 mo. Twenty-four-hour urine samples were obtained twice from all patients: one sample at baseline on a free diet and one sample after 3 mo of treatment. RESULTS A total of 210 patients were randomly assigned to receive a control diet (n = 102) or a low-sodium diet (n = 108); 13 patients (2 on the control diet, 11 on the low-sodium diet) withdrew from the trial. At the follow-up visit, patients on the low-sodium diet had lower urinary sodium (mean +/- SD: 68 +/- 43 mmol/d at 3 mo compared with 228 +/- 57 mmol/d at baseline; P < 0.001). Concomitant with this change, they showed lower urinary calcium (271 +/- 86 mg/d at 3 mo compared with 361 +/- 129 mg/d on the control diet, P < 0.001) and lower oxalate excretion (28 +/- 8 mg/d at 3 mo compared with 32 +/- 10 mg/d on the control diet, P = 0.001). Urinary calcium was within the normal range in 61.9% of the patients on the low-salt diet and in 34.0% of those on the control diet (difference: +27.9%; 95% CI: +14.4%, +41.3%; P < 0.001). CONCLUSION A low-salt diet can reduce calcium excretion in hypercalciuric stone formers. This trial was registered at clinicaltrials.gov as NCT01005082.

Severe Hypomagnesemia During Long-term Treatment With a Proton Pump Inhibitor

Severe hypomagnesemia is a serious clinical ondition that can be complicated by lifehreatening arrhythmias (ventricular tachycardia, entricular fibrillation, and torsades de pointes) nd neurologic manifestations (neuromuscular yperexcitability, frank ataxia, confusion, deirium, and seizures). Moreover, hypokalemia nd hypocalcemia frequently are documented as ccompanying electrolyte disorders. Hypomagesemia is relatively common in hospitalized atients, particularly in intensive care units. eading causes of the acquired disorder are malbsorption, uncontrolled diabetes, chemotherapy, cute pancreatitis, drugs, and refeeding. Very few cases of severe hypomagnesemia elated to long-term use of proton pump inhibiors (PPIs) have been published to date, and he likely pathogenetic mechanisms are not fully lucidated. We report a case of severe symptomatic hypoagnesemia in a patient treated with PPIs for any years because of Barrett esophagus. The ifferential diagnosis and potential pathogenetic echanisms are discussed within a more general onceptual framework of the pathophysiology tate of serum magnesium homeostasis.

The relation between the incidence of hypernatremia and mortality in patients with severe traumatic brain injury

IntroductionThe study was aimed at verifying whether the occurrence of hypernatremia during the intensive care unit (ICU) stay increases the risk of death in patients with severe traumatic brain injury (TBI). We performed a retrospective study on a prospectively collected database including all patients consecutively admitted over a 3-year period with a diagnosis of TBI (post-resuscitation Glasgow Coma Score ≤ 8) to a general/neurotrauma ICU of a university hospital, providing critical care services in a catchment area of about 1,200,000 inhabitants.MethodsDemographic, clinical, and ICU laboratory data were prospectively collected; serum sodium was assessed an average of three times per day. Hypernatremia was defined as two daily values of serum sodium above 145 mmol/l. The major outcome was death in the ICU after 14 days. Cox proportional-hazards regression models were used, with time-dependent variates designed to reflect exposure over time during the ICU stay: hypernatremia, desmopressin acetate (DDAVP) administration as a surrogate marker for the presence of central diabetes insipidus, and urinary output. The same models were adjusted for potential confounding factors.ResultsWe included in the study 130 TBI patients (mean age 52 years (standard deviation 23); males 74%; median Glasgow Coma Score 3 (range 3 to 8); mean Simplified Acute Physiology Score II 50 (standard deviation 15)); all were mechanically ventilated; 35 (26.9%) died within 14 days after ICU admission. Hypernatremia was detected in 51.5% of the patients and in 15.9% of the 1,103 patient-day ICU follow-up. In most instances hypernatremia was mild (mean 150 mmol/l, interquartile range 148 to 152). The occurrence of hypernatremia was highest (P = 0.003) in patients with suspected central diabetes insipidus (25/130, 19.2%), a condition that was associated with increased severity of brain injury and ICU mortality. After adjustment for the baseline risk, the incidence of hypernatremia over the course of the ICU stay was significantly related with increased mortality (hazard ratio 3.00 (95% confidence interval: 1.34 to 6.51; P = 0.003)). However, DDAVP use modified this relation (P = 0.06), hypernatremia providing no additional prognostic information in the instances of suspected central diabetes insipidus.ConclusionsMild hypernatremia is associated with an increased risk of death in patients with severe TBI. In a proportion of the patients the association between hypernatremia and death is accounted for by the presence of central diabetes insipidus.

The Kidney Donor Profile Index (KDPI) of marginal donors allocated by standardized pretransplant donor biopsy assessment: distribution and association with graft outcomes.

Pretransplant donor biopsy (PTDB)‐based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score <4 [median KDPI: 87; interquartile range (IQR): 78–94] and 62 with a score = 4 [median KDPI: 87; IQR: 76–93]; 102 dual transplants [median KDPI: 93; IQR: 86–96]) and 248 single standard transplant controls (median KDPI: 36; IQR: 18–51). PTDB‐based allocation of marginal grafts led to a limited discard rate of 15% for kidneys with KDPI of 80–90 and of 37% for kidneys with a KDPI of 91–100. Although 1‐year estimated GFRs were significantly lower in recipients of marginal kidneys (−9.3, −17.9 and −18.8 mL/min, for dual transplants, single kidneys with PTDB score <4 and =4, respectively; p < 0.001), graft survival (median follow‐up 3.3 years) was similar between marginal and standard kidney transplants (hazard ratio: 1.20 [95% confidence interval: 0.80–1.79; p = 0.38]). In conclusion, PTDB‐based allocation allows the safe transplantation of kidneys with KDPI in the highest range that may otherwise be discarded.

Survival in Patients Treated by Long-term Dialysis Compared With the General Population

BACKGROUND Relative survival, a methodology previously used in epidemiologic studies of cancer, compares the observed survival of a patient cohort with expected survival derived from general population life tables. We examined relative survival in patients treated by long-term dialysis in the Italian Dialysis and Transplantation Registry in order to determine the prognosis of dialysis patients. STUDY DESIGN Cohort study drawn from a registry. SETTING & PARTICIPANTS Patients enrolled in the Italian Dialysis and Transplantation Registry. FACTORS Sex, age, primary kidney disease, renal replacement therapy modality, and main comorbid conditions. OUTCOMES Death from any cause. MEASUREMENTS Relative survival ratio (the ratio of observed survival in the population of interest to the survival expected given the age- and period-specific mortality of the general population) and excess mortality rate (difference between observed and expected mortality rates). RESULTS In January 2000 to December 2008, a total of 27,642 patients were included. The 5-year relative survival estimate was 55.6% (95% CI, 54.7%-56.5%). The excess mortality rate showed a peak at 3 months (21 deaths/100 patient-years), then decreased, becoming constant from the end of year 1 to year 8, with leveling off at about 10 deaths/100 patient-years. Older age, systemic diseases, and diabetes showed the strongest association with excess mortality. Peritoneal dialysis was associated with a lower relative excess risk in only the first year of treatment. LIMITATIONS The patient cohort comprises about half the Italian patients beginning dialysis therapy in the period. CONCLUSIONS This study highlights the applicability of relative survival methods in dialysis patients. This measure allows estimation of disease prognosis and severity comparisons among chronic diseases. The excess mortality rate appears to be a more sensitive and informative measure than the simple proportion of survivors.

Mortality rate comparison after switching from continuous to prolonged intermittent renal replacement for acute kidney injury in three intensive care units from different countries

BACKGROUND Prolonged intermittent renal replacement therapy (PIRRT) is a dialysis modality for critically ill patients that in theory combines the superior detoxification and haemodynamic stability of the continuous renal replacement therapy (CRRT) with the operational convenience, reduced haemorrhagic risk and low cost of conventional intermittent haemodialysis. However, the extent to which PIRRT should replace these other modalities is uncertain because comparative studies of mortality are lacking. We retrospectively examined the mortality data from three general intensive care units (ICUs) in different countries that have switched their predominant therapeutic approach from CRRT to PIRRT. We assessed whether this practice change was associated with a change in mortality rate. METHODS Data were analysed from ICUs in New Zealand, Australia and Italy. The study population comprised all patients requiring renal replacement therapy from 1 January 1995 to 31 December 2005 (n = 1347), the period of time spanning the change from CRRT to PIRRT in each unit. Poisson regression models were used to estimate the incident rate ratio (IRR) for death, comparing the periods before and after change to PIRRT in each unit. Estimates were adjusted for patient illness severity (APACHE II score) and for the underlying time trend in mortality rate over time. RESULTS The change from CRRT to PIRRT was not associated with any increase in mortality rate, with an adjusted IRR of 1.02 (0.61-1.71). The IRR was virtually identical in the three ICUs (P-value = 0.63 for the difference in the IRR between ICUs). CONCLUSIONS Switching from CRRT to PIRRT was not associated with a change in mortality rate. Pending the results of a randomized trial, our study provides evidence that PIRRT might be equivalent to CRRT in the general ICU patient.

Polyreactive Antibodies Developing Amidst Humoral Rejection of Human Kidney Grafts Bind Apoptotic Cells and Activate Complement

Antibody mediated rejection (AMR) is associated with a variety of graft‐reactive antibodies following kidney transplant. To characterize these antibodies, we immortalized 107 B cell clones from a patient with AMR. In a previous study, we showed that six clones were reacting to multiple self‐antigens as well as to HLA and MICA for two of them, thus displaying a pattern of polyreactivity. We show here that all six polyreactive clones also reacted to apoptotic but not viable cells. More generally we observed a nearly perfect overlap between polyreactivity and reactivity to apoptotic cells. Functionally, polyreactive antibodies can activate complement, resulting in the deposition of C3d and C4d at the surface of target cells. Testing the serum of 88 kidney transplant recipients revealed a significantly higher IgG reactivity to apoptotic cells in AMR patients than in patients with stable graft function. Moreover, total IgG purified from AMR patients had increased complement activating properties compared to IgG from non‐AMR patients. Overall, our studies show the development of polyreactive antibodies cross‐reactive to apoptotic cells during AMR. Further studies are now warranted to determine their contribution to the detection of C4d in graft biopsies as well as their role in the pathophysiology of AMR.

Specialized nutritional support interventions in critically ill patients on renal replacement therapy

Purpose of reviewOptimal nutritional requirements and nutrient intake composition for patients with acute kidney injury remain a partially unresolved issue. Targeting nutritional support to the actual protein and energy needs improves the clinical outcome of critically ill patients, yet very few data are currently available on this topic in acute kidney injury. In this specific clinical condition the risk for underfeeding and overfeeding may be increased by factors interfering on nutrient need estimation, such as rapidly changing body weight due to fluid balance variations, nutrient losses and hidden calorie sources from renal replacement therapy. Moreover, as acute kidney injury is now considered a kidney-centered inflammatory syndrome, the renoprotective role of specific pharmaconutrients with anti-inflammatory properties remains to be fully defined. This review is aimed at discussing recently published results concerning quantitative and qualitative aspects of the nutritional approach to acute kidney injury in critically ill patients. Recent findingsNutrient needs in patients with acute kidney injury can be difficult to estimate, and should be directly measured, especially in the ICU setting. In fact, recent findings suggest that hidden calorie sources not routinely taken into account – for example, calories from anticoagulants and replacement solutions for renal replacement therapy – could be quantitatively relevant in these patients. Moreover, recent experimental data indicate a possible role for some pharmaconutrients with anti-inflammatory effects (glutamine, and omega-3 fatty acids), in both the prevention of renal function worsening, and in the fostering of renal function recovery after an episode of acute kidney injury. SummaryAcute kidney injury includes a highly heterogeneous group of patients with widely varying nutrient needs and intakes. Nutritional requirements, in their quantitative and qualitative aspects, should be frequently assessed, individualized, and carefully integrated with renal replacement therapy, in order to avoid both underfeeding and overfeeding, as well as to exploit possible positive pharmacologic effects of specific nutrients.

Ultrafiltration in heart failure

Fluid overload is a key pathophysiologic mechanism underlying both the acute decompensation episodes of heart failure and the progression of the syndrome. Moreover, it represents the most important factor responsible for the high readmission rates observed in these patients and is often associated with renal function worsening, which by itself increases mortality risk. In this clinical context, ultrafiltration (UF) has been proposed as an alternative to diuretics to obtain a quicker relief of pulmonary/systemic congestion. This review illustrates technical issues, mechanisms, efficacy, safety, costs, and indications of UF in heart failure. The available evidence does not support the widespread use of UF as a substitute for diuretic therapy. Owing to its operative characteristics, UF cannot be expected to directly influence serum electrolyte levels, azotemia, and acid-base balance, or to remove high-molecular-weight substances (eg, cytokines) in clinically relevant amounts. Ultrafiltration should be used neither as a quicker way to achieve a sort of mechanical diuresis nor as a remedy for an inadequately prescribed and administered diuretic therapy. Instead, it should be reserved to selected patients with advanced heart failure and true diuretic resistance, as part of a more complex strategy aiming at an adequate control of fluid retention.