Increase of continuous treatments and regional citrate anticoagulation during renal replacement therapy in the ICUs of the North-West of Italy from 2007 to 2015.

BACKGROUND: Few reports have addressed the change in renal replacement therapy (RRT) management in the Intensive care Units (ICUs) over the years in western countries. This study aims to assess the trend of dialytic practice in a 4.5-million population-based study of the northwest of Italy. METHODS: A nine-year survey covering all the RRT provided in the ICUs. Consultant nephrologists of the 26 Nephrology and Dialysis centers reported their activities in the years 2007, 2009, 2012, and 2015. RESULTS: From 2007 to 2015 the patients treated increased from 1042 to 1139, and the incidence of RRT from 254 to 263 cases/10^6 inhabitants. The workload for dialysis center was higher in the larger hub hospitals. RRT for acute kidney injury (AKI), continuation of treatment in chronically dialyzed patients, or extrarenal indications accounted for about the stable rate of 70, 25 and 5% of all RRT sessions, respectively. Continuous modality days increased from 2731 days (39.5%) in 2007 to 5076 (70.6%) in 2015, when the continuous+prolonged treatment days were 6880/7196 (95.6% of total days). As to RRT timing, in 2015 only the classical clinical criteria, and no K-DIGO stage were adopted by most Centers. As to RRT interruption, in 2015 urine volume was the first criterion. Implementation of citrate anticoagulation (RCA) for RRT patients significantly increased from 2.8% in 2007 to 30.9% in 2015, when it was applied in all 26 Centers. CONCLUSIONS: From 2007 to 2015, current practice has changed towards shared protocols, with increasing continuous modality and RCA implementation.

Differential response to renal replacement therapy in neonatal-onset inborn errors of metabolism.

Severe urea cycle defects (UCD), organic acidemias (OA) and maple syrup urine disease (MSUD) are life-threatening disorders presenting in the first days of life. Renal replacement therapy (RRT) is an emergency option in affected newborns, mostly performed as ultima ratio. We report our 10-year experience using emergency RRT in newborns with UCD, OA and MSUD. Twelve newborns (eight with UCD, two with methylmalonic acidemia and two with MSUD) underwent emergency RRT. The overall survival rate to RRT was 58.3%. Hyperammonemic newborns required earlier RRT with respect to MSUD patients (75 (65-102) vs 301 (192-410) h of life, P < 0.01). Hyperammonemic neonates surviving (n = 5) and non-surviving (n = 5) the acute neonatal decompensation showed similar birth weight (P = 0.690), duration of intubation (P = 0.917), ammonia at onset (P = 0.916) and at the start of RRT (P = 0.426), age at RRT (P = 0.999) and duration of coma before RRT (P = 0.691). Remarkably, all survivors quickly responded to RRT, with ammonia concentration less than 300 µmol/L after 8 h of treatment. One patient with UCD successfully treated by neonatal RRT died at 4 months of life because of sepsis. All patients with MSUD had normalized leucine levels after 12 h of RRT, surviving the acute neonatal decompenstation. All long-term survivors (five liver transplanted, one waiting for liver transplantation) currently show normal or near-normal neurological development (48 ± 39 months of age). Early response to RRT was associated with survival irrespective of pre-treatment picture. RRT can be considered even in huge neonatal metabolic decompensations. Early liver transplantation may be an option for select patients.

Liver transplantation for aHUS: still needed in the eculizumab era?

BACKGROUND: The risk of disease recurrence after a kidney transplant is high in patients with atypical hemolytic uremic syndrome (aHUS) and mutations in the complement factor H (FH) gene (CFH). Since FH is mostly produced by the liver, a kidney transplant does not correct the genetic defect. The anti-C5 antibody eculizumab prevents post-transplant aHUS recurrence, but it does not cure the disease. Combined liver-kidney transplantation has been performed in few patients with CFH mutations based on the rationale that liver replacement provides a source of normal FH. METHODS: We report the 9-year follow-up of a child with aHUS and a CFH mutation, including clinical data, extensive genetic characterization, and complement profile in the circulation and at endothelial level. The outcome of kidney and liver transplants performed separately 3 years apart are reported. RESULTS: The patient showed incomplete response to plasma, with relapsing episodes, progression to end-stage renal disease, and endothelial-restricted complement dysregulation. Eculizumab prophylaxis post-kidney transplant did not achieve sustained remission, leaving the child at risk of disease recurrence. A liver graft given 3 years after the kidney transplant completely abrogated endothelial complement activation and allowed eculizumab withdrawal. CONCLUSIONS: Liver transplant may definitely cure aHUS and represents an option for patients with suboptimal response to eculizumab.

Neonatal sepsis with multi-organ failure and treated with a new dialysis device specifically designed for newborns.

Neonatal sepsis due to E. coli is often complicated by multiple organ failure (MOF) and a high mortality risk. We report the case of a term newborn discharged in good condition who suddenly fell into septic shock after 11 days and required immediate resuscitation, volume expansion and a high-dosage amine infusion. Extremely severe metabolic acidosis, disseminated intravascular coagulation (DIC) with diffuse bleeding, and unstable hemodynamic status with oliguria turned into strict anuria, and the patient became anuric. The presence of DIC, with gastric and intestinal bleeding, rendered peritoneal dialysis impossible. Continuous renal replacement therapy (CRRT) was started with the new dialysis machine CARPEDIEM(®) (Cardio-Renal Pediatric Dialysis Emergency Machine), available on a trial-basis in our center, after the surgical placement of jugular double-lumen central venous catheters. A 'ready to use' neonatal kit with a low-priming volume of the extracorporeal circuit allowed a prompt hemofiltration start. The filtration CRRT was continuously performed for 48 h, then intermittently (12 h/day) for 2 more days and interrupted on day 5 for diuresis reprisal. Acute kidney injury and multi-organ failure resolved after 5 days. The child survived without neurological damage, with a normal renal function and a normal development at 9 months follow-up. In conclusion, a prompt CRRT start with this specifically designed neonatal device allowed a progressive stabilization of hemodynamics, a better control of acidosis, a reduction of amine requirement, a gradual control of fluid overload and a rapid improvement of MOF, DIC as well as a resolution of the acute kidney injury. The device also allowed the extension of CRRT in the neonatal age.

[Bioincompatibility of acetate even at low concentrations]. / Bioincompatibilita' dell'acetato anche in tracce.

Over the last 20 years a large body of evidence has demonstrated that in chronic renal failure there is progressive chronic inflammation, which increases after the start of dialysis. In this phase a fundamental role is played by bioincompatibility reactions induced by contact with the different dialysis materials: membranes, plastic lines, dialysis fluids as well as contaminants present in water. Clinically evident symptoms induced by bioincompatibility reactions are usually taken into serious account by nephrologists, while more subtle chronic effects, noxious in the long term, are often underconsidered. Since the 1990s many efforts have been addressed to membrane improvement and water treatment, while there is still a lot to be done for better dialysates. Acetate dialysis is routinely used in only about 5% of patients worldwide but over 80% of patients are exposed to the lower acetate concentrations present in standard bicarbonate dialysate. These concentrations are not negligible and are able to induce chronic reactions mainly converging on the endothelium, stimulating and maintaining the atherogenesis process with important long-term implications for cardiovascular morbidity. This review presents and discusses the available data on the cellular and molecular effects induced by acetate, even at low concentrations.

Bicarbonate dialysis, unlike acetate-free biofiltration, triggers mediators of inflammation and apoptosis in endothelial and smooth muscle cells.

BACKGROUND: We previously demonstrated that bicarbonate dialysis solutions incubated with endothelial cells (EC) enhance nitric oxide synthase (NOS). We then investigated whether blood circulated in simulated dialysis circuits triggers inflammatory and apoptotic mediators in vessel wall cells, aiming to compare the effects of bicarbonate hemodialysis (BHD) and acetate-free biofiltration (AFB). METHODS: Blood units from 22 healthy donors were dialyzed on AN69 with BHD in 11 sessions and AFB in another 11 sessions. Each dialysate remained endotoxin-free during the 60 min of dialysis. Blood samples having been re-circulated for 15 and 60 min were incubated with EC and smooth muscle cells (SMC), which were then investigated for NOS activity (3H citrulline production from 3H arginine), mRNAs transcription of the inducible isoforms of NOS (iNOS) and cyclooxygenase (COX-2) and the pro-apoptotic p53 protein. To investigate cell-cell interactions, in an-other series of 16 simulated dialyses, lympho-monocytes from blood circulated in either BHD or AFB were incubated with EC co-cultured in transwell devices with SMC. NOS activity was measured in EC and SMC. RESULTS: In comparison to AFB, blood circulated in BHD induced a significantly greater enhancement of NOS activity in EC, SMC and mRNAs transcription of pro-inflammatory iNOS, COX-2 and pro-apoptotic p53 (for each BHD data series p < 0.01 to p < 0.0001 vs. AFB). Lympho-monocytes from blood circulated in BHD but not in AFB, triggered the final SMC activation. CONCLUSIONS: Ex vivo AFB is less effective than BHD in activating vessel wall cells to synthesis/release of pro-inflammatory and pro-apoptotic mediators.

Parathyroid hormone levels in pubertal uremic adolescents treated with growth hormone.

We have previously described severe hyperparathyroidism during the pubertal growth spurt in three uremic adolescents treated with recombinant human growth hormone (rhGH). Here we investigate the possible role of puberty in the genesis of hyperparathyroidism during rhGH treatment of a large cohort of patients. Data from 67 uremic patients treated with rhGH from five Italian pediatric nephrology centers were retrospectively recorded every 3 months starting 1 year before rhGH administration. The mean (+/-SD) rhGH treatment observation period was 19.9+/-5.9 months. The mean age at the start of rhGH treatment was 8.3+/-3.6 years. Of the 67 patients, 15 reached pubertal stage 2 during the 1st year of rhGH treatment and 12 of these 15 progressed to pubertal stage 3. The relative increase in parathyroid hormone (PTH) levels after rhGH initiation was greater in pubertal [1.95, 95% confidence interval (CI) 1.43-2.66] than in prepubertal patients (1.19, 95% CI 1.01-1.40). Increases in PTH levels were significantly different between the two groups (Delta=1.64, 95% CI 1.16-3.19, P=0.007). Multiple regression analysis showed an inverse correlation between PTH and calcium levels and a positive correlation between PTH and pubertal stage 3. There was no correlation with phosphate levels and calcitriol dosage. In conclusion, these results suggest that in uremic adolescents treated with rhGH puberty may influence PTH levels.

Epidemiology of chronic renal failure in children: data from the ItalKid project.

OBJECTIVE: The ItalKid Project is a prospective, population-based registry that was started in 1990 with the aim of assessing the epidemiology of childhood chronic renal failure (CRF), describing the natural history of the disease, and identifying factors that influence its course. This article reports the epidemiologic results. METHODS: Prevalent and incident cases of CRF in children and adolescents were identified throughout Italy (total population base: 16.8 million children) by regularly asking all of the pediatric hospitals and adult nephrology units potentially involved in caring for children with kidney disease to report all cases that meet the inclusion criteria and then to update the clinical information regarding all previously reported patients on an annual basis. The inclusion criteria were 1) creatinine clearance (Ccr; according to Schwartz's formula) <75 mL/min/1.73 m2 bsa (predialysis) and 2) an age of <20 years at the time of registration. RESULTS: By December 31, 2000, 1197 patients (803 boys) had been registered. The mean incidence was 12.1 cases per million (range: 8.8-13.9), and the (point) prevalence was 74.7 per million of the age-related population. The mean age at registration was 6.9 +/- 5.4 years, and the mean Ccr was 41.7 +/- 20.5 mL/min/1.73 m2. The leading causes of CRF were hypodysplasia associated with urinary tract malformations (53.6%) and isolated hypodysplasia (13.9%), whereas glomerular disease accounted for as few as 6.8%. Hypodysplasia associated with primary vesicoureteral reflux (VUR) alone was responsible for as many as 25.8% of the cases, thus being the leading single cause with a female-to-male ratio of 1:3.2. The diagnosis of VUR was established early in life at an overall median age of 3 months (range: 0-180). However, the diagnosis was made significantly later among girls, whose median age at diagnosis was 9 months (range: 0-156; 95% confidence interval: 21.2-49.3) as against 2 months among boys (range: 0-180; 95% confidence interval: 10.9-21.2). As many as 23.6% of the registered patients had at least 1 severe associated disease (excluding urological abnormalities). A steep decline in renal survival occurred during puberty and early postpuberty, leading almost 70% of the patients to end-stage renal failure by the age of 20 years. When the population was subdivided on the basis of Ccr at the time of registration, the probability of kidney survival at 20 years of age was significantly different, being 63% in patients with mild renal failure (Ccr 51-75 mL/min), 30% in those with moderate renal failure (Ccr 25-50 mL/min), and 3% in those with severe renal failure (Ccr <25 mL/min). The incidence of renal replacement therapy was 7.3/y/100 patients, and the case-fatality rate on conservative treatment was 1.41%. CONCLUSIONS: This study provides important and recent epidemiologic information concerning CRF in children and adolescents: a mean annual incidence of 12.1 new patients per million of the age-related population with a very high proportion (57.6%) of hypodysplastic renal diseases with or without urinary tract malformation. By the age of 20 years, the cumulative probability of end-stage renal disease in the population as a whole was 68%. The probability of kidney survival sharply declined during puberty and early postpuberty. This is the first prospective evaluation of the incidence and outcome of CRF in children, including those with mild and moderate renal impairment.