Impact of therapeutic plasma exchange on intact protein S, apolipoproteins, and thrombin generation.

INTRODUCTION: Therapeutic plasma exchange (TPE), with solvent/detergent (S/D)-treated plasma as replacement fluid, is an extracorporeal blood purification technique with major impact on both coagulation and lipids. Our previous in vitro study showed that S/D-plasma enhances thrombin generation by lowering intact protein S (PS) levels. AIMS: To evaluate the impact of altered lipid balance on coagulation phenotype during heparin-anticoagulated TPE with S/D-plasma, and to investigate whether the lowered intact PS levels with concomitant procoagulant phenotype, are recapitulated in vivo. METHODS: Coagulation biomarkers, thrombin generation with Calibrated Automated Thrombogram (CAT), and lipid levels were measured before and after the consecutive 1st, 3rd and 5th episodes of TPE performed to six patients with Guillain-Barré syndrome or myasthenia gravis. The effects of in vitro dilution of S/D-plasma on thrombin generation were explored with CAT to mimic TPE. RESULTS: Patients did not have coagulation disorders, except elevated FVIII. Intact PS, lipoproteins, especially LDL, Apolipoprotein CIII (ApoC3) and ApoB/ApoA1 ratio declined (p < 0.05). In contrast, VLDL and triglyceride levels stayed intact. CAT lag time shortened (p < 0.05). In vitro dilution of S/D plasma with co-transfused Ringer's lactate and 4% albumin partially reduced its procoagulant phenotype in CAT, which is mainly seen as peak thrombin, and modestly shortened lag time. CONCLUSIONS: After the five settings of TPE using S/D-plasma in vivo, which associated with heparinization and reduced coagulation factor activities, our observations of declining natural anticoagulant intact PS and apolipoproteins refer to rebalance of the hemostatic and lipid profiles.

Similar survival on home haemodialysis and automated peritoneal dialysis: an inception cohort study.

BACKGROUND: Several studies have shown superior survival of patients on home haemodialysis (HD) compared with peritoneal dialysis (PD), but patients on automated PD (APD) and continuous ambulatory PD (CAPD) have not been considered separately. As APD allows larger fluid volumes and may be more efficient than CAPD, we primarily compared patient survival between APD and home HD. METHODS: All adult patients who started kidney replacement therapy (KRT) between 2004 and 2017 in the district of Helsinki-Uusimaa in Finland and who were on one of the home dialysis modalities at 90 days from starting KRT were included. We used intention-to-treat analysis. Survival of home HD, APD and CAPD patients was studied using Kaplan-Meier curves and Cox regression with adjustment for propensity scores that were based on extensive data on possible confounding factors. RESULTS: The probability of surviving 5 years was 90% for home HD, 88% for APD and 56% for CAPD patients. After adjustment for propensity scores, the hazard ratio of death was 1.1 [95% confidence interval (CI) 0.52-2.4] for APD and 1.6 (95% CI 0.74-3.6) for CAPD compared with home HD. Censoring at the time of kidney transplantation (KTx) or at transfer to in-centre HD did not change the results. Characteristics of home HD and APD patients at the start of dialysis were similar, whereas patients on CAPD had higher median age and more comorbidities and received KTx less frequently. CONCLUSIONS: Home HD and APD patients had comparable characteristics and their survival appeared similar.

Fluid balance-adjusted creatinine in diagnosing acute kidney injury in the critically ill.

BACKGROUND: Acute kidney injury (AKI) is often diagnosed based on plasma creatinine (Cr) only. Adjustment of Cr for cumulative fluid balance due to potential dilution of Cr and subsequently missed Cr-based diagnosis of AKI has been suggested, albeit the physiological rationale for these adjustments is questionable. Furthermore, whether these adjustments lead to a different incidence of AKI when used in conjunction with urine output (UO) criteria is unknown. METHODS: This was a post hoc analysis of the Finnish Acute Kidney Injury study. Hourly UO and daily plasma Cr were measured during the first 5 days of intensive care unit admission. Cr values were adjusted following the previously used formula and combined with the UO criteria. Resulting incidences and mortality rates were compared with the results based on unadjusted values. RESULTS: In total, 2044 critically ill patients were analyzed. The mean difference between the adjusted and unadjusted Cr of all 7279 observations was 5 (±15) µmol/L. Using adjusted Cr in combination with UO and renal replacement therapy criteria resulted in the diagnosis of 19 (1%) additional AKI patients. The absolute difference in the incidence was 0.9% (95% confidence interval [CI]: 0.3%-1.6%). Mortality rates were not significantly different between the reclassified AKI patients using the full set of Kidney Disease: Improving Global Outcomes criteria. CONCLUSION: Fluid balance-adjusted Cr resulted in little change in AKI incidence, and only minor differences in mortality between patients who changed category after adjustment and those who did not. Using adjusted Cr values to diagnose AKI does not seem worthwhile in critically ill patients.

Urinary cell cycle arrest biomarkers and chitinase 3-like protein 1 (CHI3L1) to detect acute kidney injury in the critically ill: a post hoc laboratory analysis on the FINNAKI cohort.

BACKGROUND: Acute kidney injury (AKI) is a frequently occurring syndrome in critically ill patients and is associated with worse outcomes. Biomarkers allow early identification and therapy of AKI which may improve outcomes. Urine chitinase 3-like protein 1 (uCHI3L1) was recently identified as a promising urinary biomarker for AKI. In this multicenter study, we evaluated the diagnostic performance for AKI stage 2 or greater of uCHI3L1 in comparison with the urinary cell cycle arrest biomarkers urinary tissue inhibitor of metalloproteinases-2 (TIMP-2)•insulin-like growth factor-binding protein 7 (IGFBP7) measured by NephroCheck Risk®. METHODS: Post hoc laboratory study of the prospective observational FINNAKI study. Of this cohort, we included patients with stored admission urine samples and availability of serum creatinine at day 1 of admission. Patients who already had AKI stage 2 or 3 at ICU admission were excluded. AKI was defined and staged according to the KDIGO definition and staging system. The primary endpoint was AKI stage 2 or 3 at day 1. Biomarker performance was assessed by the area under the curve of the receiver operating characteristic curve (AUC). We assessed individual performance and different combinations of urine biomarkers. RESULTS: Of 660 included patients, 49 (7.4%) had AKI stages 2-3 at day 1. All urine biomarkers were increased at admission in AKI patients. All biomarkers and most combinations had AUCs < 0.700. The combination uCHI3L1•TIMP-2 was best with a fair AUC of 0.706 (0.670, 0.718). uCHI3L1 had a positive likelihood ratio (LR) of 2.25 which was comparable to that of the NephroCheck Risk® cutoff of 2.0, while the negative LR of 0.53 was comparable to that of the NephroCheck Risk® cutoff of 0.3. CONCLUSIONS: We found that uCHI3L1 and NephroCheck Risk® had a comparable diagnostic performance for diagnosis of AKI stage 2 or greater within a 24-h period in this multicenter FINNAKI cohort. In contrast to initial discovery and validation studies, the diagnostic performance was poor. Possible explanations for this observation are differences in patient populations, proportion of emergency admissions, proportion of functional AKI, rate of developing AKI, and observation periods for diagnosis of AKI.

Burden of acute kidney injury and 90-day mortality in critically ill patients.

BACKGROUND: Mortality rates associated with acute kidney injury (AKI) vary among critically ill patients. Outcomes are often not corrected for severity or duration of AKI. Our objective was to analyse whether a new variable, AKI burden, would outperform 1) presence of AKI, 2) highest AKI stage, or 3) AKI duration in predicting 90-day mortality. METHODS: Kidney Diseases: Improving Global Outcomes (KDIGO) criteria using creatinine, urine output and renal replacement therapy were used to diagnose AKI. AKI burden was defined as AKI stage multiplied with the number of days that each stage was present (maximum five), divided by the maximum possible score yielding a proportion. The AKI burden as a predictor of 90-day mortality was assessed in two independent cohorts (Finnish Acute Kidney Injury, FINNAKI and Simple Intensive Care Studies I, SICS-I) by comparing four multivariate logistic regression models that respectively incorporated either the presence of AKI, the highest AKI stage, the duration of AKI, or the AKI burden. RESULTS: In the FINNAKI cohort 1096 of 2809 patients (39%) had AKI and 90-day mortality of the cohort was 23%. Median AKI burden was 0.17 (IQR 0.07-0.50), 1.0 being the maximum. The model including AKI burden (area under the receiver operator curve (AUROC) 0.78, 0.76-0.80) outperformed the models using AKI presence (AUROC 0.77, 0.75-0.79, p = 0.026) or AKI severity (AUROC 0.77, 0.75-0.79, p = 0.012), but not AKI duration (AUROC 0.77, 0.75-0.79, p = 0.06). In the SICS-I, 603 of 1075 patients (56%) had AKI and 90-day mortality was 28%. Median AKI burden was 0.19 (IQR 0.08-0.46). The model using AKI burden performed better (AUROC 0.77, 0.74-0.80) than the models using AKI presence (AUROC 0.75, 0.71-0.78, p = 0.001), AKI severity (AUROC 0.76, 0.72-0.79. p = 0.008) or AKI duration (AUROC 0.76, 0.73-0.79, p = 0.009). CONCLUSION: AKI burden, which appreciates both severity and duration of AKI, was superior to using only presence or the highest stage of AKI in predicting 90-day mortality. Using AKI burden or other more granular methods may be helpful in future epidemiological studies of AKI.

One- and three-year outcomes in patients treated with intermittent hemodialysis for acute kidney injury: prospective observational multicenter post-hoc FINNAKI study.

BACKGROUND: Studies reporting renal and overall survival after acute kidney injury (AKI) treated exclusively with intermittent modalities of renal replacement therapy (IRRT) are rare. This study focused on outcomes of AKI patients treated with IRRT both in intensive care units (ICUs) and non-ICU dialysis units. METHODS: This prospective observational study was carried on during a 5-month period in 17 ICUs and 17 non-ICUs. ICU and non-ICU patients (total n = 138; 65 ICU, 73 non-ICU) requiring RRT for AKI and chosen to receive IRRT were included. Patient and RRT characteristics as well as outcomes at 90 days, 1 year, and 3 years were registered. RESULTS: Characteristics of ICU and non-ICU patients differed markedly. Pre-existing chronic kidney disease (CKD) and chronic heart failure were significantly more common among non-ICU patients. At 1 year, RRT dependence was significantly more common in the non-ICU group. At 3 years, there was no significant difference between the groups either in RRT dependence or mortality. CONCLUSION: Outcome of AKI patients treated with IRRT is dismal with regard to 3-year kidney function and mortality. Although pre-existing CKD emerged as a major risk factor for end-stage renal disease after AKI, the poor kidney survival was also seen in patients without prior CKD.

Diagnostics and current care of myasthenia gravis.

Myasthenia gravis (MG) is the most common neuromuscular transmission disorder, causing weakness of skeletal muscles on exertion. The course of the disease is highly variable, symptoms and signs may change rapidly due to infection or pregnancy. MG is classified using serological, electrophysiological and pharmaceutical tools. A precise diagnosis allows for the choice of right treatment, predicts the course of disease and hence helps with the follow-up. In this review we present Finnish guidelines for diagnostics, treatment and follow-up of MG patients.

Biochemical variables and survival of patients with type 1 diabetes on renal replacement therapy.

BACKGROUND/AIMS: End-stage renal disease (ESRD) is one of the most serious complications of type 1 diabetes, but scarcely studied. Our aim was to estimate the association between biochemical variables and survival among these patients. METHODS: This was an incident cohort study of patients with type 1 diabetes entering chronic renal replacement therapy (RRT) in Finland 2000-2011 (n = 834). Biochemical variables were measured before the initiation of RRT. Adjusted relative risk of death according to biochemical variables was estimated by Cox regression. RESULTS: When adjusted for age, sex, comorbidities, and initial treatment modality of RRT, the most important predictors of death were low creatinine and albumin and high C-reactive protein. CONCLUSION: Among type 1 diabetes patients entering chronic RRT, biochemical variables independently associated with survival are creatinine, albumin and C-reactive protein. They reflect the nutritional status, proteinuria, liver function, and ongoing inflammatory process. Treatment of these might improve survival.

Modality of chronic renal replacement therapy and survival--a complete cohort from Finland, 2000-2009.

BACKGROUND: Studies on dialysis modality and survival have shown conflicting results, mostly due to insufficient and varying control of confounding factors. Using comprehensive data on a well-defined patient cohort, we therefore investigated the association of dialysis modality with survival on chronic renal replacement therapy (RRT) and whether this association varies between subgroups of patients. METHODS: Survival analyses included all adult patients entering chronic RRT in Finland between 2000 and 2009 and used information obtained from the Finnish Registry for Kidney Diseases and the Finnish Kidney Transplant Registry. In our primary intention-to-treat (ITT) analysis, we calculated relative risk of death according to dialysis modality on Day 91 from RRT start, comparing peritoneal dialysis (PD) to haemodialysis (HD). Relative risks were adjusted for putative confounders. Interactions between treatment groups and other variables were estimated. RESULTS: Of the total 4463 patients, 42% died during the 10 years of follow-up. Median survival time was 5.2 years. In unadjusted ITT analysis, relative risk of death of PD patients was 0.65 (95% CI 0.58-0.73, P < 0.001) compared with HD patients. With adjustment for 26 variables, the corresponding relative risk of death was 1.07 (95% CI 0.94-1.22, P = 0.33). When censoring at time of kidney transplantation, the result was similar with a relative risk of death of 1.09 (95% CI 0.95-1.25, P = 0.24) on PD compared with HD. CONCLUSIONS: PD is associated with several factors generally related to good prognosis. After comprehensive adjustment for putative confounding factors with the ITT analysis approach, we found no significant difference in survival between PD and HD patients.

Predicting mortality after start of long-term dialysis-International validation of one- and two-year prediction models.

BACKGROUND: Mortality prediction is critical on long-term kidney replacement therapy (KRT), both for individual treatment decisions and resource planning. Many mortality prediction models already exist, but as a major shortcoming most of them have only been validated internally. This leaves reliability and usefulness of these models in other KRT populations, especially foreign, unknown. Previously two models were constructed for one- and two-year mortality prediction of Finnish patients starting long-term dialysis. These models are here internationally validated in KRT populations of the Dutch NECOSAD Study and the UK Renal Registry (UKRR). METHODS: We validated the models externally on 2051 NECOSAD patients and on two UKRR patient cohorts (5328 and 45493 patients). We performed multiple imputation for missing data, used c-statistic (AUC) to assess discrimination, and evaluated calibration by plotting average estimated probability of death against observed risk of death. RESULTS: Both prediction models performed well in the NECOSAD population (AUC 0.79 for the one-year model and 0.78 for the two-year model). In the UKRR populations, performance was slightly weaker (AUCs: 0.73 and 0.74). These are to be compared to the earlier external validation in a Finnish cohort (AUCs: 0.77 and 0.74). In all tested populations, our models performed better for PD than HD patients. Level of death risk (i.e., calibration) was well estimated by the one-year model in all cohorts but was somewhat overestimated by the two-year model. CONCLUSIONS: Our prediction models showed good performance not only in the Finnish but in foreign KRT populations as well. Compared to the other existing models, the current models have equal or better performance and fewer variables, thus increasing models' usability. The models are easily accessible on the web. These results encourage implementing the models into clinical decision-making widely among European KRT populations.

Severe infections in peritoneal dialysis and home hemodialysis patients: An inception cohort study.

OBJECTIVES: Infections are the most common non-cardiovascular cause of death among dialysis patients. Earlier studies have shown similar or higher risk of infectious complications in peritoneal dialysis (PD) compared to hemodialysis (HD) patients, but comparisons to home HD patients have been rare. We investigated the risk of severe infections after start of continuous ambulatory PD (CAPD) and automated PD (APD) as compared to home HD. METHODS: All adult patients (n = 536), who were on home dialysis at day 90 from starting kidney replacement therapy (KRT) between 2004 and 2017 in Helsinki healthcare district, were included. We defined severe infection as an infection with C-reactive protein of 100 mg/l or higher. Cumulative incidence of first severe infection was assessed considering death as a competing risk. Hazard ratios were estimated using Cox regression with propensity score adjustment. RESULTS: The risk of getting a severe infection during the first year of dialysis was 35% for CAPD, 25% for APD and 11% for home HD patients. During five years of follow-up, the hazard ratio of severe infection was 2.8 [95% CI 1.6-4.8] for CAPD and 2.2 [95% CI 1.4-3.5] for APD in comparison to home HD. Incidence rate of severe infections per 1000 patient-years was 537 for CAPD, 371 for APD, and 197 for home HD patients. When excluding peritonitis, the incidence rate was not higher among PD than home HD patients. CONCLUSIONS: CAPD and APD patients had higher risk of severe infections than home HD patients. This was explained by PD-associated peritonitis.

Employment of patients receiving maintenance dialysis and after kidney transplant: a cross-sectional study from Finland.

BACKGROUND: Associations between mode of renal replacement therapy and employment rate have not been well characterized. STUDY DESIGN: Cross-sectional registry analysis. SETTING & PARTICIPANTS: The employment status of all prevalent 15- to 64-year-old dialysis and kidney transplant patients in Finland at the end of 2007 (N = 2,637) was analyzed by combining data from the Finnish Registry for Kidney Diseases with individual-level employment statistics of the Finnish government. PREDICTOR: Prevalence rate ratios (PRRs) of employment according to treatment modality with adjustment for age, sex, cause of end-stage renal disease (ESRD), duration of ESRD, and comorbid conditions were estimated using Cox regression with a constant time at risk. OUTCOME: Employment status of patients on dialysis therapy or after transplant. MEASUREMENTS: Clinical data were collected from the Finnish Registry for Kidney Diseases, and employment data were acquired from Statistics Finland. RESULTS: 19% of hemodialysis patients, 31% of peritoneal dialysis patients, and 40% of patients with a functioning transplant were employed; the overall employment rate for the Finnish population aged 15-64 years is 67%. Home hemodialysis patients and those treated with automated peritoneal dialysis had employment rates of 39% and 44%, respectively. In adjusted analysis, patients on home hemodialysis therapy (PRR, 1.87), on automated peritoneal dialysis therapy (PRR, 2.14), or with a kidney transplant (PRR, 2.30) had higher probabilities of employment than in-center hemodialysis patients. Patients with type 1 or 2 diabetes as the cause of ESRD had the lowest probability of employment (PRR, 0.48-0.60 compared with glomerulonephritis). Patients aged 25-54 years more frequently were employed than those younger than 25 or older than 54 years. Sex did not predict employment. For transplant recipients, longer time since transplant was associated with higher employment in addition to the mentioned factors. LIMITATIONS: Cross-sectional design. CONCLUSIONS: Employment rate of home dialysis patients was similar to that of transplant recipients and higher than that of in-center hemodialysis patients. Patients with diabetes were less likely to be employed.

Decline in glomerular filtration rate during pre-dialysis phase and survival on chronic renal replacement therapy.

BACKGROUND: Estimated glomerular filtration rate (eGFR) is widely used in follow-up and assessment of patients before start of chronic renal replacement therapy (RRT). Reported data on impact of eGFR decline pattern during pre-dialysis phase on consequent survival on RRT are, however, non-existent. METHODS: Using the database of the Finnish Registry for Kidney Diseases, we conducted a cohort study of all incident adult patients (n = 457) entering chronic RRT in Finland in 1998, with follow-up until 31 December 2008. We included those (n = 319) with three serum creatinine measurements (at ∼12 and 3 months and 1 to 2 weeks prior to RRT start) and calculated their slopes of eGFR using the modification of diet in renal disease formula. According to eGFR slopes (in mL/min/1.73m(2)/year), patients were divided into tertiles: most rapid (>8.5, n = 107), intermediate (3.4-8.5, n = 107) and slowest decline (<3.4, n = 105). RESULTS: Median survival time was 5.6 (95% confidence interval 4.2-7.0) years. Compared to the patient group with the slowest eGFR decline, age- and gender-adjusted relative risk of death was 1.1 (0.8-1.5) in the intermediate group and 1.7 (1.2-2.4, P = 0.002) in the most rapid decline group. When further adjusting for kidney disease diagnosis, comorbidities, use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, body mass index, blood haemoglobin and serum albumin, the association was no longer significant. CONCLUSIONS: Rapid decline in eGFR before entering chronic RRT associates with increased mortality on RRT. The elevated mortality appears to be caused by known risk factors for death on RRT.

[Extracorporeal blood purification for poisonings]. / Myrkytysten kehonulkoiset verenpuhdistusmenetelmät.

Most poisonings that have resulted in hospitalization in Finland are alcohol, drug or mixed poisonings of adults. If the quantity of the drug or the poison is high or organ injury is anticipated, the patients may require extracorporeal blood purification in order to eliminate the substance or its metabolic products from the circulation. Hemodialysis or hemodiafiltration are used as the treatment, if the substance having caused the poisoning is water-soluble, binds to proteins only to a small extent, and has a low molecular weight and small distribution of volume. Fat-soluble substances are eliminated by using hemoperfusion, those having bound to proteins by using albumin dialysis.

Biomarkers in kidney and heart disease.

There is much symptomatic similarity between acute kidney disease and acute heart disease. Both may present with shortness of breath and chest discomfort, and thus it is not surprising that biomarkers of acute myocardial and renal disease often coexist in many physicians' diagnostic work-up schedules. In this review we explore the similarities and differences between current and future tests of myocardial and renal injury and function, with particular emphasis on the diagnostic utility of currently available biomarkers to assist with the diagnosis of cardiorenal syndromes. Imaging studies have not traditionally been viewed as clinical biomarkers, but as tests of structure and function; they contribute to the diagnostic process, and we believe that they should be considered alongside more traditional biomarkers such as blood and urine measurements of circulating proteins and metabolites. We discuss the place of natriuretic peptides, novel tests of kidney damage as well as kidney function and conclude with a discussion of their place in guiding future research studies whose goals must include better characterization of the degree of dysfunction imposed on one organ system by failure of the other.

Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative.

A consensus conference on cardio-renal syndromes (CRS) was held in Venice Italy, in September 2008 under the auspices of the Acute Dialysis Quality Initiative (ADQI). The following topics were matter of discussion after a systematic literature review and the appraisal of the best available evidence: definition/classification system; epidemiology; diagnostic criteria and biomarkers; prevention/protection strategies; management and therapy. The umbrella term CRS was used to identify a disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ. Different syndromes were identified and classified into five subtypes. Acute CRS (type 1): acute worsening of heart function (AHF-ACS) leading to kidney injury and/or dysfunction. Chronic cardio-renal syndrome (type 2): chronic abnormalities in heart function (CHF-CHD) leading to kidney injury and/or dysfunction. Acute reno-cardiac syndrome (type 3): acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction. Chronic reno-cardiac syndrome (type 4): chronic kidney disease leading to heart injury, disease, and/or dysfunction. Secondary CRS (type 5): systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. Consensus statements concerning epidemiology, diagnosis, prevention, and management strategies are discussed in the paper for each of the syndromes.

Primary kidney disease modifies the effect of comorbidities on kidney replacement therapy patients' survival.

BACKGROUND: Comorbidities are associated with increased mortality among patients receiving long-term kidney replacement therapy (KRT). However, it is not known whether primary kidney disease modifies the effect of comorbidities on KRT patients' survival. METHODS: An incident cohort of all patients (n = 8696) entering chronic KRT in Finland in 2000-2017 was followed until death or end of 2017. All data were obtained from the Finnish Registry for Kidney Diseases. Information on comorbidities (coronary artery disease, peripheral vascular disease, left ventricular hypertrophy, heart failure, cerebrovascular disease, malignancy, obesity, underweight, and hypertension) was collected at the start of KRT. The main outcome measure was relative risk of death according to comorbidities analyzed in six groups of primary kidney disease: type 2 diabetes, type 1 diabetes, glomerulonephritis (GN), polycystic kidney disease (PKD), nephrosclerosis, and other or unknown diagnoses. Kaplan-Meier estimates and Cox regression were used for survival analyses. RESULTS: In the multivariable model, heart failure increased the risk of death threefold among PKD and GN patients, whereas in patients with other kidney diagnoses the increased risk was less than twofold. Obesity was associated with worse survival only among GN patients. Presence of three or more comorbidities increased the age- and sex-adjusted relative risk of death 4.5-fold in GN and PKD patients, but the increase was only 2.5-fold in patients in other diagnosis groups. CONCLUSIONS: Primary kidney disease should be considered when assessing the effect of comorbidities on survival of KRT patients as it varies significantly according to type of primary kidney disease.

Gemtuzumab-Ozogamicin-Related Impaired Hemoglobin-Haptoglobin Scavenging as On-Target/Off-Tumor Toxicity of Anti-CD33 AML Therapy: A Report of Two Cases.

Gemtuzumab-ozogamicin (GO) is a humanized anti-CD33 antibody, which is conjugated to a cytotoxic calicheamicin. It is used to treat acute myeloid leukemia (AML) in combination with chemotherapy. We describe here two GO-treated acute myeloid leukemia (AML) cases: both patients suffered from a toxic syndrome, which manifested as impaired hemoglobin-haptoglobin scavenging and accumulation of hemolysis-related products. Our observations and earlier reports indicated that the reaction was caused by GO-targeted destruction of CD33 + CD163+ monocytes/macrophages, which are responsible for the clearance of hemoglobin-haptoglobin complexes. The rise of plasma lactate dehydrogenase was an early sign of the reaction, and both patients had high levels of free plasma hemoglobin, but plasma haptoglobin and bilirubin levels were paradoxically normal. Symptoms included septic fever and abnormalities in cardiac tests and in the case of the first patient, severe neurological symptoms which required intensive care unit admittance. Therapeutic plasma exchanges supported the patients until the recovery of normal hematopoiesis. The symptoms may be easily confounded with infectious complications-related organ damage. Regarding the increasing use of gemtuzumab-ozogamicin and other emerging CD33-targeted cell therapies, we want to highlight this mostly unknown and probably underdiagnosed toxicity.

Predictive value of plasma proenkephalin and neutrophil gelatinase-associated lipocalin in acute kidney injury and mortality in cardiogenic shock.

BACKGROUND: Acute kidney injury (AKI) is a frequent form of organ injury in cardiogenic shock. However, data on AKI markers such as plasma proenkephalin (P-PENK) and neutrophil gelatinase-associated lipocalin (P-NGAL) in cardiogenic shock populations are lacking. The objective of this study was to assess the ability of P-PENK and P-NGAL to predict acute kidney injury and mortality in cardiogenic shock. RESULTS: P-PENK and P-NGAL were measured at different time points between baseline and 48 h in 154 patients from the prospective CardShock study. The outcomes assessed were AKI defined by an increase in creatinine within 48 h and all-cause 90-day mortality. Mean age was 66 years and 26% were women. Baseline levels of P-PENK and P-NGAL (median [interquartile range]) were 99 (71-150) pmol/mL and 138 (84-214) ng/mL. P-PENK > 84.8 pmol/mL and P-NGAL > 104 ng/mL at baseline were identified as optimal cut-offs for AKI prediction and independently associated with AKI (adjusted HRs 2.2 [95% CI 1.1-4.4, p = 0.03] and 2.8 [95% CI 1.2-6.5, p = 0.01], respectively). P-PENK and P-NGAL levels at baseline were also associated with 90-day mortality. For patients with oliguria < 0.5 mL/kg/h for > 6 h before study enrollment, 90-day mortality differed significantly between patients with low and high P-PENK/P-NGAL at baseline (5% vs. 68%, p < 0.001). However, the biomarkers provided best discrimination for mortality when measured at 24 h. Identified cut-offs of P-PENK24h > 105.7 pmol/L and P-NGAL24h > 151 ng/mL had unadjusted hazard ratios of 5.6 (95% CI 3.1-10.7, p < 0.001) and 5.2 (95% CI 2.8-9.8, p < 0.001) for 90-day mortality. The association remained significant despite adjustments with AKI and two risk scores for mortality in cardiogenic shock. CONCLUSIONS: High levels of P-PENK and P-NGAL at baseline were independently associated with AKI in cardiogenic shock patients. Furthermore, oliguria before study inclusion was associated with worse outcomes only if combined with high baseline levels of P-PENK or P-NGAL. High levels of both P-PENK and P-NGAL at 24 h were found to be strong and independent predictors of 90-day mortality. TRIAL REGISTRATION: NCT01374867 at www.clinicaltrials.gov , registered 16 Jun 2011-retrospectively registered.

Therapeutic strategies for heart failure in cardiorenal syndromes.

Cardiorenal syndromes are disorders of the heart and kidneys whereby acute or long-term dysfunction in one organ may induce acute or long-term dysfunction of the other. The management of cardiovascular diseases and risk factors may influence, in a beneficial or harmful way, kidney function and progression of kidney injury. In this review, we assess therapeutic strategies and discuss treatment options for the management of patients with heart failure with decreased kidney function and highlight the need for future high-quality studies in patients with coexisting heart and kidney disease.