Initiation And Incremental Dialysis

Initiation of dialysis and incremental dialysis Wong KW

Initiation of dialysis
Most critical decision to make along the course of chronic renal insufficiency
Negative psychological impact on patients
Important socioeconomic implications
When to start - subject to much controversy

Goals of dialysis
free of uremic symptoms
to control volume overload, acid-base and electrolyte disorders
and to provide a clearance of uremic toxins enough to allow an adequate dietary protein and caloric intake
When residual renal function fails to maintain all these vital functions, we have a solid argument for starting dialysis therapy

Complications That May Prompt Initiation of Kidney Replacement Therapy
Intractable ECV overload
Hyperkalemia
Metabolic acidosis
Hyperphosphatemia
Hypercalcemia or hypocalcemia
Anemia
Neurological dysfunction (eg, neuropathy, encephalopathy)
Pleuritis or pericarditis
Otherwise unexplained decline in functioning or well-being
Gastrointestinal dysfunction (eg, nausea, vomiting, diarrhea, gastroduodenitis)
Weight loss or other evidence of malnutrition
Hypertension

When to initiate?
The key question is whether we have to start dialysis prior to, or after the overt development of these uremic signs and symptoms
The beneficial effects that dialysis can offer to the pre-dialysis renal failure patient
the potential complications of dialysis, and the changes in the way of life that many patients have to endure, are factors which should temper this decision

When to initiate?
How early is early?
Argument - since an adequate dose of peritoneal dialysis has been established to be a weekly Kt/V of >2.0(Ccl of 9 -1 4 ml/min), dialysis should be started to augment native clearance when it falls below this level

What did the European Nephrologists think?
In an opinion survey about the initiation of dialysis carried out at the ERA-EDTA Congress (Nice, 2000) - majority of the participants answered that uremic signs and symptoms(38%), along with residual renal clearances(32%) were the most important criteria for judging when to initiate dialysis
less than 20% of participants thought that nutritional status was an important criterion to initiate dialysis
Initiation of dialysis - opinion from an International survey: Report on the Dialysis Opinion Symposium at the ERA-EDTA Congress, 18 September 2000, Nice

KDOQI Guidelines (opinion)
When to Initiate Dialysis : K t/V urea Criterion (Opinion) patients should be advised to initiate some form of dialysis when the weekly renal Kt/V urea < 2.0. Unless:
1. Stable or increased edema-free body weight.
2. Nutritional indications
3. Complete absence of clinical signs or symptoms attributable to uremia.
A weekly K r t/V urea of 2.0 approximates a kidney urea clearance of 7 mL/min and a kidney creatinine clearance that varies between 9 to 14 mL/min/1.73 m 2

KDOQI Guidelines (opinion)
patients with chronic kidney failure (e.g, GFR < 15 to 20 ml/min) who are not undergoing maintenance dialysis, if protein-energy malnutrition (PEM) develops or persists despite vigorous attempts to optimize protein and energy intake and there is no apparent cause for malnutrition other than low nutrient intake, initiation of maintenance dialysis or a renal transplant is recommended (Opinion)

KDOQI - second update of the Clinical Practice Guidelines (CPGs) and Clinical Practice Recommendations (CPRs)
Timing of therapy: When patients reach stage 5 CKD (estimated GFR < 15 mL/min/1.73 m2), nephrologists should evaluate the benefits, risks, and disadvantages of beginning kidney replacement therapy. Particular clinical considerations and certain characteristic complications of kidney failure may prompt initiation of therapy before stage 5 (B)
AJKD VOL 48, NO 1, SUPPL 1, JULY 2006

Nephrol Dial Transplant (2002) 17 [Suppl 7 ]: 7 -1 5
Dialysis should be instituted whenever the GFR is -15 ml/min and there is one or more of the following:
symptoms or signs of uraemia,
inability to control hydration status or blood pressure,
or a progressive deterioration in nutritional status
In any case, dialysis should be started before the GFR has fallen to 6 ml/min/1.73 m, even if optimal pre-dialysis care has been provided and there are no symptoms

Nephrol Dial Transplant (2002) 17 [Suppl 7 ]: 7 -1 5
High-risk patients e.g. diabetics may benefit from an earlier start. (Evidence level: C )
To ensure that dialysis is started before the GFR is 6 ml/min, clinics should aim to start at 8 -1 0 ml/min. (Evidence level: C )

Nephrol Dial Transplant (2005) 20 [Suppl 9]
Dialysis should be instituted whenever evidence of uraemia is present, or blood pressure and hydration status cannot be controlled, or when a deterioration of the nutritional status is noticed. In any case, dialysis should be started before the GFR is <6 ml/min/1.73 m2 (creatinine clearance 8 ml/min/1.73 m2). (Evidence level C)
To ensure that dialysis is not started at a GFR of <6 ml/min/1.73 m2, initiation at the level between 8 and 10 ml/min should be considered. Diabetic patients may require an earlier start. (Evidence level C)

CARI Guidelines (September 2004) No recommendations possible based on Level I or II evidence
Commence dialysis when GFR falls below approximately 10 mL/min/1.73 m2 if there is evidence of uraemia or its complications such as malnutrition. In occasional patients it may be necessary to initiate dialysis at a higher GFR. (Level III evidence)
If there is no evidence of uraemia or its complications including malnutrition, commence dialysis when GFR falls below approximately 6 mL/min/1.73 m2. (Level III evidence)

CARI Guidelines (September 2004)
To encourage informed decision making, educate patients and staff about the strength of the evidence (at best, cohort studies) regarding the rationale for e arly dialysis initiation
Monitor GFR quarterly from value of 15- 2 0 mL/min/1.73 m2 and monthly from < 10 mL/min/1.73 m2 to avoid unintentional delay in initiation of dialysis

CARI guidelines (September 2004)
Commence dialysis at first indication of malnutrition suspected to be due to uraemia and unresponsive to dietary intervention or correction of other reversible causes. (Level III evidence)
Use of a bsolute indications for dialysis initiation is a historical concept which is no longer valid, and their presence suggests delayed initiation. However, in some patients with co-morbid conditions, dialysis may be indicated for these reasons even when GFR is greater than 10 mL/min/1.73m2

Canadian guidelines ( J Am Soc Nephrol 10: S287 -S 321, 1999)
GFR<120L/week/1.73m 2 (12ml/min), if symptoms/signs of uraemia, or evidence of malnutrition - recommend dialysis (level IV)
If asymptomatic, or malnutrition - monthly surveillance (opinion)
GFR<60L/week/1.73m 2 (6ml/min) - initiation of dialysis (opinion)

Malaysian CPG
Dialysis should be initiated to promote wellness and not to rescue from illness
Dialysis should be started when:
Uraemic signs and symptoms
Weekly renal Kt/V <2.0 and/or
Indices of malnutrition developed in the absence of other causes
Dialysis should be initiated earlier in diabetics

Postulate and practice
Several series of patients taken onto RRT - RRF (weekly Kt/V) at the start of dialysis - markedly lower than that of DOQI guidelines
Ranging between 0.68, 0.72 and 1.05 in patients reviewed in USA, Canada and UK
If DOQI guidelines are to be followed - dialysis needs to be started between 20 and 11 months earlier
Heavy additional burden
Must be justified by more convincing evidence to demonstrate unequivocal benefit from early initiation of dialysis
Prospective, controlled, randomized trials

What is the evidence?
No RCTs are available yet
Several other cohort or case-control studies in dialysis patients have shown an association between serum albumin at initiation of dialysis and subsequent mortality
(Hakim & Lazarus 1995, Khan et al 1995, Spiegel et al 1993, Kopple et al 1995)

Nutrition and renal failure
There is spontaneous decline in protein intake in patients with progressive renal failure, leading to sub-clinical malnutrition
Consequently, patients with CRF must be carefully followed for evidence of weight loss, global nutritional assessment, and objective evidence of dietary protein intake from urea kinetics

Nutrition and residual renal function
Ikizler et al 1995 -
spontaneous dietary protein intake (DPI) fell with creatinine clearance (CCr).
DPI at CCr 10 mL/min was 0.54 g/kg/day, and ideal body weight fell by 0.38% for each 10 mL/min fall in CCr.
The fall in spontaneous DPI was evident when GFR fell below 25 -5 0 mL/min

Nutrition and RRF
Patients with chronic renal failure on an unrestricted diet tend to decrease their protein intake as the renal failure progresses
A direct correlation was noted between the dietary protein intake and the creatinine clearance (Ccr):
1.1 g/kg per day at a Ccr above 50 mL/min
0.85 g/kg per day between 25 and 50 mL/min
0.70 g/kg per day between 10 and 25 mL/min
0.54 g/kg per day below 10 mL/min
These changes, which presumably reflect anorexia induced by renal failure, question the safety of restricting protein intake in patients with a creatinine clearance below 25 mL/min

Nutrition
CANUSA study (McCusker et al 1996)
normalized protein catabolic rate (nPCR) at entry correlated with RRF at entry, and 2-year survival correlated with malnutrition as assessed by serum albumin, subjective global assessment score, % lean body mass or nPCR
Lower GFR was associated with lower protein intake and lower serum albumin level (Kopple et al, KI 57: 1688-1703, 2000)
Serum albumin level at the initiation of dialysis was a powerful predictor of death ( Owen WF et al. N Engl J Med 1993 Sep 30;329(14):1001-6)

Malnutrition at initiation of dialysis

Malnutrition at initiation of dialysis
It is uncertain whether malnutrition is a surrogate marker for other factors that determine mortality
In dialysis patients, increased mortality is largely due to cardiovascular causes, whereas in malnourished patients with normal renal function, increased mortality is the result of infection

Early initiation - believers
Early initiation of dialysis - on presumption that it improves nutrition, decreases hospitalization rates, reduces mortality (observational data) - first proposed by Bonomini et al

Bonomini et al, 1985
reported that an early start of dialysis was associated with reduced mortality and morbidity
Among a subset of patients who were subsequently transplanted, there was a survival advantage for those started dialysis early (n=50) vs later (n=96), as well as less vascular calcification, bacterial infection, dyslipidaemia and hospitalization

CANUSA Study (McCusker et al 1996) - significantly poorer survival for patients with lower levels of renal function when starting dialysis
The mean creatinine clearance at the start of dialysis for all patients was 38 L/wk (3.8 ml/min)
12 and 24 m onth survival for those with creatinine clearance <38 L/wk at start of dialysis was 82.1% and 73.6%, respectively, compared with 94.7% and 90.8%, respectively, for those with creatinine clearance >38 L/wk

In the CANUSA study, there was a survival advantage for higher total (residual plus dialysis) Kt/V up to 2.0, and possibly up to 2.3
Based on these data in patients on peritoneal dialysis (PD), many authors have argued that it is logical to start dialysis at a level of residual renal function equivalent to the target total Kt/V
This study was not designed to examine time of initiation of dialysis

Tattersall et al. demonstrated reduced survival in patients with less residual renal function at start of dialysis, although these patients were also significantly older and had significantly more co-morbidity
prospective cohort study of 63 patients in 1991–92
Hospitalization length of stay was greater among those with residual Kt/V <1.05 at time of initiation of dialysis
( Am J Nephrol 15: 283 -2 89, 1995)

Another study - Schulman G and Hakim RM
patients initiated on dialysis with a creatinine clearance > 10 ml/min had an 88% 10- year survival when compared to 55% in those initiated at a creatinine clearance of < 10 ml/min (mean 4 ml/min)
Improving outcomes in chronic hemodialysis patients: should dialysis be initiated earlier? Semin Dial 1996; 9(3):225-9

Early initiation
However, early initiation of dialysis expose patients : complications of dialysis, unnecessary lifestyle restriction, potential increased cost, patient fatigue
No RCTs - Confounding influences in other studies include referral time bias, age, co-morbidity, patient compliance and starting time bias
Lead time bias

Early initiation - skeptics - lead time bias
In the context of initiation of dialysis, lead-time bias refers to the effect whereby measuring survival from the start of dialysis increases apparent survival of those started with more residual renal function i.e., earlier in the course of the disease, than those who start dialysis with less residual renal function

Early initiation - skeptics - lead time bias
In NECOSAD study (Korevaar et al.) estimated the effects of lead-time bias on dialysis survival by using prediction software based on the Finnish Cancer Registry
timely initiation - associated with a small survival benefit of 2.5 months
However, the extra time free of dialysis for “l ate starters ” was only 4.1 months
This study suggested that any perceived survival benefit from early start could be accounted for by lead-time
When to initiate dialysis: effect of proposed US guidelines on survival. Korevaar et al. Lancet 2001 Sep 29; 358(9287):1046-1050

Early initiation - skeptics - QOL
In a prospective cohort study from Holland (Korevaar et al 2002), 38% of 237 incident dialysis patients commenced dialysis late, as defined by the K/DOQI guidelines. Compared with patients who have timely initiation, the HRQOL among late starters was worse during the first 6 months after initiation, but no different at 12 months.
(Evaluation of DOQI guidelines: Early start of dialysis treatment is not associated with better health-related quality of life. Am J Kidney Dis 2002; 39:108- 1 15)

Early initiation does not prolong survival?
Traynor et al ( J Am Soc Nephrol 13: 2125 -2 132, 2002) - using electronic patient record to include patients to calculate the time point at eCCr of 20ml/min (used to time survival)
Divided into early and late start groups by median eCCr for all patients at initiation of dialysis - 8.3ml/min
No significant benefit in patient survival from earlier initiation of dialysis
Cox proportional hazards model demonstrated significant inverse relationship between eCCr at start of dialysis and survival, even after adjustment of gender, age, weight, presence of DM, mode of first dialysis, Hb, albumin

Early initiation does not prolong survival?
In a post-hoc analysis of the MDRD study, comparing early (predicted MDRD GFR>7.5 ml/min; N = 1,444) with late (predicted GFR <7.5 ml/min); N = 1,476), higher MDRD GFR (but not measured creatinine clearance) at initiation was associated with an increased risk of death in multivariate Cox model (hazard ratio 1.27 for each 5 ml/min increase)
“ reflect an erroneous GFR estimation by MDRD formula”
Concluded that the data do not support early initiation of dialysis
Impact of timing of initiation of dialysis on mortality. Beddhu et at. JASN 14: 2305-2312, 2003

Early initiation of dialysis increases risk of mortality?
Kazmi et al - undertook an evaluation of the impact of comorbidity on the association between GFR at initiation and death
Results: greater GFR at initiation associated with a greater risk for death in all populations
Patients in the general dialysis population who initiated dialysis therapy at a GFR >10 mL/min/1.73 m2 had a 42% increased risk for death compared with patients with a GFR < 5 mL/min/1.73 m2 at initiation of dialysis therapy after adjusting for all covariates
Additional research required
Am J Kidney Dis. 2005 Nov;46(5):887-96

The problem of measuring residual renal function(RRF)
Selecting the best, or the least erroneous, indicator for measuring RRF
Serial measurement of creatinine, 1/creatinine, creat clearance per BSA
Calculation of GFR by (Ccr + Urea clearance per 1.73m 2 )/2
Over-estimation of GFR by Ccr measurement needs to be stressed
Use of Kt/V - indicator of RRF or adequacy of dialysis - also open to criticism due to error in evaluating the volume of distribution of urea in clinical practice

The problem of measuring residual renal function(RRF)
CARI guidelines: GFR calculated as the mean of urea and creatinine clearance corrected for BSA
NDT guidelines:
A. GFR should only be estimated using a method, which has been validated in patients with advanced renal failure. The preferred method for calculating GFR in advanced renal failure is the mean of urea and creatinine clearance . The latter is best calculated from a 24-h urine collection and normalized to 1.73 m2. (Evidence level: C)
B. Other examples of validated GFR estimations are:
MDRD equation
Indicator decay methods (e.g. iohexol, iothalamate, EDTA, inulin)
Creatinine clearance after oral cimetidine

Definite answer? IDEAL TRIAL
The IDEAL trial (Cooper et al 2004) is a multicentre RCT that aims to determine whether it is better to commence dialysis with a creatinine clearance of 10–14 or 5–7 mL/min/1.73 m2. Randomization of 800 patients should be completed by mid-2005, with a 3-year follow-up at the end of the recruitment period

Incremental dialysis?
Say we have decided to initiate dialysis early, either HD or PD,
How to start?

Incremental dialysis
Most guidelines recommend when to start (opinion based) but not HOW to start
DOQI - incremental or full PD, to keep weekly total Kt/V>2.0; twice- or thrice- weekly HD, with biocompatible membrane
Once decision made to start - ‘full dose’, ignoring the RRF component; or
“ i ncrementally” initiate dialysis adding PD or HD to the RRF component maintaining minimal total target Kt/Vurea clearance goals at all times

Should We Treat Patients with Incremental Dialysis Prescriptions?
By definition, i ncremental dialysis is the process of prescribing dialysis with the aim of maintaining a minimal total (PD, or HD and residual renal) solute clearance goals at all times, increasing the dialysis component (dose) when necessary so that when added to that solute clearance from residual renal clearance the minimal total solute clearance goals are always maintained (Golper TA: Incremental dialysis. J Am Soc Nephrol 1998;9:S107- S 111)

Incremental dialysis - Bonomini et al
Bonomini et al. - incremental approach in prescribing dialysis 1985
82 patients started HD treatment twice/week over a 15-year period with a mean creatinine clearance of 11ml/ min vs 308 patients treated by a low-protein diet for 24 - 53 months then starting dialysis with a mean RRF creatinine clearance of 2 -5 ml/min
Those started dialysis incrementally tended to preserve RRF if dehydration on dialysis was avoided
a better 12-year crude mortality rate, less severe vascular calcification at the time of transplantation, spent less days/ year hospitalized, and the total cost of medical care was less than the late starters

Incremental dialysis - Williams et al
Williams et al - initiated PD in 15 patients using one overnight polyglucose exchange
Keep weekly Kt/Vurea >2, total creatinine clearance >100L/1.73m2 at all times
4 patients increased the number of daily exchanges, 1 transplanted, 1 recovered renal function
Baseline RRF 1.96+0.38(Kt/Vurea)
Concluded some patients can be maintained on one overnight exchange for many months, most uneventful course, occasionally a decrease in RRF, requiring an increase in dialysis dose
Initial clinical experience positive in terms of patient acceptance, minimal life style disruption and ease of therapy management
Williams PF, Timely initiation of dialysis. AJKD, 1999; 34:594-595

Incremental dialysis - Devecchi et al
DeVecchi A, Scalamonga A: Preliminary experience with incremental peritoneal dialysis in 17 patients (abstract). Perit Dial Int 1999; 19(suppl 1):S23. 27
In a cohort of 17 Italian patients followed for a maximum of 21 months, the patients did well. There were 2 episodes of peritonitis and 6 exit site infections
dialysis was started when the creatinine clearance < 6 m L/min, but this equated to a measured Kt/V urea of 1.28 at start, and only when the patients went to three exchanges did the Kt/V value >2 - considered as late start by KDOQI, and a single or two exchanges did not provide for adequate clearance

Incremental dialysis - Foggensteiner et al
Another nonrandomized prospective pilot study - 39 patients
Patients were started on a single exchange of dialysate overnight. Dialysis adequacy was monitored at least every 2 months and incremental increases in dialysis were used to maintain combined urinary and dialysis Kt/V >2.0
Median actuarial survival on a single exchange before requiring incremental dialysis was 297 days
At the end of the study period, all patients were still alive: 8 remained on 1 exchange, 18 were on more than 1 exchange, 8 switched to hemodialysis, and 5 had received renal transplant
2 episodes of bacterial peritonitis, 3 pleural leaks, 1 patent processus vaginalis, and 1 inguinal hernia that required surgical intervention
Foggensteiner et al. , Peritoneal Dialysis International, Vol. 22, pp. 471 -4 76

Incremental dialysis - Keshaviah et al
Keshaviah et al, using urea kinetic model, showed - a hypothetical average sized patient, treated with CAPD with high average peritoneal transport - (initial urea clearance of 7.5ml/min, urea generation rate of 8.5g/day) could maintain a Kt/V of 2.0 for 8 months with a single 2.5L nocturnal exchange, and up to 17 months with two 2.5L nocturnal exchanges
With haemodialysis - this goal can be achieved during 5 months with one weekly HD session, gradually increased from 1 to 8 hours, followed up to 36 months by a weekly regimen of two HD sessions gradually increased duration from 1.5 to 6h each
Keshaviah et al. Timely initiation of dialysis: a urea kinetic approach. Am J Kidney Dis 1999; 33:344-8.

The Wake Forest Experience - Burkart et al
Pilot study to gain clinical experience with an i ncremental approach to the initiation of dialysis
Patients recruited to start dialysis once weekly Kt/Vurea <2.0, and if one or more DOQI criteria present
Incremental dialysis to keep Kt/Vurea >2.0 per week
15 patients (13 PD, 2 HD)
At the end of observation period - all patients increased no. of daily exchanges
Improvement in blood pressure control, decrease in no. of antihypertensives
3 died (one from line sepsis after AVR, one from pneumonia, and one from peritonitis while on full dose PD)
Miscellaneous complications - Tenckhoff migration, hernia repair, pleural leak, damaged Tenckhoff, elective transplant nephrectomy, one episode of peritonitis
They concluded incremental dialysis can be used to maintain total solute clearance goals, patients accepted the approach and readily changed prescription when instructed
Peritoneal Dialysis International, Vol. 20, pp. 418 -4 22

Incremental dialysis
These clinical experiences can be interpreted as favorable toward i ncremental initiation of dialysis.
However, long-term outcomes are not yet known, and this may dissuade clinicians from using this approach

Some Considerations for Incremental Dialysis
PD or HD?
Initiation of dialysis using PD would potentially - a beneficial effect on preservation of renal function
CAPD or APD? - preliminary observations that APD may be more disadvantageous than CAPD for the preservation of RRF
Cost?
Bonomini et al. described that total health system costs were reduced by the healthy start approach. More data to suggest that a healthy start is medically better and less costly are needed (Bonomini V, Baldrati I, Stefoni S: Comparative cost/benefit analysis in early and late dialysis. Nephron 1983;33:1 -4 )

Potential Obstacles
Failure to follow patients in a timely manner for initiation of ‘healthy start’ dialysis
Patient and family must become knowledgeable of the modality options available, with understanding of the need to adjust dialysis doses for further deterioration of RRF
Close monitoring and proactive interventions to maintain total solute clearance - requiring fully committed members of the renal replacement team
To measure total solute clearance - familiar and that works - but no published outcome data for those initiated with incremental approach

Risk of incremental dialysis?
Risk of infection
CAPD registry showed risk of peritonitis significantly less with fewer exchanges per day ( Final report of the CAPD Registry edited by Lindblad AS, Novak JW, and Nolph KD. Dordecht: Kluwer Academic, 1989:223-8)
Earlier “burnout”
Measures to preserve RRF - avoidance of nephrotoxic drugs, minimal use of contrast, good control of BP, ?use of more biocompatible membranes

Incremental dialysis advantages and disadvantages
Advantages
Cost savings
Reduced glucose exposure and protein loss
Less membrane ‘fatigue’
Greater patient acceptance
Disadvantages
Frequent and close monitoring of RRF
Frequent prescription changes
Uncertainty about the effect on outcome

Alternative to early start of dialysis?
Dietary protein restriction - ameliorates uremic symptoms and slows progression of renal failure
Modification of Diet in Renal Disease (MDRD) study(1994), demonstrated a small but not statistically significant benefit in the progression of renal disease from dietary protein restriction
Secondary analyses of the data showed clinical benefit only in patients with severe renal failure as- signed to the low-protein group
Issues - availability of dietitian, inducing malnutrition, compliance

Can renal replacement be deferred by a supplemented very low-protein diet?
76 patients with a residual GFR of <15 -1 0 ml/min -submitted to a diet of 35 kcal BW/day containing 0.3 g protein/kg/BW supplemented with 10 g of essential amino acids or 2.8 g/10 kg BW of keto-acids
During the 93 patient-years period of observation -
the annual mortality was 2.5%
hospitalization episodes 0 -2 per patient-year.
The median renal survival to dialysis was 363 days ranging from 1 week to 4 years.
No significant deterioration of biological nutritional indices was observed between the start of dietary treatment and initiation of dialysis
Walser M, Hill S J Am Soc Nephrol 1999; [10]: 110 -1 16

Finally,
it can be reasonably stated that timely initiation of dialysis treatment cannot be based merely on numerical data, but should be decided according to the overall clinical tolerance of each individual patient to his or her advanced stage of uraemia, the most important parameters to be considered being; adequate control of blood pressure and quality of nutritional status. Initiating dialysis at the right time for a given patient with the most appropriate technique represents a sophisticated exercise of clinical medicine, which remains, and will remain a balanced mixture of Science and Art

Initiation And Incremental Dialysis

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