Renal recovery after severe acute kidney injury in critically ill myeloma patients: a retrospective study

Renal recovery after severe acute kidney injury in critically ill myeloma patients: a... Background: Despite substantial improvements in the management of multiple myeloma, renal failure remains an impor- tant burden that tremendously impairs prognosis. The purpose of this study was to describe the characteristics and to establish prognostic factors of renal recovery in myeloma patients admitted to the intensive care unit (ICU) for acute kidney injury (AKI) Stage 3 treated with renal replacement therapy (RRT). Methods: A retrospective single-centre cohort study was performed, including consecutive myeloma patients admitted to one medical ICU between 1 January 2007 and 1 September 2015 and treated with RRT. Patients were evaluated 60 days after initiation of RRT and divided into three groups: alive without dialysis, alive and dialysis-dependent or deceased. A univariate analysis was performed to identify factors associated with renal recovery (alive without dialysis 60 days after initiation of RRT). Results: Fifty patients were included in the study. Mean age was 63 (interquartile range: 58–70) years and 32 (64%) were male. Patients were admitted to the ICU 4 (1–7) years after the diagnosis of myeloma. Twenty-one (42%) had already been treated with high-dose therapy combined with autologous stem cell transplantation. Baseline renal function evaluated by estimated glomerular filtration rate (GFR) before ICU admission was 63 (44–90) mL/min/1.73 m . The mean SOFA score at Day 1 was 7 (4–8). The three main reasons for ICU admission were AKI (n¼ 31, 62%), acute pulmonary oedema (n ¼ 17, 32%) and sepsis (n ¼ 10, 20%). During ICU stay, RRT was implemented in all patients, 16 (32%) patients required invasive mechani- cal ventilation and 12 (24%) received vasopressors. The mean ICU and hospital length of stay were 6 (1–7) and 28 (13–34) days, respectively. At Day 60, 23 (46%) patients were alive without dialysis, 17 (32%) had died and 10 (20%) were still under- going dialysis. Among the 23 patients who recovered, the mean duration of dialysis was 6 (2–18) days and renal function was not significantly different from baseline [estimated GFR at baseline¼ 65 (25–74) mL/min/1.73 m versus 63 (56–70) mL/ min/1.73 m at Day 60, P¼ 0.70]. By univariate analysis, two factors were associated with nonrecovery of renal function at Day 60: a history of high-dose therapy combined with autologous stem cell transplantation [odds ratio (OR)¼ 6.1, 95% confi- dence interval (CI) 1.7–21.6; P¼ 0.008] and a proteinuria at ICU admission >370 mg/mmol creatinine (OR ¼ 4.2, 95% CI 1.1–17; Received: December 7, 2016. Editorial decision: May 18, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/20/3959730 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Renal recovery in intensive care myeloma patients | 21 P¼ 0.02). None of the other variables related to the haematological malignancy or to the ICU stay was associated with renal recovery at Day 60. Conclusions: AKI Stage 3 in critically ill myeloma patients was associated with a lower than expected hospital mortality. Patients with a high level of proteinuria and a history of high-dose therapy combined with autologous stem cell transplan- tation were less likely to recover their renal function at Day 60. Key words: dialysis, intensive care, multiple myeloma, prognosis, proteinuria ventilation, continuous or intermittent dialysis), the myeloma Introduction characteristics before (time from diagnosis, treatments Myeloma is the second most common haematological malig- received, baseline renal function and disease activity according nancy [1] and remains the first neoplasm responsible for end- to the International Myeloma Working Group definition [10]) stage renal disease [2]. and at the time of AKI (serum free light chains, serum peak Despite substantial improvements in its management, renal immunoglobulin), and the follow-up after ICU discharge (length failure occurs in up to 50% of patients [with 10% needing renal of dialysis maintenance therapy, response to treatment and replacement therapy (RRT)] [3] and tremendously impairs prog- vital status). Baseline renal function was defined as the best nosis, with a median survival of 3.5–10 months [4] for those renal function in the month before ICU admission, using the under dialysis. Reversibility of renal failure can improve this CKD-EPI (Chronic Kidney Disease - Epidemiology Collaboration) otherwise grim prognosis [3]. equation. Therefore, the question of recovery is crucial in the manage- Outcome was collected 60 days after RRT implementation. ment of acute kidney injury (AKI) requiring dialysis and in the Recovery group was defined as patients alive and free of dialysis course of myeloma. and nonrecovery as a composite endpoint of death and dialysis More than 10% of myeloma patients [5] will require intensive dependence, as advocated by the National Institute of Diabetes, care unit (ICU) admission, mostly for AKI (39–51%, 24–44% of Digestive and Kidney Diseases [11]. Admissions were divided which needing RRT) [6]. between 2007–11 and 2012–15, which corresponds to the middle Rates of renal recovery are largely variable, ranging from of the study period and to the authorization of SC bortezomib 17% [4] to 75% [7] in recent trials, but to our knowledge no pre- by the European Medicines Agency (2012), to assess for improve- vious study has evaluated the prognosis of AKI in myeloma ment of overall prognosis. patients specifically in the ICU setting. Baseline and follow-up characteristics were described by The purpose of this study was to describe the impact of means and standard deviation (SD), SD or interquartile range severe AKI on both a patient’s and kidney’s prognosis in crit- (IQR) for continuous variables normally distributed or with ically ill myeloma patients and to identify factors associated skewed distribution, respectively, and by percentages for catego- with renal recovery after initiation of RRT. rical variables. Proteinuria was divided according to the median value in our sample to take into account the supersaturation phe- nomenon that occurs in urine. Materials and methods Characteristics between recovery and nonrecovery groups were compared using Mann–Whitney test for continuous data We performed a retrospective cohort study including consecu- and Fisher’s exact test for categorical data. tive myeloma patients admitted to the medical ICU of St Louis All tests were two-sided, and P < 0.05 were considered statis- University Hospital, Paris, France (a 650-bed hospital with 330 tically significant. Analyses were done using the Statview 5.0 beds dedicated to haematology and oncology) between 1 software package (SAS Institute, Cary, NC, USA). January 2007 and 1 September 2015 and treated by RRT through- out the ICU stay. Medical records were reviewed and screened for variables of interest. Inclusion criteria were as follows: Results (i) multiple myeloma diagnosis according to the International Patient characteristics Myeloma Working Group diagnostic criteria [8] A total of 50 patients were included in the study. One was lost (ii) severe AKI, defined as Stage 3 of the Kidney Disease: to follow-up at Day 60. Patients’ characteristics are described in Improving Global Outcomes criteria (i.e. three times baseline Table 1. increase in serum creatinine or increase in serum creatinine Mean age was 63 (IQR: 58–70) years and 32 (64%) were male. to 4.0 mg/dL or urine output of< 0.3 mL/kg/h for 24 h or anu- Patients were admitted into the ICU 4 (0.8–5.3) years after the ria for 12 h) treated by RRT [9] 2 diagnosis of myeloma, after two (one to three) lines of (iii) baseline glomerular filtration rate (GFR) >15 mL/min/1.73 m . chemotherapy. Patients with amyloidosis or light-chain deposition disease Bence Jones proteinuria was noted at ICU admission in 35 (LCDD) were excluded, so that proteinuria, if present, was exclu- (70%) cases. Six patients had proteinuria of other or unknown sively composed of free light chains (FLC). Proteinuria was con- origin and among them only one had predominant albuminuria sidered significant if >50 mg/mmol. (96 mg/mmol). Nine patients had other causes of AKI (hypercal- Data were abstracted from the medical charts and we caemia, sepsis, dehydration, nephrotoxic drugs, etc.) without included variables related to the ICU stay (Sequential Organe significant proteinuria (<50 mg/mmol). Failure Assessment (SOFA) at Day 1, Simplified Acute Among those (n¼ 35) with presumed myeloma cast nephr- Physiology Score II (SAPS II), use of vasopressors or mechanical opathy, a superimposed triggering event was identified in 18 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/20/3959730 by Ed 'DeepDyve' Gillespie user on 16 March 2018 22 | A. Joseph et al. Table 1. Characteristics of patients included (n¼ 50) (51%) cases: dehydration in 7 [diarrhoea or vomiting (n ¼ 5), hae- morrhage (n ¼ 2)], sepsis in 5, exposure to nephrotoxic drugs in Demographic and clinical data for all patients (n ¼ 50) 5 [iodinated contrast product (n¼ 5), Non-steroidal anti-inflam- matory drugs (NSAIDs) (n¼ 3)] and hypercalcaemia in 1 patient. Age [mean (IQR)] (years) 62.6 (58–70) Myeloma was newly diagnosed for 19 (38%) patients and Male sex, n (%) 32 (64) relapsing for 19 (38%). Time from myeloma diagnosis to ICU 4 (0.8–5.3) Other patients had partial response (n ¼ 1, 2%), stable (n ¼ 2, admission [mean (IQR)] (years) 4%) or progressive (n ¼ 9, 18%) disease. None was considered in Myeloma status at ICU admission, n (%) Newly diagnosed 19 (38) good or very good response at the time of AKI diagnosis. Partial response 1 (2) Most often received chemotherapeutic drugs prior to ICU Stable disease 2 (4) admission were: bortezomib (34, 68%), cyclophosphamide (26, Relapse 19 (38) 52%), melphalan (27, 54%) and thalidomide (25, 50%). Four Progressive disease 9 (18) patients had never been treated and received their first chemo- Number of lines of chemotherapy prior 2 (1–3) therapy in the ICU. At the time of admission, 22 patients (44%) to ICU admission [mean (IQR)] were receiving bortezomib, 10 (22%) cyclophosphamide, 9 (18%) Chemotherapy received prior to admission, n (%) thalidomide and 9 (18%) were not currently treated. Bortezomib 34 (68) Twenty-one (42%) patients had already been treated with Cyclophosphamide 26 (52) high-dose therapy combined with autologous stem cell trans- Melphalan 27 (54) plantation (HDT-ASCT) 3 years (1–5) before ICU admission, Thalidomide 25 (50) including four patients treated 2, 10, 10 and 16 days before Corticosteroids 33 (66) admission. None 4 (8) Baseline renal function before ICU admission, estimated by Chemotherapy at the time of admission, n (%) the CKD-EPI GFR, was 63 (44–90) mL/min/1.73 m . The mean Bortezomib 22 (44) SOFA score at Day 1 was 6.6 (4–8) and the three main reasons for Cyclophosphamide 10 (20) ICU admission were AKI (n ¼ 31, 62%), acute pulmonary oedema Melphalan 6 (12) (n ¼ 17, 32%) and sepsis (n ¼ 10, 20%). During ICU stay, RRT was Thalidomide 9 (18) implemented in all patients [continuous veno-venous haemofil- Revlimid 7 (14) tration for 5 (10%) patients], 16 (32%) patients required invasive Corticosteroids 24 (48) None 9 (18) mechanical ventilation and 12 (26%) received vasopressors. The High-dose therapy combined with 21 (42) mean ICU and hospital length of stay were 6 (1–7) and 28 (13–34) autologous stem cell transplantation, n (%) days, respectively. SOFA score at Day 1 (mean þ IQR) 7 (4–8) SAPS II [mean (IQR)] 53 (40–63) Reason for ICU admission, n (%) Outcome Renal failure 31 (62) Outcomes are described in Figure 1: 60 days after initiation of Respiratory failure 10 (20) RRT, 23 (46%) patients were alive without dialysis, 17 (34%) had Cardiac failure 3 (6) Coma 3 (6) died and 10 (20%) were still under RRT. Among the 23 patients Other 3 (6) who recovered, the mean time of dialysis was 6 (2–18) days. Aplasia, n (%) 4 (8) Mean GFR at Day 60 in the recovery group was 65 (25–74) mL/ RRT 50 (100) min/1.73 m , which was not statistically different from baseline Length of RRT [mean (IQR)] (days) 7.5 (4–41) (P¼ 0.70). Noninvasive ventilation, n (%) 5 (10) Mechanical ventilation, n (%) 16 (32) Vasopressors, n (%) 12 (24) Comparison between recovery and nonrecovery groups) ICU length of stay [mean (IQR)] (days) 6 (1–7) In univariate analysis, two factors were associated with a Hospital length of stay [mean (IQR)] (days) 28 (13–34) Laboratory data decreased likelihood of renal recovery at Day 60 (Tables 2 and 3): Type of paraprotein, n (%) a history of HDT-ASCT [odds ratio (OR) 6.1, 95% confidence inter- IgG 27 (54) val(CI)1.7–21.6; P< 0.01] and a proteinuria at ICU admission IgA 12 (24) >370 mg/mmol creatinine (OR ¼ 4.2, 95% CI 1.1–17; P¼ 0.02). IgD 1 (2) There was a nonstatistically significant trend toward lower Light chain, n (%) monoclonal spike (24.5 versus 13.7 g/L, P¼ 0.15) and less use of Kappa 32 (64) bortezomib (OR ¼ 4, 95% CI 1.1–14.4; P¼ 0.06) in the nonrecovery Lambda 20 (36) group. Light chain only, n (%) 10 (20) Age (65.5 versus 60.5 years, P¼ 0.10), time from diagnosis (4.6 Kappa 8 (80) versus 3.5, P¼ 0.98), SOFA score at Day 1 (6.9 versus 6.6, P¼ 0.59) Lambda 2 (20) and baseline GFR (58.2 versus 66.2 mL/min/1.73 m ,P¼ 0.37) Proteinuria [mean (IQR)] (mg/mmol creatinine) 393 (84–557) were not different between the two groups. Neither were calcae- Bence Jones proteinuria, n (%) 35 (70) mia, exposition to nephrotoxic drugs (NSAIDs, iodinated con- Baseline GFR [mean (IQR)] 63 (44–90) trast products, angiotensin-converting enzyme inhibitors or (mL/min/1.73 m ) aminoglycosides), use of vasopressors or preserved diuresis (all Albuminemia [mean (IQR)] (g/L) 31.6 (26.0–36.0) P> 0.05). The serum free light chain was available in 27 (55%) Monoclonal peak [mean (IQR)] (g/L) 18.0 (1.2–33.9) patients and was not associated with recovery, using the Calcaemia [mean (IQR)] (mmol/L) 2.56 (2.47–2.65) median FLC level in our sample as a threshold (P> 0.45). Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/20/3959730 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Renal recovery in intensive care myeloma patients | 23 Fig. 1. Flow chart and outcomes of patients admitted for Stage 3 AKI and need for RRT. Table 2. Comparison between recovery and nonrecovery groups for continuous variables Recovery (n ¼ 23) Nonrecovery (n ¼ 27) P-value Age (years) 65.5 (58.0–70.7) 60.5 (55.2–67.4) 0.10 Time from myeloma diagnosis (years) 4.6 (2.4–6.9) 3.5 (1.5–5.5) 0.98 SOFA score at Day 1 6.9 (4.3–8.8) 6.6 (4.5–7.5) 0.59 SAPS II score 52.6 (40.0–61.3) 53.7 (40.5–63.5) 0.94 Baseline GFR (mL/min/1.73 m ) 58.2 (47–65) 66.2 (44–96) 0.37 Monoclonal spike (g/L) 24.5 (1.6–40.8) 13.7 (1.1–24.5) 0.15 Serum albumin (g/L) 32.1 (26.3–37) 31.3 (27–36) 0.67 Calcemia (mmol/L) 2.62 (2.3–2.8) 2.47 (2.2–2.5) 0.12 Data are presented as means (IQR). P-values were calculated using the MannWhitney test. Table 3. Comparison between recovery and nonrecovery groups for categorical variables Recovery (n ¼ 23) Nonrecovery (n ¼ 27) OR (95% CI) P-value n (%) n (%) Mechanical ventilation 7 (30.4) 9 (33.3) 1.1 (0.4–3.8) 0.83 Vasopressor drugs 3 (13.0) 9 (33.3) 3.3 (0.6–19.2) 0.09 Proteinuria >370 mg/mmol 7 (30.4) 18 (81.5) 4.2 (1.1–17) 0.02 Nephrotoxic drug exposure 15 (65.2) 15 (55.6) 0.7 (0.2–2.1) 0.49 Iodinated contrast exposure 0 (0) 5 (18.5) 11.5 (0.6–220) 0.09 Preserved diuresis 10 (43.5) 8 (29.6) 0.6 (0.2–1.8) 0.31 Serum free light chain >5000 mg/L 2 (8.7) 5 (18.5) 2.4 (0.4–13.7) 0.56 HDT-ASCT 4 (17.4) 17 (63.0) 6.1 (1.7–21.6) 0.01 Bortezomib 12 (52.2) 22 (81.5) 4 (1.1–14.4) 0.06 Admission between 2007 and 2011 12 (52.2) 16 (59.3) 1.3 (0.4–4.1) 0.62 Notably, none of the five patients who received iodinated con- 1.2–14, P¼ 0.02) but was not associated with dialysis depend- trast products recovered. ency at Day 60 (P¼ 0.12). There was no significative trend over time for renal recovery Among the 33 patients alive at Day 60, 2 required haemodial- (2007–11: 46% versus 2012–15: 48%, P¼ 0.62). There was no influ- ysis 9 and 29 months after ICU admission, while 2 patients ence of primary admission diagnosis on renal recovery (renal treated by RRT at Day 60 recovered 2.3 and 3.5 months later. failure versus others, P¼ 0.75). The mean follow-up for these 33 patients was 20 months In post hoc analysis, we found that a history of HDT-ASCT and for the 12 who died before the end of follow-up, the mean drove the association with increased mortality (OR¼ 4, 95% CI overall survival time was 19 months. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/20/3959730 by Ed 'DeepDyve' Gillespie user on 16 March 2018 24 | A. Joseph et al. During the same period, 21 myeloma patients underwent Previous studies reported age and baseline renal function as RRT without being admitted in the ICU: 11 for end-stage renal determinants of recovery after AKI [16, 17] in the overall popula- disease, 8 for AKI and 2 with unknown baseline renal function tion. In our study, homogeneity in age probably prevented any who underwent RRT since the diagnosis of multiple myeloma difference from appearing, but baseline GFR, provided that statis- and did not recover. Among the eight AKI patients not admitted tical power was sufficient, did not seem to be associated with in the ICU, at Day 60, four were still undergoing RRT, three were recovery in the context of myeloma. The specific mechanisms of alive without dialysis and one was deceased. The characteris- aggression of myeloma-related AKI, largely independent of base- tics of these patients (age, number of previous treatments, his- line renal function, probably account for this finding. Indeed, pre- tory of stem cell transplantation) did not differ from those cipitation of light chains largely depends on their tubular admitted in the ICU. concentration, which is expected to be affected marginally by GFR (in favour of higher tubular concentration in the best base- line renal function) but mostly from diuresis and tumour load. Indeed, renal prognosis of myeloma patients in the ICU setting Discussion has not been assessed yet, while studies conducted outside the ICU pointed to proteinuria and calcaemia [12] as prognostic factors In this study, 32% of multiple myeloma patients admitted in the of recovery from AKI. If our study confirmed proteinuria as an ICU and treated with RRT finally died while 41% recovered their important prognostic factor, it does not support a role for hypercal- renal function 60 days after initiation of RRT, without a signifi- caemia, which may be related to the introduction of bisphospho- cant decrease in renal function. Proteinuria >370 mg/mmol cre- nate therapy (six patients in our study received bisphosphonate atinine and a history of HDT-ASCT were associated with during their hospitalization) in comparison with older studies. nonrecovery of renal function. Decisions regarding admission or limitation of the therapeu- This study is the first to assess renal recovery in critically ill tic efforts should take into account these results, and we hope myeloma patients with severe AKI, in the era of novel therapies this study, along with others describing an improved overall such as bortezomib, lenalidomide and thalidomide. and intensive care prognosis of myeloma patients [6, 14], will Studies from the late 1990s reported rates of renal recovery encourage discussion between haematologists, renal and inten- as low as 8% [12] to 15% [13] for patients undergoing dialysis, sive care physicians and aid decision-making in clinical painting a bleak picture of myeloma patients requiring RRT and practice. promoting a nihilistic attitude toward their ICU admission. Our study also has several limitations. Statistical power was With the advent of novel agents’ induction therapies, recent limited by a small number of cases and some missing data, studies have spread hope of improving these patients’ outcome probably preventing several intuitive factors (e.g. monoclonal with rates of recovery as high as 75% and survival improving peak, serum free light chain excess) from becoming statistically from 18 to 32 months in the most recent studies [14]. significant. Serum free light chain was obtained in only 55% of First of all, our study describes rates of survival and renal patients. This may be due in part to the time frame of the study recovery higher than previously reported, with 46% of the (2007–15) but precludes any definitive conclusion upon the patients alive and free of dialysis at Day 60. prognostic value of their measurement. Proteinuria was a sig- Interestingly, we identified that prognostic factors of renal nificant prognostic factor only when considered as a categorical recovery were largely independent of classic intensive care vari- variable, probably due to a supersaturation phenomenon defin- ables, but instead relied on tumour burden and haematological ing a risk threshold. The strength of the association and the prognostic factors. intuitive plausible mechanism make a statistical artifact very History of HDT-ASCT was unexpectedly associated with unlikely. The usual caveats of a retrospective single centre poor renal recovery. This might be explained by severity of AKI study, such as recruitment bias or standardization of practice, occurring in this setting (which was the case for four patients also apply and should be taken into account. A recruitment bias who were hospitalized shortly after graft infusion), and patients is unlikely, as most patients with AKI requiring RRT were admit- with uncontrolled disease who were in relapse after the ASCT ted in the ICU and the patients who were not admitted do not procedure. Although previous studies have reported that the appear different in terms of initial characteristics or outcome. haematological prognosis usually does not or marginally influ- Moreover, patients’ characteristics were inhomogeneous, ence the prognosis in the ICU [15], our experience with a tar- representing several disease stages and degrees of severity (e.g. geted population of critically ill myeloma patients with severe 38% initial diagnosis of myeloma versus 38% relapse). Instead of AKI was different. This might be explained by the fact that the representing a bias, we believe this pragmatic approach allows main organ dysfunction in our study (AKI) was closely linked to us to draw conclusions about a broad range of myeloma the underlying disease activity. patients admitted in the ICU. Notably, the association between HDT-ASCT and nonrecov- Renal recovery after AKI is an area of active research, and ery remained significant if we excluded the four patients who defining renal recovery has been controversial [11]. were admitted during engraftment. In our study, we used an endpoint that combines survival and Proteinuria was mainly constitutive of monoclonal light chains, dialysis independency at Day 60, as advocated by the National as patients diagnosed with amyloidosis or LCDD were excluded, Institue of Diabetes and Digestive and Kidney Diseases (NIDDK) andonlyfourpatientshad proteinuriacomposedof <50% mono- workshop on trial methodology [18]. One could argue that results clonal light chains. Therefore, albuminuria was unlikely to influ- could have been driven by only one of these two factors. In this ence results concerning prognostic value of proteinuria. sense, we saw in supplementary analyses that a history of HDT- The time of ICU admission (2007–11 versus 2012–15) had no ASCT was more associated with survival. Nevertheless, we think influence on renal recovery, despite several improvements in that, apart from allowing a higher number of patients in each myeloma and AKI care in general. This lack of improvement group and reducing the number of analyses, this definition of may be explained by the limited number of patients included in recovery is more relevant to clinical practice, as it combines two the present study and by a broader ICU admission policy of important goals in the care of myeloma patients on RRT. myeloma patients in the ICU. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/20/3959730 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Renal recovery in intensive care myeloma patients | 25 7. Hutchison CA, Bradwell AR, Cook M et al. Treatment of acute Importantly, data concerning survival and recovery of renal function was obtained in nearly all patients (one patient was renal failure secondary to multiple myeloma with chemo- lost to follow-up while still under dialysis after Day 30). therapy and extended high cut-off hemodialysis. Clin J Am Soc Nephrol 2009; 4: 745–754 8. Rajkumar SV, Dimopoulos MA, Palumbo A et al. International Myeloma Working Group updated criteria for Conclusion the diagnosis of multiple myeloma. Lancet Oncol 2014; 15: AKI Stage 3 in critically ill myeloma patients was associated with e538–e548 lower hospital mortality and higher rate of renal recovery than pre- 9. Palevsky PM, Liu KD, Brophy PD et al. KDOQI US commentary viously described. Renal recovery is inversely associated with more on the 2012 KDIGO clinical practice guideline for acute kid- aggressive malignancies, with a higher level of proteinuria and a ney injury. Am J Kidney Dis 2013; 61: 649–672 history of HDT-ASCT being risk factors for death or dialysis 10. Kumar S, Paiva B, Anderson KC et al. International Myeloma dependence. These results can influence the decision to admit mye- Working Group consensus criteria for response and minimal loma patients in the ICU for RRT and provide a support for discus- residual disease assessment in multiple myeloma. Lancet sion between haematologists, renal and intensive care physicians. Oncol 2016; 17: e328–e346 11. Kellum JA. How can we define recovery after acute kidney injury? Considerations from Epidemiology and Clinical Trial Conflict of interest statement Design. Nephron Clin Pract 2014; 127: 81–88 None declared. 12. Blade ´ J, Fernandez-Llama P, Bosch F et al. Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern References Med 1998; 158: 1889–1893 1. Greenlee RT, Murray T, Bolden S et al. Cancer statistics, 2000. 13. Irish AB, Winearls CG, Littlewood T. Presentation and sur- CA Cancer J Clin 2000; 50: 7–33 vival of patients with severe renal failure and myeloma. QJM 2. Tsakiris DJ, Stel VS, Finne P et al. Incidence and outcome of 1997; 90: 773–780 patients starting renal replacement therapy for end-stage 14. Dimopoulos MA, Delimpasi S, Katodritou E et al. Significant renal disease due to multiple myeloma or light-chain improvement in the survival of patients with multiple mye- deposit disease: an ERA-EDTA Registry study. Nephrol Dial loma presenting with severe renal impairment after the Transplant 2010; 25: 1200–1206 introduction of novel agents. Ann Oncol 2014; 25: 195–200 3. Knudsen LM, Hjorth M, Hippe E. Renal failure in multiple 15. Massion PB, Dive AM, Doyen C et al. Prognosis of hematologic myeloma: reversibility and impact on the prognosis. Nordic malignancies does not predict intensive care unit mortality. Myeloma Study Group. Eur J Haematol 2000; 65: 175–181 Crit Care Med 2002; 30: 2260–2270 4. Haynes RJ, Read S, Collins GP et al. Presentation and survival 16. Schmitt R, Coca S, Kanbay M et al. Recovery of kidney func- of patients with severe acute kidney injury and multiple tion after acute kidney injury in the elderly: a systematic myeloma: a 20-year experience from a single centre. Nephrol review and meta-analysis. Am J Kidney Dis 2008; 52: 262–271 Dial Transplant 2010; 25: 419–426 17. Hickson LJ, Chaudhary S, Williams AW et al. Predictors of 5. Porcher R, Le ´ vy V, Fermand JP et al. Evaluating high dose outpatient kidney function recovery among patients who therapy in multiple myeloma: use of quality-adjusted sur- initiate hemodialysis in the hospital. Am J Kidney Dis 2015; vival analysis. Qual Life Res 2002; 11: 91 65: 592–602 6. Peigne V, Rusinova K, Karlin L et al. Continued survival gains 18. Palevsky PM, Molitoris BA, Okusa MD et al. Design of clinical in recent years among critically ill myeloma patients. trials in acute kidney injury: report from an NIDDK workshop Intensive Care Med 2009; 35: 512–518 on trial methodology. Clin J Am Soc Nephrol 2012;7:844–850 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/20/3959730 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Renal recovery after severe acute kidney injury in critically ill myeloma patients: a retrospective study

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Abstract

Background: Despite substantial improvements in the management of multiple myeloma, renal failure remains an impor- tant burden that tremendously impairs prognosis. The purpose of this study was to describe the characteristics and to establish prognostic factors of renal recovery in myeloma patients admitted to the intensive care unit (ICU) for acute kidney injury (AKI) Stage 3 treated with renal replacement therapy (RRT). Methods: A retrospective single-centre cohort study was performed, including consecutive myeloma patients admitted to one medical ICU between 1 January 2007 and 1 September 2015 and treated with RRT. Patients were evaluated 60 days after initiation of RRT and divided into three groups: alive without dialysis, alive and dialysis-dependent or deceased. A univariate analysis was performed to identify factors associated with renal recovery (alive without dialysis 60 days after initiation of RRT). Results: Fifty patients were included in the study. Mean age was 63 (interquartile range: 58–70) years and 32 (64%) were male. Patients were admitted to the ICU 4 (1–7) years after the diagnosis of myeloma. Twenty-one (42%) had already been treated with high-dose therapy combined with autologous stem cell transplantation. Baseline renal function evaluated by estimated glomerular filtration rate (GFR) before ICU admission was 63 (44–90) mL/min/1.73 m . The mean SOFA score at Day 1 was 7 (4–8). The three main reasons for ICU admission were AKI (n¼ 31, 62%), acute pulmonary oedema (n ¼ 17, 32%) and sepsis (n ¼ 10, 20%). During ICU stay, RRT was implemented in all patients, 16 (32%) patients required invasive mechani- cal ventilation and 12 (24%) received vasopressors. The mean ICU and hospital length of stay were 6 (1–7) and 28 (13–34) days, respectively. At Day 60, 23 (46%) patients were alive without dialysis, 17 (32%) had died and 10 (20%) were still under- going dialysis. Among the 23 patients who recovered, the mean duration of dialysis was 6 (2–18) days and renal function was not significantly different from baseline [estimated GFR at baseline¼ 65 (25–74) mL/min/1.73 m versus 63 (56–70) mL/ min/1.73 m at Day 60, P¼ 0.70]. By univariate analysis, two factors were associated with nonrecovery of renal function at Day 60: a history of high-dose therapy combined with autologous stem cell transplantation [odds ratio (OR)¼ 6.1, 95% confi- dence interval (CI) 1.7–21.6; P¼ 0.008] and a proteinuria at ICU admission >370 mg/mmol creatinine (OR ¼ 4.2, 95% CI 1.1–17; Received: December 7, 2016. Editorial decision: May 18, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/20/3959730 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Renal recovery in intensive care myeloma patients | 21 P¼ 0.02). None of the other variables related to the haematological malignancy or to the ICU stay was associated with renal recovery at Day 60. Conclusions: AKI Stage 3 in critically ill myeloma patients was associated with a lower than expected hospital mortality. Patients with a high level of proteinuria and a history of high-dose therapy combined with autologous stem cell transplan- tation were less likely to recover their renal function at Day 60. Key words: dialysis, intensive care, multiple myeloma, prognosis, proteinuria ventilation, continuous or intermittent dialysis), the myeloma Introduction characteristics before (time from diagnosis, treatments Myeloma is the second most common haematological malig- received, baseline renal function and disease activity according nancy [1] and remains the first neoplasm responsible for end- to the International Myeloma Working Group definition [10]) stage renal disease [2]. and at the time of AKI (serum free light chains, serum peak Despite substantial improvements in its management, renal immunoglobulin), and the follow-up after ICU discharge (length failure occurs in up to 50% of patients [with 10% needing renal of dialysis maintenance therapy, response to treatment and replacement therapy (RRT)] [3] and tremendously impairs prog- vital status). Baseline renal function was defined as the best nosis, with a median survival of 3.5–10 months [4] for those renal function in the month before ICU admission, using the under dialysis. Reversibility of renal failure can improve this CKD-EPI (Chronic Kidney Disease - Epidemiology Collaboration) otherwise grim prognosis [3]. equation. Therefore, the question of recovery is crucial in the manage- Outcome was collected 60 days after RRT implementation. ment of acute kidney injury (AKI) requiring dialysis and in the Recovery group was defined as patients alive and free of dialysis course of myeloma. and nonrecovery as a composite endpoint of death and dialysis More than 10% of myeloma patients [5] will require intensive dependence, as advocated by the National Institute of Diabetes, care unit (ICU) admission, mostly for AKI (39–51%, 24–44% of Digestive and Kidney Diseases [11]. Admissions were divided which needing RRT) [6]. between 2007–11 and 2012–15, which corresponds to the middle Rates of renal recovery are largely variable, ranging from of the study period and to the authorization of SC bortezomib 17% [4] to 75% [7] in recent trials, but to our knowledge no pre- by the European Medicines Agency (2012), to assess for improve- vious study has evaluated the prognosis of AKI in myeloma ment of overall prognosis. patients specifically in the ICU setting. Baseline and follow-up characteristics were described by The purpose of this study was to describe the impact of means and standard deviation (SD), SD or interquartile range severe AKI on both a patient’s and kidney’s prognosis in crit- (IQR) for continuous variables normally distributed or with ically ill myeloma patients and to identify factors associated skewed distribution, respectively, and by percentages for catego- with renal recovery after initiation of RRT. rical variables. Proteinuria was divided according to the median value in our sample to take into account the supersaturation phe- nomenon that occurs in urine. Materials and methods Characteristics between recovery and nonrecovery groups were compared using Mann–Whitney test for continuous data We performed a retrospective cohort study including consecu- and Fisher’s exact test for categorical data. tive myeloma patients admitted to the medical ICU of St Louis All tests were two-sided, and P < 0.05 were considered statis- University Hospital, Paris, France (a 650-bed hospital with 330 tically significant. Analyses were done using the Statview 5.0 beds dedicated to haematology and oncology) between 1 software package (SAS Institute, Cary, NC, USA). January 2007 and 1 September 2015 and treated by RRT through- out the ICU stay. Medical records were reviewed and screened for variables of interest. Inclusion criteria were as follows: Results (i) multiple myeloma diagnosis according to the International Patient characteristics Myeloma Working Group diagnostic criteria [8] A total of 50 patients were included in the study. One was lost (ii) severe AKI, defined as Stage 3 of the Kidney Disease: to follow-up at Day 60. Patients’ characteristics are described in Improving Global Outcomes criteria (i.e. three times baseline Table 1. increase in serum creatinine or increase in serum creatinine Mean age was 63 (IQR: 58–70) years and 32 (64%) were male. to 4.0 mg/dL or urine output of< 0.3 mL/kg/h for 24 h or anu- Patients were admitted into the ICU 4 (0.8–5.3) years after the ria for 12 h) treated by RRT [9] 2 diagnosis of myeloma, after two (one to three) lines of (iii) baseline glomerular filtration rate (GFR) >15 mL/min/1.73 m . chemotherapy. Patients with amyloidosis or light-chain deposition disease Bence Jones proteinuria was noted at ICU admission in 35 (LCDD) were excluded, so that proteinuria, if present, was exclu- (70%) cases. Six patients had proteinuria of other or unknown sively composed of free light chains (FLC). Proteinuria was con- origin and among them only one had predominant albuminuria sidered significant if >50 mg/mmol. (96 mg/mmol). Nine patients had other causes of AKI (hypercal- Data were abstracted from the medical charts and we caemia, sepsis, dehydration, nephrotoxic drugs, etc.) without included variables related to the ICU stay (Sequential Organe significant proteinuria (<50 mg/mmol). Failure Assessment (SOFA) at Day 1, Simplified Acute Among those (n¼ 35) with presumed myeloma cast nephr- Physiology Score II (SAPS II), use of vasopressors or mechanical opathy, a superimposed triggering event was identified in 18 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/20/3959730 by Ed 'DeepDyve' Gillespie user on 16 March 2018 22 | A. Joseph et al. Table 1. Characteristics of patients included (n¼ 50) (51%) cases: dehydration in 7 [diarrhoea or vomiting (n ¼ 5), hae- morrhage (n ¼ 2)], sepsis in 5, exposure to nephrotoxic drugs in Demographic and clinical data for all patients (n ¼ 50) 5 [iodinated contrast product (n¼ 5), Non-steroidal anti-inflam- matory drugs (NSAIDs) (n¼ 3)] and hypercalcaemia in 1 patient. Age [mean (IQR)] (years) 62.6 (58–70) Myeloma was newly diagnosed for 19 (38%) patients and Male sex, n (%) 32 (64) relapsing for 19 (38%). Time from myeloma diagnosis to ICU 4 (0.8–5.3) Other patients had partial response (n ¼ 1, 2%), stable (n ¼ 2, admission [mean (IQR)] (years) 4%) or progressive (n ¼ 9, 18%) disease. None was considered in Myeloma status at ICU admission, n (%) Newly diagnosed 19 (38) good or very good response at the time of AKI diagnosis. Partial response 1 (2) Most often received chemotherapeutic drugs prior to ICU Stable disease 2 (4) admission were: bortezomib (34, 68%), cyclophosphamide (26, Relapse 19 (38) 52%), melphalan (27, 54%) and thalidomide (25, 50%). Four Progressive disease 9 (18) patients had never been treated and received their first chemo- Number of lines of chemotherapy prior 2 (1–3) therapy in the ICU. At the time of admission, 22 patients (44%) to ICU admission [mean (IQR)] were receiving bortezomib, 10 (22%) cyclophosphamide, 9 (18%) Chemotherapy received prior to admission, n (%) thalidomide and 9 (18%) were not currently treated. Bortezomib 34 (68) Twenty-one (42%) patients had already been treated with Cyclophosphamide 26 (52) high-dose therapy combined with autologous stem cell trans- Melphalan 27 (54) plantation (HDT-ASCT) 3 years (1–5) before ICU admission, Thalidomide 25 (50) including four patients treated 2, 10, 10 and 16 days before Corticosteroids 33 (66) admission. None 4 (8) Baseline renal function before ICU admission, estimated by Chemotherapy at the time of admission, n (%) the CKD-EPI GFR, was 63 (44–90) mL/min/1.73 m . The mean Bortezomib 22 (44) SOFA score at Day 1 was 6.6 (4–8) and the three main reasons for Cyclophosphamide 10 (20) ICU admission were AKI (n ¼ 31, 62%), acute pulmonary oedema Melphalan 6 (12) (n ¼ 17, 32%) and sepsis (n ¼ 10, 20%). During ICU stay, RRT was Thalidomide 9 (18) implemented in all patients [continuous veno-venous haemofil- Revlimid 7 (14) tration for 5 (10%) patients], 16 (32%) patients required invasive Corticosteroids 24 (48) None 9 (18) mechanical ventilation and 12 (26%) received vasopressors. The High-dose therapy combined with 21 (42) mean ICU and hospital length of stay were 6 (1–7) and 28 (13–34) autologous stem cell transplantation, n (%) days, respectively. SOFA score at Day 1 (mean þ IQR) 7 (4–8) SAPS II [mean (IQR)] 53 (40–63) Reason for ICU admission, n (%) Outcome Renal failure 31 (62) Outcomes are described in Figure 1: 60 days after initiation of Respiratory failure 10 (20) RRT, 23 (46%) patients were alive without dialysis, 17 (34%) had Cardiac failure 3 (6) Coma 3 (6) died and 10 (20%) were still under RRT. Among the 23 patients Other 3 (6) who recovered, the mean time of dialysis was 6 (2–18) days. Aplasia, n (%) 4 (8) Mean GFR at Day 60 in the recovery group was 65 (25–74) mL/ RRT 50 (100) min/1.73 m , which was not statistically different from baseline Length of RRT [mean (IQR)] (days) 7.5 (4–41) (P¼ 0.70). Noninvasive ventilation, n (%) 5 (10) Mechanical ventilation, n (%) 16 (32) Vasopressors, n (%) 12 (24) Comparison between recovery and nonrecovery groups) ICU length of stay [mean (IQR)] (days) 6 (1–7) In univariate analysis, two factors were associated with a Hospital length of stay [mean (IQR)] (days) 28 (13–34) Laboratory data decreased likelihood of renal recovery at Day 60 (Tables 2 and 3): Type of paraprotein, n (%) a history of HDT-ASCT [odds ratio (OR) 6.1, 95% confidence inter- IgG 27 (54) val(CI)1.7–21.6; P< 0.01] and a proteinuria at ICU admission IgA 12 (24) >370 mg/mmol creatinine (OR ¼ 4.2, 95% CI 1.1–17; P¼ 0.02). IgD 1 (2) There was a nonstatistically significant trend toward lower Light chain, n (%) monoclonal spike (24.5 versus 13.7 g/L, P¼ 0.15) and less use of Kappa 32 (64) bortezomib (OR ¼ 4, 95% CI 1.1–14.4; P¼ 0.06) in the nonrecovery Lambda 20 (36) group. Light chain only, n (%) 10 (20) Age (65.5 versus 60.5 years, P¼ 0.10), time from diagnosis (4.6 Kappa 8 (80) versus 3.5, P¼ 0.98), SOFA score at Day 1 (6.9 versus 6.6, P¼ 0.59) Lambda 2 (20) and baseline GFR (58.2 versus 66.2 mL/min/1.73 m ,P¼ 0.37) Proteinuria [mean (IQR)] (mg/mmol creatinine) 393 (84–557) were not different between the two groups. Neither were calcae- Bence Jones proteinuria, n (%) 35 (70) mia, exposition to nephrotoxic drugs (NSAIDs, iodinated con- Baseline GFR [mean (IQR)] 63 (44–90) trast products, angiotensin-converting enzyme inhibitors or (mL/min/1.73 m ) aminoglycosides), use of vasopressors or preserved diuresis (all Albuminemia [mean (IQR)] (g/L) 31.6 (26.0–36.0) P> 0.05). The serum free light chain was available in 27 (55%) Monoclonal peak [mean (IQR)] (g/L) 18.0 (1.2–33.9) patients and was not associated with recovery, using the Calcaemia [mean (IQR)] (mmol/L) 2.56 (2.47–2.65) median FLC level in our sample as a threshold (P> 0.45). Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/20/3959730 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Renal recovery in intensive care myeloma patients | 23 Fig. 1. Flow chart and outcomes of patients admitted for Stage 3 AKI and need for RRT. Table 2. Comparison between recovery and nonrecovery groups for continuous variables Recovery (n ¼ 23) Nonrecovery (n ¼ 27) P-value Age (years) 65.5 (58.0–70.7) 60.5 (55.2–67.4) 0.10 Time from myeloma diagnosis (years) 4.6 (2.4–6.9) 3.5 (1.5–5.5) 0.98 SOFA score at Day 1 6.9 (4.3–8.8) 6.6 (4.5–7.5) 0.59 SAPS II score 52.6 (40.0–61.3) 53.7 (40.5–63.5) 0.94 Baseline GFR (mL/min/1.73 m ) 58.2 (47–65) 66.2 (44–96) 0.37 Monoclonal spike (g/L) 24.5 (1.6–40.8) 13.7 (1.1–24.5) 0.15 Serum albumin (g/L) 32.1 (26.3–37) 31.3 (27–36) 0.67 Calcemia (mmol/L) 2.62 (2.3–2.8) 2.47 (2.2–2.5) 0.12 Data are presented as means (IQR). P-values were calculated using the MannWhitney test. Table 3. Comparison between recovery and nonrecovery groups for categorical variables Recovery (n ¼ 23) Nonrecovery (n ¼ 27) OR (95% CI) P-value n (%) n (%) Mechanical ventilation 7 (30.4) 9 (33.3) 1.1 (0.4–3.8) 0.83 Vasopressor drugs 3 (13.0) 9 (33.3) 3.3 (0.6–19.2) 0.09 Proteinuria >370 mg/mmol 7 (30.4) 18 (81.5) 4.2 (1.1–17) 0.02 Nephrotoxic drug exposure 15 (65.2) 15 (55.6) 0.7 (0.2–2.1) 0.49 Iodinated contrast exposure 0 (0) 5 (18.5) 11.5 (0.6–220) 0.09 Preserved diuresis 10 (43.5) 8 (29.6) 0.6 (0.2–1.8) 0.31 Serum free light chain >5000 mg/L 2 (8.7) 5 (18.5) 2.4 (0.4–13.7) 0.56 HDT-ASCT 4 (17.4) 17 (63.0) 6.1 (1.7–21.6) 0.01 Bortezomib 12 (52.2) 22 (81.5) 4 (1.1–14.4) 0.06 Admission between 2007 and 2011 12 (52.2) 16 (59.3) 1.3 (0.4–4.1) 0.62 Notably, none of the five patients who received iodinated con- 1.2–14, P¼ 0.02) but was not associated with dialysis depend- trast products recovered. ency at Day 60 (P¼ 0.12). There was no significative trend over time for renal recovery Among the 33 patients alive at Day 60, 2 required haemodial- (2007–11: 46% versus 2012–15: 48%, P¼ 0.62). There was no influ- ysis 9 and 29 months after ICU admission, while 2 patients ence of primary admission diagnosis on renal recovery (renal treated by RRT at Day 60 recovered 2.3 and 3.5 months later. failure versus others, P¼ 0.75). The mean follow-up for these 33 patients was 20 months In post hoc analysis, we found that a history of HDT-ASCT and for the 12 who died before the end of follow-up, the mean drove the association with increased mortality (OR¼ 4, 95% CI overall survival time was 19 months. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/20/3959730 by Ed 'DeepDyve' Gillespie user on 16 March 2018 24 | A. Joseph et al. During the same period, 21 myeloma patients underwent Previous studies reported age and baseline renal function as RRT without being admitted in the ICU: 11 for end-stage renal determinants of recovery after AKI [16, 17] in the overall popula- disease, 8 for AKI and 2 with unknown baseline renal function tion. In our study, homogeneity in age probably prevented any who underwent RRT since the diagnosis of multiple myeloma difference from appearing, but baseline GFR, provided that statis- and did not recover. Among the eight AKI patients not admitted tical power was sufficient, did not seem to be associated with in the ICU, at Day 60, four were still undergoing RRT, three were recovery in the context of myeloma. The specific mechanisms of alive without dialysis and one was deceased. The characteris- aggression of myeloma-related AKI, largely independent of base- tics of these patients (age, number of previous treatments, his- line renal function, probably account for this finding. Indeed, pre- tory of stem cell transplantation) did not differ from those cipitation of light chains largely depends on their tubular admitted in the ICU. concentration, which is expected to be affected marginally by GFR (in favour of higher tubular concentration in the best base- line renal function) but mostly from diuresis and tumour load. Indeed, renal prognosis of myeloma patients in the ICU setting Discussion has not been assessed yet, while studies conducted outside the ICU pointed to proteinuria and calcaemia [12] as prognostic factors In this study, 32% of multiple myeloma patients admitted in the of recovery from AKI. If our study confirmed proteinuria as an ICU and treated with RRT finally died while 41% recovered their important prognostic factor, it does not support a role for hypercal- renal function 60 days after initiation of RRT, without a signifi- caemia, which may be related to the introduction of bisphospho- cant decrease in renal function. Proteinuria >370 mg/mmol cre- nate therapy (six patients in our study received bisphosphonate atinine and a history of HDT-ASCT were associated with during their hospitalization) in comparison with older studies. nonrecovery of renal function. Decisions regarding admission or limitation of the therapeu- This study is the first to assess renal recovery in critically ill tic efforts should take into account these results, and we hope myeloma patients with severe AKI, in the era of novel therapies this study, along with others describing an improved overall such as bortezomib, lenalidomide and thalidomide. and intensive care prognosis of myeloma patients [6, 14], will Studies from the late 1990s reported rates of renal recovery encourage discussion between haematologists, renal and inten- as low as 8% [12] to 15% [13] for patients undergoing dialysis, sive care physicians and aid decision-making in clinical painting a bleak picture of myeloma patients requiring RRT and practice. promoting a nihilistic attitude toward their ICU admission. Our study also has several limitations. Statistical power was With the advent of novel agents’ induction therapies, recent limited by a small number of cases and some missing data, studies have spread hope of improving these patients’ outcome probably preventing several intuitive factors (e.g. monoclonal with rates of recovery as high as 75% and survival improving peak, serum free light chain excess) from becoming statistically from 18 to 32 months in the most recent studies [14]. significant. Serum free light chain was obtained in only 55% of First of all, our study describes rates of survival and renal patients. This may be due in part to the time frame of the study recovery higher than previously reported, with 46% of the (2007–15) but precludes any definitive conclusion upon the patients alive and free of dialysis at Day 60. prognostic value of their measurement. Proteinuria was a sig- Interestingly, we identified that prognostic factors of renal nificant prognostic factor only when considered as a categorical recovery were largely independent of classic intensive care vari- variable, probably due to a supersaturation phenomenon defin- ables, but instead relied on tumour burden and haematological ing a risk threshold. The strength of the association and the prognostic factors. intuitive plausible mechanism make a statistical artifact very History of HDT-ASCT was unexpectedly associated with unlikely. The usual caveats of a retrospective single centre poor renal recovery. This might be explained by severity of AKI study, such as recruitment bias or standardization of practice, occurring in this setting (which was the case for four patients also apply and should be taken into account. A recruitment bias who were hospitalized shortly after graft infusion), and patients is unlikely, as most patients with AKI requiring RRT were admit- with uncontrolled disease who were in relapse after the ASCT ted in the ICU and the patients who were not admitted do not procedure. Although previous studies have reported that the appear different in terms of initial characteristics or outcome. haematological prognosis usually does not or marginally influ- Moreover, patients’ characteristics were inhomogeneous, ence the prognosis in the ICU [15], our experience with a tar- representing several disease stages and degrees of severity (e.g. geted population of critically ill myeloma patients with severe 38% initial diagnosis of myeloma versus 38% relapse). Instead of AKI was different. This might be explained by the fact that the representing a bias, we believe this pragmatic approach allows main organ dysfunction in our study (AKI) was closely linked to us to draw conclusions about a broad range of myeloma the underlying disease activity. patients admitted in the ICU. Notably, the association between HDT-ASCT and nonrecov- Renal recovery after AKI is an area of active research, and ery remained significant if we excluded the four patients who defining renal recovery has been controversial [11]. were admitted during engraftment. In our study, we used an endpoint that combines survival and Proteinuria was mainly constitutive of monoclonal light chains, dialysis independency at Day 60, as advocated by the National as patients diagnosed with amyloidosis or LCDD were excluded, Institue of Diabetes and Digestive and Kidney Diseases (NIDDK) andonlyfourpatientshad proteinuriacomposedof <50% mono- workshop on trial methodology [18]. One could argue that results clonal light chains. Therefore, albuminuria was unlikely to influ- could have been driven by only one of these two factors. In this ence results concerning prognostic value of proteinuria. sense, we saw in supplementary analyses that a history of HDT- The time of ICU admission (2007–11 versus 2012–15) had no ASCT was more associated with survival. Nevertheless, we think influence on renal recovery, despite several improvements in that, apart from allowing a higher number of patients in each myeloma and AKI care in general. This lack of improvement group and reducing the number of analyses, this definition of may be explained by the limited number of patients included in recovery is more relevant to clinical practice, as it combines two the present study and by a broader ICU admission policy of important goals in the care of myeloma patients on RRT. myeloma patients in the ICU. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/20/3959730 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Renal recovery in intensive care myeloma patients | 25 7. Hutchison CA, Bradwell AR, Cook M et al. Treatment of acute Importantly, data concerning survival and recovery of renal function was obtained in nearly all patients (one patient was renal failure secondary to multiple myeloma with chemo- lost to follow-up while still under dialysis after Day 30). therapy and extended high cut-off hemodialysis. Clin J Am Soc Nephrol 2009; 4: 745–754 8. Rajkumar SV, Dimopoulos MA, Palumbo A et al. International Myeloma Working Group updated criteria for Conclusion the diagnosis of multiple myeloma. Lancet Oncol 2014; 15: AKI Stage 3 in critically ill myeloma patients was associated with e538–e548 lower hospital mortality and higher rate of renal recovery than pre- 9. Palevsky PM, Liu KD, Brophy PD et al. KDOQI US commentary viously described. Renal recovery is inversely associated with more on the 2012 KDIGO clinical practice guideline for acute kid- aggressive malignancies, with a higher level of proteinuria and a ney injury. Am J Kidney Dis 2013; 61: 649–672 history of HDT-ASCT being risk factors for death or dialysis 10. Kumar S, Paiva B, Anderson KC et al. International Myeloma dependence. These results can influence the decision to admit mye- Working Group consensus criteria for response and minimal loma patients in the ICU for RRT and provide a support for discus- residual disease assessment in multiple myeloma. Lancet sion between haematologists, renal and intensive care physicians. Oncol 2016; 17: e328–e346 11. Kellum JA. How can we define recovery after acute kidney injury? Considerations from Epidemiology and Clinical Trial Conflict of interest statement Design. Nephron Clin Pract 2014; 127: 81–88 None declared. 12. Blade ´ J, Fernandez-Llama P, Bosch F et al. Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern References Med 1998; 158: 1889–1893 1. Greenlee RT, Murray T, Bolden S et al. Cancer statistics, 2000. 13. Irish AB, Winearls CG, Littlewood T. Presentation and sur- CA Cancer J Clin 2000; 50: 7–33 vival of patients with severe renal failure and myeloma. QJM 2. Tsakiris DJ, Stel VS, Finne P et al. Incidence and outcome of 1997; 90: 773–780 patients starting renal replacement therapy for end-stage 14. Dimopoulos MA, Delimpasi S, Katodritou E et al. Significant renal disease due to multiple myeloma or light-chain improvement in the survival of patients with multiple mye- deposit disease: an ERA-EDTA Registry study. Nephrol Dial loma presenting with severe renal impairment after the Transplant 2010; 25: 1200–1206 introduction of novel agents. Ann Oncol 2014; 25: 195–200 3. Knudsen LM, Hjorth M, Hippe E. Renal failure in multiple 15. Massion PB, Dive AM, Doyen C et al. Prognosis of hematologic myeloma: reversibility and impact on the prognosis. Nordic malignancies does not predict intensive care unit mortality. Myeloma Study Group. Eur J Haematol 2000; 65: 175–181 Crit Care Med 2002; 30: 2260–2270 4. Haynes RJ, Read S, Collins GP et al. Presentation and survival 16. Schmitt R, Coca S, Kanbay M et al. Recovery of kidney func- of patients with severe acute kidney injury and multiple tion after acute kidney injury in the elderly: a systematic myeloma: a 20-year experience from a single centre. Nephrol review and meta-analysis. Am J Kidney Dis 2008; 52: 262–271 Dial Transplant 2010; 25: 419–426 17. Hickson LJ, Chaudhary S, Williams AW et al. Predictors of 5. Porcher R, Le ´ vy V, Fermand JP et al. Evaluating high dose outpatient kidney function recovery among patients who therapy in multiple myeloma: use of quality-adjusted sur- initiate hemodialysis in the hospital. Am J Kidney Dis 2015; vival analysis. Qual Life Res 2002; 11: 91 65: 592–602 6. Peigne V, Rusinova K, Karlin L et al. Continued survival gains 18. Palevsky PM, Molitoris BA, Okusa MD et al. Design of clinical in recent years among critically ill myeloma patients. trials in acute kidney injury: report from an NIDDK workshop Intensive Care Med 2009; 35: 512–518 on trial methodology. Clin J Am Soc Nephrol 2012;7:844–850 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/20/3959730 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Clinical Kidney JournalOxford University Press

Published: Feb 1, 2018

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