The grey line of dialysis initiation: When dialysis should ...reference group with an eGFR of >5 to 10 ml/min per 1.73 m. 2. at dialysis start, a Cox model adjusted for potential confounding

The grey line of dialysis initiation: When dialysis should be started?

Which treatment ?

Bengt Lindholm

Baxter Novum and Renal Medicine

Karolinska Institutet

Stockholm

Sweden

Update on Cutting-edge Cardiovascular and Renal Medicine Themes Paris, 15-17 December 2011

http://www.karolinska.se/tillKi.aspx�

CKD Patients Are More Likely To Die Than Progress To ESRD

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Disenrolled Event free RRT Died

RRT=renal replacement therapy

Keith D et al. Arch Int Med 2004,164, 659-63

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The Scylla and Charybdis of dialysis initiation

• Increasing mortality risks as GFR declines.

• Could therefore replacement of renal function by dialysis at an earlier stage of kidney failure convey survival benefits?

• On the other hand, if dialysis is associated with increased risks, mortality could increase.

• What are the gains by starting dialysis earlier?

• Which modality should we choose?

Dialysis - “Only Half A Success Story”

1970s 1980s 1990s 2000

• Vascular access • Home dialysis

• Water purification • Dialysis x 3/week

• Biocompatible membranes

• Bicarbonate dialysis

• Increased transport of small proteins • Daily dialysis

http://www.homebybaxter.com

Slide courtesy of Peter Stenvinkel

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General population

Dialysis patient

His grandmother What in the uremic milieu transforms the phenotype of the vascular endothelial cell from antiatherosclerotic to proatherosclerotic?

40-year old healthy female 40-year old

dialysis patient

Why does a 40-year old dialysis patient have the biological age of an 80-year old?

A major question in nephrology


Left Ventricular Hypertrophy, Ischemic Heart Disease, Vascular Calcification, Heart failure, Sudden Death

CKD patients are burdened by many “novel” risk factors in addition to conventional risk factors

CKD-MBD

Ca, P, PTH, FGF23 ↑

Conventional

High BP, DM

Hyperlipidemia

Obesity

Insulin Resistance

Systemic Inflammation Acute Phase Response

Dialysis-Related

Fluid Overload

Infections

Unphysiology

Sudden death

Proinflammatory Cytokine Release

Uremia-Related Uremic toxins

Malnutrition

Inflammation

Oxidative stress

Endothelial Dysfunction

Dialysis controls only to some extent factors involved in uremic complications

• Adequate clearances and removal of solutes – Small solutes (Kt/V urea, creatinine clearance) – Middle molecules

• Ultrafiltration and fluid- and electrolyte-balance • Blood pressure control • Adequate nutrition and nutritional status • Control of acidosis • Minimal anemia • Calcium-phosphate-PTH control • Control of inflammation • Management of cardiovascular disease, diabetes and

other comorbidities • MDt/P

Natural kidneys HD PD

Solute transport Convection Diffusion Diffusion Mode of action Continuous Intermittent ”Continuous” Volume control Na reabsorption Ultrafiltration Ultrafiltration biofeedback (hydrostatic) (osmotic) Metabolic functions H+, K+ excretion Supply HCO3

- Supply HCO3-

glucose, protein K+ removal K+ removal AA reabsorption Endocrine functions EPO, calcitriol 0 0 renin

Dialysis therapy cannot replace all functions of the kidneys

Weekly clearances Liters/Week

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Pre-dialysis CKD stage 4-5

HD CAPD

Urea (MW 60)

Creatinine (MW 113)

Inulin (MW 5200)

Dialysis does not even come close to replacing solute removal of the kidneys

Why Start Dialysis ”Early”?

The case for starting dialysis early:

• “Why should we allow endogenous renal clearances to fall below the minimal clearances that we target once dialysis has commenced? “

“The internist knows everything but does not do anything”

“The surgeon does everything but does not know anything”

“The nephrologist knows everything and does everything…

but too late”


Earlier initiation of dialysis: History

• Bonomini et al (1985)1: higher survival in those who started dialysis early (initial creatinine clearance 11 mL/min) than in those who started late (initial creatinine clearance <5 mL/min).

• Tattersall et al (1995)2: initial KT/V urea lower in patients who died

than in those who survived during the first 10 months of dialysis • Fink et al3 (1999) recorded an inverse relation between GFR and

survival. • However these studies were retrospective, used estimation of renal

function from a serum sample, or had small number of patients or did not take into account the possible effect of lead-time.

1Bonomini et al. Kidney Int 17:S57-S59, 1985; 2Tattersall J, Greenwood R, Farrington K: Am J Nephrol 15: 283-289, 1995; 3Fink et l. Am J Kidney Dis 34: 694–701, 1999


• In 1996, the CANUSA study demonstrated that survival was greater in patients commencing peritoneal dialysis with more preserved levels of kidney function1.

1Churchill DN, Taylor DW, Keshiviah PR; Canada-USA (CANUSA) peritoneal dialysis study group: Adequacy of dialysis and nutrition in continuous peritoneal dialysis: Association with clinical outcomes. J Am Soc Nephrol 7:198-207, 1996.

Kt/V is established for PD and HD. Why not in pre-dialysis?

Our patients are dying! We have to do something!

The DOQIa process

aUS National Kidney Foundation– Dialysis Outcomes Quality Initiative (NKF-DOQI)

Early initiation of dialysis: History

In 1997, US NKF-DOQI workgroup on the initiation of long-term dialysis therapy proposed:

• Dialysis should start when renal KT/V for urea had fallen to 2.0 per week.

• This value equals a GFR of about 10.5 mL/minute.

• A lower Kt/V urea would be acceptable only when dietary protein intake (normalized protein equivalent of nitrogen appearance, nPNA) was at least 0.8 g/kg daily.

NKF-DOQI. Clinical practice guidelines for hemodialysis and peritoneal dialysis adequacy. Am J Kidney Dis 1997; 30(Suppl 2):S1–136.


European Best Practice Guidelines 20021

• At the time the EBPG guideline was being prepared, dialysis tended to be started with an estimated glomerular filtration rate (eGFR) of ~6 mL/min and there was an impression that dialysis was started too late in many cases.2

• EBPG recommended initiation of dialysis at GFR level of 8 - 10 mL/minute/1.73 m2

• Implementation of the new guidelines resulted in earlier initiation of dialysis treatment during the coming decade.

1Tattersall et al When to start dialysis. Nephrol Dial Transplant 2002; 17 (Suppl 10): 10; ERA-EDTA. European guidelines on best practice for the management of peritoneal dialysis. 2002. 3

Implementation of recommendations in new guidelines resulted in earlier dialysis initiations in the US

Rosansky S et al. CJASN 2011;6:1222-1228

©2011 by American Society of Nephrology

Earlier initiation of dialysis in the US Data from the US Renal Data System (USRDS) between 1996 and 2008

• The proportion of patients initiating HD with an estimated glomerular filtration rate (eGFR) >10 ml/min/1.73 m2 increased from 20% to 52%.

• Those with a starting eGFR of ≥15 ml/min/1.73 m2 increased from 4% to 17%. USRDS 2009 Annual Data Report. National Institutes of Health, USA, 2009;

Rosansky, SJ et al. : Early start of hemodialysis may be harmful. Arch. Intern. Med. 2010

Earlier initiation of dialysis in Canada

• 25 910 patients from the Canadian Organ Replacement Register (2001-2007).

• Early initiation of dialysis defined as GFR>10.5 mL/min per 1.73 m²

• Between 2001 and 2007, mean estimated GFR at initiation of dialysis increased from 9.3 to 10.2 ml/min (p < 0.001).

• The proportion of early starts rose from 28% to 36%.

Clark WF et al. Association between estimated glomerular filtration rate at initiation of dialysis and mortality. CMAJ. 2011 Jan 11;183(1):47-53.

What was the impact of earlier start of dialysis on survival ?

Was it beneficial? Or harmful?

What happened after these guidelines were implemented?

• Several observational studies compared outcomes in patients starting dialysis at various levels of eGFR.

• These studies included large numbers of patients, in some cases >100,000, in registry-type data sets, including the United States Renal Data System (USRDS), Bureau of National Health Insurance in Taiwan, European Registry, Renal Epidemiology and Information Network French Registry and the Canadian Organ Replacement Registry.

• These studies all demonstrated a progressively reduced mortality with starting dialysis at lower levels of eGFR.

Tattersall et al: When to start dialysis: updated guidance following publication of the Initiating Dialysis Early and Late (IDEAL) study. Nephrol Dial Transplant (2011) 26: 2082–2086

Higher eGFR at start of dialysis associated with higher mortality in Europe

• 11 472 patients from 9 European renal registries. • Mean eGFR was 8.6 ml/min/1.73 m2. • An increase in eGFR of 1 ml/min/1.73 m2 was associated with a higher

mortality risk (HR = 1.03; 95% CI: 1.03-1.04) that remained similar after adjustment for age, gender, primary renal disease, treatment modality, country and comorbidity.

• The findings were consistent across gender, treatment modalities, geographical regions and time periods (2003 vs 1999)

• Association between a higher eGFR at the start of dialysis and mortality was the strongest in the youngest age groups and in patients with glomerulonephritis.

• Analyses at centre level showed that a 10% increase in the percentage of patients starting dialysis at high eGFR levels (>10.5 ml/min) was associated with a 22% higher mortality risk (HR = 1.22; 95% CI: 1.18-1.26).

• Higher eGFR at the start of dialysis was associated with a higher mortality risk.

Stel VS et al. Nephrol Dial Transplant. 2009 Oct;24(10):3175-82

Early start associated with higher mortality in the US

• 896,546 patients entering the U.S. Renal Data System 1995 to 2006 were classified into groups by estimated GFR (eGFR) at dialysis initiation.

• 99,231 patients had an early dialysis start (eGFR >15 ml/min per 1.73 m2) • 113,510 had a late start (eGFR ≤5 ml/min per 1.73 m2). • The following variables were significantly (P < 0.001) associated with an early start:

white race, male gender, greater comorbidity index, presence of diabetes, and peritoneal dialysis.

• Compared with the reference group with an eGFR of >5 to 10 ml/min per 1.73 m2 at dialysis start, a Cox model adjusted for potential confounding variables showed an incremental increase in mortality associated with earlier dialysis start.

• The group with the earliest start had increased risk of mortality, whereas late start was associated with reduced risk of mortality.

• “Late initiation of dialysis is associated with a reduced risk of mortality, arguing against aggressive early dialysis initiation based primarily on eGFR alone”.

Wright S, et al. Timing of dialysis initiation and survival in ESRD. Clin J Am Soc Nephrol. 2010 Oct;5(10):1828-35.

Earlier initiation of dialysis in Canada 25 910 patients from the Canadian Organ Replacement Register (2001-2007).

• Mean GFR was 15.5 mL/min among those with early initiation and 7.1 mL/min among those with late initiation.

• The unadjusted hazard ratio (HR) for mortality with early relative to late initiation was 1.48 (95% CI 1.43-1.54).

• HR decreased to 1.18 (95% CI 1.13-1.23) after adjustment for demographic characteristics, serum albumin, primary cause of end-stage renal disease, vascular access type, comorbidities, late referral and transplant status.

• A higher eGFR at initiation of dialysis was associated with increased risk of death. Clark WF et al. CMAJ. 2011 Jan 11;183(1):47-53

Studies from Taiwan and Sweden on effect of starting early on dialysis

• Observational study from Taiwan among 23,551 incident HD patients with a median eGFR at dialysis initiation of 4.7 ml/min suggested that initiating dialysis at higher eGFR was associated with increased mortality risk.

• Population-based, prospective, observational cohort study of all Swedish citizens with a certain degree (mean eGFR 16.1 ml/min) of CKD showed that initiating dialysis at a below-median eGFR was associated with a reduced risk of death. Hwang, SJ et al. Nephrol. Dial. Transplant. 25, 2616–2624 (2010).

Evans M,et al. J Intern Med. 2011 Mar;269(3):289-98.

Early start of HD in patients without co-morbidity

• 81,176 patients commencing in-center HD in the US, were selected for lack of comorbidity by excluding patients with diabetes and those aged >65 years, and were analyzed by starting eGFR and category of plasma albumin—a surrogate for unmeasured morbidity.

• Starting eGFR had little effect on survival of the sicker patients. • Among fitter patients, the higher the starting eGFR, the greater the

relative increase in mortality: HR 1.53 and 2.18 for eGFR of 10–15 ml/min/1.73 m2 and >15 ml/min/1.73 m2, respectively).

• Early start of HD seemed in fact to be harmful, questioning the trend to early HD initiation.

• Initiation of HD should not be based on an arbitrary level of eGFR or on serum creatinine level unless accompanied by other definitive indications.

Rosansky, SJ et al. : Early start of hemodialysis may be harmful. Arch. Intern. Med. 2010

Initiating Dialysis Early and Late (IDEAL) study

• Performed in Australia and New Zealand, patients (N= 828) were enrolled over 8 years.

• Patients were randomly assigned to planned initiation of dialysis when their eGFR was 10–14 ml/min/1.73 m2 (early start) or when their eGFR was 5–7 ml/min/1.73 m2 (late start).

• 75.9% of the patients in the late-start group initiated dialysis above the target eGFR owing to symptom development.

Cooper BA et al. A randomized, controlled trial of early versus late initiation of dialysis. N. Engl. J. Med. 363, 609–619 (2010).

Initiating Dialysis Early and Late (IDEAL) study

• During a median follow-up of 3.59 years, 37.6% of early starters and 36.6% of late starters died (hazard ratio [HR] for early initiation 1.04, 95% Ci 0.83–1.30; P = 0.75).

• The IDEAL study showed that early initiation of dialysis had no significant effect on the rate of death from any cause or on cardiovascular, infectious or other complications of dialysis itself.


Initiating Dialysis Early and Late (IDEAL) study: Conclusions

• “… with careful clinical management, dialysis can be delayed for some patients until eGFR drops below 7 ml/min/1.73 m2 or until more traditional clinical indicators are present.”


Possible explanations why starting dialysis early appears to be harmful.

• Renal function estimated by s-creatinine (as with eGFR) may be useless or even misleading as a guide on when to start dialysis.

• The wide range of eGFR when dialysis starts suggests that nephrologists are:

• ignoring eGFR in planning the start to dialysis, or • that eGFR does not represent renal function very

well, or that • patients have widely differing tolerance to

uremia.

Tattersall et al. Nephrol Dial Transplant (2011) 26: 2082–2086

Possible explanations why starting dialysis early appears to be harmful.

• Observational studies do not prove that starting dialysis with higher eGFR causes the worse outcome.

• Patients with low muscle mass will have a lower creatinine generation rate.

• Patients with fluid overload will dilute their serum creatinine.

• Both groups will have higher co-morbidity, yet have lower s-creatinine.

• Since eGFR is calculated from s-creatinine, eGFR will be overestimated in these patients and they are more likely to be included in ‘earlier’ start groups .


eGFR estimated by MDRD formula does not reflect GFR in ESRD patients1

• S-creatinine is determined by GFR, and by muscle mass

• eGFR by MDRD equation was compared with

measured GFR (mGFR, mean of creatinine and urea clearance) just before the start of dialysis.

• The relationship of eGFR and mGFR with

mortality and muscle mass was analysed.

1Grootendorst et al for the NECOSAD Study Group. Nephrol Dial Transplant. 2011 Jun;26(6):1932-7.

eGFR estimated by MDRD formula does not reflect GFR in ESRD patients1

• In 569 ESRD patients with 24-h urine collections and a plasma sample available at the start of dialysis mGFR was 6.0 (2.6) and eGFR was 6.8 (2.4) mL/min/1.73 m2.

• Although eGFR overestimated mGFR with only 0.8 mL/min/1.73 m2 limits of agreement ranged from - 4.1 to + 5.6 mL/min/1.73 m2.

• The highest eGFR values were associated with the highest mortality rates [adjusted hazard ratio 1.4 (1.0, 1.9)]. eGFR but not mGFR was associated with muscle mass (P = 0.001).

• Estimation of GFR by equations using s-creatinine in the denominator cannot be used for this purpose in patients with ESRD because the effect of GFR on p-creatinine is overruled by that of muscle mass.

Grootendorst et al for the NECOSAD Study Group. Nephrol Dial Transplant. 2011 Jun;26(6):1932-7.

Survival versus measured GFR and estimated GFR

Grootendorst D C et al. Nephrol. Dial. Transplant. 2011;26:1932-1937

© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: [email protected]

N= 569 ESRD ; 24-h urine collections and a plasma sample available at the start of dialysis mGFR was 6.0 (2.6) and eGFR was 6.8 (2.4) mL/min/1.73 m2.

Muscle mass was not associated with measured GFR but with eGFR.

Grootendorst D C et al. Nephrol. Dial. Transplant. 2011;26:1932-1937


Measured GFR eGFR

Additional possible explanations why starting dialysis early appears to be harmful

• Patients with symptoms or co-morbidity are more likely to be started on dialysis early.

• Patients are only included in these studies if they actually started dialysis.

• Only the fittest patients survive long enough to be included in the late start groups.

• If deaths within the first 90 days of starting dialysis are excluded this could enhance this ‘survivor bias’. Tattersall et al. Nephrol Dial Transplant (2011) 26: 2082–2086

eGFR is a poor predictor of concentration for a broad range of uremic toxins

• eGFR is poorly associated with concentrations of uremic toxins in patients with different degrees of CKD,

• eGFR correlates differently with each individual solute

• eGFR can not be considered representative for evaluating the accumulation of solutes in the course of CKD

Eloot S et al. eGFR is a poor predictor of concentration for a broad range of uremic toxins. Clin J Am Soc Nephrol. 2011 Jun;6(6):1266-73.

eGFR is a deceiving predictor of uremic solute concentration and their biological action

• eGFR is a deceiving predictor of uremic solute concentration and their biological action

• This inconsistency is very likely the result of the impact of other factors affecting concentration, such as

• tubular secretion,

• generation by intestinal flora,

• metabolism.

Vanholder R et al. An Obituary for GFR as the Main Marker for Kidney Function? Semin Dial. 2011 Dec 6.

Could dialysis in fact be harmful ?

• Dialysis and especially intermittent dialysis leads to accelerated loss of residual renal function - a powerful predictor of mortality

• Dialysis introduces risk of access related infections

• Dialysis induces an inflammatory reponse

• Dialysis, especially intermittent dialysis, leads to unphysiological fluctuations in solutes and fluid that increase the risk for sudden cardiac death

Mortality increases immediately after dialysis initiation and then declines indicating harmful effect

of dialysis

Incident hemodialysis patients. Adj: age/gender/race/primary diagnosis; ref: incident hemodialysis patients, 2005.

USRDS 2010

Initiation of Dialysis Introduces the Risk For Access Infections

• Unpure water?

• Dialyzer?

• Use of catheters

USRDS 2004 Annual Data Report

Dialysis related Infections

PD vs HD; Septicemia RR 2.10 (p<0.001)

The problem of sudden cardiac death (SCD) in dialysis patients

• SCDs account for 26.1% of deaths in patients with ESRD.

• These deaths do not appear to be caused by coronary artery disease, as is the case for most SCDs in the general population.

• Cardiomyopathy and ischemic heart disease predispose to conduction abnormalities and arrythmogenesis, which can be exacerbated by electrolyte shifts, sympathetic overactivity, and baroreflex abnormalities.

• Inflammatory markers and diabetes are predictors of sudden death.

Green D, et al. Am J Kidney Dis. 2011 Jun;57(6):921-9.

Increased mortality after the long interdialytic interval in HD

The long (2-day) interdialytic interval is a time of heightened risk: • All-cause mortality (22.1 vs. 18.0 deaths per 100 person-years,

P<0.001), • Mortality from cardiac causes (10.2 vs. 7.5, P<0.001), • Infection-related mortality (2.5 vs. 2.1, P=0.007), • Mortality from cardiac arrest (1.3 vs. 1.0, P=0.004), • Mortality from myocardial infarction (6.3 vs. 4.4, P<0.001), • Admissions for myocardial infarction (6.3 vs. 3.9, P<0.001), • Congestive heart failure (29.9 vs. 16.9, P<0.001), • Stroke (4.7 vs. 3.1, P<0.001), • Dysrhythmia (20.9 vs. 11.0, P<0.001), • Any cardiovascular event (44.2 vs. 19.7, P<0.001).

Foley RN, Gilbertson DT, Murray T, Collins AJ. N Engl J Med. 2011 Sep 22;365(12):1099-107.

What has been the impact of the IDEAL study?

European Renal Best Practice (ERBP) advisory board: When to start dialysis: updated guidance following publication of

the Initiating Dialysis Early and Late (IDEAL) study

• The 2002 guidance is not significantly changed. The evidence levels are increased by the studies published since 2002.

• The caution against using s-creatinine and creatinine clearance to guide dialysis start is strengthened.

• A caution that eGFR calculated by the MDRD method is not useful in determining need for dialysis has been added.

• The emphasis on using GFR of 6 mL/min/1.73m2 as an absolute lower limit to starting dialysis is made more vague.

Tattersall et al: Nephrol Dial Transplant (2011) 26: 2082–2086

• “Lack of any validated and objective measurement of the uremic state which could be used to guide the decision on when to start dialysis.”

• “Any future RCT on dialysis outcome should include measurements of renal function, rather than estimation from s-creatinine.”




Can we get any advantage in terms of survival by initiation of dialysis before

there are clear clinical indications?


Recomendations from the US

• The trend to an early start is based on conventional wisdoms regarding benefits of dialytic clearance, that albumin levels are nutritional markers, and early dialytic therapy is justified to improve nutrition especially in diabetics and that waiting until low levels of eGFR (i.e., <6 ml/min per 1.73 m(2)) may be dangerous.

• Dialysis initiation is justified at GFR levels of 5-9

ml/min/1.73 m2, if accompanied by uremia symptoms or fluid management issues

Rosansky S, Glassock RJ, Clark WF. Early start of dialysis: a critical review. Clin J Am Soc Nephrol. 2011 May;6(5):1222-8.

European Renal Best Practice (ERBP) advisory board

In patients with a GFR <15 mL/min/1.73m2 , dialysis should be considered when there is one or more of the following: • symptoms or signs of uremia, • inability to control hydration status or blood

pressure o • progressive deterioration in nutritional status. • Note that the majority of patients will be

symptomatic and need to start dialysis with GFR in the range 6-9 mL/min/1.73m2 (1A Strong recommendation based on high-quality evidence). Tattersall et al. Nephrol Dial Transplant (2011) 26: 2082–2086



• High-risk patients e.g. diabetics and those whose renal function is deteriorating more rapidly than eGFR 4 mL/min/year require particularly close supervision.

• Where close supervision is not feasible and in patients whose uremic symptoms may be difficult to detect, a planned start to dialysis while still asymptomatic may be preferred (1C Strong recommendation based on low-quality evidence).




• Asymptomatic patients presenting with advanced CKD may benefit from a delay in starting dialysis in order to allow preparation, planning and permanent access creation rather than using temporary access (2C Weak recommendation based on low-quality evidence).


How should dialysis be started?

• Starting dialysis early - especially when using conventional HD - does not necessarily confer benefit.

• Alternative approaches, including more frequent HD and home-based therapies (PD and home HD) are promising. Lindholm B, Davies S. ESRD in 2010: Timing of dialysis initiation and choice of dialysis modality.

Nat Rev Nephrol. 2011 Feb;7(2):66-8

Factors influencing modality choice

Common objective criteria: • Patient survival • Quality of life • Feasibility • Technique survival • Costs or cost-effectiveness Subjective criteria: • Patient choice – influenced by many factors such

as available training resources, contact with other patients, education.....

• Health care provider´s preferences

What influences patient choice of treatment modality at the pre-dialysis stage?

• 242 pre-dialysis patients rated factors affecting their treatment choice.

• 70% choose HD, 20% PD and 10% opted for conservative management, CM.

• Patients choosing PD were younger (55 years HD 68 years, CM 84 years for CM) and had less co-morbidity.

• 50 % of patients who chose PD attended a formal education day compared to 32.9% that chose HD and 0% that chose CM (P = 0.011).

Chanouzas et al. Nephrol Dial Transplant. 2011

Other factors predicting modality choice

• Being married (PD 95.7%, HD 53.8%, CM 41.7%; P < 0.001),

• Being employed (PD 33.3%, HD 11.5%, CM 0%; P = 0.015)

• Having another person living at home (PD 100%, HD 69.5%, CM 50%; P = 0.003).

Chanouzas et al. Nephrol Dial Transplant. 2011

PD Home HD

Centre HD

End of life care

Transplant

Complimentary not competing therapies: PD as first line dialysis modality

Advantages with PD

• Equal or better initial patient survival

• Equal or better quality of life

• Technique survival: improving

• Declining infection rates

• Lower risk of hepatitis

• Preserves renal function better than HD

• Less anemia and lower EPO/ESA doses

• Blood pressure and volume control improving • Similar graft function post transplant

• More cost-effective

What is the evidence for similar survival with PD and HD ?

Studies comparing outcomes with PD and HD

• Case reports • Retrospective studies Evidence

• Cross-sectional studies 1980- • Registries 1990s – (large size) • Prospective studies 1980- (many) • Small RCTs 2003 (n=1) • Large RCTs 2011 (n=1; ongoing)

0 12 24 36 48 600

50

100

HDPD

p=0.02

Time from randomisation (months)

Per

cent

Sur

viva

l

Korevaar KI 2003; 64:2222 Adjusted RR for HD vs. PD 3.6 (-0.8-15.4) p=0.09

N= 38/773 patients 18 HD 20 PD

PD vs. HD: Randomised Trial

Two recent studies confirm that patient survival does not differ between HD and PD

Mehrotra, R et al. Arch. Intern. Med. (2010): • Among 620,020 HD patients and 64,406 PD patients from all

US centers, PD outcomes steadily improved between 1996 and 2004.

• In the most recent cohort, similar outcomes with HD and PD.

Weinhandl, E.D. et al. J. Am. Soc. Nephrol. 21, 499–506 (2010): • Propensity-matched mortality comparison of 6,337 incident

HD–PD patient pairs • Survival from first day on dialysis was higher for PD patients

than for HD patients (HR 0.92; 95% CI 0.86–1.00; P = 0.04). • The greatest benefit to starting with PD was seen in patients

aged <65 years without diabetes and comorbidity.

Mehrotra, R. et al. Arch Intern Med 2011;171:110-118.

Survival of incident PD and HD patients in the United States stratified by cohort periods 1996-1998, 1999-2001 and 2002-2004

Mehrotra et al 2010: Conclusions

• In the largest study to date, there was no significant overall difference in outcomes of patients with ESRD who began treatment with either HD or PD in 2002-2004—the most contemporary cohort for which data are available.

• Progressive improvements in outcomes of PD patients (relative to HD patients) were seen in virtually all of the 8 subgroups examined.

Mehrotra, R et al. Arch. Intern. Med. (2010)

Weinhandl et al. JASN 21:499-506, 2010

”... Mortality risk was 8% lower for PD than for matched HD patients.

Survival PD vs. HD Propensity analysis yielding

carefully matched cohorts, 2 x 6337 patients

Weinhandl et al. JASN 21:499-506, 2010

+8% better 4 years survival with PD

van de Luijtgaarden M W et al. Nephrol. Dial. Transplant. 2011

Survival curves for PD and HD patients stratified for gender.

van de Luijtgaarden M W et al. Nephrol. Dial. Transplant. 2011;ndt.gfq845


7 European renal registries; 15,828 incident PD and HD patients (1998-2006) with available comorbidity data.

PD

HD

Overall survival benefit of PD HR (adj) 0.82 (0.75-0.90), Patients without comorbidity HR(adj) 0.65 (0.53-0.80)

• In general, modality choice was consistent with expected survival.

• However, elderly patients, non-diabetic patients and those with malignancy were less likely to receive PD, even though they had decreased mortality risk on PD.

van de Luijtgaarden M W et al. Nephrol. Dial. Transplant. 2011;ndt.gfq845

Survival in patients starting dialysis

• Most recent studies show equal, or better initial patient survival with PD compared with HDa

• Patient survival with PD is improving faster than survival with HD according to US data

aIn USA, Canada, and Europe, but not in Australia/New Zealand

The impact of dialysis modality on quality of life: A systematic review

Boateng EA, East L. J Ren Care. 2011 Dec;37(4):190-200.

• 26 of the 574 studies identified were included. • QOL tools used include SF-36, Kidney Disease

Quality of Life (KDQOL) and CHOICE Health Experience Questionnaire (CHEQ).

• PD patients mostly rate their QOL higher than HD patients.

• Yet HD patients may enjoy a relatively better QOL in the physical dimensions over time.

• Mental health components are comparable between both dialysis populations.

PD Home HD

Centre HD

End of life care

Transplant

Complimentary not competing therapies: What about home hemodialysis?

Short-daily HD

• Survival with short-daily HD and the impact of dialysis duration, frequency, dose and site (home [n = 189] versus hospital [n = 73]) was investigated in a multicenter study (European and US).1

• Four factors were independently associated with survival: age (HR 1.05), secondary renal disease (HR 2.30), weekly dialysis hours (HR 0.84), and home dialysis (HR 0.50).

1Kjellstrand, C. et al. Survival with short-daily hemodialysis: association of time, site, and dose of dialysis. Hemodial. Int. 14, 464–470 (2010)

Lower mortality risk with home HD

• In 26,016 patients starting renal replacement therapy in Australia and New Zealand, the adjusted mortality hazard ratios (HR) relative to conventional facility HD were:

• 0.51 (95% CI, 0.44-0.59) for conventional home HD, • 1.16 (95% CI, 0.94-1.44) for frequent/extended facility HD, • 0.53 (95% CI, 0.41-0.68) for frequent/extended home HD, • 1.10 (95% CI, 1.06-1.16) for PD. • The apparent benefit of home HD on mortality risk was less

for patients who were nonwhite, non-Asian, and older. • This study supports a survival advantage of home HD

without a difference between conventional and frequent/extended modalities.

Marshall MR et al. Am J Kidney Dis. 2011 Nov;58(5):782-93.

Short-daily hemodialysis

• The benefits of short-daily hemodialysis are supported by the results of the randomized controlled Frequent Hemodialysis Network (FHN) Daily trial showing that more frequent HD resulted in improved health status and reduced left ventricular hypertrophy.1

1The FHN Trial Group. in-center HD six times per week versus three times per week. N. Engl. J. Med 2010;363:2287-2300.

1-year Mortality and Change in LVM

FHN Trial Group. N Engl J Med.2010;363:2287-2300.

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Conventional HD, n=120; Frequent HD, n=125; LVM = left ventricular mass.

RR-HD-159 27/04/11

FHN Trial Group. N Engl J Med.2010;363:2287-2300.

Patients were randomized to HD 6 times per week (frequent HD, n=125) or 3 times per week (conventional HD, n=120) for 12 months.

Benefits of Early Referral to a Nephrologist

Metabolic and Hematologic Parameters • Regulation of Ca, PO4, and PTH homeostasis • Correction of metabolic acidosis • Correction of anemia with appropriate attention to ESA and iron therapy • Nutritional advice Planned Transition to Renal Replacement Therapy • Informed choice of dialysis modality • Timely placement of access (peritoneal catheter of arteriovenous fistula) • Planned commencement of dialytic therapy • Assessment of the appropriateness of preemptive transplantation • Social supports in place Management of “Nonrenal” Risks • Appropriate blood pressure management • Assessment and management of vascular disease and heart failure

Pollock et al Advances in Chronic Kidney Disease, Vol 14, No 3 (July), 2007: pp e27-e34

Outcomes of early versus late nephrology referral in CKD: a systematic review.

• 27 longitudinal cohort studies were included in the final review, providing data on 17,646 participants; 11,734 were referred early and 5912 (33%) referred late.

• Reduced mortality and hospitalization, better uptake of peritoneal dialysis, and earlier placement of AV fistula for HD with early nephrology referral.

Smart NA, Titus TT. Am J Med. 2011 Nov;124(11):1073-80

After unplanned dialysis start: Effect of in-hospital education on the adoption of

home dialysis (PD or HHD)

• Patients received multimedia chronic kidney disease education by the same advanced care nurse practitioner before discharge from the hospital.

• 228 patients acutely started renal replacement therapy. 71 patients chose home dialysis (PD=49; HHD=22), 132 chose to remain on in-center HD, and 25 died before discharge from the hospital.

• Home dialysis is feasible after urgent dialysis start. Education should be promoted among patient experiencing acute-start dialysis.

Rioux et al Clin J Am Soc Nephrol. 2011 Apr;6(4):799-804.

Comparable outcome of acute unplanned PD and HD

• Incident dialysis patients with initiation of unplanned and acute PD (n=66) or HD (n=57) at a single center.

• Dialysis modality (PD versus HD) in an acute unplanned dialysis setting showed no significant influence on survival.

• HD patients had a significantly higher risk of bacteremia, perhaps due to central venous dialysis catheter.

• PD seems to be a safe and efficient, at least comparable, alternative to HD in acute unplanned dialysis settings.

Koch et al Nephrol Dial Transplant (2011)

Incremental PD as an approach to dialysis inititiation

• The ''incremental approach'‘: dialysis dose is gradually increased as the GFR declines.

Casino FG. G Ital Nefrol. 2010 Nov-Dec;27(6):574-83. Bertoli SV, Musetti C, Ciurlino D. G Ital Nefrol. 2010 Jul-Aug;27(4):374-82 Domenici A et al. Int J Nephrol 2011;

Incremental PD as an approach to dialysis inititiation

• Starting PD or HD with an incremental modality could be appropriate for asymptomatic patients with objective signs of mild uremia and a measured GFR around 10 mL/min/1.73 m2.

• Reduced dialysis dose and/or frequency could suffice to control mild uremia, while possibly preserving the RRF owing to the reduced contact time between blood and bio-incompatible dialysis materials.

Casino FG. The grey line of dialysis initiation: as early as possible that is, by the incremental modality]. G Ital Nefrol. 2010 Nov-Dec;27(6):574-83.

When should dialysis be started? Which treatment ? Conclusions

• Starting dialysis early solely based on an eGFR of 7–15 ml/min/1.73 m2 is not justified - and could be harmful.

• Caution: Although some studies indicate that starting below 7 ml/min/1.73 m2 is not associated with increased mortality risk, this may reflect survivor bias.

• The whole idea of dependency on the single metric of eGFR may in fact be flawed; alternative systematic measures of the clinical requirement to commence dialysis are required.

Lindholm B, Davies S. Nat Rev Nephrol 2010

When to initiate dialysis? When GFR 5-9 ml/min per 1.73 m2 and there are uremia-related complications such as: • Pericarditis • Coagulopathy • Gastroenteropathy with nausea with or without vomiting • Anorexia and unexplained weight loss • Encephalopathy with increasing confusion • Volume overload/hypertension unresponsive to diuretic

therapy • Resistant hyperkalemia

Rosansky S, Glassock RJ, Clark WF. Early start of dialysis: a critical review. Clin J Am Soc Nephrol. 2011 May;6(5):1222-8.

Which treatment ?

• As the commencement of dialysis is likely itself a risk, perhaps more so with HD than with PD, patients should not be exposed to dialysis until clinically necessary.

• For many patients, PD is the ideal home-based treatment.

• The marginal differences in outcome between PD and in-center HD do not justify the lack of access to PD.

• For selected patients, home HD (with its option to increase dialysis hours) and more-frequent HD, are promising.

Lindholm B, Davies S. Nat Rev Nephrol 2010

The grey line of dialysis initiation: When dialysis should be started? Which treatment?

When should dialysis be started? • When GFR <15 mL/min/1.73m2 , and if patient has uremic

symptoms and signs; • Dialysis is usually indicated when GFR is 5-9

mL/min/1.73m2 . • But, there is no single criterion. Which treatment? • If no contraindications and if it is feasible and patient is

able/willing: • 1. renal transplantation, • 2. home-based dialysis therapy, and, as last choice, • 3. in-center hemodialysis

No treatment can stand alone PD, HD, and transplantation are complementary, not

competing therapies. However, in-center dialysis should be last option

In-center HD

Home-based dialysis PD or Home HD

Transplantation

Pre-ESRD Care

Integrated ESRD Care

Transplantation is the goal

1st dialysis option: Home-based dialysis therapies

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The grey line of dialysis initiation: When dialysis should ...reference group with an eGFR of >5 to 10 ml/min per 1.73 m. 2. at dialysis start, a Cox model adjusted for potential confounding