Different profiles of acute graft pyelonephritis among kidney recipients from standard or elderly donors.

Background: Acute graft pyelonephritis (AGPN) is a relatively common complication in kidney transplants (KTs); however, the effects on allograft function, diagnostic criteria, and risk factors are not well established. Methods: Retrospective analysis of all consecutive adult KTs was performed between 01 January 2011 and 31 December 2018 (follow-up ended on 31 December 2019) to examine the association between the diagnosis of AGPN (confirmed with magnetic resonance imaging [MRI]) during the first post-transplantation year and graft outcomes. Results: Among the 939 consecutive KTs (≈50% with donors ≥60 years), we identified 130 MRI-confirmed AGPN episodes, with a documented association with recurrent and multidrug-resistant bacterial urinary tract infections (UTIs) (p < 0.005). Ureteral stenosis was the only risk factor associated with AGPN (OR 2.9 [95% CI, 1.6 to 5.2]). KTs with AGPN had a decreased allograft function at the first year (ΔeGFR 6 mL/min/1.73 m2 [-2-15] in non-AGPN vs. -0.2 [-6.5-8.5] in AGPN, p < 0.001), with similar and negative profiles in KTs from standard or elderly donors. However, only KTs with AGPN and a donor <60 years showed reduced death-censored graft survival (p = 0.015); most of this subgroup received anti-thymocyte globulin (ATG) induction (40.4% vs. 17.7%), and their MRI presented either a multifocal AGPN pattern (73.9% vs. 56.7%) or abscedation (28.3% vs. 11.7%). No difference was noted in death-censored graft survival between early (<3 months post-KT) or late (3-12 months) AGPN, solitary/recurrent forms, or types of multidrug-resistant pathogens. Linear regression confirmed the independent role of multifocal pattern, abscedation, ATG induction, and donor age on the eGFR at the first year. Conclusion: AGPN, influenced by multifocal presentation, ATG induction, donor age, and abscedation, affects kidney function and significantly impacts allograft survival in KTs with donors <60 years.

Effect of phospholipid curcumin Meriva® on liver histology and kidney disease in nonalcoholic steatohepatitis a randomized, double-blind, placebo-controlled trial.

BACKGROUND AIMS: Nonalcoholic steatohepatitis (NASH) confers an increased liver-related and kidney morbidity. Phospholipid curcumin (Meriva ® ) is a phospholipid formulation with ameliorated systemic curcumin absorption and delivery. We assessed safety and efficacy of Meriva ® in NASH. APPROACH: In this double-blind trial, 52 biopsy-proven NASH patients(71% with stage ≥F2 fibrosis, 58% with stage A2-G2/A2-G3a CKD) were randomized 1:1 to receive Meriva ® 2 g/day or placebo for 72 weeks. Primary end-point was NASH resolution with no worsening of fibrosis. Secondary end-points included: a ≥1 stage liver fibrosis improvement with no NASH worsening; regression of significant(i.e. stage≥F2) fibrosis and of chronic kidney disease(CKD); improvement in renal, glucose, lipid and inflammatory parameters. We also explored treatment effect on hepatic activation of Nuclear Factor(NF)-kB, a key proinflammatory transcription factor and a major target of curcumin. RESULTS: Fifty-one patients(26 on Meriva ® and 25 on placebo) completed the trial. Sixteen(62%) patients on Meriva ® vs. three(12%) patients on placebo had NASH resolution(RR=5.33[95%CI=1.76-12.13]; p=0.003). Thirteen(50%) patients on Meriva ® vs. 2(8%) patients on placebo had ≥1 stage fibrosis improvement(RR=6.50[(1.63-21.20]; p=0.008). Eleven(42%) patients on Meriva ® vs. 0(0%) on placebo had regression of significant liver fibrosis(RR=18.01[1.43-36.07]; p=0.02). Hepatic NF-kB inhibition predicted NASH resolution(AUC=0.90,95%CI=0.84-0.95) and fibrosis improvement(AUC=0.89,95%CI=0.82-0.96). Thirteen(50%) patients on Meriva ® vs. 0(0%) on placebo had CKD regression(RR=10.71[1.94-17.99)]; p=0.004). Compared with placebo, Meriva ® improved eGFR(difference in adjusted eGFR change: +3.59[2.96-4.11] mL/min/1.73 m 2 /year, p =0.009), fasting glucose(-17 mg/dL;95%CI=-22, -12), HbA1c(-0.62%;95%CI=-0.87%, -0.37%), LDL-C(-39 mg/dL; 95%CI=-45, -33), triglycerides(-36 mg/dL, 95%CI= -46, -26), HDL-C(+10 mg/dL; 95%CI=+8, +11) and inflammatory markers. Adverse events were rare, mild and evenly distributed. CONCLUSION: In NASH patients, Meriva ® administration for 72 weeks was safe, well-tolerated, improved liver histology, possibly through NF-kB inhibition, kidney disease, and metabolic profile.

CytoSorb® in burn patients with septic shock and Acute Kidney Injury on Continuous Kidney Replacement Therapy is associated with improved clinical outcome and survival.

BACKGROUND: In burn patients, septic shock and acute kidney injury (AKI) with use of continuous renal replacement therapy (CRRT) severely increase morbidity and mortality. Sorbent therapies could be an adjunctive therapy to address the underlying metabolic changes in inflammatory and anti-inflammatory cytokines dysregulated production. METHODS: A retrospectively observational study of 35 severe burn patients admitted to the Burn Center (Turin, Italy, from January 2017 to December 2022), who underwent CRRT for AKI-associated septic shock. Out of 35 patients, 11 were treated with CytoSorb® as adjunctive therapy to CRRT (Sorbent group) and 24 patients only with CRRT (Control group). RESULTS: The application of CytoSorb® took place in a very dispersed way. Out of 11 patients, 7 started the CRRT together with the sorbent application. The patients of the sorbent group exhibited a significant reduction in norepinephrine use compared to that of the control group. A clinical improvement over the first 4 days of Cytosorb® was observed in both survivors and no survivors of the sorbent group, with significant norepinephrine decreased use on day 4 compared to day 1. In-hospital mortality was 45.4% and 70.8% in the sorbent and control group, respectively, and significantly better at Kaplan-Meier survival analysis at 270 days (p = 0.0445). In both groups, all survivor patients recovered renal function at discharge, whereas no survivors did not. CONCLUSIONS: Adjunctive treatment with CytoSorb® for burn patients with AKI-CRRT and septic shock poorly responsive to standard therapy led to a significant clinical improvement, and was associated with a lower mortality rate compared to CRRT alone.

Safety and Metabolic Tolerance of Citrate Anticoagulation in Critically Ill Polytrauma Patients with Acute Kidney Injury Requiring an Early Continuous Kidney Replacement Therapy.

For severe polytrauma patients with an early AKI requiring renal replacement therapy, anticoagulation remains a great challenge. Due to a high bleeding risk, hemodynamic instability, and increased lactate levels, continuous modality (CKRT) and citrate anticoagulation seem to be the most appropriate. However, their safety with regard to the potential risk of impaired citrate metabolism is not documented. A retrospective study of 60 severe polytrauma patients admitted to the emergency department between January 2000 and December 2021 was conducted; the patients requiring CKRT during the first 72 h were treated with citrate (n. 46, group Citrate) or with heparin (n. 14, group Heparin). Out of 60 patients, 31 survived (51.7%). According to logistic regression analysis, age and SOFA score were significant predictors of mortality. The incidence of rhabdomyolysis was more common in the survivors (77.4 vs. 51.7%), and Kaplan-Meyer analysis showed a better trend towards survival at 90 days for the group Citrate than the group Heparin (p 0.0956). In the group Citrate, hemorrhagic episodes were significantly less common (0.045 vs. 0.273 episodes/day, p < 0.001); the effective duration (h/day) of CKRT was longer; and the effective net ultrafiltration rate (mL/kg/h) and blood flow rate were lower. For severe polytrauma patients, early, soft CKRT with citrate anticoagulation at a low blood flow rate and circuit citratemia showed a better safety and hemodynamic stability, suggesting that citrate should be the first choice anticoagulant in this subset of patients.

Clearance of NT-proBNP and Procalcitonin during Continuous Venovenous Hemodialysis with the Medium Cutoff Filter in Patients with Rhabdomyolysis-Associated Early Acute Kidney Injury.

INTRODUCTION: In polytrauma patients with AKI continuous venovenous hemodialysis (CVVHD) with medium cutoff membrane filters is commonly adopted to increase the removal of both myoglobin and inflammatory mediators, but its impact on increasing molecular weight markers of inflammation and cardiac damage is debated. METHODS: Twelve critically ill patients with rhabdomyolysis (4 burns and 8 polytrauma patients) and early AKI requiring CVVHD with EMIc2 filter were tested for 72 h on serum and effluent levels for NT-proBNP, procalcitonin (PCT), myoglobin, C-reactive protein (CRP), alpha1-glycoprotein, albumin, and total protein. RESULTS: The sieving coefficients (SCs) for proBNP and myoglobin were as higher as 0.5 at the start, decreased to 0.3 at the 2nd h, and then slowly declined to the final value of 0.25 and 0.20 at the 72nd h, respectively. PCT showed a negligible SC at the 1st h, a peak of 0.4 at the 12th h, and a final value of 0.3. SCs for albumin, alpha1-glycoprotein, and total protein were negligible. A similar trend was observed for the clearances (17-25 mL/min for proBNP and myoglobin; 12 mL/for PCT; <2 mL/min for albumin, alpha1-glycoprotein, and total protein). No correlation was found between systemic determinations and filter clearances of proBNP, PCT, and myoglobin. Net fluid loss/hour during CVVHD positively correlated with systemic myoglobin for all patients and NT-proBNP in the burn patients. CONCLUSION: CVVHD with EMiC2 filter showed low clearances for NT-proBNP and procalcitonin. CVVHD did not significantly affect the serum levels of these biomarkers, which could be adopted in the clinical management of early CVVHD patients.

Relationship between Cytomegalovirus Viremia and Long-Term Outcomes in Kidney Transplant Recipients with Different Donor Ages.

OBJECTIVES: To explore the Cytomegalovirus (CMV) burden on the long-term post-transplant course in different donor ages, we evaluated the incidence and risk factors for CMV in our kidney-transplanted patients (KTs) with extensive adoption of expanded-criteria donors (ECDs). METHODS: Retrospective evaluation of 929 consecutive first KTs (49.5% receiving an organ from a donor ≥ 60 years) performed between 01-2003 and 12-2013. Overall survival was estimated using Kaplan-Meier curves; cumulative incidence function was additionally analyzed to consider the potential role of death with a functioning graft as a competitive event with graft dysfunction and to avoid overestimation. Apart from regular DNAemia monitoring in all patients, prophylaxis was adopted in high-risk groups (D+/R- or recipients of anti-thymocyte globulin induction), with pre-emptive therapy in the remaining groups. RESULTS: CMV incidence was 19.5% (4-34.9% according to serostatus combination: D-/R-, D-/R+, D+/R+, D+/R-). Donor and recipient age, recipient pre-transplant hypertension, DR antigen compatibility, cold ischemia time, and post-transplant early complications, including rejection, urologic and renal artery stenosis, and lower renal function and proteinuria ≥ 0.5 g/day at one year after KT were associated with CMV. CMV determined lower death-censored graft survival (DCGS) (p < 0.01), with a prominent effect in R+ (p < 0.01) and without impact in R- (p = 0.32 in D-/R- and p = 0.006 in D+/R-). Interestingly, CMV occurrence influenced DCGS only in KTs who received grafts from donors < 50 or 50-69 years old (p < 0.01), while it was not significant with older donors (p = 0.07). The analysis of the cumulative incidence of graft loss accounting for death as a competing risk confirmed all these findings. In multivariate analysis, CMV replication/disease in the first year was an independent predictor for DCGS (HR 1.73 [1.3-2.3]). CONCLUSIONS: In a large population with extensive ECD adoption, CMV viremia in the first year demonstrates its harmful effect with an independent role for graft loss and significant impact among R+ recipients and KTs with donors < 70 years.

Extracellular Vesicles: New Players in the Mechanisms of Sepsis- and COVID-19-Related Thromboinflammation.

Sepsis and COVID-19 patients often manifest an imbalance in inflammation and coagulation, a complex pathological mechanism also named thromboinflammation, which strongly affects patient prognosis. Extracellular vesicles (EVs) are nanoparticles released by cells into extracellular space that have a relevant role in cell-to-cell communication. Recently, EVs have been shown to act as important players in a variety of pathologies, including cancer and cardiovascular disease. The biological properties of EVs in the mechanisms of thromboinflammation during sepsis and COVID-19 are still only partially known. Herein, we summarize the current experimental evidence on the role of EVs in thromboinflammation, both in bacterial sepsis and in COVID-19. A better understanding of EV involvement in these processes could be useful in describing novel diagnostic and therapeutic applications of EVs in these diseases.

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.

Colistin Therapy, Survival and Renal Replacement Therapy in Burn Patients: A 10-Year Single-Center Cohort Study.

Purpose: Colistin is still a therapeutic cornerstone against multidrug-resistant gram-negative bacteria (MDRGN), mostly when other antibiotics do not gain adequate activity on these strains. In the present study, we evaluated in a cohort of burn patients the relationship between colistin therapy, survival and requirement of renal replacement therapy (CRRT). Patients and Methods: Retrospective study of 133 burn patients treated with iv colistimethate sodium (loading dose 9.0 × 106 IU, maintenance dose 4.5 × 106 IU BID) and 35 treated with other antibiotics for MDRGN infection including Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae between January 2008 and December 2017. Multivariate analysis with logistic regression was used to determine the effect of the predictors such as age, total body surface area (TBSA), third-degree burn areas, Revised Baux score, Charlson comorbidity score, length of stay, colistin dose and duration of treatment, mechanical ventilation, and need of CRRT on in-hospital mortality. To investigate the relationship between colistin and renal function, we focused on survivor patients as the completion of the therapeutic course of colistin represented the basic requirement to analyze its impact on the kidney. Results: Out of 133 colistin- and 35 other antibiotics-treated patients, 83 (62.4%) and 31 (88.6%) survived, and 53 (39.8%) and 3 (9.7%) required CRRT, respectively. The severity of burns, as well as CRRT requirement and mortality, was significantly higher in colistin-treated patients than in other antibiotics-treated patients. Age and TBSA% were the significant predictors of mortality. Out of 83 colistin-treated survivors, 19 (22.9%) required CRRT (9 before and 10 after the start of colistin), and 64 (77.1%) had a normal renal function. No difference about the colistin dose and baseline characteristics, but the revised Baux score was found between the 9 patients requiring CRRT before the colistin course and the 10 patients after. Similarly, among the 64 patients not undergoing CRRT, no difference was found between the patients treated with the cumulative dose of colistin <99.0 × 106 IU (n = 33, median daily dose of 4.0 × 106 IU) and >99.0 × 106 IU (n = 31, median daily dose of 9.0 × 106 IU) about the baseline characteristics and the daily median plasma creatinine over 24 days of therapy. Conclusion: Colistin therapy was associated with more severe burns, mortality, and CRRT requirement. A short course therapy, at appropriate cumulative dosage, can lead to clinical success without a significant association with severe renal impairment.

Bacterial and Viral Infection and Sepsis in Kidney Transplanted Patients.

Kidney transplanted patients are a unique population with intrinsic susceptibility to viral and bacterial infections, mainly (but not exclusively) due to continuous immunosuppression. In this setting, infectious episodes remain among the most important causes of death, with different risks according to the degree of immunosuppression, time after transplantation, type of infection, and patient conditions. Prevention, early diagnosis, and appropriate therapy are the goals of infective management, taking into account that some specific characteristics of transplanted patients may cause a delay (the absence of fever or inflammatory symptoms, the negativity of serological tests commonly adopted for the general population, or the atypical anatomical presentation depending on the surgical site and graft implantation). This review considers the recent available findings of the most common viral and bacterial infection in kidney transplanted patients and explores risk factors and outcomes in septic evolution.

Long-Term Preservation of Renal Function in Septic Shock Burn Patients Requiring Renal Replacement Therapy for Acute Kidney Injury.

BACKGROUND: The real impact of septic shock-associated acute kidney injury (AKI) on the long-term renal outcome is still debated, and little is known about AKI-burn patients. In a cohort of burn survivors treated by continuous renal replacement therapy (CRRT) and sorbent technology (CPFA-CRRT), we investigated the long-term outcome of glomerular and tubular function. METHODS: Out of 211 burn patients undergoing CRRT from 2001 to 2017, 45 survived, 40 completed the clinical follow-up (cumulative observation period 4067 months, median 84 months, IR 44-173), and 30 were alive on 31 December 2020. Besides creatinine and urine albumin, in the 19 patients treated with CPFA-CRRT, we determined the normalized GFR by 99mTc-DTPA (NRI-GFR) and studied glomerular and tubular urine protein markers. RESULTS: At the follow-up endpoint, the median plasma creatinine and urine albumin were 0.99 (0.72-1.19) and 0.0 mg/dL (0.0-0.0), respectively. NRI-GFR was 103.0 mL/min (93.4-115). Four patients were diabetic, and 22/30 presented at least one risk factor for chronic disease (hypertension, dyslipidemia, and overweight). Proteinuria decreased over time, from 0.47 g/day (0.42-0.52) at 6 months to 0.134 g/day (0.09-0.17) at follow-up endpoint. Proteinuria positively correlated with the peak of plasma creatinine (r 0.6953, p 0.006) and the number of CRRT days (r 0.5650, p 0.035) during AKI course, and negatively with NRI-GFR (r -0.5545, p 0.049). In seven patients, urine protein profile showed a significant increase of glomerular marker albumin and glomerular/tubular index. CONCLUSIONS: Burn patients who experienced septic shock and AKI treated with CRRT had a long-term expectation of preserved renal function. However, these patients were more predisposed to microalbuminuria, diabetes, and the presence of risk factors for intercurrent comorbidities and chronic renal disease.

Metformin, chronic nephropathy and lactic acidosis: a multi-faceted issue for the nephrologist.

Metformin is currently considered a first-line therapy in type 2 diabetic patients. After issuing warnings for decades about the risks of lactic acidosis in patients with chronic nephropathy, metformin is now being re-evaluated. The most recent evidence from the literature has demonstrated both a low, acceptable risk of lactic acidosis and a series of favorable effects, which go beyond its hypoglycemic activity. Patients treated with metformin show a significant mortality reduction and lower progression towards end-stage renal disease in comparison with those treated with other hypoglycemic drugs. Concerning lactic acidosis, in the last few years it has been shown how lactic acidosis almost always developed when patients kept taking the drug in the face of a concomitant disease or situation such as sepsis, fever, diarrhea, vomiting, which reduced metformin renal clearance. Actually, clearance of metformin is mainly renal, both by glomerular filtration and tubular secretion (apparent clearance 933-1317 ml/min, half-life < 3 h). As regards treatment, in cases of lactic acidosis complicated by acute kidney injury, continuous renal replacement therapy (CRRT) plays a crucial role. Besides the elimination of metformin, CRRT  improves survival by correcting acidosis, electrolyte alterations, and maintaining fluid balance. Lactic acidosis almost always develops because of preventable drug accumulation. Therefore, prevention is a key factor. Patients should be aware that discontinuation for a limited time does not affect their health, even when it may be inappropriate, but it may avoid a serious, potentially fatal adverse event.

Coupled-plasma filtration and adsorption for severe burn patients with septic shock and acute kidney injury treated with renal replacement therapy.

BACKGROUND: Coupled-plasma filtration adsorption (CPFA) is a sorbent-based technology aimed at removing soluble mediators of septic shock. We present our experience on the use of CPFA in septic shock severe burn patients with acute kidney injury (AKI) needing renal replacement therapy (RRT) with the main goal to evaluate efficacy and safety of CPFA in this specific subset of septic shock patients. METHODS: In this observational study, we retrospectively reviewed the medical notes of all burn patients admitted to our adult Burn Center who received CPFA, as part of the septic shock treatment requiring RRT, between January 2001 and December 2017 (CPFA group). We compared CPFA group with all the burn patients admitted to our Center in the same period of time, with the same range of relevant clinical characteristics, who developed AKI and were treated with RRT, but not CPFA (control group). We collected demographic characteristics, burn size, Sequential Organ Assessment Failure (SOFA) score, microbiological data, and patient outcome, in terms of in-hospital mortality rate and the probability of survival calculated using the revised Baux score. We also collected data regarding CPFA safety (hemorrhagic episodes, catheter associated-complications, hypersensitivity reactions) and efficiency (number and duration of CPFA sessions, plasma treated amount, plasma processed dose). RESULTS: 39 severe burn patients were treated with CPFA (CPFA group) (mean age 46.0 years, range 40.0-56.0 years; mean burn size 48.0% TBSA, range 35.0-60.0% TBSA), and 87 patients treated with RRT, but not CPFA, who had similar clinical characteristics (control group). Observed mortality rate was 51.3% in the CPFA group and 77.1% in the control group (p 0.004). Regarding factors affecting survival in the CPFA group, SOFA score on the 1st day of CPFA resulted significant (OR 2.016, 95% CI, 1.221-3.326; p < 0.004) in the multivariate analysis logistic model. CONCLUSIONS: CPFA treatment for burn patients with AKI-RRT and septic shock, sustained by bacterial strains non or poorly responsive to therapy, was associated with a lower mortality rate, compared to RRT alone. However, further research, such as large prospective studies, is required to clarify the role of CPFA in the treatment of burns with septic shock and AKI-RRT.

Furosemide as a functional marker of acute kidney injury in ICU patients: a new role for an old drug.

New pharmacokinetics insight suggests that the furosemide pharmacology occurring in ICU patients with AKI is similar, but not equal to that described in chronic stable renal patients. Even if the diuretic response to furosemide is expressed by a steep dose-response curve positively correlated with renal function, pharmacodynamic limitations occur when creatinine clearance is < 20 ml/min or urine output is < 500 ml/12 h. In such cases, other factors specifically due to acute tubular injury can interfere with the furosemide-induced diuretic output. As modality of administration recent reports and metanalysis, even if not conclusive, suggest that for the same given dose a continuous infusion of furosemide was superior in diuretic response. For septic shock patients on CVVHDF where treatment adds an additional clearance of furosemide the maximum diuretic response is achieved by a continuous infusion of 20 mg/h of furosemide. At this infusion rate the reached plasma level was < 20 mg/L, a range considered safe and not ototoxic. Therefore, the severity of AKI establishes whether a patient will respond to furosemide. In this review we summarized all these recent updates, also suggesting that the diuretic response under continuous infusion may allow assessing glomerular and tubular functions with increased reliability than a bolus dose. However, validation studies are still needed to support continuous infusion as a stress test.

Urine volume as a predicting factor for furosemide clearance during continuous infusion in AKI septic shock patients on hemodiafiltration.

BACKGROUND: This study assessed the contribution of intracorporeal (IC) and extracorporeal clearance (EC) of furosemide in patients with septic acute kidney injury (AKI), and the relationship between plasma concentrations and urine volume. METHODS: Prospective cohort observational study of 15 patients with septic AKI undergoing continuous veno-venous hemodiafiltration (CVVHDF) divided according to urine volume (< 500 ml/12 h, Oliguria group, n = 5; > 500 ml/12 h, Diuresis group, n = 10) during continuous infusion of furosemide (120 mg/12 h) at steady-state condition. Plasma and effluent furosemide concentrations were determined by high-performance liquid chromatography (HPLC)-mass spectrometry every 12 h for 48 h. RESULTS: Furosemide plasma concentrations and total body clearance (TBC) were 6.14 mg/l and 22.1 ml/min for the Oliguria group, and 2.63 mg/l and 54.4 ml/min for the Diuresis group, respectively (p < 0.05). When urine volume was < 500 ml/24 h, the furosemide plasma concentrations peaked at the potentially toxic value of 13.0 mg/l. Furosemide EC was not relevant for the Diuresis group, but it represented 18% of TBC for the Oliguria group. Furosemide plasma concentrations correlated positively with dose infusion for both groups (r = 0.728 and 0.685, p < 0.05), and negatively with urine volume only for the Diuresis (r = - 0.578, p < 0.01) but not for the Oliguria group (r = - 0.089, p = 0.715). CONCLUSIONS: For patients with urine volume > 500 ml/12 h continuous infusion of furosemide up to 480 mg/24 h leads to increasing urine volume, which can predict furosemide plasma levels within its safety range. When the urine volume is lower, the furosemide plasma levels are increased beyond any further diuretic efficacy.

Urinary protein profiles in ketorolac-associated acute kidney injury in patients undergoing orthopedic day surgery.

BACKGROUND: Parenteral administration of ketorolac is very effective in controlling postoperative pain for orthopedic surgery. Ketorolac can induce clinically relevant renal alterations in elderly patients, whereas its short course is considered safe for young adults with normal preoperative renal function. In this study, of a cohort of young adults undergoing elective orthopedic day surgery, we sought cases complicated by readmission due to acute kidney injury (AKI). PATIENTS AND METHODS: Among 1397 young adults, aged 18-32 years who were admitted to undergo orthopedic day surgery from 2013 to 2015, four patients (0.29%, three males/one female) treated in postprocedure with ketorolac (from 60 to 90 mg/day for 1-2 days) were readmitted for suspected severe AKI. We evaluated functional outcome, urinary protein profiles and kidney biopsy (1 patient). RESULTS: After day surgery discharge, they experienced gastrointestinal disturbances, flank pain and fever. Readmitted on post-surgery days 3-4, they presented with oliguric AKI (creatinine range 158.4-466.4 µmol/L) and frank proteinuria (albumin range 2.1-6.0 g/L). Urine protein profiles demonstrated a nonselective glomerular proteinuria, with a significant 9.4-fold increase in glomerular/tubular index on day 6. Kidney biopsy on day 19 showed normal glomeruli and minimal tubular alterations and negative immunofluorescence. All patients recovered their renal function, and after 20 days proteinuria disappeared. CONCLUSION: AKI can ensue even in young adults who have undergone a short course of ketorolac, when they suffered from relative dehydration, abdominal disturbances, flank pain and oliguria after discharge. Urine findings were characterized by a marked nonselective glomerular proteinuria disappearing in 2-3 weeks.

[Nephrologist and ICU: the need of new expertise].

Episodes of dialytic Acute Kidney Injury (AKI stage III KDIGO) can lead to chronic kidney disease (CKD), even after a long time. Prelimary data indicate that the relationship between AKI and CKD is affected by dialysis technical modalities and factors in part modifiable, such as an early dialysis timing, dose adeguacy, continuous treatment, use of biocompatible membranes and regional citrate anticoagulation. However, in most ICUs involvement of nephrologist consultant is marginal. Of more, nephrological follow-up after discharge, which allows to slow down the progression rate of CKD even just by a correct pharmacological and dietetic approach (sartans, ACEis), is an uncommon practice. Indeed, a better organ survival could lead to a delay of the dialytic treatment, reducing the costs sustained by the National Health Service. To face such challenges locally, in Piedmont and Aosta Valley the Dialysis Units were required to put themselves at disposal for ICU needs both in terms of dedicated staff and resources. Additionally, since many years consultant nephrologists have established the "Acuti" work-group, which has been able to provide an high level of professional expertise, while incentivizing innovation and training in ICU environment. In order to cope with these new requirements a redefinition of the nephrologist's role in ICU through a constant exchange with the intensive care background is needed.

Metformin-Associated Lactic Acidosis Undergoing Renal Replacement Therapy in Intensive Care Units: A Five-Million Population-Based Study in the North-West of Italy.

BACKGROUND: Metformin-associated lactic acidosis (MALA) is a severe complication of drug administration with significant morbidity and mortality. So far no study in large population areas have examined the incidence, clinical profile and outcome of acute kidney injury (AKI)-MALA patients admitted in intensive care units (ICUs) and treated by renal replacement therapy (MALA-RRT). METHODS: Retrospective analysis over a 6-year period (2010-2015) in Piedmont and Aosta Valley regions (5,305,940 inhabitants, 141,174 diabetics treated with metformin) of all MALA-RRT cases. RESULTS: One hundred and seventeen cases of AKI-MALA-RRT were observed (12.04/100,000 metformin treated diabetics, 1.45% of all RRT-ICU patients). Survival rate was 78.3%. The average duration of RRT was 4.0 days at mean dialysis effluent of 977 mL/kg/day. At admission most patients were dehydrated, and experienced shock and oliguria. CONCLUSION: Our data showed that MALA-RRT is a common complication, needing more prevention. Adopted policy of early, extended, continuous and high efficiency dialysis could contribute to an observed high survival rate. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=471917.

Citrate pharmacokinetics at high levels of circuit citratemia during coupled plasma filtration adsorption.

BACKGROUND: The heparin requirement for coupled plasma filtration adsorption (CPFA) is usually high. Heparin administration often cannot be adherent to prescription, leading to a premature clotting of circuit and an insufficient volume of treated plasma. Regional citrate anticoagulation (RCA) could be an attractive alternative; however, no data are available on citrate pharmacokinetics at high levels of circuit citratemia. METHODS: Fifteen septic shock patients with acute kidney injury undergoing CPFA with RCA at target circuit citratemia of 6 mmol/L were treated with CPFA-haemofiltration in pure predilution (CPFA-HF predilution group, n = 5 patients), or predilution haemodiafiltration (CPFA-HDF predilution group, n = 5 patients) or pre- and postdilution haemofiltration (CPFA-HF pre/postdilution group, n = 5 patients). Citrate pharmacokinetics was carried out through its determination in systemic and circuit blood, and effluent at time 0, 0.2, 1, 3, 6 and 9 h. RESULTS: The systemic concentrations of citrate in the CPFA-HF predilution group significantly increased over the sessions (from basal level of 0.21 to 0.76 mmol/L at 3 h), whereas they did not change in CPFA-HDF predilution and CPFA-HF pre/postdilution groups. Circuit plasma citrate concentrations (from 3 to 8 mmol/L) correlated strongly with circuit iCa++ levels (Spearman R = -0.7022, P < 0.01). Sieving coefficients of citrate were near the unit in all three groups and unrelated to blood and infusion flow rates in predilution. However, the amount of citrate removed by effluent was ∼40% for the CPFA-HF predilution group and reached 60% for both the CPFA-HDF predilution and CPFA-HF pre/postdilution groups (P < 0.05). As for the efficiency of plasmafiltration, the plasmafiltrate volume (from 17 to 20 mL/kg/day) was not significantly different among the groups. CONCLUSIONS: These results demonstrated that in refractory septic shock patients on CPFA at circuit citratemia of 6 mmol/L both HDF predilution and HF pre/postdilution were the best dialysis modalities to maintain a normal systemic citratemia through a high rate of citrate loss in the effluent.