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Renua Aiyegbusi, an intern with the NSMC, created this visual abstract for this week’s chat

Additionally, since this is a CJASN article, Michelle Lim made this visual abstract for CJASN

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#NephJC Chat Tuesday May 14, 9 pm EasternWednesday May 15, 9 pm Indian Standard TimeWednesday May 15, 8 pm BST, 12 noon Pacific

 

CJASN May 2019,  14 (5) 656-663; DOI: https://doi.org/10.2215/CJN.10640918

Rate of Correction of Hypernatremia and Health Outcomes in Critically Ill Patients.

Chauhan KPattharanitima PPatel NDuffy ASaha AChaudhary KDebnath NVan Vleck TChan LNadkarni GNCoca SG.

PMID: 30948456 Full text at CJASN (free from May 13 to 20, 2019) Introduction

Hypernatremia (serum sodium concentration >145 mEq/L) is a common electrolyte disorder and is especially common among elderly institutionalized individuals. Hypernatremia can also be seen among hospitalized patients, especially intubated patients in the intensive care unit without access to water. Upon admission to the ICU, approximately 2% of patients are already hypernatremic and another 7% develop hypernatremia during the hospitalization. It is associated with increased length of stay and mortality.

Though hypernatremia is defined and named after sodium, it is not a sodium disorder, it is a water disorder. Hypernatremia develops when there is loss of water that is not compensated for either by an adequate ingestion of water or by an adequate generation of electrolyte free water by the kidney. Additionally, gain of sodium can cause hypernatremia if the increased sodium load is not adequately matched with water ingestion and generation of electrolyte free water by the kidney. Hypernatremia is thus the convergence of too little water and/or too much salt.

Since hypernatremia that occurs during hospitalization is typically iatrogenic and treatable, It has been suggested as a quality of care indicator. But since there is no compelling data showing improved outcomes from the treatment of hypernatremia, some have questioned this metric.

The clinical approach to the patient with hypernatremia is to first deal with emergencies, and then to anticipate and prevent dangers induced by therapy.

Damned if you do

“The double edged sword in dysnatremias on brainy issues.”

Acute hypernatremia (<48hrs) may induce lethargy, weakness, seizures or even coma, and should be immediately corrected. For patients with chronic hypernatremia (>48hrs), where an osmotic brain adaptation has occurred but not less symptomatic, expert opinion favors a slower rate of correction to avoid cerebral edema.

Damned if you don’t (apologies to Tomas Berl)

On the other hand, slow correction prolongs hypernatremia and its associated morbidity. In retrospective analysis, slow correction is associated with both a failure to correct the sodium at all, and with an increased hospital mortality. This has been reported in two studies: in patients who presented with hypernatremia to the emergency and in a single-center study of US veterans who developed hypernatremia during hospitalization. In both studies, most patients were still hypernatremic three days after presenting with or developing hypernatremia.

In contrast to hyponatremia, where speed limits for sodium correction have been extensively studied, there is little evidence of morbidity from rapid correction of hypernatremia. The experts Adrogue and Sterns suggested a slower reduction rate of no more than 0.5 mmol/L per hour, with an absolute change of 10 mmol/L per day to avoid cerebral edema, seizure, and permanent neurologic damage from rapid correction. This recommendation is founded on data from a case-control study of age matched infants with and without seizures during fluid resuscitation for hypernatremic dehydration secondary to acute gastroenteritis. The cases (seizures, group I) had higher BUN than the controls.

Table 1 from Kahn et al, Intensive Care Medicine, 1979.

The authors focused on the rate of fluid resuscitation and the drop in sodium to differentiate the cases from the controls:

Table 13from Kahn et al, Intensive Care Medicine, 1979.

Note that the controls had an average sodium decrease faster than the 0.5 mmol/L/hr recommendation. Adrogue has a second reference to support the slow rehydration. This had 18 infants who had no seizures and an average sodium lowering rate of 0.3 mmol/L/hr, and found that with oral rehydration achieving a mean sodium decrease of 0.32 mmol/L/h, no seizures were observed. Sterns’ reference, a retrospective study from a NICU is also probably not applicable to an internal medicine cohort with univariate risk factors including, first time mom and maternal age being younger. Additionally the seizure group (group 2 here) is quite a bit sicker:

Though to his credit, Sterns walks away from the data to inject a bit of rationality in the discussion:

Limiting correction of chronic hypernatremia so that the plasma sodium concentration is decreased by less than 0.5 mmol per liter per hour reduces the risk of cerebral edema and seizures associated with rehydration. However, the fear of these complications, which have been reported only in young children, should not deter the aggressive rehydration of adults with acute hypernatremia to avoid brain hemorrhage or osmotic demyelination (Table 2). In contrast to the risk of inadvertent overcorrection in patients with hyponatremia, there is little risk of inadvertent overcorrection in patients with hypernatremia, and adults with hypernatremia are often undertreated.

In children with DKA, about 1% develop cerebral edema which has a mortality rate of 50-80%. There is some data that aggressive glucose lowering may cause an osmotic cerebral edema. However the data is far from conclusive.

The bottom line is that there is theoretical risk of cerebral edema from the rapid correction of hypernatremia but hard data, especially for adults, is scant. In fact there is some data that under treating hypernatremia may put patients at risk. This is the environment that this week’s NephJC article wanders into: is there risk of seizures, poor neurologic outcome, or death from the rapid treatment of hypernatremia, or can we safely ignore this dogma?

The StudyMethodsQuestion:

Is there an association between the rate of correction of hypernatremia and adverse patient outcomes?

Methods

A retrospective observational study from a single-center tertiary care hospital (Beth Israel Deaconess Medical Center in Boston, MA) from 2001 to 2012.

The data was abstracted from from the Medical Information Mart for Intensive Care-III (MIMIC-III) database.

Inclusion criteria:

  1. Serum sodium > 155 mmol/L during an inpatient stay

  2. Over 18 years old

Exclusion criteria

  1. No serum Na+  value after peak

Definitions:

Chronic Hypernatremia: either admission with a serum sodium over 155 or a serum Na > 145 mmol/L for > 48 hours in the hospital.

Formula for correction:

Slow correction <0.5 mmol/hr (ie 12 mmol/24 hours)
Rapid correction > 0.5 mmol/hr

In addition to this grouping of rapid and slow, the authors also used a few other grouping by performing several subanalysis with varying hypernatremia correction rates of

  • > 8,

  • > 10, and

  • > 12 mmol/L per 24 hours

Outcomes

The main outcomes of interest were

  • mortality and

  • the incidence of neurologic outcomes (cerebral edema, seizures and and alteration of consciousness.

Both of these were measured at 30 days. ICD 9 codes were used for the neurological complications, and imaging reports, and discharge summary were manually reviewed by two independent clinicians to identify cause of cerebral edema and to determine whether it was attributable to rapid hypernatremia correction.

Statistical Analyses

The primary analysis was conducted explore differences be-tween patients who experienced overall slow correction versus rapid correction stratified by two groups: admission hypernatremia and hospital-acquired hypernatremia. They further divided categories into those who did achieve a normal sodium (< 145 mmol/L) versus those that never achieved it.

A Kaplan–Meier survival curve was used to assess diference in mortality between groups. to assess the survival rate difference inpatients between different sodium correction rates. Logistic regression was used to determine the rate of correction’s influence on mortality over time, with adjustment of age, sex, DNR status, and Charlson comorbidity index included in the model. A subgroup analysis considering patients with in-hospital Na > 145 for 48 hours as having chronic hypernatremia was also done.

Funding Source

Research reported in this publication was supported by the NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) of the National Institutes of Health.

Results

Over the period of the study, from 2001 – 2012, the authors included 449 patients from the 41, 149 patients with sodium values in the MIMICS II database.

Supplemental figure 1 from Chauhan et al, CJASN 2019

See more details of those 449 patients came from, and the rates of correction below:

When there isn’t a traditional figure 1, Swap forces us to make one.

Characteristic Differences

Table 1 below describes the baseline characteristics by correction rates in both groups. The slower correction rate in both groups were sicker patients.

Patients with rapid sodium correction with hypernatremia on admission were more likely to be female, have depression, and were less likely to have CKD. Patients with rapid sodium correction with hospital-acquired-hypernatremia had lower serum bicarbonate, lower prevalence of stroke, and shorter hospital stay.


And the business end of table 1.

Table 2 Describes the Distribution of the sodium level, difference, and correction time. The peak serum sodium was higher in Admission-Hypernatremia group.

The time to correction to serum sodium <145  in the Hospital-Acquired group was 14.7hr from peak sodium, with a higher median rate of correction (0.9mmol/hr)  vs 18 hr from peak to <145 and median rate of correction (0.7mmol/hr) in the Admission group.

Association of Serum Sodium Correction Rate with in-hospital Mortality

There was no difference in mortality between patients on rapid vs slow correction in both groups, not even on the multivariable analysis.

In the categorial analysis with different cut-offs correction values at 24 hours. There was a trend for lower mortality in the admission hypernatremia with rapid correction rate.

Rapid correction and Neurological Sequelae

Among both groups of patients, the manual review found no patients that had documented worsening mental status, seizures, or generalized cerebral edema that could be attributed to correction of serum sodium

There were patients who did have these complications, but they were attributed to intracerebral hemorrhage, stroke, epilepsy, brain tumors, and brain trauma.

Discussion

This is the largest adult cohort study focusing on the neurologic complications and mortality after hypernatremia correction in critically ill adults.

There wasn’t any evidence that rapid correction of hypernatremia was associated with a higher risk for mortality, or neurological sequelae (seizure, alteration of consciousness, and/or cerebral edema) in critically ill adult patients with either admission or hospital-acquired hypernatremia. The latter result is based on a the manual review performed by the authors.

This retrospective study adds to the existing literature which has consistently been unable to show any reduction in adverse neurologic (or other) outcomes with slow correction of hypernatremia. In addition, as seen in two prior studies, there was a trend towards harm with slow correction. It is contrast to the study done in neonates which did report a higher risk of death and convulsions with rapid correction. The authors speculate that this could be due to the difference in brain volume: cranial vault size which is maximal at 6 years, and could limit adaptation in neonates and children, more than in adults.

Limitations

The study design is a retrospective chart review, and not a prospective study or a clinical trial.

The attribution of the neurological sequelae was done by two of the investigators and not by a blinded adjudication committee (as in done in trials); and actual progress notes were available only for 47 patients - in other cases the judgment was made on the basis of the imaging reports. Nevertheless, this was performed independently by the two authors.

The authors point out in their discussion of the limitations some additional potential issues:

They had limited information about the intravenous fluids used for correction, and whether those..

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The full filtrate met last week to chat up CREDENCE. Hear the podcast on the web, or subscribe with the following feed link:

http://nephjc.com/freelyfiltered?format=rss

iTunes support coming soon (hopefully).

Now with more realistic cover art

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This visual abstract is by NSMC Intern, Mario Funes

Here is the visual abstract from The George Institue

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NephJC’s podcast has a new name. Introducing Freely Filtered, a NephJC podcast. Note the “a” rather than “the.” We were rejected from iTunes so while we plan a tactical strike on Cupertino you can manually subscribe with the RSS feed:

http://nephjc.com/drivetime?format=rss

Here is a link if you want to listen through a web browser.

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#NephJC Chat

Tuesday April 23, 2019 at 9 pm Eastern

Wednesday April 24, 2019 at 9 pm Indian Standard Time

Wednesday April 24, 2019 at 8 pm GMT, 12 noon Pacific  

N Engl J Med. 2019 Apr 14. doi: 10.1056/NEJMoa1811744. [Epub ahead of print]

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.

Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators.


PMID: 30990260 Full text at NEJM (free now since online first, till it appears in an issue)

Other Useful Links:

  • Supplementary appendix (PDF at link)

  • Protocol paper (open access)

  • Editorial (gated) “Clinical Credence’ by Ingelfinger and Rosen

  • Slideset at George Institute website (4MB .PPTX file)

Introduction

Diabetes is a global epidemic. The number of adults living with diabetes has nearly quadrupled since 1980. An estimated 422 million adults are living with diabetes (WHO global report, 2016). Since 30-40% of people with diabetes ultimately develop diabetic kidney disease we can expect a parallel increase in this complication.

Diverse pharmacotherapies have been investigated to halt the progression of diabetic kidney disease. From UKPDS to CREDENCE, we have indeed come a long way (see Figure 1). The RAS (renin-angiotensin system) antagonists delay the progression of diabetic nephropathy. RAS blockade in diabetic nephropathy may be necessary - but is clearly not sufficient. Despite maximal RAS blockade, proteinuria does not completely regress and a substantial proportion of patients with diabetic nephropathy progress to kidney failure. Intensive glycemic control and intensive BP control likewise do not eliminate progression of kidney disease.

While many anti-hyperglycemic agents have been introduced in the last 2 decades, only a handful of them have effects on altering the course of disease progression. Linagliptin is renoprotective in several animal models, this has not been replicated in human studies. CARMELINA did not demonstrate evidence of renoprotection. For the GLP-1 analogues, the most that we have is a modest effect on albuminuria, but nothing on GFR or outcomes that matter. With a better understanding of anti-oxidant pathways, early studies involving bardoxolone beamed signals of hope, but the glory was short-lived as the subsequent trial suggested its association with increased cardiovascular morbidity.

We have now something to cheer about - the SGLT2 inhibitors. They reduce glycemia by causing glycosuria by blocking the SGLT2 transporters in the proximal tubule. This natriuretic effect may hold the key to their kidney effects - since this mediates the effect on the glomerular hyperfiltration via the tubuloglomerular feedback. See this AJKD blog from 2018 by Anna Burgner for a lucid explanation of how this works.

The first suggestion of their utility was whispered by the EMPA-REG trial where use of empagliflozin decreased risk of doubling of creatinine (44%) and end-stage kidney disease (55%) without any difference in the degree of albuminuria. We covered the renal results on NephJC here - the renal outcomes beyond new onset nephropathy were post hoc outcomes. A similar pretty picture was painted on the CANVAS too where canagliflozin reduced the risk of sustained and adjudicated major kidney outcomes. Discussed here on NephJC, on the basis of the prespecified hypothesis testing sequence the renal outcomes were not viewed as statistically significant. They did show a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73) and the composite outcome of a sustained 40% reduction in the estimated GFR, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60). These were mostly driven by the albuminuria and 40% GFR outcome, since the patients in CANVAS and EMPAREG were low risk for progression of CKD.

Another wrinkle in the story is the signal of higher amputations reported in CANVAS - and then reinforced by observational data from elsewhere.

The results of CREDENCE trial have been welcomed by the world with a thunderous applause. This trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) was designed to assess the effects of canagliflozin on primarily the renal outcomes in patients with established nephropathy. To note, CREDENCE was initiated in 2014, before the results of EMPAREG came out. Another point is that there was a suggestion that the efficacy of these drugs decreased with decreasing GFR - and the previous trials mostly enrolled patients with preserved GFR. This makes the enrolment and outcomes of CREDENCE all the more important to understand.

The StudyMethods

This was a randomized, double-blind, placebo-controlled trial conducted at 690 sites in 34 countries across North America, Latin America, South Africa and Asia Pacific.

Inclusion criteria

  1. Age ≥ 30 years

  2. Type 2 Diabetes mellitus with an HbA1C ≥ 6.5% and ≤12.0% (≤ 10.5% in Germany)

  3. Estimated GFR 30 - 60 ml/min/1.73m^2 (using CKD-EPI equation)

  4. Patients needed to be on a stable maximum tolerated daily dose of ACEi or ARB for at least 4 weeks prior to randomisation (however dual RAS blockade and MRAs/DRIs were not allowed).

  5. Albuminuria defined by urine albumin to creatinine ratio (UACR) of 300 – 5000 mg/g.

Because the trial was designed to study the impact of Canagliflozin on the progression of CKD, the intent was that at least 60% of the patient population have CKD stage 3 (rather than stage 2), with an eGFR of 30-60 ml/min/1.73m2.

Exclusion criteria

  1. Type 1 Diabetes mellitus

  2. History of diabetic ketoacidosis

  3. History of hereditary glucose-galactose malabsorption or primary renal glycosuria

  4. Renal disease that required treatment with immunosuppressive therapy

  5. Known significant liver disease

  6. Current or history of NYHA Class IV heart failure

  7. Blood potassium level > 5.5 mmol/L at the time of screening

What was done next…

Patients who met the eligibility criteria were enrolled in a 2-week, single-blind placebo-run in period. Patients who failed to take ≥80% of the scheduled run-in treatment were deemed ineligible.

Eligible patients were randomized (1:1) to receive either Canagliflozin (100mg orally once daily) or matching placebo. Randomization was stratified according to the category of estimated GFR at the time of screening

  • 30 to <45 ml/min/1.73m2.

  • 45 to <60 ml/min/1.73m2.

  • 60 to <90 ml/min/1.73m2

Background care

Glycemic control was reinforced with diet, exercise counselling and also as per the discretion of the responsible physician.

Patients were followed up at 3, 13 and 26 weeks, then alternated between telephone calls and out-patient visits every 13 weeks.

Figure 2 from Jardine MJ et al, American Journal of Nephrology, 2017

Primary outcome

Composite of

  • End-stage kidney disease (defined as dialysis for at least 30 days) or an eGFR of <15ml/min/1.73m^2 sustained for at least 30 days

  • Doubling of serum creatinine

  • Death from renal or cardiovascular disease

Secondary outcomes

Secondary end points were analysed in a pre-specified hierarchical order

  • 1st - composite of cardiovascular death or hospitalisation for heart failure

  • 2nd- composite of cardiovascular death, MI, or stroke

  • 3rd - hospitalisation for heart failure

  • 4th-  composite of ESKD, doubling of s.creatinine or renal death

  • 5th-  cardiovascular death

  • 6th- death from any cause

  • 7th- composite of cardiovascular death, MI, stroke or hospitalisation for heart failure or unstable angina

Heirarchical analysis meant that statistical significance was required before testing the next hypothesis in the sequence mentioned.

Statistics simplified

The trial was event-driven – meaning that the study was driven by the occurrence of the primary outcome rather than being of fixed observation time. Idea was to detect a 20% risk reduction in the primary end-point with 90% power. Why was a figure of “20% risk reduction” chosen? – that’s because a 20% relative risk reduction was considered clinically meaningful, commensurate with the similar reduction seen in trials involving RAS blockade, namely, RENAAL and IDNT trials. This required enrolment of at least 4200 patients (844 events).

Prespecified stopping guidance that was provided to the data monitoring committee by the steering committee proposed possible recommendation of early cessation if clear evidence of benefit was observed for the primary outcome (P<0.01) and the composite of end-stage kidney disease or death from renal or cardiovascular causes (P<0.025), with consideration of the overall balance of risks and benefits.

Funding

Funded by Janssen Research and Development as a collaboration between the sponsor, an academic-led steering committee, and an academic research organization, George Clinical. Members of the steering committee designed the trial, supervised its conduct, and were responsible for reporting the results. Analyses were performed by the sponsor and independently confirmed at George Clinical with the use of original data. The first draft of the manuscript was drafted by the first and last author.

Results

Figure S1 from Perkovic et al, NEJM, 2019

Table 1 depicts the baseline demographic characteristics of patients. This was a population of patients that is very familiar to us: all diabetic nephropathy, duration of diabetes ~ 15.5 years. About two-thirds were on insulin and over half on metformin. Despite the 30 ml/min GFR floor, about 170 participants with GFR 15-30 snuck in (see table S1). Of more interest to us, 10% had nephrotic range proteinuria and another three-quarters had non-nephrotic, but macroalbuminuria.

Table 1 from Perkovic et al, NEJM, 2019

Table S2 from Perkovic et al, NEJM 2019

Excerpt from Table S1, Perkovic et al, NEJM, 2019

Primary outcomes

Instead of 844 outcomes, the DSMB recommended the trial be halted based on the stopping rules mentioned above, after the interim analyses. By the time all events were adjudicated and recorded, ~ 500 primary outcome events had occured.

There was a 30% relative risk reduction in the primary composite end-point of ESKD, doubling of serum creatinine and renal or cardiovascular death, with line segments diverging as early as 12 months after randomization (event rate – 43.2 vs 61.2 per 1000 patient-years respectively in canagliflozin vs placebo arms).

If we dissect the primary outcomes into individual components, the relative risks of ESKD, doubling of serum creatinine and death due to cardiovascular cause were reduced by 32%, 40% and 22% respectively.

On subgroup analysis, with respect to relative risk reduction in the primary outcomes, the effect was consistent across all the subgroups - as shown below. Pay attention to the interaction p values (last column) in the figures below.

Figure 2 from Perkovic et al, NEJM 2019

Figure S3 from Perkovic et al, NEJM 2019

Secondary outcomes

Patients in to the canagliflozin arm had a lower risk of most secondary outcomes (statistically significant for secondary outcomes listed as 1st to 4th). However, there was no significant difference in the risk of cardiovascular death, so the subsequently listed outcomes in the hierarchy were not formally evaluated.

The significantly lower rates of cardiovascular events in CREDENCE mirror the results of CANVAS, EMPA-REG OUTCOME and DECLARE-TIMI 58 trials.

Canagliflozin group fared better in terms of the degree of albuminuria too, being 31% lower as compared to placebo. The difference appears almost immediately as depicted in the figure… suggesting an early hemodynamic mechanism probably mediated by reduced intraglomerular pressure.

This may be supported by early GFR decline seen in the first few weeks of initiation of Canagliflozin. But thereafter, the slope of decline of eGFR remains gentler for Canagliflozin, for a difference of 2.74 ml/min/1.73m^2.


Could these outcomes be due to the effect on BP and blood sugar?

Probably not. Let’s see why..

Glycemic control:

Baseline mean HbA1C across both the groups was 8.3%. While the mean levels were lower in Canagliflozin arm the difference was marginal (mean being -0.25% and end of study difference being just -0.11%). As seen from the table S2 above, this occurred despite insulin and other hypoglycemic use being higher in the placebo group. However, at these levels of glycemia, we don’t have any data to support an..

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Omar Taco with a very colorful visual abstract for this week’s discussion of the ASCEND trial of depression on hemodialysis.

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Nephrology Jrnl Club by Swapnil Hiremath - 1M ago
#NephJC Chat

Tuesday April 9th 9pm Eastern

Wednesday April 10th 9pm IST

Wednesday April 10th 8pm GMT, 12 noon Pacific


Ann Intern Med. 2019 Feb 26. doi: 10.7326/M18-2229. [Epub ahead of print]

Comparative Efficacy of Therapies for Treatment of Depression for Patients UndergoingMaintenance Hemodialysis: A Randomized Clinical Trial.

Mehrotra RCukor DUnruh MRue THeagerty PCohen SDDember LMDiaz-Linhart YDubovsky AGreene TGrote NKutner NTrivedi MHQuinn DKVer Halen NWeisbord SDYoung BAKimmel PLHedayati SS.

PMID: 30802897Introduction

Depression is widely recognized as the most common mental health condition among patients on maintenance hemodialysis (HD), affecting about 25%, a rate that is over four-fold higher than in the general population . Patients on HD face several unique physical and psychological stresses that contribute to this, including comorbidities, dietary restrictions, high pill burden, and the need to attend for prolonged thrice-weekly treatment. These factors contribute to a decrement in both physical and psychological well-being. The presence of depression is associated with lower quality of life, increased hospitalizations, non-adherence with treatment including shortened treatments and skipping dialysis treatments, and decreased adherence with fluid restriction.

Unfortunately, depression is under recognized and under treated. Patients are often reluctant to accept the diagnosis of depression and are also reluctant to accept treatment. There are additional challenges that must be considered in the HD population:

  • When we do recognise depression in dialysis patients?

  • What do we do next?  

Treatments include cognitive behavioral therapy (CBT) which helps patients with behavioral modification strategies and offers problem solving skills, and antidepressant medications including selective serotonin re-uptake inhibitors (SSRI). However, evidence for the efficacy of antidepressant therapies in this population is limited.

The CAST Randomized Clinical Trial was published in 2017 and included 201 patients with non-dialysis dependent chronic kidney disease and at least moderate depressive symptoms. The use of sertraline vs placebo did not result in a statistically significant difference in symptom improvement over 12 weeks (−4.1 points vs −4.2 points on the 16-item Quick Inventory of Depression Symptomatology).

The ASSertID trial was a randomized, double-blind, placebo-controlled trial of sertraline over 6 months in patients on hemodialysis with depression to determine study feasibility, safety, and effectiveness. They found a high proportion of depresssion (32.3%) as diagnosed by the Beck Depression Index Score. They found no significant differences between sertraline and placebo groups however the authors highlighted several issues including a high drop-out rate and recruitment issues. One problem was that a lot of patients were already on antidepressants and so declined to participate.

Patients on HD have unique risk factors that affect the risk-benefit equation for both safety of pharmacological treatment and acceptance of CBT. Safety is a particular concern, especially from a cardiovascular perspective given the high prevelance of cardiovascular disease in this patient group, the risk of interaction with other medications, and electrolyte shifts on HD. A study in the April 2019 issue of JASN sought to address this. Check out the VA by @Stones_ below. They found an increased risk of sudden cardiac death among HD patients receiving SSRIs with higher potential to prolong QT interval (citalopram and escitalopram) versus lower (fluoxetine, fluvoxamine, paroxetine, sertraline) . This risk was enhanced among elderly females, those with pre-existing conduction disorders, and those taking other QT-prolonging medications.

So far, we know that depression is common in CKD patients, and it is hard to treat - and hard to do trials in this population. Pharmacotherpay that works in the general population carries risks, and may not be effective. Can we ascend from the depths of this depressing set of facts?

The StudyMethods

ASCEND, A Trial of Sertraline vs. CBT for End-stage Renal Disease Patients with Depression was designed to inform care of patients with a major depressive disorder undergoing HD. This was an was an open-label, parallel-group, multicenter, randomized controlled trial.

The aim was to determine the effect of an engagement interview on treatment acceptance (Phase 1) and to compare the efficacy of CBT versus sertraline (Phase 2) for treating depression in patients on HD. Participants were randomised 1:1 for both phases.

Participants were enrolled between March 2015 and August 2017 and were followed through November 2017. They were receiving in-centre hemodialysis at 41 dialysis facilities at 3 clinical sites—1 each in Albuquerque, New Mexico; Dallas, Texas; and Seattle, Washington—operated by 6 dialysis providers.


Phase 1:

This involved engagement interview aimed toward increasing participants’ willingness to accept the diagnosis and treatment; face to face intervention by trained therapists while patients received outpatient HD. Used motivational interviewing, participants were also given a 20 minute DVD to improve their understanding of depression and it’s treatment.

  • Primary outcome was the proportion of patients initiating treatment for depression either inside or outside of the trial within 28 days of the intervention

  • Secondary outcome was the percentage willing to accept treatment within 14 days

Phase 2:

  • Participants assigned to the CBT group were scheduled for 10 sessions of 60 minutes each over 12 weeks while they received outpatient HD. The sessions were conducted face-to-face by 5 therapists; each patient saw the same therapist for all 10 sessions. Patients self-reported their depressive symptoms by using the Quick Inventory of Depressive Symptoms–Self-Report (QIDS-SR) every 2 weeks for the first 6 weeks and every 3 weeks for the next 6 weeks

  • Participants in the sertraline group had their dose titrated every 2 weeks for the first 6 weeks and then maintained for 6 weeks. Depression severity was assessed with the QIDS-SR and drug tolerability with the Frequency, Intensity, and Burden of Side Effects Ratings scale. Sertraline therapy was started with 25 mg/d during the first week and increased to 50 mg/d in the second week with a goal dose of  200mg, unless limited by adverse effects.

Primary outcome was the 16-item Quick Inventory of Depressive Symptoms–Clinician Rated (QIDS-C) score at 12 weeks.

Secondary outcomes were patient-reported outcomes at 12 weeks; computer-assisted telephone interviewing and measures of adherence

Statistical Analysis 180 randomly assigned patients would provide 80% power with a 2-sided of 0.05 to detect a difference in the mean 12-week QIDS-C score of between 0.327 (R = 0.70) and 0.419 (R = 0.40) of 1 SD.

Funding source: The trial was funded by PCORI, which had no role in the conduct, analysis or interpretation.


Results

Of the 184 participants enrolled in Phase 1, 179 (97%) completed the study visit (90 in the engagement and 89 in the control group). The engagement interview and control visit lasted 53.3 (SD, 16.6) and 30.3 (SD, 15.1) minutes, respectively.

Figure 1 from Mehrotra et al, Annals 2019

Of the 60 patients randomly assigned to the CBT group, 2 died and 2 withdrew consent. The participants completed a median of 5 sessions by 6 weeks and 10 sessions by 12 weeks; 80% completed 8 and 73% completed 10 sessions in 12 weeks. Of the 60 patients randomly assigned to the sertraline group, 2 withdrew consent. At weeks 6 and 12, a total of 78% of the participants were receiving sertraline. The median prescribed dose of sertraline at 6 and 9 weeks was 150 mg, with 55% and 49%, respectively, receiving a dose of 150 mg or higher.


Primary End Points

Phase 1: The primary outcome was assessed for 170 (92%) of participants (86 engagement and 84 control group). The proportion of participants who accepted treatment for depression within 28 days did not differ between the engagement and control groups (66% vs. 64%, respectively; P = 0.77; estimated risk difference, 2.1% [95% CI, 12.1% to 16.4%]).

Phase 2: QIDS-C scores decreased in both groups; CBT baseline, 12.2 [SD, 5.1]; 12 weeks, 8.1 [SD, 5.1]), sertraline baseline, 10.9 [SD, 4.9]; 12 weeks, 5.9 [SD, 4.5]. Depression scores at 12 weeks were lower in the sertraline than the CBT group (P =0.035). The proportion of patients with a decrease in QIDS-C score of at least 50% or a QIDS-C score less than 5 at 12 weeks was greater in the sertraline group; however estimates were imprecise and had wide CIs (≥50% decrease in score: 36% in the CBT and 43% in the sertraline group; rate ratio, 1.18 [CI, 0.75 to 1.87]. No changes in QIDS-C score were observed among the participants who declined treatment within or outside the study.


Secondary End Points

Phase 1: Between the engagement and the control group, no difference was found in the proportion of patients intending to start treatment for depression 2 weeks after the visit (81% vs. 81%; P = 0.96; estimated risk difference, 0.3% [CI, 11.2% to 11.8%]).

Phase 2: At 12 weeks, 5 of 9 patient reported outcome measures (BDI-II, Sheehan Disability Scale, energy/vitality subscale of Short Form-36, Satisfaction With Life Scale, and Pittsburgh Sleep Quality Index) were better for the sertraline than the CBT group.

Adverse Events:
Serious adverse events occurred in both groups: 13 events in 11 patients in the CBT group, 18 events in 14 patients in the sertraline group. “Non-serious” adverse events were more frequent in the sertraline (56 events in 25 patients) than the CBT (17 events in 12 patients) group.

Discussion

The authors cite 3 key findings from this study:

  1. Engagement interview had no effect on patients’ acceptance of depression diagnosis or treatment

  2. Depressive symptoms and other patient-reported outcomes improved in both the sertraline and CBT groups; outcome scores were modestly better in the sertraline group

  3. Adverse events occurred more frequently in the sertraline group than the CBT group

Strengths of this study include a diverse patient population, high adherence to assigned intervention and close follow up period. Limitations include a lack of a “no treatment” control group,  the comparative effect of 2 treatments on secondary patient-reported outcomes was attenuated toward the null on multiple imputation and short follow up period.

In conclusion, recognition, diagnosis and treatment of depression in the dialysis population remains a clinical challenge.

Summary by Laura Slattery

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