Indications for initiation of dialysis in chronic kidney disease

Author 
Anthony Bleyer, MD, MS 

Section Editors 
Steve J Schwab, MD 
Jeffrey S Berns, MD 

Deputy Editor 
Alice M Sheridan, MD 

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2013. | This topic last updated: Dec 6, 2012.

INTRODUCTION  — The decision to initiate dialysis in a patient with chronic kidney disease (CKD) involves the consideration of subjective and objective parameters by the physician and the patient. There are no absolute laboratory values that indicate a requirement to begin dialysis. The decision is partly based on the patient’s perception of his or her quality of life and anxiety about starting a complex, potentially life-long therapy, In addition, the nephrologist’s perception about the patient’s state of health, decline of kidney function, and potential hazards of therapy influence the timing of initiation of renal replacement therapy. In short, the decision of when to start dialysis is clearly one of the most difficult decisions that both the patient and the nephrologist must make.

This topic reviews the clinical indications for the initiation of chronic dialysis. 

The selection of dialysis modality is discussed separately. (See "Dialysis modality and patient outcome" and "Choosing a modality for chronic peritoneal dialysis" .) Considerations regarding transplantation are also discussed separately. (See "Evaluation of the potential renal transplant recipient" and "Patient survival after renal transplantation" .)

INDICATIONS  — There are a number of clinical indications to initiate dialysis in patients with CKD. These include [ 1-3 ]:

Pericarditis or pleuritis (urgent indication)Progressive uremic encephalopathy or neuropathy, with signs such as confusion, asterixis, myoclonus, wrist or foot drop, or, in severe cases, seizures (urgent indication)A clinically significant bleeding diathesis attributable to uremia (urgent indication)Persistent metabolic disturbances that are refractory to medical therapy; these include hyperkalemia, metabolic acidosis, hypercalcemia, hypocalcemia, and hyperphosphatemiaFluid overload refractory to diureticsHypertension poorly responsive to antihypertensive medicationsPersistent nausea and vomitingEvidence of malnutrition

The first five of the above indications are potentially acutely life-threatening and should not be allowed to develop prior to initiation of dialysis in patients with known CKD under medical care. The last two develop more insidiously and can also be due to other comorbidities or drug effects. They are no less dangerous.

Relative indications  — Since an important goal of dialysis is to enhance the quality of life as well as to prolong survival, it is therefore important to consider less acute indications for dialysis such as anorexia and nausea, impaired nutritional status, increased sleepiness, and decreased energy level, attentiveness, and cognitive tasking.

Unfortunately, the expressions of these signs and symptoms are variable in patients with slowly progressive renal disease. The following are some of the factors that may contribute to this variability.

Some patients accommodate to these symptoms and downgrade their sense of well–being as renal failure progresses.Many of the medications given to patients with CKD have side effects that mimic uremic symptoms. As examples, oral iron therapy often leads to nausea and centrally-acting antihypertensive drugs can induce drowsiness independent of the degree of renal failure.

These factors illustrate the need to identify more objective markers of renal failure to lessen the subjective component of the decision to initiate dialysis.

QUANTITATIVE MEASUREMENTS OF END-STAGE RENAL DISEASE  — The two most widely evaluated quantitative measurements of end-stage renal disease have been estimation of the glomerular filtration rate (GFR) and assessment of nutritional status.

Estimation of GFR  — Previously, 24 hour urine collections were performed to determine urea and creatinine clearance. However, inaccurate urine collections often caused incorrect determinations of clearance. These methods have been replaced by equations that estimate glomerular filtration rate based upon the serum creatinine. Estimation equations including the Cockcroft-Gault, the Modification of Diet in Renal Disease (MDRD) Study, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) are reliable and reasonably accurate within the ranges of glomerular filtration rate that are generally present among patients who are being followed for the initiation of dialysis.

A detailed discussion of GFR estimation formulas can be found elsewhere. (See "Assessment of kidney function" .)

The clearance of 125-I-iothalamate, Cr-51-EDTA, 99m-Tc-DTPA, or inulin, are considered to be highly accurate and can occasionally be used in the rare circumstances where it is felt the current estimation techniques may be unreliable. A retrospective study in the United States found that the GFR at initiation of dialysis varied with patient age [ 4 ]. Based upon the United States Renal Data Systems database from 1995 to 1999, the creatinine clearance at initiation was 14.76, 13.38, 11.63, and 11.60 mL/min among those aged 20 to 44, 45 to 64, 65 to 74, and greater than 75 years, respectively. 

Nutritional status  — Many studies have shown an increased mortality risk associated with malnutrition in patients on maintenance dialysis [ 5,6 ]. As an example, an inverse relationship has been shown between the plasma albumin concentration and mortality risk in this setting [ 7,8 ]. The risk of death is increased when the plasma albumin concentration is below 3.5 to 4 mg/dL (35 to 40 g/L) ( figure 1 ). (See "Patient survival and maintenance dialysis" .)

The United States Renal Data Systems analysis extended this observation by evaluating the relationship between the plasma albumin concentration at the time of initiation of dialysis and subsequent survival [ 8 ]. The risk of death in patients starting hemodialysis with hypoalbuminemia was substantially higher than in patients with a normal plasma albumin concentration ( figure 2 ). This relationship persisted even when diabetic patients, who may have significant proteinuria, were excluded from the analysis [ 9 ]. Worse outcomes in patients with lower plasma albumin concentrations at the initiation of dialysis have also been noted in patients with continuous peritoneal dialysis [ 10 ].

The significance of hypoalbuminemia in patients with nephrotic syndrome (other than diabetes) and end-stage renal disease is undetermined at present. In this setting, the low plasma albumin concentration may not reflect malnutrition, but rather inflammation and/or ongoing urinary losses if not oliguric. This is discussed elsewhere. (See "Assessment of nutritional status in end-stage renal disease", section on 'Albumin' .)

The serum creatinine is another marker of nutritional status at the time of dialysis initiation. The creatinine level reflects muscle mass as well as renal function. Thus, a patient who requires dialysis because of uremic symptoms or other indications but has a lower than usual plasma creatinine concentration may have a reduced muscle mass and be malnourished. Data from the USRDS are consistent with this hypothesis as the late mortality rate was increased in patients with a plasma creatinine concentration below 10 mg/dL (884 µmol/L) at the start of dialysis ( figure 2 ) [ 8 ]. In comparison, the BUN level did not show a correlation with mortality risk.

These data strongly suggest that malnutrition, as suggested by a low plasma albumin and/or a history of anorexia, nausea, or decreased protein and caloric intake, at the initiation of dialysis for symptomatic uremia, is an important prognostic variable. Other markers of malnutrition may also prove useful, including the plasma concentrations of transferrin, somatomedin C, prealbumin, and cholesterol [ 11 ]. (See "Assessment of nutritional status in end-stage renal disease" .)

A simple determinant of nutritional status that can be easily monitored is protein intake, assuming that the patient is not on a low protein diet. Patients with CKD on an unrestricted diet tend to decrease their protein intake as the renal failure progresses. The magnitude of this effect was demonstrated in a report that evaluated 90 patients with CKD who received no dietary intervention [ 12-14 ]. 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/min0.85 g/kg per day between 25 and 50 mL/min0.70 g/kg per day between 10 and 25 mL/min0.54 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.

These decrements in dietary protein intake can be followed by assessing daily urinary urea nitrogen and non–urea nitrogen losses. If daily intake is relatively constant and the patient is in a steady state (as evidenced by a stable BUN and body weight), then urinary nitrogen excretion is roughly equal to nitrogen intake. The former can be estimated from the following [ 15 ]:

 Urinary nitrogen excretion   =   Urine urea nitrogen   +   Nonurea nitrogen

Nonurea nitrogen excretion is relatively constant, averaging 30 mg/kg per day.

Each gram of nitrogen is derived from 6.25 grams of protein. Thus,

 Estimated protein intake   =   6.25 (Urine urea nitrogen  +  30 mg/kg)

If, for example, 24-hour urine urea nitrogen excretion is 8.2 grams in a 60 kg woman excreting 3.5 g of protein per day, then:

 Estimated protein intake   =   6.25 (8.2  +  1.8)   =   62.5 grams

Thus, protein intake is approximately 1 g/kg per day. Moderate urinary protein loss can be ignored, but each gram excreted above 5 g/day should be added to the above formula.

A useful measurement of protein metabolism is the protein equivalent of nitrogen appearance (eg, excretion) normalized using the ideal body weight (nPNA) which is equivalent to the normalized protein catabolic rate. Values below 0.8 g/kg per day are considered indicative of a malnourished state. (See "Protein catabolic rate in maintenance dialysis" .)

To best assess nutritional status, the serum albumin concentration and edema-free body weight should be serially measured, approximately every one to three months for those with estimated GFRs <20 ml/min per 1.73m2, and possibly even more frequently for those with estimated GFRs ≤15 mL/min per 1.73m2 [ 16 ].

Effect of dialysis  — Although the initiation of dialysis improves appetite in symptomatic uremia, there is a paucity of randomized control trial data showing that it is clearly associated with an improvement in nutritional status. Two observational studies reported that initiation of dialysis was associated with clear improvement in nutritional indices:

Over a one year period, different nutritional indices were evaluated every three months after dialysis initiation among 50 hemodialysis patients [ 17 ]. Marked improvements were observed in the serum albumin, serum prealbumin, nPNA, fat mass, and others. The degree of improvement was dependent upon nutrition at baseline, with the lower the baseline value the lower its value at one year.Among 97 patients initiating maintenance dialysis therapy, multiple nutritional indices, including predialysis serum albumin, iron, transferrin saturation, creatinine, and the nPNA, significantly increased over the first six months of therapy, with many indices continuing to increase at study end [ 18 ]. In addition, dietary intake, as shown by the nPNA, directly correlated with serum albumin value.

Given that dialysis was initiated based upon varying criteria, these two studies do not address the question of whether early or late initiation of dialysis is optimal. However, these results support the view that dialysis initiation improves nutritional parameters slowly in the first year after beginning renal replacement therapy. Preventing malnutrition (which may be difficult to discern in the obese) prior to dialysis initiation may be a key factor for improving outcomes once patients start dialysis.

DOES EARLY DIALYSIS OR REFERRAL IMPROVE SURVIVAL/OUTCOMES?

Survival and dialysis complications  — There is conflicting evidence concerning the effect of the early initiation of dialysis on survival. Some retrospective and uncontrolled prospective studies have reported a benefit associated with early initiation [ 19-22 ] whereas others have reported increased mortality [ 23-26 ].

The only randomized controlled trial that examined mortality and time of dialysis initiation, the IDEAL study, found no difference in survival between early or late initiation of dialysis. In this study, 828 patients with progressive CKD and an estimated GFR between 10 and 15 mL/min per 1.73 m2 (as determined by the Cockcroft-Gault equation) were randomly assigned to dialysis initiation when the estimated GFR was either 10 to 14 mL/min per 1.73 m2 or 5 to 7 mL/min per 1.73 m2 [ 27 ]. The median time to the initiation of dialysis was 1.8 and 7.4 months in the early and late start groups, respectively. At a median followup period of 3.6 years, the two groups had no significant difference in survival (38 and 37 percent mortality, hazard ratio of 1.05 with early initiation, 95% CI 0.83-1.30) as well as no difference in cardiovascular events, infections, or dialysis complications.

However, these results do not imply that the initiation of dialysis can be delayed until the GFR is between 5 to 7 mL/min per 1.73 m2 in all patients. The design of the IDEAL study permitted clinicians to initiate dialysis based upon the presence of symptoms due to uremia (such as uremic symptoms, volume overload, and other features) as well as on the estimated GFR. As a result, 76 percent of patients assigned to the late start arm initiated dialysis when the GFR was much greater than 5 to 7 mL/min per 1.73 m2. This resulted in a mean GFR of 9.8 mL/min per 1.73 m2 at the start of dialysis for the late start group, which was only 2.2 mL/min per 1.73 m2 less than the mean start GFR for the early group (12 mL/min per 1.72 m2). Thus, approximately 88 percent of all enrolled patients had initiated dialysis with an estimated GFR of approximately 10 mL/min per 1.73 m2 or more, either because of symptoms or enrollment in the early dialysis arm.

An accompanying editorial to the IDEAL study stated that the results of this trial largely supports current practice that dialysis initiation should be based upon clinical factors rather than the estimated GFR alone [ 28 ]. Patients with progressive CKD require close followup, early nephrology referral, and adequate advance dialysis planning (including the presence of a functioning peritoneal or vascular access and referral for transplantation). In this study, for example, patients were followed by a nephrologist for approximately 2.5 years before dialysis was initiated.

We suggest that, among patients with progressive CKD, clinicians must be vigilant for the presence of symptoms and/or signs of uremia and patients should also be fully informed of any symptoms of uremia to be able to contact their physicians appropriately. Dialysis should be considered based upon clinical factors plus the estimated GFR. Dialysis should be initiated in the patient with symptoms and/or signs due to uremia. (See 'Indications' above and 'Relative indications' above.)

Among asymptomatic patients with progressive CKD, the timing of initiation of dialysis is unclear and there is no specific threshold GFR level that has been established for the initiation of dialysis. To help avoid the onset of possible life-threatening complications of uremia, the initiation of dialysis should be considered in the asymptomatic patient with an extremely low GFR, such as an estimated GFR of approximately 8 to 10 mL/min per 1.73 m2. However, some clinicians may choose to closely monitor (weekly) asymptomatic patients with progressive CKD even when GFR is below this level, with the initiation of dialysis upon the onset of uremicsigns/symptoms. Nevertheless, as noted in the IDEAL trial, the vast majority of patients are initiated on dialysis because of the onset of uremic symptoms at a GFR of approximately 10 mL/min per 1.73 m2 or above. Even if dialysis is not begun immediately in an individual with a low GFR, it is important that at least placement of dialysis access has been carried out or carefully considered. Among all patients, vascular access should be constructed prior to the need for dialysis whenever possible. (See "Creating an arteriovenous fistula for hemodialysis", section on 'Timing of AVF creation' .)

The following are some of the more recent National and International Guidelines for the initiation of dialysis, which were published before the results of the IDEAL trial were reported:

The 2006 National Kidney Foundation Dialysis Outcomes Quality Initiative (K/DOQI) for peritoneal dialysis and hemodialysis adequacy published guidelines concerning the initiation of dialysis among patients with renal insufficiency [ 2,3 ]. The work group suggested that the benefits and risks of initiating renal replacement therapy should be considered in patients with GFR less than 15 mL/min per 1.73 m2 (stage 5 chronic kidney disease). As noted above however, the results of the IDEAL trial suggest that dialysis initiation should be based upon clinical factors rather than the estimated GFR alone [ 28 ]. The 2006 K/DOQIguidelines also note that the initiation of dialysis prior to stage 5 chronic kidney disease may be required in patients with certain characteristics and/orcomplications, such as declining health due to the loss of kidney function [ 2,3 ].The 2005 European Best Practice Guidelines for peritoneal dialysis suggest that dialysis be initiated before the GFR is less than 6 mL/min per 1.73 m2, with consideration of initiation when the GFR is approximately 8 to 10 mL/min per 1.73 m2 [ 29-31 ].

There may be two additional advantages to early dialysis: control of hypertension and increased dietary intake [ 22 ]. Reversal of volume overload with dialysis often leads to a reduction in blood pressure, which is typically volume-dependent in CKD. (See "Overview of hypertension in acute and chronic kidney disease" .) Perhaps more importantly, patients on dialysis require at least 1 g/kg of protein per day to replace dialysis losses and maintain nitrogen balance. Thus, early institution of dialysis can allow a more liberal diet in terms of both food and fluid. On the other hand, delaying the initiation of dialysis provides an opportunity to establish a functional vascular access if this was not possible previously, and to increase time for potential kidney transplantation.

Peritoneal dialysis  — Peritoneal dialysis poses a unique challenge with regards to the timing of initiation of dialysis. Unlike a hemodialysis access, which is preferably created weeks to months before dialysis is started, a peritoneal dialysis catheter is generally placed only 10 to 14 days before it is used. After the catheter is placed however, the patient must be trained to perform dialysis, which is difficult to accomplish if he or she is uremic. As a result, among patients who require the acute initiation of chronic dialysis, hemodialysis is often initiated first, even if peritoneal dialysis is the preferred modality over the long term. For this reason, the timing of initiation of peritoneal dialysis is a more complex decision that requires coordination between the nephrologist, the patient, and the dialysis center that will perform the training.

Possible value of early referral  — A related issue to the criteria for the initiation of dialysis is the timing of referral of patients with CKD to a nephrologist. Referral occurs at variable levels of renal function, but often late in the course of progressive renal failure, just before or even after the onset of symptomatic uremia. Late referral reflects in part the absence of clear criteria for the initiation of dialysis.

However, early referral affords the opportunity to assess the rate of progression of kidney disease, to exclude any reversible causes of a declining GFR, and to permit close followup and adequate advance dialysis planning. It may also improve patient outcomes. This is discussed in detail separately. (See "Late referral to nephrologists of patients with chronic kidney disease" .)

Avoiding the emergent start of dialysis  — A problem with waiting too long for the initiation of dialysis is patients occasionally require an emergent dialysis start, often requiring hospitalization. A Canadian retrospective study of 377 incident dialysis patients at two tertiary care centers from January 2006 to April 2011 identified diabetic nephropathy, a history of pulmonary edema in the six months prior to dialysis initiation, and chronic obstructive pulmonary disease as independent risk factors for the emergent start of dialysis [ 32 ]. These findings would perhaps lead nephrologists to consider dialysis a little earlier in this patient population. In addition, this study suggests that careful review of a nephrologist’s past results in this area may be helpful in improving future practices.

INITIATION OF DIALYSIS AND DIALYSIS DISEQUILIBRIUM  — An important potential complication of the initiation of dialysis is the dialysis disequilibrium syndrome. This disorder, which appears to be related in part to a rapid reduction in the plasma osmolality due to urea removal, can produce a variety of symptoms including headache, nausea, vomiting, blurring of vision, muscle twitching, disorientation, tremor, and seizures. Patients with underlying neurologic disease or marked azotemia are at increased risk. (See "Dialysis disequilibrium syndrome" .)

INFORMATION FOR PATIENTS  — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient information: Peritoneal dialysis (The Basics)" and "Patient information: Hemodialysis (The Basics)" )Beyond the Basics topics (see "Patient information: Dialysis or kidney transplantation — which is right for me? (Beyond the Basics)" and "Patient information: Hemodialysis (Beyond the Basics)" and "Patient information: Peritoneal dialysis (Beyond the Basics)" )

SUMMARY AND RECOMMENDATIONS

There are no absolute levels of kidney function that indicate a requirement for dialysis. Clinical indications to initiate dialysis include pericarditis or pleuritis, progressive uremic encephalopathy or neuropathy, with signs such as confusion, asterixis, myoclonus, wrist or foot drop, or, in severe cases, seizures, a clinically significant bleeding diathesis attributable to uremia, fluid overload refractory to diuretics, hypertension poorly responsive to antihypertensive medications, persistent metabolic disturbances that are refractory to medical therapy (including hyperkalemia, metabolic acidosis, hypercalcemia, hypocalcemia, and hyperphosphatemia), persistent nausea and vomiting and evidence of malnutrition. However, many of these indications are potentially life-threatening and should not be allowed to develop prior to initiation of dialysis in patients with known CKD under medical care. (See 'Indications' above.)The two most widely evaluated quantitative measurements of end-stage renal disease have been estimation of the glomerular filtration rate (GFR) and assessment of nutritional status. There is an increased mortality risk associated with hypoalbuminemia at the time of initiation of dialysis. (See 'Quantitative measurements of end-stage renal disease' above.)There is conflicting evidence concerning the effect of the early initiation of dialysis on survival. We suggest that, among patients with progressive CKD, clinicians must be vigilant for the presence of symptoms and/or signs of uremia. Patients should also be fully informed of any symptoms of uremia to be able to contact their physicians appropriately. Dialysis should be considered based upon clinical factors plus the estimated GFR. Dialysis should be initiated in the patient with symptoms and/or signs due to uremia. The initiation of dialysis should be considered in the asymptomatic patient with an extremely low GFR, such as an estimated GFR of approximately 8 to 10 mL/min per 1.73 m2. However, some clinicians may choose to closely monitor asymptomatic patients with progressive CKD even when GFR is below this level, with the initiation of dialysis upon the onset of uremic signs/symptoms.The timing of initiation of peritoneal dialysis poses a unique challenge because the catheter is usually placed within two weeks of being used and because the patient requires training that takes place only after the catheter is placed. Planning the initiation of peritoneal dialysis requires coordination between the nephrologist, the patient, and the dialysis center that will perform the training. (See 'Peritoneal dialysis' above.)

ACKNOWLEDGMENT  — The editorial staff at UpToDate, Inc. would like to acknowledge Nuhad Ismail, MD, who contributed to an earlier version of this topic review.

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