Abstract
There is limited evidence on the optimal timing of dialysis initiation in children. An estimate of the glomerular filtration rate (GFR) provides useful information in guiding this decision, but should not be utilized in isolation, especially since estimates of GFR are less precise at low levels of GFR. Available evidence suggests that the decision to initiate dialysis should be largely based on the presence of specific indications, including uremic symptoms, malnutrition and refractory laboratory abnormalities, and psychosocial considerations. Appropriate preparation of the patient and family for dialysis is critical to optimize patient outcomes.
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Introduction
The initiation of chronic dialysis in a child is a dramatic event for the patient and family. There are absolute indications for initiating dialysis in some patients (e.g., bilateral nephrectomy, uremic pericarditis). In other patients, the reasons behind the timing of dialysis initiation are less clear. The pediatric nephrologist integrates a great deal of information—laboratory data, clinical impressions, and psychosocial issues—in order to reach a decision regarding the timing of dialysis initiation. An assessment of kidney function is usually a critical part of this process. There is considerable debate regarding the merits of “early” initiation of dialysis in adults. The data needed to address this issue in children is sparse, and the debate is complicated in children by issues such as growth, psychosocial factors, an impending kidney transplant, and the need for a lifetime of renal replacement therapy.
Methodology for Measuring Kidney Function
Assessment of a patient’s kidney function, usually defined as the patient’s glomerular filtration rate (GFR) , is useful for determining when to initiate dialysis. This purposely ignores other aspects of kidney function, such as erythropoietin production and synthesis of calcitriol, because dialysis does not replace these functions. However, GFR may be transiently affected by a variety of factors other than the intrinsic kidney disease. For example, intravascular volume depletion, nonsteroidal anti-inflammatory drugs, and antihypertensive therapy, especially angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) , may decrease GFR. In such instances, a fall in GFR should be interpreted cautiously. A potentially reversible process warrants a repeat measurement of kidney function after eliminating the possible underlying cause of the decrease in the GFR.
The gold standard for measuring GFR is inulin clearance , but this technique is usually only available in a research setting. Alternative exogenous substances for measuring GFR include chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA), diethylenetriaminepentaacetic acid (DTPA), iohexol, and iothalamate [1, 2]. There is evidence for a good correlation between inulin clearance and some of these alternatives [3], although the accuracy may decrease in the setting of a low GFR [4, 5] and in patients with edema [6]. These techniques are expensive and require multiple blood draws over 3 to 4 hours, making them impractical for frequent monitoring. Single-sample methods, while more convenient , are especially problematic when the GFR is low [7].
Creatinine clearance (CrCl) is a widely used approach for estimating GFR. Like inulin, creatinine is freely filtered at the glomerulus, but unlike inulin, there is secretion of creatinine by the proximal tubule. This causes the CrCl to overestimate GFR. The effect of creatinine secretion is small at a normal GFR, causing a 5–10% overestimation of GFR. The relative impact of creatinine secretion increases as GFR decreases, leading to a more significant overestimation of GFR. In one study of adults with a mean GFR of 22 ml/min, the CrCl was close to double the inulin clearance [8]. Further, a variety of factors influence creatinine secretion. Creatinine secretion is lower in patients with polycystic kidney disease and higher in patients with glomerular disease [9]. Some medications, such as cimetidine, trimethoprim, and some fibrates, decrease creatinine secretion. Advanced liver disease may increase creatinine secretion. Finally, a valid calculation of CrCl requires an accurately timed urine collection. All of these factors limit the accuracy of CrCl , especially at the low levels of GFR when decisions regarding dialysis initiation are necessary.
Despite its limitations, CrCl is an easy and inexpensive surrogate for GFR. CrCl is calculated via the following equation:
where CrCl is the creatinine clearance (ml/min/1.73 m2); U vol, urine volume (mL); U Cr, urine creatinine concentration (mg/dL); Min, collection period in minutes (1440 for 24 hours); S Cr, serum creatinine (mg/dL); and BSA, body surface area in m2.
A CrCl requires a timed urine collection, usually 12 or 24 hours, necessitating bladder catheterization in the absence of urinary continence. This is a significant impediment to repeat measurements in young children.
At low levels of GFR, the percentage of filtered urea that is reabsorbed is approximately equal to the percentage of filtered creatinine that is secreted. Therefore, the mean of CrCl and urea clearance is another way of estimating GFR; it is quite accurate at low levels of GFR in adults [10, 11].
In children, an estimated GFR (eGFR) may be calculated from the serum creatinine using an equation that uses patient height and a constant of 0.413 irrespective of age and gender [12]. The equation is referred to as the “CKiD creatinine equation ” or the “modified Schwartz equation .”
This equation and subsequent referenced equations in this chapter are based on measuring creatinine using the enzymatic method traceable to isotope dilution mass spectrometry (IDMS traceable) . A different constant was used for estimating GFR with an equation using the Jaffe method for determination of creatinine [13]. Hence, it is critical to be aware of the laboratory methodology that is being utilized when applying these formulas.
The accuracy of these formulas has been questioned by a number of studies [14, 15]. The formulas appear especially problematic in malnourished children and at the low levels of kidney function where decisions regarding dialysis initiation need to be made [15]. There are multiple factors that decrease the accuracy of formulas that depend on the serum creatinine concentration to estimate GFR. The serum creatinine concentration depends on the balance between creatinine generation and excretion. Creatinine is largely derived from breakdown of muscle creatine. Thus, creatinine generation is proportional to muscle mass, which varies greatly in children and is mostly related to size, but also varies due to gender, age, and individual differences. In adults, there are racial differences in creatinine generation [16].
Children with uremia may lose muscle mass due to malnutrition, possibly reducing the rise in serum creatinine concentration. Spinal cord injury and amputation are other potential causes of a misleadingly low serum creatinine. During cooking, creatine in meat is converted to creatinine. Therefore, serum creatinine is partially influenced by the amount of dietary meat, which often decreases in kidney insufficiency due to phosphorus restriction and anorexia. Extrarenal creatinine excretion increases in patients with chronic kidney disease (CKD) [17]. Moreover, tubular creatinine secretion increases as the GFR decreases [8]. Extrarenal excretion and tubular secretion blunt the increase in serum creatinine concentration that should occur as GFR decreases. As stressed above, medications and the specific disease causing CKD can affect creatinine secretion as well [9].
The serum protein cystatin C , an endogenous protein produced by all nucleated cells, is an alternative to creatinine for estimating GFR [18] and is preferred in children with decreased GFR [15, 19] and obese children [20]. There are also equations that use a combination of cystatin C and creatinine to determine eGFR [12, 18, 21]. A more complex formula, derived from the CKiD study, utilizes creatinine, cystatin C, blood urea nitrogen (BUN), height, and sex for estimating GFR [22].
For adult patients, the CKD-EPI creatinine equation [23] has generally replaced older equations such as the Cockcroft-Gault [24] and the Modification of Diet in Renal Disease (MDRD) equation [25]. There are also CKD-EPI equations that utilize cystatin C alone or cystatin C and serum creatinine [26].
In young adults, there are clearly limitations of the creatinine-derived equations. For an 18-year-old, the CKD-EPI creatinine equation provides a higher eGFR than the CKiD creatinine equation [27, 28]. Neither equation is accurate in young adults when compared to iohexol GFR [28]. The CKD-EPI equations using either cystatin C alone or cystatin C with creatinine are the best options, though an average of the CKD-EPI creatinine equation and the CKiD creatinine equation is also a reasonable option [28].
Predialysis Patient Monitoring and Preparation for Dialysis
Systematic patient monitoring is necessary in children with CKD to minimize complications such as malnutrition, hypertension, renal osteodystrophy, and poor growth. In addition, regular monitoring identifies children who have relative or absolute indications for starting dialysis. Anticipation of the need for dialysis permits non-emergent placement of a peritoneal dialysis catheter , creation of a vascular access for hemodialysis, or performance of a preemptive kidney transplant. Table 9.1 outlines the necessary components for monitoring children with an eGFR < 30 ml/min/1.73 m2.
In addition to medical monitoring, it is important that children and families are psychologically prepared for dialysis. This includes reviewing treatment options and exploring accommodations that will be needed at home and for the child’s education.
Indications for Initiating Dialysis
Absolute Indications for Initiating Dialysis
A variety of signs and symptoms are absolute indications for dialysis initiation. These are manifestations of kidney failure that cause significant morbidity and mortality. There is usually a dramatic or marked improvement with the initiation of dialysis. An alternative explanation for the clinical finding should be considered, especially if the GFR is unexpectedly high or if dialysis does not result in improvement.
Neurologic consequences of uremia that are absolute indications for dialysis include encephalopathy, confusion, asterixis, seizures, myoclonus, and wrist or foot drop. Children should begin dialysis if there is hypertension that does not respond to antihypertensive therapy or pulmonary edema due to volume overload unresponsive to diuretics. Other absolute indications for starting dialysis are pericarditis, bleeding diathesis, and refractory nausea and emesis, especially if associated with weight loss.
Bilateral nephrectomy , as may be necessary in some children with congenital nephrotic syndrome or autosomal recessive polycystic kidney disease, is an absolute indication for dialysis.
Beyond anuria, there is debate regarding whether there is a level of GFR that is an absolute indication for dialysis. There are recommendations that the presence of malnutrition is an indication for dialysis initiation. Again, there is no consensus regarding the measurement of malnutrition, the degree of malnutrition that must be present, or the role of alternative strategies to alleviate malnutrition prior to the institution of dialysis.
Relative Indications for Initiating Dialysis
Uremic Symptoms
While severe uremic symptoms are absolute indications for dialysis, less dramatic symptoms are relative indications. These include fatigue and weakness, cognitive dysfunction, decreased school performance, pruritus, depression, nausea, emesis, anorexia, restless leg syndrome, and poor sleep patterns. The persistence and severity of these symptoms are important criteria. This is especially true when evaluating gastrointestinal symptoms. Intractable emesis is an absolute indication for dialysis, while occasional emesis, especially if there are no signs of malnutrition, may not require dialysis initiation.
Many of the symptoms that can be associated with uremia have alternative explanations. Medications may cause fatigue, depression, or nausea. Anemia, a correctable problem, may contribute to fatigue. Depression and poor school performance may be related to psychosocial issues. Comorbid conditions may also cause significant symptoms. Conversely, many patients with uremic symptoms may minimize or deny symptoms in an effort to avoid dialysis or because they perceive these symptoms , which may have developed quite gradually, as normal.
Hyperkalemia
Hyperkalemia is a potentially life-threatening complication of CKD [29, 30]. As GFR decreases, the remaining nephrons compensate by increasing potassium excretion, but there is a linear relationship between GFR and the ability to excrete a potassium load [31]. Hyperkalemia usually does not become problematic until the GFR is less than 10–20 ml/min/1.73m2, unless the potassium intake is excessive or excretion is reduced [31]. Hyperkalemia develops at a higher GFR in adults and children with hyporeninemic hypoaldosteronism, which may also cause a type IV renal tubular acidosis [31]. Similarly, other patients have a decreased tubular responsiveness to aldosterone, and this pseudohypoaldosteronism may cause hyperkalemia at higher levels of GFR [31]. These patients may also have type IV renal tubular acidosis. Medications, especially ACE inhibitors , calcineurin inhibitors, and potassium-sparing diuretics, are another important cause of reduced urinary potassium excretion.
Treatment of hyperkalemia in association with CKD relies on decreasing dietary potassium intake and increasing potassium excretion. In older children, avoidance of foods with high potassium content can have a dramatic effect on potassium intake. Whereas in older children who are receiving liquid formula supplementation it is possible to select a formula with a low potassium content, the potassium content of infant formula does not vary greatly, limiting the effectiveness of formula selection. It should be noted, however, that soy-based and elemental formulas are especially high in potassium. Human milk has a lower potassium content than most formulas, while cow’s milk has about twice the potassium content of most infant formulas. A reduction in the potassium delivery from infant formula is possible by fortifying the formula with sugar (e.g., Polycose) and/or fat. With a higher caloric content, less formula, and hence less potassium, is needed to provide adequate calories. Alternatively, Renastart™, a formula with a very low potassium concentration, is used as a dietary supplement or is combined with another formula; it is not meant to be given as the sole source of nutrition [32].
Increasing potassium excretion can help ameliorate the hyperkalemia of CKD. Loop diuretics increase urinary potassium excretion. Discontinuation of medications that decrease urinary potassium excretion, such as ACE inhibitors, ARBs, nonsteroidal anti-inflammatory drugs, or potassium-sparing diuretics, can have a significant effect on the serum potassium level [33, 34]. Although not usually a significant mechanism of potassium excretion, stool potassium losses become more important as kidney function declines [35]. Constipation should be treated since it may decrease stool potassium losses [36]. Sodium polystyrene sulfonate (Kayexalate®), an exchange resin, binds potassium in the gastrointestinal tract , significantly increasing stool potassium losses. Pretreatment of formula with sodium polystyrene sulfonate is effective, but may cause constipation and problems with other electrolytes, including hypernatremia due to increased formula sodium content [37,38,39]. Newer oral potassium exchange resins include patiromer [40] and sodium zirconium cyclosilicate [41, 42]. There is some experience pre-treating formula with patiromer [43].
Because of the effectiveness of dietary and medical interventions, the initiation of chronic dialysis is seldom necessary solely to manage hyperkalemia. Nevertheless, repeated episodes of severe hyperkalemia may be considered an absolute indication for dialysis. Poor adherence to dietary restriction or medications usually contributes to refractory hyperkalemia. Hemodialysis and peritoneal dialysis are quite effective at correcting hyperkalemia, although dietary restriction, and occasionally medical management , is usually still necessary.
Hyperphosphatemia
A decrease in filtered phosphate parallels the decrease in GFR characteristic of CKD. With mild to moderate kidney insufficiency, an increase in the fractional excretion of phosphate by the remaining nephrons initially compensates for the loss of functioning nephrons, permitting the serum phosphorus to remain normal [44]. As the GFR falls, compensation is inadequate, and hyperphosphatemia ensues, typically at CKD stage III [45, 46]. Hyperphosphatemia causes secondary hyperparathyroidism by suppressing 1,25-dihydroxyvitamin D production and calcium levels and through direct stimulation of PTH secretion [47]. Correction of hyperphosphatemia is essential for controlling secondary hyperparathyroidism. In addition, hyperphosphatemia may elevate the serum calcium-phosphorus product and contribute to vascular calcifications [48, 49]. In adult patients with CKD, serum phosphate levels predict mortality and progression of CKD [49,50,51], while fibroblast growth factor 23 (FGF23) levels, which increase in response to hyperphosphatemia, are a predictor of CKD progression in children [52].
The successful management of hyperphosphatemia in CKD depends on a reduction in phosphate intake by a combination of dietary phosphate restriction and the use of phosphate binders [53]. Early in kidney failure, before hyperphosphatemia develops, a reduction in phosphate intake helps to control secondary hyperparathyroidism [47]. As kidney function declines, dietary restriction alone, because of nutritional constraints and limitations of food palatability, is often inadequate to control hyperphosphatemia, necessitating the use of phosphate binders. Calcium carbonate and calcium acetate are effective phosphate binders in children with CKD, although excessive use may cause hypercalcemia and contribute to systemic calcifications [54]. Sevelamer, a calcium-free phosphate-binding agent, has been effectively utilized to control hyperphosphatemia in children [55]. Additional calcium-free phosphate binders include lanthanum carbonate, sucroferric oxyhydroxide, and ferric citrate [56,57,58,59].
A majority of the available phosphate binders must be administered in large doses (several grams per day) to be effective; unfortunately, the need to swallow large numbers of large-sized tablets or capsules limits the acceptability of medical therapy in children. Hence, poor adherence to dietary and medical therapy is the most important obstacle to the successful control of hyperphosphatemia.
While dialysis therapy removes phosphate, it is almost never adequate to control hyperphosphatemia by itself. There is a continued need for dietary restriction and phosphate binders. The initiation of dialysis because of refractory hyperphosphatemia is seldom effective at controlling hyperphosphatemia since the underlying problem, non-adherence to therapy, is still present. Hence, isolated hyperphosphatemia is seldom the only indication for dialysis, unless there is a belief that the combination of dialytic phosphate removal and improved adherence, perhaps due to the more regimented medical care required by dialysis, will facilitate control of hyperphosphatemia. The presence of refractory hyperparathyroidism further lowers the threshold for dialysis initiation.
Malnutrition
Uremia causes symptoms such as emesis and anorexia that may prevent adequate caloric intake. In adults and children, dietary protein and energy intake declines as the GFR decreases [60,61,62,63,64]. In children, this may adversely affect growth [65]. Infants during the first 6 months of life, when growth is rapid, are particularly vulnerable to the negative effects of poor nutrition.
Studies in adult patients show an association between malnutrition when starting dialysis and decreased patient survival [62, 63, 66,67,68,69,70,71,72,73,74,75]. Nutritional parameters improve in adult patients after the initiation of dialysis [60, 63, 76,77,78,79,80,81]. When looking at body fat as an index of nutritional status, poor nutritional status at the start of dialysis was associated with a greater increase in body fat [78]. In other studies, there was a positive correlation between the nutritional status at the start of dialysis and the follow-up nutritional status, suggesting that dialysis may not completely compensate for poor nutrition at dialysis initiation [77, 79].
The improved survival with an increased dialysis dose, the mortality risk associated with malnutrition, and the improvement in nutritional status associated with dialysis are the basis for recommendations to initiate dialysis therapy when a patient has advanced CKD and malnutrition [82,83,84]. Yet, there are no prospective studies demonstrating that the early initiation of dialysis improves outcome. Aggressive nutritional supplementation, possibly using an enteral feeding gastrostomy tube, may reverse malnutrition in some children without the need for dialysis [85, 86].
There is no one ideal marker of malnutrition. Signs of poor nutrition in children with CKD may include inadequate weight gain, poor linear growth, and loss of muscle mass. If malnutrition is not improved via conservative interventions, then the child with advanced CKD should begin dialysis.
Growth Failure
Growth retardation is a common complication of CKD in children [87]. The causes of “uremic” growth failure include malnutrition (most markedly in infants), electrolyte and fluid losses (in children with hypo-/dysplastic kidney disorders), metabolic acidosis, osteodystrophy, and, most importantly beyond infancy, impaired function of the somatotropic hormone axis. Electrolyte and bicarbonate losses can usually be managed conservatively, with favorable effects on growth rates. Forced feeding usually improves the nutritional status, but linear growth may not respond to nutritional recovery once growth failure is established [88]. In children with stable pre-dialytic CKD, recombinant growth hormone therapy is indicated. The efficacy of this therapy strongly depends on residual kidney function, mandating a timely start of treatment [89, 90]. Unresponsiveness to recombinant growth hormone may be considered as an argument to start dialysis, although improved growth rates are not consistently observed after initiation of standard peritoneal or hemodialysis [91]. However, a subsequent study demonstrated that short daily hemodiafiltration improved responsiveness to growth hormone, leading to remarkable, complete catch-up growth [92]. Hence, the availability of an intense hemodialysis program may be an argument to start dialysis in a child with growth hormone-resistant growth failure.
Timing of Elective Dialysis Initiation
The level of kidney function that is an absolute indication for initiating dialysis in children is uncertain. The adult literature is fraught with conflicting conclusions and opinions [93,94,95]. The debate is complicated by uncertainty regarding the best methodology for evaluating residual kidney function (see Section “Predialysis Patient Monitoring and Preparation for Dialysis”). The IDEAL study directly addressed this question in adults [96]. Patients were randomized to dialysis initiation at an eGFR of 10–15 ml/min/1.73 m2 (early-start) or at an eGFR of 5–7 ml per minute (late-start). The late-start group began dialysis close to 6 months later than the early-start group, but there was no difference in mortality or other adverse events between the two groups. Hence, planned, early initiation of dialysis was not associated with a clinical benefit [96].
In children, there are limited published studies. In a study of children in the United States Renal Data System (USRDS) , higher eGFR at dialysis initiation was associated with a higher mortality, especially among patients who initiated hemodialysis [97]. In another study of children in the USRDS, mortality also increased as eGFR at dialysis initiation increased, especially among patients 6 years and older [98]. In a European study, there was no difference in mortality based on level of eGFR at dialysis initiation [99]. There are no randomized studies in children.
Estimated GFR at Dialysis Initiation
In adults, prior to the publication of the IDEAL trial, the eGFR at dialysis initiation was gradually increasing in many countries. However, this trend has either stabilized or reversed since the publication of the IDEAL trial [100, 101].
In a large cohort of European pediatric patients, the median eGFR at initiation of renal replacement therapy (RRT) was 10.4 ml/min/1.73 m2, with the small percentage of patients who received a preemptive transplant having a significantly higher eGFR at the time of transplant (13.5 ml/min/1.73 m2) [102]. Variables associated with a lower eGFR at onset of RRT included younger age, female gender, and a short interval between the first visit to a pediatric nephrologist and commencement of RRT.
In a study of Canadian children, the median eGFR at dialysis initiation was 8.1 ml/min/1.73 m2 [103]. Canadian children with a genetic cause of end-stage kidney disease (ESKD) , living further from a treatment facility, and females were more likely to initiate dialysis at a higher eGFR. In a study of children in the USRDS, a higher eGFR at dialysis initiation was more common in whites, females, underweight or obese patients, and patients with glomerulonephritis as the underlying etiology of ESKD [97].
Consensus Statements Regarding Dialysis Initiation
The results of the IDEAL study have influenced guidelines on the timing of dialysis initiation; prior guidelines were more likely to reference a GFR threshold for initiating dialysis. The 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend dialysis initiation for specific indications, including symptoms or signs of kidney failure, refractory volume overload, hypertension or nutritional deterioration, and cognitive impairment [104]. Per these guidelines, this “often but not invariably” ensues at a GFR between 5 and 10 ml/min/1.73m2.
The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend similar clinical criteria to KDIGO for initiating dialysis [105]. The KDOQI guidelines do not provide a GFR criterion, citing the challenges of estimating GFR and the lack of evidence that decision-making based on GFR is beneficial. The European Best Practice Board (EBPB) guidelines on when to start dialysis were specifically updated in response to the IDEAL study [106]. These guidelines recommend consideration of initiation of dialysis when the GFR is <15 ml/min/1.73m2 and there are specific indications, including signs or symptoms of uremia, uncontrolled hypertension or volume overload, or a deterioration in nutritional status. In addition, the EBPB guidelines emphasize that this will occur in the majority of patients at a GFR of 6–9 ml/min/1.73m2 and that patients with rapid deterioration require close supervision [106].
The Canadian Society of Nephrology guidelines , updated in 2014, recommend an “intent to defer” strategy that involves careful monitoring of patients with a GFR < 15 ml/min/1.73m2, with dialysis initiation when there are clinical indications. However, unlike other guidelines, it is recommended to initiate dialysis if the eGFR is 6 ml/min/1.73m2 or less [107].
Arguments for Early (“Timely”) Initiation
This was based on the observation that adults who start dialysis with a lower GFR have increased morbidity and mortality [108,109,110]. This may be secondary to the effects of malnutrition since decreased residual kidney function is associated with poor nutrition and poor nutrition when starting dialysis is associated with increased morbidity and mortality (see Section “Malnutrition”). Moreover, in the 1990s, many adult patients initiated dialysis at a lower GFR than was recommended [111,112,113]. This led to the argument that more timely initiation of dialysis has the potential to lessen the high mortality in adult dialysis patients.
Since these observations , there has been a trend toward earlier initiation of dialysis in adults [100, 101]. This has been associated with subsequent observations suggesting that early initiation of dialysis may be harmful, with increasing mortality in patients who start early [114, 115]. However, this detrimental effect of early dialysis may be secondary to increased age and comorbidity in the patients who start early [116]. A lower serum creatinine, which results in a higher estimate of GFR, may also be explained by decreased muscle mass and poor nutritional status [117]. Hence, some patients with putative early initiation of dialysis may have a falsely elevated eGFR due to poor nutritional status, a well-defined risk factor for morbidity and mortality. This would create additional bias suggesting that early initiation of dialysis is harmful. Similarly, a falsely low creatinine may also be present in malnourished children or children with comorbidities that may limit muscle mass (e.g., neurologic injury that prevents ambulation), and thus observational studies that analyze eGFR at dialysis initiation in children must be interpreted with caution.
Arguments for Delayed Initiation
While a number of studies have shown a worse outcome in adults who have a lower GFR at dialysis initiation, there are a variety of biases that make interpretation difficult [110]. These include lead-time bias, referral time bias, and patient selection [83]. Lead-time bias refers to the fact that patients who start dialysis at lower GFR are further along in their disease than patients who start at a higher GFR. A fairer comparison is survival from a time when patients had the same GFR. After accounting for lead-time, two studies found no survival benefit for early dialysis initiation [118, 119]. Moreover, and as noted above, early initiation of dialysis may be associated with increased mortality [114, 115]. In adult and pediatric patients, late referral to a nephrologist is a predictor of poor outcomes [120,121,122,123,124]. Such patients are more likely to have a lower GFR at dialysis initiation, again tending to bias the outcome against late initiation of dialysis. In addition, late referral patients are more likely to have a history of non-compliance with follow-up and more significant comorbid conditions [110].
Early initiation of dialysis exposes the patients to risks of complications from dialysis therapy, including peritonitis, irreversible loss of peritoneal function, access infections, and loss of large blood vessels for vascular access [125]. These issues are especially important in children given the need for a lifetime of ESKD care. In addition, especially in the case of peritoneal dialysis, there is a risk of family and patient “burn-out” as the time on dialysis increases. Hemodialysis may prevent school attendance and certainly requires an extended amount of time at the dialysis unit. Many children feel “washed out” after completing hemodialysis, limiting the ability to complete homework or play with friends. Morning hypotension may prevent school attendance in children receiving peritoneal dialysis.
Residual kidney function is associated with better outcomes in adults receiving dialysis [126, 127], and dialysis accelerates the loss of residual kidney function [128]. This is more significant with hemodialysis than continuous ambulatory peritoneal dialysis, in both adults and children [129,130,131,132]. The use of automated PD may [133, 134] or may not provoke a more rapid decline in residual kidney function than classical CAPD [132, 135]. Of particular relevance to children, it appears that short, high-turnover NIPD may exert similarly detrimental effects on residual kidney function as intermittent extracorporeal procedures.
While some children may bypass dialysis and receive a preemptive transplant, this exposes the child to the risks of long-term immunosuppression (infection and malignancy) and the growth-stunting effects of corticosteroids. Moreover, early transplantation should, statistically, lead to earlier graft failure. These factors argue against overly aggressive use of preemptive transplantation.
In some children, dialysis may be delayed because a living-related transplant is imminent. This avoids the morbidity of dialysis initiation. In other cases, psychosocial issues may delay dialysis initiation. In both of these instances, the possible benefits of early initiation are counterbalanced by the other factor.
Choice of Mode of Dialysis
Kidney transplantation is the optimal therapy for children with ESKD [136, 137]. However, transplantation is often not an immediate option because of the lack of a suitable donor. For some patients, psychosocial issues may also need to be addressed before proceeding with transplantation.
The majority of adult patients receive treatment with hemodialysis. In pediatric patients, peritoneal dialysis is the more frequently used modality, though there is a trend for increased use of hemodialysis in the United States [138]. There is debate in the adult literature regarding the optimal form of therapy; however, there are no randomized studies that properly address this issue. Selection bias has made it difficult to perform comparative studies of morbidity and mortality between peritoneal dialysis and hemodialysis in pediatric patients [139].
Peritoneal dialysis may be especially advantageous during the first 2 years of therapy [140, 141]. This may be related to the improved preservation of residual kidney function with peritoneal dialysis [129, 130, 142]. In addition, the inability of peritoneal dialysis to match the weekly urea clearance of hemodialysis may be less of a problem when the patient has residual kidney function, as is common during the first 2 years of therapy [143]. Finally, membrane failure may decrease the benefits of peritoneal dialysis after the first 2 years of dialysis [125]. Prolonged treatment with peritoneal dialysis may lead to membrane failure, which is associated with increased mortality [144, 145]. Moreover, a high transporter state in children on peritoneal dialysis is associated with poor growth [146]. The advantages of peritoneal dialysis during the first 2 years are especially relevant for children since they receive transplants sooner than adult patients due to the availability of living-related donors and their higher priority on the cadaveric transplant list.
The adult literature supports the premise that the preferred mode of dialysis may depend on the patient population [147,148,149]. In children, peritoneal dialysis has a number of advantages. A home-based therapy is less disruptive with school and social activities. In infants, the performance of hemodialysis is associated with a significant risk for morbidity and mortality, especially if anuria is present [150]. Problems include difficulties with vascular access, refractory anemia, inadequate urea removal, and the risk of hemodynamic instability [150]. In addition, nutrition in infants is dependent on a high fluid intake, making it very difficult for thrice-weekly hemodialysis to provide adequate fluid removal unless the patient has substantial residual kidney function.
The choice of dialysis modality is based on a number of considerations. There are relative and absolute contraindications for both modalities (see Tables 9.2 and 9.3). Psychosocial considerations are quite important given the family commitment needed to make peritoneal dialysis successful. Unless there are contraindications, peritoneal dialysis is the optimal modality for the majority of children, although both the family and the patient must be comfortable with the decision.
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Zahr, R.S., Greenbaum, L.A., Schaefer, F. (2021). The Decision to Initiate Dialysis in Children and Adolescents. In: Warady, B.A., Alexander, S.R., Schaefer, F. (eds) Pediatric Dialysis. Springer, Cham. https://doi.org/10.1007/978-3-030-66861-7_9
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