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New Evidence for an Old Strategy to Help Delay the Need for Dialysis
Allon N. Friedman, MD
A fundamental medical decision that nephrologists commonly confront is when to initiate renal replacement therapy in an individual with advanced chronic kidney disease (CKD). The implications of this decision are far-reaching and not without risks. Initiation of dialysis profoundly affects quality of life, incurs significant financial costs, and mandates use of precious dialysis resources. Other risks include accelerating the loss of residual renal function and dialysis-related morbidities such as access complications. The negative consequences of initiating dialysis can be especially deleterious in the elderly, who are very sensitive to lifestyle changes and who suffer the highest overall hospitalization and complication rates and most truncated life expectancy on dialysis of any age group.
Moreover, nephrologists find themselves contending with the challenge of initiating dialysis in elderly individuals more and more frequently, as their numbers on dialysis have more than doubled over the past decade.1 Unfortunately, North American and European guidelines on dialysis initiation provide limited assistance because of a heavy reliance on opinion-based recommendations.
In this month’s issue of the American Journal of Kidney Diseases, Brunori et al describe the results of a provocative trial that could provide some relief for clinicians and their elderly patients by helping to postpone the need for renal replacement therapy. The centerpiece of the strategy involves the use of a calorically-replete diet with very low protein content that is supplemented with keto-analogues of amino acids and essential amino acids (in sum, a “supplemented very low protein diet,” or sVLPD). The supplements are included to prevent essential amino acid deficiencies and avoid negative protein balance.
The dietary approach itself is not new. Nephrologists have for decades recognized that strict limitations on protein consumption can ameliorate or resolve troublesome manifestations of uremia such as anorexia, nausea, vomiting, and mental status changes, and that replacing amino acids with their keto-analogues can preserve normal protein balance without exacerbating uremia.8 What makes this particular report unique is that it is the first randomized controlled trial to compare the effects of a sVLPD versus initiation of dialysis on 2 hard, clinically relevant endpoints—survival and hospitalization.
One hundred twelve elderly Italian patients 70 or older with very advanced CKD (glomerular filtration rate between 5 and 7 mL/min [0.08-0.12 mL/s]) but without uremic symptoms were randomly assigned to initiate hemodialysis or the sVLPD during a hospital admission scheduled to evaluate the need for dialysis. Individuals initiated on renal replacement therapy were treated in the usual manner, while those randomized to dietary treatment were re-evaluated in clinic every 4 or 5 weeks. Follow-up lasted a total of 48 months.
The study was designed to prove non-inferiority of the dietary strategy compared with dialysis; that is, the investigators wanted to show that the diet was, at the very least, no worse than dialysis with regards to patient survival, the primary outcome. The pre-specified definition of non-inferiority was quite liberal and could have included a scenario whereby the mortality rate in the sVLPD group was double that in the dialysis cohort. The authors did, in fact, find that survival in the diet group was not inferior to that in dialysis patients over the first 12 months in both intention-to-treat and per-protocol analyses. In addition, no differences were identified in the number of hospitalizations and days hospitalized between the 2 study arms after accounting for the hospitalization needed to create the initial dialysis access. Of the original 56 subjects in the dietary arm, 71% switched over to dialysis a median of 10 months after the study began, primarily because of electrolyte and fluid derangements. Interestingly, the sVLPD did not adversely affect markers of nutrition (eg, albumin and cholesterol), at least over the first 6 months when dropout was minimal, confirming previous findings and allaying fears about protein-energy malnutrition.
The trial design had some limitations. The unblinded nature of the study, unavoidable as it was, could have led to treatment bias if clinicians took unusually good care of subjects in the dietary group, leading to a delay in need for dialysis, or, if the decision to switch someone from the diet to the dialysis group was delayed in order to make the diet appear more effective than it really was. Finally, the study did not include quality of life measurements, which may be as or more important than life expectancy to certain elderly CKD patients.
The external validity of the study population is also unclear. The 1-year mortality rate of the end-stage renal disease patients recruited was approximately 15%, which is just slightly higher than rates for similarly aged individuals in the United States without kidney disease1 (rates rise to nearly 50% in US elderly patients on dialysis). This suggests that the authors recruited a selected patient population not representative of most elderly patients with kidney failure. As the authors readily acknowledge, the dietary strategy they employ is not suitable for everyone. Notably, patients with diabetes and nephrotic-range proteinuria were excluded from the protocol outright. Yet even after excluding these high-risk groups, there was difficulty with study recruitment, which ultimately met only 67%, or even less,10 of the prespecified goal. Part of the problem may have been due, as the authors suggest, to the supervising physicians’ lack of familiarity with or confidence in the sVLPD. However, patients may also have expressed ambivalence about the need to adhere to what is essentially a vegan diet. This issue encapsulates the primary difficulty with the dietary approach. Dietary prescriptions are notoriously hard to follow, especially when the limitations involve protein, a ubiquitous macronutrient in Western diet. Furthermore, close nutritional supervision is required in all cases. Though limited nutritional counseling is presently available though Medicare, it may not be comparable to the intensive support offered to the study patients.
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作者:admin@医学,生命科学 2011-03-10 05:12
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