When to start dialysis?

Nephrol Dial Transplant (2006) 21 [Suppl 2]: ii20 ii24 doi:10.1093/ndt/gfl139 Original Article When to start dialysis? C. E. Douma 1 and W. Smit 2 1 Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands and 2 Department of Nephrology, Academic Medical Center, University of Amsterdam, The Netherlands Abstract In an attempt to decrease mortality in dialysis patients, the care for end-stage renal disease patients has been a focus of nephrologists for many years. Good pre-dialysis care has been found to improve mortality numbers in several studies. However, it is still not exactly clear, when the best moment has arrived to start renal replacement therapy. By illustrating two totally different patient cases the effect of outcome and quality of life are discussed demonstrating on the one hand the role of clinical parameters, and on the other hand the influence of biochemical parameters. Keywords: biochemical parameters; clinical parameters; Cockcroft Gault formula; dialysis initiation; MDRD formula Introduction Despite improvements in dialysis techniques, the mortality of patients with end-stage renal disease (ESRD) is still high. In an attempt to decrease mortality, in the past few years the attention has been more focused on pre-dialysis care. Recently, Khan et al. [1] found in a retrospective cohort study that patients who did not receive nephrology care during the two years before initiation of dialysis had a higher mortality rate in the first year after commencing dialysis, than patients who had been regularly visiting a nephrologist. Also, other studies describe a lower mortality rate when patients were presented to a nephrologist earlier [2,3]. However, when a patient with ESRD is visiting a nephrologist, the question arises When is the best moment to start renal replacement therapy? In this review, the parameters Correspondence and offprint requests to: C. E. Douma MD, PhD, Department of Nephrology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Email: ce.douma@vumc.nl used to make this decision and the effects on outcome will be discussed. First, the problem will be illustrated by two patient cases. Patient 1 A 52-year-old man, known to have had hypertension for over 20 years, was referred to our hospital with a blood pressure of 250/140 mmhg. His plasma creatinine was 5.7 mg/dl (509 mmol/l), urea 43.8 mmol/l, potassium 5.6 mmol/l, calcium 2.05 mmol/l, albumin 38 g/l, phosphate 2.54 mmol/l and creatinine clearance was 16 ml/min. The patient had stopped his medication, an ACE inhibitor and diuretics, a year ago. Two years ago his blood pressure was 130/80 mmhg with a plasma creatinine of 1.7 mg/dl (154 mmol/l). The patient was feeling well; he had no complaints and no oedema. Pre-dialysis care was started. He received information about renal replacement therapy and treatment with antihypertensive drugs was resumed, combined with potassium- and phosphate binders. In the following weeks his plasma creatinine and urea increased, but he still had no complaints or oedema. An ultrasound of the kidneys showed kidneys of 10.4 and 10.8 cm. After being given ample information he chose peritoneal dialysis (PD). However, a peritoneal catheter implantation was not yet planned as the patient refused this. He claimed he needed more time to think about the forthcoming changes in his life. Eight weeks after the first presentation the plasma urea was above 60 mmol/l and the phosphate was 3.35 mmol/l. The creatinine clearance dropped to 10 ml/min. Due to the rapid decrease of renal function, haemodialysis (HD) was initiated with a jugular vein catheter. Patient 2 The second patient was a 74-year-old man with a 15-years history of diabetes mellitus (DM) type II and angina pectoris due to bi-vascular coronary artery disease. In one year his creatinine clearance decreased from 31 to 25 ml/min. Because of his many complaints ß The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

When to start dialysis? of nausea, vomiting and weight loss, the digestive tract was examined excluding a malignancy. Although the decrease in renal function was slow, he experienced increasing complaints. As no other explanation was found for these problems, HD was started at a creatinine clearance of 17 ml/min. Two weeks after starting dialysis the patient reported feeling much better, his appetite increased and the weight loss stopped. These cases confirm the data of Malangone et al. [4], who found no correlation at the start of dialysis treatment between the severity of clinical signs and biochemical parameters of renal function. The decision to start dialysis is based on a combination of clinical symptoms and biochemical parameters. Which parameters do we use in the decision to initiate dialysis treatment? Clinical parameters Pulmonary oedema, uncontrollable hypertension, hyperkalaemia, pericarditis and encephalopathy are absolute indications for starting dialysis. In addition to these life-threatening complications of decreased renal function there are also relative indications such as nausea, vomiting, weight loss, pruritus and malnutrition [5]. In a cross-sectional study with 1785 clinically stable patients with a mean GFR of 40 ml/min, the dietary protein and energy intake and the measurements of nutritional status progressively declined as the GFR decreased [6]. This association between GFR and nutritional parameters was not influenced by restricted diets. Biochemical parameters Serum creatinine and creatinine clearance, calculated from 24 h urine collections and serum creatinine, are often used to describe renal function. Serum creatinine is easy to measure but it is not a very accurate test. The serum levels are not only determined by glomerular filtration but also by physical exercise and muscle mass, diet and creatinine degradation in the gut. A decline in renal function is often accompanied by loss of muscle mass, malnutrition and a restriction of protein intake, and a stable serum creatinine is not equal to stable renal function. Shemesh et al. [7] already demonstrated in 1985 that in patients with various glomerular diseases, the creatinine clearance was much higher compared with the clearance of inulin. Blocking tubular creatinine secretion by cimetidine minimizes this difference. In this study, it was found that creatinine is hypersecreted progressively by remnant renal tubules as the renal function declines. In patients with renal failure, creatinine clearance overestimates the glomerular filtration rate (GFR). Urea is generated by the liver from excess nitrogen intake and plasma urea is higher in patients with gastrointestinal bleeding and in patients receiving steroids. Urea clearance underestimates GFR due to tubular reabsorption and this tubular urea reabsorption is approximately similar to the tubular ii21 creatinine secretion. Consequently, the mean of urea and creatinine clearance provides a more accurate estimate of the GFR [8]. The National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) recommends initiating dialysis treatment when the weekly urea clearance, normalized to body water volume, the Kt/V urea, is <2.0 per week [9,10]. A lower Kt/V urea was only acceptable when the patient had a stable or oedema-free body weight without signs of protein energy malnutrition and the absence of clinical signs or symptoms attributable to uraemia. This guideline is opinion based. A renal Kt/V urea of 2.0 per week is comparable to a renal creatinine clearance of 9 14 ml/min/1.73 m 2. Renal Kt/V urea has not been used clinically as a parameter of kidney function, but a Kt/V urea of 2.0 per week was the target dose of adequately dialysed PD patients. However, in the ADEMEX trial, a prospective randomized controlled trial in PD patients, two patient groups with different Kt/V targets were compared. One group of patients was treated with four daily exchanges of 2 l of standard dialysis solution, while the patients in the intervention group were prescribed a modified PD regimen to achieve a creatinine clearance of at least 60 l per week per 1.73 m 2 [11]. As expected, the total creatinine clearance was higher in the intervention group (62.9 vs 54.1 l per week per 1.73 m 2, P<0.001) and also the total Kt/V urea was higher (2.27 vs 1.80 per week, P<0.001). These differences in dialysis adequacy did not affect survival, even when the groups were stratified according to a variety of factors. Therefore, it was concluded that an increase in peritoneal small solute clearance within the range achieved in this study did not lead to improved survival. Kuhlmann et al. [12] studied retrospectively the validity of renal Kt/V urea in pre-dialysis patients. In patients with a plasma creatinine ranging from 0.6 to 9.1 mg/dl, a reciprocal relationship was found between renal Kt/V urea and plasma creatinine concentrations. They analysed the pre-dialysis patients as a subgroup and found no correlation between renal Kt/V urea and serum creatinine concentrations in this group of patients. This lack of correlation was also evident in patients with a renal Kt/V urea <2.0 per week. The renal Kt/V urea correlated best with the urea clearance which could be explained by the fact that renal Kt/V urea is derived directly from this urea clearance. The GFR is most widely accepted as an index of renal function. After an injection of a tracer, the rate of fall in blood concentration is calculated. However, the GFR can also be affected by other factors. It is influenced by, for example, pregnancy, renal hypoperfusion, non-steroidal anti-inflammatory drugs, volume status, high protein load, the level of arterial blood pressure and some antihypertensive medications [13]. A GFR of 10.5 ml/min is supposed to be comparable to a Kt/V urea of 2.0 per week. Because measuring a GFR is labour intensive and therefore not useful for daily clinical practice,

ii22 other methods have been suggested to predict GFR. The Cockroft and Gault equation uses plasma creatinine as well as the patient s age, weight and sex for the calculation [14]: Creatinine clearance ¼½ð140 ageþweight constantš=plasma creatinine The constant is 1 for men and 0.85 for women. If the patient s muscle mass is lower than average for sex and weight, the predicted GFR will be overestimated. This overestimation of GFR is particularly important in the low range. Therefore Tattersall et al. [15] recommended abandoning this method. Levey et al. [8] compared seven equations with predicted GFR in patients who enrolled for the baseline period of the modification of diet in renal disease (MDRD) study. The most accurate prediction method included demographic variables (age, sex and ethnicity) and serum and urine variables. The MDRD formula is: GFR ¼198 ½PcrŠ 0:858 ½ageŠ 0:167 ½0:822 if patient is femaleš ½1:178 if patient is blackš ½SUNŠ 0:293 ½UUNŠ 0:249 where Pcr denotes, plasma creatinine level in mg/dl; SUN, serum urea nitrogen level in mg/dl; and UUN, urine urea nitrogen level in g/day. Recently patients with type I diabetes were studied and the MDRD equation substantially underestimated iothalamate GFR, whereas the Cockcroft Gault formula underestimated it when it was <120 ml/min/1.73 m 2 and overestimated it when iothalamate GFR was >130 ml/min/1.73 m 2 [16]. Other important biochemical derangements are hyperkalaemia and metabolic acidosis. Severe hyperkalaemia is highly dangerous because it can lead to arrhythmias. Metabolic acidosis can cause osteomalacia and malnutrition. By increasing bicarbonate levels in HD and PD patients with low plasma bicarbonate, the nutritional markers were also improved [15]. Effects on outcome Serum albumin at the start of dialysis was a powerful predictor of death in a retrospective study in patients starting maintenance HD [17]. Furthermore, a lower GFR was associated with lower protein intake and lower serum albumin levels [6]. These facts suggest that earlier start of dialysis will prevent malnutrition and thereby decrease mortality. However, starting dialysis treatment also exposes the patients to the risks and inconvenience of dialysis. Bonomini et al. [18] performed an observational study in 82 patients who started dialysis treatment early (creatinine clearance >11 ml/min) and 308 patients who started late (creatinine clearance <5 ml/min). The early group consisted of patients who had clinical signs and C. E. Douma and W. Smit symptoms that were resistant to conventional therapy, patients who found it impossible to comply with dietary restrictions and those who accepted early start of dialysis voluntarily. After 12 years follow-up they found a lower mortality in the group with early starters, a lower hospitalization rate and the patients were more likely to work full-time. Tattersall et al. [19] reported in 63 consecutive patients with ESRD, a relationship between renal Kt/V urea at start and clinical outcome. In the first 6 months after start, a lower initial Kt/V urea was accompanied by a higher mortality rate. In addition, a large prospective cohort study in Canada and the USA showed a one and two year lower survival rate in patients with lower creatinine clearance at the start of dialysis [20]. More recently, a large prospective multicentre study was performed in the Netherlands in patients with ESRD [21]. Timely starters were defined as patients with a renal Kt/V urea >2.0 per week. Also classified as timely starters were patients where the renal Kt/V urea was lower, but the npna (protein equivalent of total nitrogen appearance normalized to body weight) was >0.8 g/kg daily and the body mass index was at least 20 kg/m 2. Late starters had more comorbidity and lower serum albumin concentrations than timely starters, although these differences were not significant. The two-year survival was 75% in late starters and 84% in timely starters. A GFR of 1 ml/min/1.73 m 2 at start increases the mortality risk by 22%. No significant correlation was found for estimated protein intake. In the discussion, the authors suggest that the gain in survival time in timely starters was probably caused by lead-time instead of actual improvement. Traynor et al. [22] retrospectively studied 235 electronic patient records at the renal unit of Glasgow Royal Infirmary. They calculated the time point when the creatinine clearance was 20 ml/min for each patient. The median creatinine clearance at the start was 8.3 ml/min. The patients who had a creatinine clearance below the median at start were late starters, the other patients were called early starters. A total of 184 patients without DM were analysed separately. This was due to the patients with DM who started with a higher creatinine clearance and had more severe proteinuria and comorbidity. The 10 year survival after a creatinine clearance of 20 ml/min was similar between the two groups. They concluded that there was no benefit from earlier initiation of dialysis. In a prospective study [23], a higher estimated GFR by MDRD at initiation of dialysis was even associated with an increased risk of death. These correlations were not found when measured creatinine clearances were used. The authors suggested a higher creatinine production in a healthier state, leads to better nutrition and better muscle mass. Furthermore, in the first three months after the start of dialysis treatment the decline in renal GFR was most pronounced [24]. This residual renal function has an important effect on morbidity and mortality in dialysis patients [25,26]. Therefore, combining these facts, earlier start of dialysis treatment could lead to a faster decline of residual renal function, which in turn has

When to start dialysis? a negative effect on survival. In conclusion, it is not demonstrated that earlier start of dialysis treatment will improve mortality. Effects on quality of life Of course it is important to study the effects on mortality, but it is at least as important to take into account how patients experience an earlier start of dialysis. Dialysis treatment has a major impact on the daily life of the patient, with all the potential risks. In the prospective the Netherlands Cohort Study on the Adequacy of Dialysis (NECOSAD) [21], the effect of late vs timely initiation of dialysis treatment on the health-related quality of life (HRQOL) was studied [27]. Late starters had lower HRQOL scores for a number of dimensions at the start of dialysis treatment. However, after one year of dialysis treatment these differences had disappeared. To summarize, patients who initiate late start dialysis have a longer dialysis-free time compared with the early start dialysis patients, and have a lower HRQOL score. However, within a year there is no significant difference in the HRQOL score. Conclusions The above-mentioned studies show that group data do not indicate any benefit for an early start of dialysis, but the two cases demonstrate that the inter-individual differences are enormous. In the first patient no clinical complaints were present. But because there was a rapid decline in renal function, the decision was made to start dialysis when the creatinine clearance reached 10 ml/min, so that complications, such as pericarditis could be prevented. However, the patient refused catheter implantation at that time, resulting in the absence of a permanent access when dialysis treatment had to be initiated. The second patient had more complaints than usually seen in patients with similar renal function. A marked improvement was observed in this particular patient after the initiation of HD. In conclusion, for each individual patient we should weigh the pros and cons of starting dialysis. And, despite many different guidelines, the decision should be tailor-made for each patient. Conflict of interest statement. None declared. References 1. Khan SS, Xue JL, Kazmi WH et al. Does predialysis nephrology care influence patient survival after initiation of dialysis? Kidney Int 2005; 67: 1038 1046 2. Campbell JD, Ewigman B, Hosokawa M, Van Stone JC. The timing of referral of patients with end-stage renal disease. Dial Transplant 1989; 18: 660 686 3. Sesso R, Belasco AG. Late diagnosis of chronic renal failure and mortality in maintenance dialysis. Nephrol Dial Transplant 1996; 11: 2417 2420 ii23 4. Malangone JM, Abuelo JG, Pezzullo JC, Lund K, McGloin CA. Clinical and laboratory features of patients with chronic renal disease at the start of dialysis. Clin Nephrol 1989; 31: 77 87 5. 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ii24 in continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1999; 34: 1056 1064 26. Merkus MP, Jager KJ, Dekker FW, de Haan RJ, Boeschoten EW, Krediet RT. Predictors of poor outcome in chronic dialysis patients: The Netherlands Cooperative Study on the Adequacy of Dialysis. The NECOSAD Study Group. Am J Kidney Dis 2000; 35: 69 79 C. E. Douma and W. Smit 27. Korevaar JC, Jansen MAM, Dekker F, Boeschoten EW, Bossuyt PMM, Krediet RT, for the NECOSAD Study Group. 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: 108 115