Incremental Dialysis

Incremental Dialysis
Dr Abdullah Ansari
SR Nephrology
SGPGI Lucknow

Introduction
• RRT options and practice varies worldwide
• It is influenced by patient’s choice, nephrologist’s practice pattern,
health system, payer practice, public policy and socioeconomic
factors
• In India, hemodialysis remains the dominant RRT modality, and the
practice is largely influenced by socioeconomics factors since third
party payer is limited

Introduction
• Most ESRD patients have some of native kidney function remaining
when they initiate dialysis
• For selected patients who have significant RKF, the dialysis dose can
be adjusted for the clearance provided by native kidneys

Talk outline
Historical background
The concept of incremental dialysis
The residual kidney function and its significance
Incremental hemodialysis
Observational studies on incremental HD
The candidates for incremental HD
The potential benefits and risks associated with incremental HD
Incremental peritoneal dialysis
The intact nephron hypothesis in reverse

Historical background
• Historically, clinicians have always incorporated residual kidney
function into peritoneal dialysis prescription
• However, the practice has not been widely used for hemodialysis,
since its intermittent nature makes incorporation of RKF difficult
• RKF may decrease rapidly once patients are started on HD
• In contrast, RKF is preserved for a longer time among PD patients

The dogma of thrice a week HD
The dogma of thrice weekly HD is based on a target Kt/Vurea, developed
in the early 1980s
 Patient outcomes were studied initially in the NCDS study and
subsequently in the HEMO trial
 Both these landmark trials used a thrice-weekly HD
 The enrolled patients had little or no RKF
 Creatinine clearance ≤3 mL/minute in NCDS study and urea clearance ≤1.5
mL/min per 35 L body water in HEMO study

Prognosis for dialysis patients
• Mortality has improved modestly, but still 6-8 times higher than the
general Medicare population
• The median life expectancy is about 3 years on HD
• Hospitalizations remain high, 1.7 hospitalizations per year on average
and a 35% risk of 30-day readmission to hospital, more than double
of the general Medicare population
• Health-related quality of life is also substantially lower

“Maintenance dialysis on the whole is non-physiological and
can be justified only because of the finiteness of its
alternative.”
Dr Benjamin Burton Director AKCUP, NIDDK Journal of Dialysis, 1976

one size fits all
• The poor prognosis and lack of convincing
evidence that Kt/V based prescription can
benefit patient mortality and quality of life
• There should be a shift from a “one size fits all”
protocolized dialysis initiation toward a more
“individualized approach”

Concept of Incremental
dialysis

What is Incremental Dialysis?
• The concept of adjusting dialysis dose according to RKF so that the
dialysis dose is individualized
• The basis is to supply sufficient dialysis to achieve adequate
 volume control
 solute clearance
and then increasing the dose of dialysis as RKF declines

The principle of Incremental Dialysis
Urea
removed
during
dialysis
Residual
renal urea
clearance
(KRU)
Total
composite
clearance

The principle of Incremental Dialysis

Incremental Peritoneal Dialysis

The candidates for Incremental Dialysis
• Intermediate transition, possible candidate for incremental dialysis (blue-line trajectory)
• Gradual transition, ideal candidate for incremental dialysis (green-line trajectory)
• Abrupt transition, likely not a candidate for incremental dialysis (red-line trajectory)

Does an Incremental Start Mean An Earlier
Start?
• Not starting before it is needed, but starting at the correct time to
ease the patient into the burden of transitioning into dialysis

Indications of Incremental Dialysis
• HD or PD initiation
• Resumption of dialysis after renal allograft failure
• Conversion from failing PD to HD

Importance of Residual kidney function
RKF has been associated with numerous patient benefits including
• Volume control
• Survival
• Middle molecules clearance
• Reduced inflammation

RKF and volume control
• Patients with RKF have the advantage of improved volume control
due to
 lower ultrafiltration volumes
 less intradialytic hypotension
 myocardial stunning
subsequent reduction in cardiovascular mortality

RKF and mortality
Obi et al. (2016): a retrospective study of 5686 patients initiating maintenance HD, higher RKF
at 1 year was associated with better survival
van der Wal et al. (2011): a prospective study of 1191 HD and 609 PD patients, anuria was
found to be associated with a 1.5 times higher risk of mortality than patients with RKF
Shafi et al. (2010): a prospective study of 767 HD patients, urine output > 250 mL/day at 1
year indicating preserved RKF was independently associated with lower all-cause mortality
Vilar et al. (2009): a retrospective study of 650 patients on incremental HD, mortality was
significantly lower in patients with KRU ≥ 1 ml/min at 6, 12 and 24 months

RKF and middle molecules clearance
• The clearance of middle molecules such as β2-microglobulin is highly
dependent on RKF
• Residual tubular function represent important removal pathways for
β2-m and other compounds like hippurate, p-cresol, indoxyl sulphate
• This extends to very low levels of RKF: patients with KRU <0.5mL/min
have significantly higher serum β2-m levels than those with values
between 0.5 and 1mL/min
• These middle molecules are poorly removed by HD and HDF

RKF and inflammation/other benefits
• RKF may also play a role in reduction of inflammatory markers,
including C-reactive protein and interleukin-6
• This has been observed in nephrectomized rats through a reduction in
clearance of inflammatory markers (Bemelmans et al 2017, Poole et
al 1990)
• Several other benefits to HD patients including better quality of life,
better nutritional status, less anemia with less use of epoetin alpha,
and better control of serum phosphorus

RKF decline in hemodialysis
• The fluctuations in blood pressure and volume status during HD
• This can lead to cumulative ischemic damage in the remaining
nephrons, leading to rapid decline of RKF
• The generation of inflammatory cytokines from the flow of blood
through an extracorporeal circuit may also hasten renal decline

RKF decline in Peritoneal Dialysis
• The decline of RKF may occur more slowly in PD patients compared to
that in their pre-dialysis period
• PD removes fluid and solute without any significant fluctuations in
hemodynamics
• This continuous and gentle fluid and solute removal assists in
offloading hyperfiltration of the remaining nephrons
• This nephroprotective effect may be analogous to renin-angiotensin
blockade, by decreasing glomerular hypertension and hyperfiltration

Shafi et al. 2010
• Study design: Prospective cohort
• Study duration (yr): 3
• HD (n): 767
• RKF Metric: preserved RKF was defined as urine
output > 250 mL/day
Results:
• Preserved RKF at 1 year was independently
associated with lower all-cause mortality and a
trend toward lower cardiovascular mortality
• Participants with urine output at baseline
reported better QOL and had lower C-reactive
protein and interleukin 6 levels
• EPO dose 12,000 U/wk lower in those with urine
output at year 1 compared with those without

Vilar et al. 2009
• Study design: Retrospective cohort of
incremental HD patients
• KRU > 1 mL/min (n): 499
• KRU < 1 mL/min (n): 151
• RKF Metric: KRU-interdialytic urine collection
Results:
• Lower mortality in those with KRU > 1 mL/min
at 6, 12 and 24 months after HD initiation
• Lower erythropoietin requirements in KRU > 1
mL/min
• Albumin and nPCR higher in those with KRU >
1 mL/min
• Lower creatinine, ultrafiltration requirement
and serum potassium in KRU > 1 mL/min

Zhang et al, 2014
• Twice-weekly (n): 30
• Thrice weekly (n): 55
• RKF Metric: RKF loss defined as urine
output < 200 mL/day
Results:
• RKF loss reported in 60% (n = 18) in twice-
weekly vs 82% (n = 45) in thrice weekly
group

Factors affecting of RKF decline on dialysis
initiation
These can be broadly classified as
• Demographic characteristics
• Comorbid conditions
• HD prescription characteristics

• Demographic characteristics
 Nonwhite race associated with faster RKF decline
 Gender has a variable association, one analysis of USRDS data
reporting female sex, whereas another study reported male sex
associated with faster RKF decline
• Comorbid conditions associated with faster RKF decline
 Diabetes, poorly controlled hypertension and cardiovascular disease
 Intradialytic hypotension during the first 3 months of dialysis
 Proteinuria even after 6 months of dialysis initiation

• HD prescription characteristics that may slow the decline of RKF
 Biocompatible dialysis membranes
 High flux dialysers
 Ultrapure dialysate
 Online hemodiafiltration

RKF and intra-dialytic hypotension
• The decline in RKF is greatest during the initial 3 months of HD and is
significantly associated with episodes of intra-dialytic hypotension
• Intra-dialytic hypotension and excessive ultrafiltration induces myocardial
stunning
Excessive
ultrafiltration
Intra-dialytic
hypotension
Myocardial
stunning
Decline in
RKF

RKF and intra-dialytic hypotension
• The standard approach of ‘drying-out’ patients until symptomatic
hypotension is reached may be harmful
• Dry weight assessment should be attempted with care to avoid intra-
dialytic hypotension
• The use of bioimpedance in assessing volume status

RKF and frequent dialysis regimes
• High frequency of dialysis accelerates RKF decline
• This is related to a greater tendency to intra-dialytic hypotension and/or
increased inflammation associated with prolonged extracorporeal exposure
In a secondary analysis of the Frequent Hemodialysis Network (FHN) study,
67% of incident HD patients randomized to frequent nocturnal HD (ie >4
times per week) had urine output decline to zero, compared to only 32% of
control patients on thrice-weekly HD

How to slow the decline of RKF once dialysis
is initiated ?
Avoidance of nephrotoxins (aminoglycosides, NSAIDs, radio-contrast)
Control hypertension while minimizing intradialytic hypotension
Adjustment of the HD prescription (high-flux biocompatible dialyzer membranes
and ultrapure dialysate water)
Possible consideration of a low protein diet (0.6 - 0.8 g/kg/day) on non-dialysis days
Individualization of initial dialysis prescription with consideration of an incremental
approach

Measurement of RKF
• It is important to monitor RKF regularly due to
 The progressive decline of RKF with time
 The inter-patient variability in rate of decline
• Ideally, urine collection should span the whole inter-dialytic period rather
than 24 hours since urine volume may vary significantly during the inter-
dialytic period
• Patients and dialysis staff must be motivated, involved and educated on the
importance of regular urine collections

Measurement of RKF
RKF in the setting of dialysis can be assessed in different ways:
1. Residual urea clearance (KRU) which slightly underestimates GFR
due to tubular reabsorption
2. Residual creatinine clearance (KRC) which it overestimates GFR due
to tubular secretion
3. Composite clearance (KRU + KRC) which is used in clinical practice
with the assumption that tubular function mirrors GFR

Measurement of adequacy
Peritoneal dialysis
• It is straightforward to combine
peritoneal clearance to RKF since both
are forms of continuous clearance
• Total solute removal can be
calculated from collections of spent
peritoneal dialysis effluent and urine
carried out over the same 24-h period
Hemodialysis
• The residual urea clearance (KRU)
occurs continuously and urea removal
during HD occurs intermittently
• KRU cannot be simply added to
dialyser urea clearance to calculate
total Kt/Vurea, making it technically
complex

Converting intermittent HD clearance to
equivalent continuous clearance
European Best Practice Guideline
Casino and Lopez method
• The combined KRU and dialyser
clearance is estimated as ‘equivalent
renal urea clearance’ (EKRc)
• The EKRc is computed as a ratio of
weekly urea generation (G) to time-
averaged urea concentration (TAC)
normalized to the volume of urea
distribution for an average man
KDOQI recommendations
Gotch’s method
• The dialyser clearance is converted to
a continuous equivalent clearance
termed as ‘standard Kt/V’ (stdK)
• The stdK is computed as the weekly
urea generation (G) factored by the
average weekly pre-dialysis serum
urea concentration normalized to the
volume of urea distribution

Kidney Disease Outcomes Quality Initiative
(KDOQI) 2015 guidelines
The guidelines does not provide a clear approach for its use
The ungraded KDOQI recommendations are:
1. In patients with significant residual native kidney function (Kr), the dose
of HD may be reduced provided Kr is measured periodically
2. For HD schedules other than thrice weekly, a target standard Kt/V of 2.3
per week with a minimum delivered dose of 2.1 using a method of
calculation that includes the contributions of ultrafiltration and residual
kidney function

Clinical outcomes with Incremental
Hemodialysis
• There are no clinical trials that directly compare standard thrice-
weekly therapy HD with incremental HD
• There are a few observational studies that examined clinical
outcomes in those undergoing infrequent or incremental HD

Observational studies of Incremental
Hemodialysis
• These observational studies suggest that twice-weekly HD may be
associated with a slower decline in RKF compared to thrice-weekly HD
• The presence of RKF also modified the association of an incremental
HD regimen with mortality
• Incremental HD patients showed similar survival among patients with
substantial RKF at baseline, but higher mortality risk if they had
inadequate baseline renal urea clearance

Hanson et al, 1999 (US)
• Study design: Retrospective cohort
• RKF Metric: eGFR
Results:
• Lower mortality for twice weekly group
(RR = 0.76, P = .02), but when adjusted
for eGFR at time of dialysis start,
mortality was similar between two groups
(RR = 0.85, P = .31)

Lin et al, 2009 (Taiwan)
• RKF Metric: Urine output & residual GFR
Results:
• Twice-weekly group had higher mean
urine output than thrice-weekly group
(1.7 L vs 0.61 L; P = .001) and residual GFR
(1.9 mL/min vs 0.71 mL/min; P = .001)
• Less frequent hospitalization in twice
weekly group (63% vs 33%; P = .012)
• No difference in nutrition or inflammation
indices between groups

Stankuviene et al, 2010 (Lithuania)
• Total cohort (n) = 2428
58.5% 3x week
36.2% 2x week
5.3% 1x week
Results:
• Higher mortality in twice weekly group
(RR 1.98; P <.001)

Lin et al, 2012 (China)
Shanghai Renal Registry
• Study design: Cohort cohort
Results:
• Similar survival in both groups (RR = 0.78;
P = .145)

Caria et al, 2014 (Italy)
• Twice weekly (n): 38 (with low protein diet)
• RKF Metric: GFR loss per month
Results:
• GFR loss of 0.13 mL/min/month in twice-
weekly vs 1.53 mL/min/month in thrice-
weekly group
• Survival 95% vs 87% in twice vs thrice
• Hospitalization in 24 months was 3.7
days/patient in twice-weekly vs 6.1
days/patient in thrice weekly group

Obi et al, 2016 (US)
• RKF Metric: UOP and KRU
Results:
• Slower RKF decline over time in twice vs
thrice weekly group (UOP to ≤600 mL/d
RR 1.15, P < .001)
• Similar overall survival between groups (P
= .3)

Hwang et al, 2016 (Korea)
• RKF Metric: KRU corrected for 1.73 m2
body surface area
Results:
• RKF at 36 months 2.9 mL/min in twice-
weekly vs 1.0 mL/min in thrice weekly (P
<.001)
• Higher mortality in twice weekly group
compared to thrice-weekly group (P =.04)

Wang et al, 2016 (US)
Results:
• No significant difference in albumin
creatinine mortality associations (1.8-fold
higher risk of mortality in twice-weekly
and 2.2-fold increased risk of mortality,
P=.7667)

Park et al, 2017 (Korea)
• Incremental HD (n): 105
• Thrice weekly HD (n): 207
• RKF Metric: daily urine volume
Results:
• All-cause mortality was comparable
between the two groups
• The HRQOL tended to be better in the
incremental group
• The daily urine volume at 12 months was
similar between the two groups

Mukherjee et al, 2017 (India)
• Study duration (yr): 1.5
Results:
• There was no significant difference in the
hospitalization rates or mortality rates in
the two groups
• Weight gain, ultrafiltration rates, blood
pressures, and hemoglobin remained
more favorable in the thrice-weekly
patients

• 22 studies (75,292 participants), 15 in HD and 7 in PD were analyzed
• Mean age at dialysis start was 62 and 57 years in HD and PD subjects,
respectively

Overall risk of mortality in subjects treated with incremental
versus full dialysis
• 10 studies in HD and only 1 study in PD
included
• Incremental dialysis (HD or PD)
patients did not show higher risk of all-
cause mortality when compared to full
dose [95% CI 0.85–1.52]
• Incremental dialysis associated with
no increase in mortality risk

Random-effect overall mean difference in GFR loss in subjects
treated with incremental versus full dialysis
• 3 studies in HD and 2 study in PD included
• RKF loss (ml/min/month) was − 0.13 (95%
CI − 0.18, − 0.08) in incremental dialysis and
− 0.74 (95% CI − 1.15, − 0.33) in full dialysis
• Overall, time to full-dose dialysis was 12.1
months (95% CI 9.8–14.3) with no
difference between HD and PD (P = 0.217)
• Incremental dialysis allows longer
preservation of RKF thus deferring full-
dose dialysis by about 1 year

RCTs of Incremental Hemodialysis

Is Incremental Hemodialysis harmful ?
• There appears to be no harm on reducing dialysis dose from thrice to
twice weekly so long as RKF is significant
• In developing world constrained by financial pressures, an
incremental approach may have an economic benefit
• It may benefit the frail or elderly, who may find the frequent trips to
dialysis units tiring and debilitating

No standardization
• However, there appears to be no standardized method of applying
incremental HD
• Infrequent regimes are currently being used arbitrarily, with no
systematic process of deciding which patients require less dialysis and
then escalating dialysis dose appropriately as RRF declines over time

How to prescribe Incremental HD ?
The amount of prescribed dialysis can be decreased by
• Reducing the dialysis time (time per session or number of sessions)
• Altering operating conditions such as dialyzer size and type, dialysate
flow rate, or blood flow rate

Incremental dialysis for preserving RKF

Candidates for incremental hemodialysis ?
Urine output at the initiation of HD must be sufficient (with or without
diuretics) to keep interdialytic weight gain to <2 kg
Ultrafiltration at HD to remove that volume should be well tolerated
Limited or readily manageable cardiovascular or pulmonary symptoms
without clinically significant fluid overload
Suitable body size relative to residual kidney functions, patients with larger
body size suitable for twice‐weekly HD if not hypercatabolic

Candidates for incremental hemodialysis ?
Serum potassium and phosphorus well controlled with diet and binders
Good nutritional status without florid hypercatabolic state
Lack of profound anemia and appropriate response to anemia therapy
Infrequent hospitalization and easily manageable comorbid conditions
Satisfactory health‐related quality of life and functional status

Potential benefits
Preservation of residual kidney function: associated with improved patient survival,
better quality of life and improved overall nutritional status and less anemia
Longevity of vascular access: related to less frequent fistula or graft cannulations and
decreased access complications
Quality of life: decreased hemodialysis sessions will increase convenience and improve
quality of life
Economic benefits: esp in developing world where health care system are constrained
by poor finances
Mortality benefits: longer patient survival observed in some studies, and survivals
similar to those of thrice-weekly HD in other studies

Potential risks
Under-dialysis due to unrecognized loss of kidney function: require close
monitoring of native kidney function
Reluctance among patients to increase to thrice-weekly hemodialysis or increase
treatment duration: Patients must be made aware early on starting dialysis
Excess interdialytic weight gain: Need high UF, intra-dialytic hypotension, inability
to achieve dry weight
Increased risk of heart failure: Chronic overload, LV Hypertrophy, CHF
Decline in nutritional status, hyperphosphatemia, acidemia, and hyperkalemia:
Patients to be carefully selected and regularly monitored for these conditions

Potential risks
• Possible increased risk of mortality: in absence of significant RKF
Foley et a (2011): a study of 32065 patients on conventional thrice-weekly HD
 All cause mortality was significantly higher on the day after the long 2-day
interdialytic interval compared to other days
 Large interdialytic weight gains over the 2-day interval require rapid ultrafiltration
rates, with subsequent myocardial stunning and cardiac adverse events

Incremental Peritoneal
Dialysis

What is Incremental PD ?
• Starting with less than the “usual” PD prescription in patient with RKF
• Increasing the dose of PD over time as the RKF declines

PD patients and RKF
The CANUSA study and its subsequent reanalysis demonstrated that
residual renal solute clearances were more predictive of mortality than
peritoneal clearance
• RKF has been associated with longer survival and improved quality of
life in PD patients
• PD is the preferred RRT modality for RKF preservation
• PD can slow the decline of RKF compared to the natural slope of RKF
decline prior to dialysis initiation

Adequacy of Incremental PD
• Incremental PD has traditionally focused on the sum of residual renal
and peritoneal clearances to achieve a specific Kt/Vurea
• A minimum weekly Kt/V target of 1.7 as suggested by the NKF-KDOQI
and ISPD 2006 Guidelines
• A clinically driven incremental PD prescription has the benefit of
obviating the need for Kt/Vurea and focuses on patient and laboratory
data to determine dialysis adequacy

Why Incremental PD ?
Reduces burden of treatment if with significant RKF
Less local and systemic glucose exposure
Fewer exchanges, so less risk of peritonitis
Resource sparing (uses less dialysate per day)
Allows time to become comfortable with the therapy

How to prescribe Incremental PD ?
CAPD
One exchange overnight
• a 1.5% solution will likely be absorbed, depends on the fluid status
• can use 2.5% solution or icodextrin
• the icodextrin will usually result in ultrafiltration

CAPD
Dry night, 2 exchanges 4 hr each during the day
• this works well in patients with RKF
• good for those who don’t like fluid in the abdomen overnight

APD
Night cycles, day dry (NIPD)
• don’t have to worry about fluid absorption during the long day dwell
• Example: 3-4 X 1.5 L exchanges over 8 hours

The Volume Can Also be Increased Incrementally
• No need for a full 2 or 2.5L dwell volume at the outset
• Allow time for adjustment to the sensation

Empirical Incremental PD prescription
• BSA 1. 73 m2
• Fill volume 2 litres
GFR (ml/min) Exchanges/day
> 10 1
7 – 10 2
5 – 6 3
< 5 4

Why Not Incremental PD ?
• The patient may refuse to increase the dose of PD once the RKF
declines
• If the RKF declines rapidly without an increase in PD dose, the patient
may become underdialyzed
• The 24 hr urine needs to monitored for residual GFR
• If the patient “forgets”, a stable serum creatinine usually reflects a
stable RKF in PD

Golper and Mehrotra expanded on Bricker’s intact nephron hypothesis, and
suggested that an incremental approach to the initiation of dialysis might
help preserve RKF by both reducing nephron hyperfiltration and deactivating
certain adaptive stimuli which occur in the setting of reduced nephron
numbers

Take home messages
Dialysis dose should be INDIVIDUALIZED rather
than “one size fits all“ approach
Assessment of dialysis adequacy should include
dialysis dose, duration, frequency and RKF
RCTs are needed to determine risk benefit ratio
of infrequent dialysis regimens

Incremental Dialysis

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