Predictors of Survival on Renal Replacement Therapy

Background and aims. Patients with end-stage renal disease and on chronic renal replacement therapy are at increased risk of death compared to a population of the same age without end-stage renal disease. Despite some improvement in prognosis of end-stage renal disease patients during recent decades, the expected outcome remains dismal. Several factors are associated with impaired survival of patients with end-stage renal disease: especially high age, low serum albumin, chronic inflammation, and comorbidities such as diabetes and heart failure. However, a major portion of factors behind impaired survival have been insufficiently identified, and their prognostic weight is largely unknown. We therefore targeted for further exploration and measurement of factors potentially associated with survival of patients on chronic renal replacement therapy. Study patients and methods. In the four studies of this thesis, we investigated the survival of cohorts of adult patients in Finland after the start of chronic renal replacement therapy. These cohorts were in Study I, 1,604 patients with type 1 diabetes and 1,556 with glomerulonephritis who started chronic RRT during 1980–2005; in Study II, 319 patients during one year (1998) preceding start of chronic renal replacement therapy and thereafter; in Study III, all 4,463 patients who started chronic renal replacement therapy in 2000–2009; in Study IV, all 6,103 patients who entered chronic dialysis in 2000–2012. Data on patient cohorts came from the Finnish Registry for Kidney Diseases, a database including comprehensive information on Finnish patients on chronic renal replacement therapy since 1964. In Study III, data also came from the Finnish Kidney Transplant Registry. The statistical methods mainly employed in our survival analyses were Kaplan-Meier curves, the log rank test, and Cox proportional hazards regression and binary logistic regression for multivariable modeling. Results. In Study I, we showed that survival of patients with type 1 diabetes receiving chronic renal replacement therapy has improved significantly and consistently over the years and in all age-groups. Patients entering chronic renal replacement therapy in 2000–2005 had a 77% lower risk of death than those entering in 1980–1984. Said another way, median survival time of patients with type 1 diabetes on chronic renal replacement therapy has increased from 3.6 years to more than eight. In Study II, we detected a significantly higher age-adjusted mortality in those on chronic renal replacement therapy whose decline in estimated glomerular filtration rate during the predialysis phase had been the fastest. Their mortality risk was 73% higher in the patient tertile of fastest decliners compared to the slowest. This association, however, proved not to be causal, but instead jointly caused by many confounding factors, especially age, end-stage renal disease diagnoses type 1 diabetes and amyloidosis, and the comorbidities myocardial infarction and cancer. In Study III, results of our primary adjusted analyses (intention-to-treat) indicated no significant difference in risk of death between patients on chronic renal replacement therapy who started with peritoneal dialysis compared to those who started with hemodialysis. Without adjustment, the relative risk of death of peritoneal dialysis patients was 0.65 (95% CI 0.58-0.73, p<0.001) compared to hemodialysis patients. With adjustment for 26 potentially confounding variables, the corresponding relative risk was, however, 1.07 (95% CI 0.94-1.22, p=0.33). Results from our secondary analysis method (as-treated) and further with full adjustment, however, indicated a 17 to 33% higher relative risk of death for patients exclusively treated by peritoneal dialysis compared to those treated by hemodialysis exclusively. In Study IV, we developed one- and two-year all-cause mortality prediction models for patients starting chronic dialysis. These models were based on a less recent training cohort and validated with a more recent validation cohort. As a result, area under the curve for the one-year model (with seven variables) reached 0.77 and for the two-year model (with six variables) 0.74. Because mortality in the more recent patient cohort was significantly lower than in the less-recent cohort, both models slightly overestimated mortality risk. Conclusions. Based on studies described in this thesis, survival of Finnish patients with type 1 diabetes and end-stage renal disease has significantly improved since the beginning of the 1980s, despite their conspicuous increase in age, and has improved relatively more in patients with type 1 diabetes than in patients with glomerulonephritis, suggesting progress both in dialysis therapy and overall management of patients with end-stage renal disease and, quite evidently, also in management of diabetes. Furthermore, factors behind the rapid decline in estimated glomerular filtration rate during the year preceding the start of chronic renal replacement therapy, and effects of these factors on subsequent survival are now better characterized. Rate of decline in estimated glomerular filtration rate is not a causal factor for survival, but instead a marker of other factors associated with end-stage renal disease patients’ survival. In addition, based on this research, no overall difference appeared in survival regarding modality of dialysis. Patients starting chronic dialysis differ significantly between dialysis modalities with respect to many patient-level prognostic factors, but after comprehensive adjustment for these putative confounders, no survival advantage of one dialysis modality over another emerged. And lastly, important factors affecting one- and two-year mortality of Finnish patients starting chronic dialysis are now identified and their prognostic weight can be investigated. Based on these findings, we constructed two models for survival estimation hopefully to be implemented in individualized treatment-planning of patients approaching chronic renal replacement therapy.Tutkimuksen taustaa ja tavoitteet. Loppuvaiheen munuaisten vajaatoiminnan aktiivihoidossa olevia potilaita hoidetaan munuaisten korvaushoidolla eli dialyysillä tai heillä on toimiva munuaissiirrännäinen. Vaikka näiden potilaiden eloonjäämisennuste on kohentunut jonkin verran viime vuosikymmenien aikana, heidän kuolleisuutensa on edelleen merkitsevästi suurempi kuin saman ikäisellä, munuaisiltaan terveellä väestöllä. Ennustetta heikentävät erityisesti korkea ikä, matala seerumin albumiinipitoisuus, krooninen tulehdustila ja liitännäissairaudet kuten diabetes ja sydämen vajaatoiminta. Ennustetekijöitä on toistaiseksi kuitenkin tunnistettu vajavaisesti, ja tekijöiden ennusteellinen merkitys on epäselvä. Tämän väitöskirjatyön tavoitteena oli tunnistaa loppuvaiheen munuaisten vajaatoimintaa sairastavien potilaiden eloonjäämisennusteeseen vaikuttavia tekijöitä ja arvioida niiden painoarvoa. Tutkimuspotilaat ja –menetelmät. Väitöskirjan neljässä osatyössä tutkimme eloonjäämistä neljässä, pitkäaikaisen munuaisten korvaushoidon aloittaneen aikuispotilaan ryhmässä. Osatyöhön I valittiin Suomen kaikki ne tyypin 1 diabetesta (yhteensä 1604) ja munuaiskerästulehdusta (yhteensä 1556) sairastavat potilaat, jotka aloittivat munuaisten korvaushoidon vuosina 1980–2005. Osatyössä II tutkittiin munuaisten korvaushoidon vuonna 1998 aloittaneita potilaita (yhteensä 319). Osatyöhön III otettiin mukaan kaikki 4463 vuosina 2000–2009 ja osatyöhön IV kaikki 6103 vuosina 2000–2012 dialyysin Suomessa aloittaneet potilaat. Potilasryhmien tiedot saatiin Suomen munuaistautirekisteristä, joka sisältää kattavaa ja monipuolista tietoa Suomessa pitkäaikaisen munuaisten korvaushoidon aloittaneista potilaista vuodesta 1964 lähtien. Osatyössä III käytimme myös tietoja, jotka saimme HYKS:n munuaissiirtoyksikön valtakunnallisesta seurantarekisteristä. Tärkeimmät käyttämämme tilastolliset menetelmät olivat Kaplanin-Meierin menetelmä, log rank -testi ja Coxin suhteellisten riskitiheyksien regressio sekä monen selittäjän binaarinen logistinen regressio. Tulokset. Osatyössä I osoitimme, että tyypin 1 diabetesta sairastavien, pitkäaikaisessa munuaisten korvaushoidossa olevien potilaiden eloonjäämisennuste on parantunut merkitsevästi viimeisten vuosikymmenien aikana. Ennuste on parantunut kaikissa ikäryhmissä. Vuosina 2000–2005 pitkäaikaiseen munuaisten korvaushoitoon tulleiden kuolemanriski oli 77% pienempi kuin vuosina 1980–1984 hoidon aloittaneilla. Eloonjäämisajan keskiluku munuaisten korvaushoidossa nousi samassa ajassa 3,6:sta vuodesta yli 8:an vuoteen. Osatyössä II totesimme, että ikävakioitu kuolemanriski oli merkitsevästi suurempi niillä pitkäaikaisessa munuaisten korvaushoidossa olevilla potilailla, joiden laskennallinen munuaiskerässuodoksen laskunopeus dialyysiä edeltävässä ns. predialyysivaiheessa oli ollut nopein. Kuolemanriski oli 73% suurempi, kun verrattiin laskennallisen munuaiskerässuodoksen laskun osalta nopeinta potilaskolmannesta hitaimpaan kolmannekseen. Kyseessä ei kuitenkaan ollut syy-seuraussuhde munuaiskerässuodoksen laskunopeuden ja kuolemanriskin välillä, vaan kuolemanriskin erilaisuus johtui useasta sekoittavasta tekijästä, kuten ikä, munuaisten vajaatoiminnan aiheuttanut sairaus (tyypin 1 diabetes ja amyloidoosi) ja sellaiset liitännäissairaudet kuten sydäninfarkti ja syöpä. Osatyössä III verrattiin kuolemanriskiä pitkäaikaisen vatsakalvodialyysin ja hemodialyysin aloittaneiden potilaiden välillä. Vakioidussa pääanalyysissä (intention-to-treat) ei ilmennyt eroa kuolemanriskissä. Ilman vakiointia vatsakalvodialyysin aloittaneiden suhteellinen kuolemanriski oli 0,65 (95% CI 0,58-0,73, p<0.001) verrattuna hemodialyysin aloittaneisiin. Kun kuolemanriski vakioitiin 26:lla mahdollisella sekoittavalla tekijällä, niin vastaava suhteellinen kuolemanriski oli 1,07 (95% CI 0,94-1,22, p=0.33). Toissijaisena käyttämämme, täysin vakioitu analyysitapa (as-treated) osoitti 17-33% korkeampaa kuolemanriskiä yksinomaan vatsakalvodialyysissä olleilla potilailla verrattuna pelkästään hemodialyysillä hoidettuihin potilaisiin. Osatyössä IV kehitimme yksi- ja kaksivuotiskuolemanriskiä ennustavat mallit. Mallien rakentaminen suoritettiin pitkäaikaisen munuaisten korvaushoidon vuosina 2000–2008 aloittaneiden potilaiden tietojen pohjalta, ja mallit validoitiin (vahvistettiin) uudemmalla potilasryhmällä (vuosina 2009–2012 hoidon aloittaneet). Mallien kyky ennustaa yksilöllistä kuolemanriskiä (area under the curve, AUC) oli yksivuotismallilla (seitsemän muuttujaa) 0,77 ja kaksivuotismallilla (kuusi muuttujaa) 0,74. Molemmat mallit yliarvioivat kuolemanriskiä jonkin verran johtuen validointiryhmän merkitsevästi vähäisemmästä kuolleisuudesta verrattuna ryhmään, jonka tiedoilla mallit rakennettiin. Päätelmät. Tämän väitöskirjatyön osatöiden perusteella voidaan sanoa seuraavaa: 1) Tyypin 1 diabetesta sairastavien suomalaisten, pitkäaikaisessa munuaisten korvaushoidossa olevien potilaiden eloonjääminen on parantunut merkitsevästi vuodesta 1980 lähtien. Eloonjäämisennuste on parantunut siitäkin huolimatta, että munuaisten korvaushoidon aloittavat potilaat ovat vuosi vuodelta iäkkäämpiä. Ennuste on kohentunut tyypin 1 diabeetikoilla suhteellisesti enemmän kuin munuaiskerästulehdusta sairastavilla potilailla viitaten kehitykseen sekä munuaisten korvaushoitojen tekniikoissa ja pitkäaikaisessa korvaushoidossa olevien hoidossa ylipäätään, että varsin selvästi myös kehitykseen diabeteksen hoidossa. 2) Predialyysivaiheen laskennallisen munuaiskerässuodoksen laskunopeuteen vaikuttavat tekijät on nyt tunnistettu aiempaa tarkemmin ja arvioitu näiden tekijöiden liittyminen eloonjäämisennusteeseen pitkäaikaisessa munuaisten korvaushoidossa. Laskennallisen munuaiskerässuodoksen laskunopeus predialyysivaiheessa ei ole suoraan kuolemanriskiin vaikuttava tekijä, vaan osoitin muista, kuolleisuuteen liittyvistä tekijöistä. 3) Eloonjäämisennusteessa ei ole eroa vatsakalvo- ja hemodialyysin aloittavien potilaiden välillä Suomessa. Näihin kahteen dialyysin päämuotoon valikoituvat potilaat ovat hyvin erilaisia monien ennusteeseen liittyvien tekijöiden suhteen. Kun suoritetaan kattava vakiointi näiden mahdollisesti sekoittavien tekijöiden suhteen, ei voida todeta eroa eloonjäämisennusteessa dialyysihoitomuotojen välillä. 4) Pitkäaikaisen dialyysin aloittavien potilaiden eloonjäämisen yksi- ja kaksivuotisennusteeseen vaikuttavat tekijät on nyt kartoitettu Suomessa. Näiden tekijöiden avulla on muodostettu mallit, jotka toivotaan otettavan käyttöön arvioitaessa pitkäaikaista dialyysihoitoa aloittavien potilaiden yksilöllistä eloonjäämisennustetta

Eculizumab Treatment for Postpartum HELLP Syndrome and aHUS—Case Report

Preeclampsia is a pregnancy-specific disorder affecting ca 3% of all pregnant women. Preeclampsia is the source of severe pregnancy complications. Later life consequences for mother and infant include increased risk of cardiovascular disease. Preeclampsia is caused by the dysfunction of the endothelium with subsequent activation of complement and coagulation systems. HELLP syndrome is considered to be an extreme complication of preeclampsia but it can also present independently. Diagnostic symptoms in HELLP syndrome are Hemolysis, Elevated Liver enzymes, and Low Platelets. Similar phenotype is present in thrombotic microangiopathies (TMAs) and HELLP syndrome is considered part of the TMA spectrum. Here, we present a case of severe preeclampsia and HELLP syndrome, which exacerbated rapidly and eventually led to need of intensive care, plasma exchange, and hemodialysis. The patient showed signs of hemolysis, disturbance in the coagulation, and organ damage in liver and kidneys. After comprehensive laboratory testing and supportive care, the symptoms did not subside and treatment with complement C5 inhibitor eculizumab was started. Thereafter, the patient started to recover. The patient had pregnancy-induced aHUS. Earlier initiation of eculizumab treatment may potentially shorten and mitigate the disease and hypothetically decrease future health risks of preeclamptic women.Peer reviewe

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.Peer reviewe

Reply to : High levels of plasma biomarkers at 24 h were found to be strong predictors of 90-day mortality: beware of some potential confounders!

Non peer reviewe

Pharmacological Management of Cardiorenal Syndromes

Cardiorenal syndromes are disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The pharmacological management of Cardiorenal syndromes may be complicated by unanticipated or unintended effects of agents targeting one organ on the other. Hence, a thorough understanding of the pathophysiology of these disorders is paramount. The treatment of cardiovascular diseases and risk factors may affect renal function and modify the progression of renal injury. Likewise, management of renal disease and associated complications can influence heart function or influence cardiovascular risk. In this paper, an overview of pharmacological management of acute and chronic Cardiorenal Syndromes is presented, and the need for high-quality future studies in this field is highlighted

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.Peer reviewe

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.Peer reviewe

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) mu mol/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.Peer reviewe

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

BackgroundMortality 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). MethodsWe 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. ResultsBoth 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. ConclusionsOur 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.Peer reviewe

Urine NGAL as a biomarker for septic AKI : a critical appraisal of clinical utility-data from the observational FINNAKI study

Background: Neutrophil gelatinase-associated lipocalin (NGAL) is released from kidney tubular cells under stress as well as from neutrophils during inflammation. It has been suggested as a biomarker for acute kidney injury (AKI) in critically ill patients with sepsis. To evaluate clinical usefulness of urine NGAL (uNGAL), we post-hoc applied recently introduced statistical methods to a sub-cohort of septic patients from the prospective observational Finnish Acute Kidney Injury (FINNAKI) study. Accordingly, in 484 adult intensive care unit patients with sepsis by Sepsis-3 criteria, we calculated areas under the receiver operating characteristic curves (AUCs) for the first available uNGAL to assess discrimination for four outcomes: AKI defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria, severe (KDIGO 2-3) AKI, and renal replacement therapy (RRT) during the first 3 days of intensive care, and mortality at day 90. We constructed clinical prediction models for the outcomes and used risk assessment plots and decision curve analysis with predefined threshold probabilities to test whether adding uNGAL to the models improved reclassification or decision making in clinical practice. Results: Incidences of AKI, severe AKI, RRT, and mortality were 44.8% (217/484), 27.7% (134/484), 9.5% (46/484), and 28.1% (136/484). Corresponding AUCs for uNGAL were 0.690, 0.728, 0.769, and 0.600. Adding uNGAL to the clinical prediction models improved discrimination of AKI, severe AKI, and RRT. However, the net benefits for the new models were only 1.4% (severe AKI and RRT) to 2.5% (AKI), and the number of patients needed to be tested per one extra true-positive varied from 40 (AKI) to 74 (RRT) at the predefined threshold probabilities. Conclusions: The results of the recommended new statistical methods do not support the use of uNGAL in critically ill septic patients to predict AKI or clinical outcomes.Peer reviewe