Nutrition in children with CRF and on dialysis

The objectives of this study are: (1) to understand the importance of nutrition in normal growth; (2) to review the methods of assessing nutritional status; (3) to review the dietary requirements of normal children throughout childhood, including protein, energy, vitamins and minerals; (4) to review recommendations for the nutritional requirements of children with chronic renal failure (CRF) and on dialysis; (5) to review reports of spontaneous nutritional intake in children with CRF and on dialysis; (6) to review the epidemiology of nutritional disturbances in renal disease, including height, weight and body composition; (7) to review the pathological mechanisms underlying poor appetite, abnormal metabolic rate and endocrine disturbances in renal disease; (8) to review the evidence for the benefit of dietetic input, dietary supplementation, nasogastric and gastrostomy feeds and intradialytic nutrition; (9) to review the effect of dialysis adequacy on nutrition; (10) to review the effect of nutrition on outcome.
The importance of nutrition in normal growth
Normal growth can be divided into four important phases: prenatal, infantile, childhood and pubertal. Nutrition is important at all phases of growth, but particularly so during the infantile phase because the rate of growth is higher than at any other time of life (other than prenatally) and is less dependent on growth hormone (GH) than during other phases. Rate of growth gradually decreases from >25 cm/year at birth to an average of 18 cm/year at age 1 year and 10 cm/year by the age of 2. Half of adult height is achieved by the age of 2 years, so that irrecoverable loss of growth potential can occur during this phase. At birth, 170 kcal/day are stored in new tissue, falling to 50–60 at 6 months, 30–40 by 1 year and 20–30 by the age of 2 years. During the childhood phase, growth becomes more dependent on the GH/insulin-like growth factor-1 (IGF-1) axis; growth rate decelerates continuously until the pubertal phase. The pubertal phase results from the coordination of GH and sex steroid production. Together they have an anabolic effect on muscle mass, bone mineralization and body proportions. It is another phase of rapid growth so that nutrition can again modify the genetic growth potential [1].
Methods of assessing nutritional status
Normal nutrition can be defined as maintenance of normal growth and body composition. Although it is agreed that nutritional assessment is important in chronic renal failure (CRF), there is no single or easy definition or measure of inadequate nutritional status: measurement of nutritional parameters are complicated in CRF because of salt and water imbalances and the potential inappropriateness of using age matched controls in a population that is short and may be delayed in puberty; it has been suggested that it is more appropriate, therefore, to express measures relative to height age (age at which the child’s height would be the 50th centile) and/or pubertal stage. The reader is referred to extensive and excellent reviews on this subject [2, 3].
Anthropometric measures
The most commonly used assessment of nutrition is height and weight, along with head circumference in younger children, plotted on percentile charts. Anthropometric and nutritional measures are usefully expressed as a score of the number of standard deviations (SDs) from the mean for a normal population of the same age [e.g. height or weight SD score (HtSDS, WtSDS), also called z scores]. This allows comparison with the normal population and helps follow progress in the individual patient. However, although a normal rate of growth can be considered to represent adequate nutrition, weight loss and alterations in body composition occur before height velocity is affected [2], and poor growth can occur due to reasons other than nutrition (see below).
Another way of expressing the relative weight and height is the body mass index (BMI, Ht/Wt2), which is important because extremes are associated with increased morbidity and mortality [4]. Because BMI varies considerably throughout childhood, reaching a trough at 4–6 years of age, it has been suggested that it should be calculated according to height age [5]. It must be borne in mind that BMI does not distinguish between fat mass and fat-free mass (FFM) and an appropriate BMI for age (whether height age or chronological age) does not necessarily indicate ideal body composition; weight gain may be due to the laying down of excess fat rather than a balance of fat and lean tissue.
Skinfold thickness is a measure of subcutaneous fat and mid-arm circumference (MAC) is a reflection of muscle mass and may therefore be more useful in determining body composition than the calculation of BMI alone. Decreased values have been found in children with CRF [6–9]. However, both are rather unreliable tools because consistent measurements are difficult, values may not be representative of visceral fat and fat or muscle mass, oedema will influence values, regional fat and muscle distribution may be different in CRF and values vary according to age in normal children.
Dietary assessment
The paediatric renal dietician is crucial to the successful management of nutrition in children with renal disease. Monthly review has been recommended for under twos on dialysis, and three- to four-monthly in those over that age [10]; and six-monthly or one- to three monthly in children with moderate and severe CRF, respectively [3]. The purpose is to prevent the development of malnutrition. Children entirely dependent on enteral feeds may need to be seen more often, particularly in infancy when feed adjustments may be necessary as often as weekly. Assessment of intake in children taking an oral diet can depend on prospective dietary diaries, usually over 3 days, or retrospective recall. It has been estimated that 5.9 contacts per patient (in clinic or by phone) per month in children <5 years of age and 3.1 in children >5 years of age are necessary to successfully support families of children on peritoneal dialysis (PD). This intensive input resulted in improvement of HtSDS and WtSDS from −1.2 and −1.32 to −1.14 and −0.73, respectively, over a 3-year period [11]. Protein intake can also be calculated using well established formulae (protein catabolic rate, nPCR [2]).
Serum albumin
Serum albumin has been identified as a surrogate marker for nutritional status and morbidity/mortality in patients with end-stage renal failure (ESRF). Patients <18 years of age initiating dialysis with hypoalbuminemia are at a higher risk for death: in 1,723 children each fall of serum albumin by 1 g/dl at the start of dialysis was associated with a 54% higher risk of death. This was independent of other potential confounding variables [12].
Although serum albumin may be a reflection of nutrition, low levels may be due to haemodilution, nephrotic syndrome or chronic infection/inflammation [13]. To remove the effect of fluid overload, therefore, it has been suggested that if practical, levels should be checked post dialysis [14]. Chronic inflammation in itself will lead to malnutrition [15]. Low serum albumin is more common in children on PD: low levels were present in 35.9% of assays in 39 children on PD over a 2-year period compared with none in 32 children on haemodialysis (HD), even though protein intake (estimated by nPCR) was similar, averaging 1.1 g/kg per day. Thus, children maintained on PD are at greater risk of protein malnutrition compared with peers treated with HD [16]. This may be due in part to losses in PD fluid: average losses of free amino acids (AA) vary with transporter status from 0.02 to 0.03 g/kg/day [17]. There is an inverse correlation between body weight and surface area and peritoneal protein loss, such that infants have nearly twofold greater peritoneal protein losses per metre-square body surface area than those weighing more than 50 kg. Such protein losses in infants impair normal growth and may contribute to permanent loss of growth potential [18].
Dual energy X-ray absorptiometry (DEXA) and other methods
A whole body DEXA scan can estimate fat mass, lean mass and bone mineral density (BMD), but is affected by body water content. Other methods include bioelectrical impedance analysis (BIA) [19], total body potassium, densitometry and in vivo neutron activation analysis, but these are predominantly used as research tools [2].
Nutritional requirements for normal children
Recommended daily amounts (RDA) and recommended intakes (RI) for energy, protein and nutrients vary between countries. Regardless of the national dietary recommendations that are used it is important to consider that these are estimates of requirements for normal healthy populations of people and are not recommendations for absolute intakes for individuals. They serve as a guide for the energy and nutrients that an individual may require for normal growth, maintenance, development and activity. Requirements for any particular nutrient will differ between individuals.
The United Kingdom dietary reference values (DRV) [20] are for infants fed artificial formulas and for older infants, children and adults consuming food. DRVs are not set for breast-fed babies, as it is considered that human milk provides the necessary amounts of nutrients. In some cases the DRVs for infants aged up to 3 months who are formula-fed are in excess of those which would be expected to derive from breast milk; this is because of the different bioavailability of some nutrients from breast and artificial milk.
The DRV for energy intake is assumed to be normally distributed and is expressed as the estimated average requirement (EAR). For protein and other nutrients, requirements are expressed as reference nutrient intakes (RNI), set at 2 SDs above the average. Therefore, intakes of protein and nutrients above this amount will almost certainly be adequate for all individuals in a population. For some nutrients where there is insufficient data to establish DRVs with great confidence safe intakes are set—a level or range of intake at which there is no risk of deficiency.
Daily DRVs for energy, protein and some nutrients are given in Table 1. If a diet for a normal child is adequate in calcium, iron and vitamin C and the child is receiving adequate energy from a mixed diet, then most other nutrients are likely to be taken in adequate amounts.
Table 1UK dietary reference values for normal populations of children [20] (mo months, yr years)AgeEARRNIRNIRNIRNIEnergy (kcal)Protein (g)Calcium (mmol)Iron (mg)Vitamin C (mg)0–3 mo115–100/kg2.1/kg13.11.7254–6 mo95/kg1.6/kg13.14.3257–9 mo95/kg1.5/kg13.17.82510–12 mo95/kg1.5/kg13.17.8251–3 yr95/kg1.1/kg8.86.9304–6 yr90/kg1.1/kg11.36.1307–10 yr1,970/day28.3/day13.88.730Boy 11–14 yr2,220/day42.1/day25.011.335Girl 11–14 yr1,845/day41.2/day20.014.835Boy 15–18 yr2,755/day55.2/day25.011.340Girl 15–18 yr2,110/day45.0/day20.014.840
Nutritional requirements for children with CRF, on dialysis and post transplant
Energy
It is unlikely that energy requirements for children with CRF are different from those of normal children, and energy intakes below the EAR will contribute to growth failure. Restoration of normal energy requirements to 100% EAR allows for catch-up growth in children under 2 years and shows some benefit in older children (see section on Dietary supplements). If recurrent vomiting resulting from abnormal gastric motility and delayed gastric emptying is not treated, energy intake may need to be increased by up to 30% daily to replace lost feed and food in order to preserve growth; once vomiting is controlled growth is maintained on normal energy requirements [21]. To ensure an adequate energy intake it is advisable to use the EAR for height age if the child is below the 2nd centile for height.
There is no evidence that intakes for children on dialysis should exceed those for normal children [10], though dietary energy intake may need to be reduced for children on PD to compensate for the energy derived from dialysate glucose, estimated at 8–12 kcal/kg/day if there is excessive weight gain [7, 22].
Post-transplant energy requirements should match those of normal children, though care needs to be taken with increased appetite in response to steroid administration. Up to 13% of transplanted chidren become obese [23, 24]. A reduction in energy intake is indicated where there is excessive weight gain and will help correct any dyslipidaemia.
Protein
Protein intakes in CRF must provide at least 100% RNI if protein is not to become the limiting factor for growth. Inadequate protein will impact on body composition with a preponderance of fat rather than lean tissue. Adequate energy must be given to promote deposition of protein [25]. To ensure an adequate protein intake, it is advisable to use the RNI for height age if the child is below the 2nd centile for height.
In children undergoing PD, protein intake must provide at least 100% RNI plus an allowance for both replacement of transperitoneal losses and replacement of daily nitrogen losses in order to achieve positive nitrogen balance [7, 18, 22]. There are few studies describing the optimal amount of protein for children on PD and the existing data does not include all age groups. Taking this into account, and the wide variability in transperitoneal losses of protein, recommended intakes for protein for populations of children on PD may be considered generous. Routine assessment of growth, albumin and urea levels will determine the required intake for the individual child. For chronic haemodialysis, the Kidney Disease Outcomes Quality Initiative (K/DOQI) recommends the RDA for age plus an increment of 0.4 g/kg/day to achieve positive nitrogen balance [10]. This recommendation is based on work done in adults on HD who failed to maintain nitrogen balance on 1.1 g protein/kg/day [26]. Published recommended intakes for the US and the UK shown in Tables 2 and 3 are for populations and may need adjustment for the individual.
Table 2US recommended dietary protein for children on maintenance dialysis [10] Age (yr)RDA (g/kg/day)Protein intake for HD (g/kg/day)Protein intake for PD (g/kg/day)Infants0–0.52.22.62.9–3.00.6–1.01.62.02.3–2.4Children1–61.21.61.9–2.07–101.01.41.7–1.811–141.01.41.7–1.8Males15–180.91.31.4–1.5Females15–180.81.21.4–1.5Table 3UK guidelines on dietary protein for children on maintenance dialysis [27] AgeRNI (g/kg/day)Protein intake for HD (g/kg/day)Protein intake for PD (g/kg/day)Infants0–3 mo2.12.52.8–2.94–12 mo1.5–1.61.92.2–2.3Children1–3 yr1.11.51.8–1.94 yr–puberty1.01.4–1.51.7–1.9Pubertal1.01.3–1.41.6–1.8Post–pubertal0.91.2–1.31.4–1.5
Post-transplant protein requirements should match those of normal children.
Vitamins and minerals
Little is known about the requirements of children with CRF. It would be reasonable to give the RNI for vitamins, minerals and micronutrients as for normal children, with the exception of calcium, phosphate, magnesium, sodium and potassium, which may be deranged and must be determined for the individual child. UK RNIs are shown in Table 4.
Table 4Micronutrient guidelines for children with CRF [28] InfantsChildrenThiamin (mg)0.2–0.30.5–1.0Riboflavin (mg)0.40.6–1.3Niacin (mg)3.88–18Vitamin B6 (mg)0.2–0.70.7–2.0Vitamin B12 (μg)0.3–0.50.5–1.5Folic acid (μg)*50–50070–1000Vitamin C (mg)2525–40Vitamin A (μg)*350350–700Vitamin D (μg)*7–8.5–Zinc (mg)4.0–5.05.0–9.5Copper (μg)0.2–0.30.3–1.0
*Vitamin A - care should be taken not to give excessive amounts of vitamin A, as the resultant high serum levels can lead to hypercalcaemia, anaemia and hyperlipidaemia [29]. A common practice guideline is not to exceed 200% of the RNI from the diet and/or supplements.
*Vitamin D - there is no need to achieve the RNI for vitamin D, as it cannot be converted to the activated form (as which it is usually supplemented). Recent recommendations for adults are to assess 25 and 1, 25-vitamin D levels and replace as needed, but there are no equivalent recommendations for children.
*Folic acid - hyperhomocysteinaemia is an independent risk factor for cardiovascular disease [30, 31]. Additional folic acid may be given to effectively lower plasma homocysteine levels. A common practice guideline is to supplement when the glomerular filtration rate (GFR) is <40 ml/min/1.73 m2, but the doses used are arbitrary.
Infants: 250 μg/kg to maximum of 2.5 mg daily
Children 1–5 years: 2.5 mg daily
Children >5 years: 5 mg daily
In adults on PD, blood concentrations of some water soluble vitamins (C, B6 and folic acid) are reported to be low. This is due to a combination of inadequate intake, increased transperitoneal losses and increased needs. In children supplements of these vitamins have been given with the result that blood concentrations have met or exceeded normal values [32, 33]. Accordingly, based on these authors’ recommendations and the RNIs above, the following intakes are suggested [27]:
Vitamin C: 15 mg (infants)-60 mg (children) daily
Vitamin B6: 0.2 mg (infants)-1.5 mg (children) daily
Folate: 60 μg (infants)-400 μg (children) daily
These amounts may well be met from food, feeds and nutritional supplements so it is important to assess the dietary contribution before routinely giving medicinal supplements. Whilst adequate vitamin C needs to be given to offset dialysate losses excessive intakes should be avoided, as the resulting elevated oxalate levels may lead to cardiovascular complications [34]. If folic acid is given to lower plasma homocysteine this will more than compensate for dialysate losses of folate. The K/DOQI recommends that supplementation should be considered if dietary intake alone does not meet or exceed the dietary reference intake, if blood vitamin levels are below normal values, or if there is clinical evidence of deficiency [10].
There are no reported specific micronutrient requirements for children on HD and post transplant and 100% of the RNIs can be considered the goal for these children.
Calcium and phosphate
Control of phosphate, calcium and parathyroid hormone (PTH) levels is necessary to prevent renal bone disease. Dietary phosphate may need to be restricted when the GFR falls below the normal range, and almost always when below 50 ml/min/1.73 m2. The following common practice guidelines will help maintain serum phosphate within acceptable reference ranges, although phosphate binders may also be necessary.
Infants <10 kg: <400 mg daily
Children 10–20 kg: <600 mg daily
Children 20–40 kg: <800 mg daily
Children >40 kg: <1,000 mg daily
Iron, copper and zinc
Anaemia can be prevented by the prescription of iron supplements and erythropoietin (rhuEPO). Advice to increase dietary haem iron and reduce the inhibition of non-haem iron absorption by: phytates in wholegrains and legumes; polyphenols in tea, coffee and cocoa; calcium in dairy products; and simultaneous administration of phosphate binders and antacids should be given. It may be necesary to give intravenous iron if stores are low. Low dietary intakes of copper and zinc are reported [35] in children on PD. The K/DOQI recommends the intake of these to be monitored every 4–6 months and supplements given if necessary [10].
Reports of spontaneous nutritional intake in children with CRF
Several studies have demonstrated decreased spontaneous intake in children with CRF. Four-day weighed dietary records from 50 children with a GFR <65 ml/min/1.73 m2 and 93 healthy children showed an energy intake 76–88% of the RI in CRF patients and 90%–93% in controls. Protein intake was 2.1–3.1 g/kg per day in controls and 1.6–2.7 g/kg per day in CRF patients, so that overall, the energy intake was 10% and the protein intake 33% lower in CRF patients than in healthy children [36]. Other studies have shown low energy intake (87% RNI) but high protein/energy ratio, protein (223%), carbohydrate (73%), fat (110%), polyunsaturated (55%), monounsaturated (129%) and saturated fatty acid (111%), with relative distribution of calories of 15% from proteins, 48% from carbohydrates and 37% from lipids in 15 children with moderate CRF [14]; and RIs in 82 children with CRF were <86% for energy and >161% for protein [12].
Although energy intake is low, it may be proportionate to body weight: 4-day food records from 120 children with CRF found an energy intake of 80% of RI for age, decreasing with increasing age. However, this was in the normal range when factored by body weight. The protein intake was 153% of the RDA [37].
Intake deteriorates with severity of CRF: energy intakes correlated negatively with GFR in 95 children with CRF, and fell to 85% of EAR when the GFR was <25 ml/min/1.73 m2 [38]. Nitrogen balance studies have been performed in 19 children on PD. Protein intake was 1.64 g/kg/day (126% of the RDA), and the calorie intake reached 75% of RDA. Nitrogen losses were 0.205 g/kg/day, and nitrogen balance was positive in three quarters of studies, correlating with nitrogen and calorie intake [39].
Intake also decreases with time: 3-day semi-quantitative dietary diaries in 51 children with a GFR <75 ml/min/1.73 m2 assessed over 2 years showed protein intake to decrease by 0.4 g/kg per day, and calcium by −20% RNI [40]. Energy and protein intake (energy more than protein), all anthropometric measurements and plasma proteins and AAs were low in 24 children on continuous ambulatory PD (CAPD), particularly in those <10 years of age [13].
Low intakes of calcium [35–38], zinc [35, 37, 40, 41] and vitamins [37, 40, 42] are also reported.
The epidemiology of nutritional disturbances in renal disease, including height, weight and body composition
Height and weight
It is during the infantile phase of growth that the most significant loss of height potential can occur, but also it is the phase during which there is the greatest potential for catch-up with nutritional intervention. Many infants with CRF are already growth-retarded by the time they are first seen in a paediatric nephrology service: a loss of HtSDS from birth of −1.68 SD (up to −5 SD/year) has been reported [43]. Approximately one-third of the reduction in height occurs during foetal life and one-third during the first 3 months, accompanied by a similar decline in head circumference [44–46]. Mean HtSDS below the lower limit of normal has been reported in most studies [43–46]. However, catch-up can occur, even on dialysis [47–49]. Poor nutritional status is associated with starting PD at a younger age [50]. Interestingly, infants who grew well continued with catch-up in early childhood [43, 47].
During the childhood phase, growth in CRF usually parallels the centiles but without catch-up [43, 46]. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) CRF database (<20 years of age, GFR <75 ml/min/1.73 m2) has shown a mean HtSDS that has changed little since 1996 when it was −1.5 in 1,725 patients, to −1.4 (one third >−1.88) in 3,863 patients in 1998 and −1.4 in 4,666 patients in 2001 [51–53]. European study group data on 321 children aged 1–10 years with congenital CRF reported a mean HtSDS of −2.37. Increasing severity of CRF adversely affects growth: when the patients were divided into those with a GFR greater or less than 25 ml/min/1.73 m2, the HtSDS was −1.65 and −2.79, respectively [44]. Reports of growth on dialysis vary from improvement [54], to no change [55] to declining HtSDS [56], with a worsening of nutritional status in children dialysed for more than a year [50].
The pubertal phase of rapid growth is another period when loss of height potential can occur. Early studies demonstrated that puberty was delayed, with an irreversible decline in height SDS, particularly in patients on dialysis [57, 58]. However, others have reported normal pubertal progression and growth [43, 46, 59].
Body composition
Children with CRF and short stature are significantly protein-depleted for age, although not for height: 17 patients, mean age 12.9 years had total body nitrogen (TBN) and TBN/height of 54% and 63%, respectively, when predicted from age, but 100% when predicted from height. Energy and protein intakes were 65% and 172% of RDA, respectively. This suggests that chronic energy deficiency may contribute to impaired protein deposition which, in turn, may be important in the pathogenesis of growth failure in CRF [25].
It has been suggested that the ratio of the length of trunk to limb is low in CRF, suggesting a disproportionately greater effect of disease and/or treatment on spinal growth [60] although not all have found this [61].
BIA in children starting PD showed an improvement of hydration and nutrition after 6 months, although levels remained below normal, suggesting that introduction of dialysis should not be left until malnutrition has developed [62, 63]. DEXA studies of 20 PD patients receiving the RDA for energy and a daily protein intake of 144.3% and 129.9% RI at months one and six showed an increase in BMD, bone mineral content (BMC) and FFM. However, the daily protein intake showed a negative correlation with these parameters and also plasma bicarbonate, suggesting that a high protein intake may negatively affect bone mineralization and FFM by its effect on acid-base status [64].
Disturbances in plasma and intracellular AAs have been found in CRF. Muscle isoleucine and valine levels and the valine/glycine ratio were low in children with CRF who were short but had no other signs of malnutrition (normal skinfold thickness, MAC and serum proteins) [65]. Levels have been studied in ten children on CAPD. Although plasma levels of essential AAs (EAAs) were low, only muscle intracellular leucine and valine were low, whereas both plasma and intracellular levels of some non-essential AAs were high. No correlations were found between plasma and muscle AAs and indicators of nutritional status, except muscle branched-chain AA levels with BMI [66].
The pathological mechanisms underlying poor appetite, abnormal metabolic rate and endocrine disturbances in renal disease
Poor appetite is common in children with CRF and may in part be due to abnormal taste sensation [67]. Appetite is also affected by cytokines, and their roles in CRF, along with their effect on metabolic rate, have been extensively and excellently reviewed [68, 69]. Malnutrition may be an inappropriate term in CRF because it infers that dietary replacement would be curative (which is not always the case in CRF), and the term cachexia, which implies replacement of muscle with fat and declining plasma proteins, may be more appropriate [68, 69]. Cachexia may result not only from anorexia but also from acidosis and inflammation (which are common in CRF), which cause elevated levels of cytokines such as leptin, TNF-α, IL-1 and IL-6. These act through the hypothalamus to affect appetite and metabolic rate and maintain the constancy of fat stores.
Leptin is produced by adipocytes and is probably the most important cytokine involved in this process. When body fat falls, levels of leptin decline and the brain responds by increasing appetite and metabolic efficiency; in contrast, when leptin levels rise, food intake is decreased and metabolic rate increases. However, leptin is excreted by the kidney and not cleared by dialysis, so levels can be paradoxically high in malnourished patients, contributing further to decreased food intake and increased metabolic rate. Serum leptin levels were >95th percentile in 45% of 134 children with varying severity of CRF, and correlated positively with their percentage body fat and GFR and negatively with spontaneous energy intake [70]. Leptin levels also correlate with CRP, a marker of inflammation, and with insulin resistance [67, 69]. Leptin signalling in the brain occurs through the hypothalamic melanocortin receptors, and may offer a new area for therapeutic intervention in the cachexia of CRF. The part played by the short-term regulators of satiety, such as ghrelin (which stimulates appetite), is not yet fully understood [68, 69].
Abnormalities of the GH/IGF-1 axis occur in CRF. Whether they are primarily due to CRF itself or secondary to malnutrition is controversial [71, 72]. GH levels are normal to high and IGF-1 levels are low in both CRF and malnutrition [73]. IGF-1 decreases according to nutritional status in children on HD [71]. Leptin levels correlate positively with IGF-1 and negatively with GH in children with starvation [73]. However, in CRF this relationship is disrupted: in 17 children on HD with energy and protein intakes of 40–70 kcal/kg per day and 1–1.54 g/kg per day, respectively, who had reduced anthropometric measurements, although IGF-I levels were low, leptin levels were high [74].
Evidence for the benefit of dietetic input, dietary supplementation, nasogastric and gastrostomy feeds and intradialytic feeding
There are very few controlled trials, so recommendations are based on the evidence available. Some, but not all, reports have been able to establish a relationship between nutritional intake and growth. Growth velocity correlated positively with energy intake in 17 children with CRF [75], and with energy but not protein intake in 15 children on CAPD [76]. Growth velocity was inversely correlated with dietary protein intake and positively correlated with caloric intake both before the initiation of rhGH therapy and after the first year of treatment in 31 children on dialysis [77]. The advantage of input from a dietitian has been specifically demonstrated in two studies [11, 40], but it is likely that in all studies dietetic input was necessary.
Dietary supplements
Because of the importance of nutrition in the first two years of life it might be expected that enteral nutrition would be most effective at this age. Most studies have therefore concentrated on this age group, and there is evidence to show that nutritional supplementation is of benefit. Eight studies have demonstrated an improvement in growth [21, 47, 78–83], three showed an initial decline followed by stabilisation [84–86], three showed no effect on growth [11, 87, 88] and one showed a decline in HtSDS [89]. All but one study [86] used feeds administered by nasogastric or gastrostomy tubes and aim for at least the EAR for energy and RNI for protein, with a protein supplement for dialysis.
An early study of nasogastric feeding in 14 children weighing <10 kg demonstrated a benefit on HtSDS and WtSDS in 11 [78]. Twenty-six children aged <2 years with a GFR <26 ml/min/1.73 m2 were treated with a whey-based infant formula (supplemented with fat and/or carbohydrate) which provided 100% of the RNI for protein for Ht age and 100% of the EAR for energy for chronological age. HtSDS increased from −2.9 to −2.1 over 2 years [21]. A similar feed resulted in improvement in HtSDS from −2.34 at 6 months of age to −1.93 at 2 years in 24 infants with a GFR <20 ml/min/1.73 m2, and from −2.17 to −1.24 in 13 infants on dialysis over a similar time-frame, although a protein supplement for dialysis was included [47]. A further study from the same centre showed an increase in HtSDS from −1.8 to −0.8 at 2 years in 20 infants on PD [79]. Three studies, each reporting the results of nasogastric feeding in three young children with CRF, have shown benefit in eight out of the nine children [80–82]. It is important not to restrict the salt and water content of the diet in the salt-wasting polyuric infant: a feed providing just over the RDA for calories and protein diluted to 0.3–0.5 kcal/ml with additional 2–4 mEq of sodium/100 ml in 24 infants resulted in improvement of HtSDS by 1.37 SD at 1 year and 1.82 SD at 2 years [83].
Three studies have shown an initial decline followed by normalisation of growth. Twelve infants with CRF dropped to a HtSDS of −2 by 12 months of age and then stabilised at that level [84]. Decline in HtSDS was arrested in eight children <2.5 years of age after starting gastrostomy feeds [85] and stabilised after 3 months in the only study using supplementation without nasogastric or gastrostomy feeds [86]. In three studies, enteral feeds made no impact on growth: there was no change in infants with CRF [87], HD [88] or PD [11]. In one study, a decline in HtSDS occurred in 82 children <2 years of age at the start of dialysis [89].
Whether supplemental feeds benefit children over 2 years of age has been challenged [90]. Six studies have included older children [21, 80, 81, 85, 89, 91]. Of these there was an improvement in growth in three [80, 81, 91]. Dietary advice and supplements of glucose polymer and vitamins (as Ketovite) were given to 65 children aged 2–16 years with a GFR <75 ml/min/1.73 m2 if their EAR and RNI, respectively, fell below 80% as assessed by annual 3-day dietary diaries. Mean HtSDS was maintained in those with a GFR of 25–75 and significantly increased in children with a GFR <25 ml/min/1.73 m2. There was an increase in HtSDS and/or BMI SDS in all the patients on supplements, and change in energy intake correlated with change in HtSDS in those with a GFR <25 ml/min/1.73 m2 [91]. Three children with a GFR of 20–25 ml/min/1.73 m2 fed overnight by nasogastric tube for 11–16 months with increasing amounts until weight gain occurred improved their HtSDS [81], as did three children with CRF over the course of a year [80]. Two studies have shown no change in HtSDS. Nine children aged 2–5 years, treated with a whole protein enteral feed supplemented with fat and/or carbohydrate showed no change in HtSDS (−2.3 to −2.0) [21], as did seven children in given gastrostomy feeds [85]. One study has demonstrated an ongoing decline in HtSDS in children aged 2–5 years at the start of dialysis, 14 of whom were given supplements and 20 not [89].
Complications of gastrostomy are uncommon, but include gastro-colic fistulae, paraoesophageal herniae and, in children on PD, post-surgical peritonitis and an increased risk of exit site infection and dialysis catheter removal from infection, a risk that might be reduced if open rather than percutaneous surgery is used [92, 93]. After removal the track usually closes spontaneously [94]. There have been concerns that enteral tube feeding precludes the development of normal feeding behaviour [95]. However, other studies have shown that, despite long term nasogastric or gastrostomy feeding, oral feeding is resumed in the majority of children after successful transplantation [21, 96]. Positive reinforcement at feeding times using behavioural therapy techniques allowed five infants who had PD and nasogastric tube feeding initiated in the first month of life, and who showed persistent food refusal, to convert to oral feeding [97]. Our impression is that spontaneous oral intake increases with long-term tube feeding; indeed, over a period of 31 months energy intake from the feed did not increase, implying that oral intake had improved over this time to support the demonstrated growth [21]. Reports of the use of Nissen fundoplication are principally from one group [21, 47, 54, 79, 88, 92], making assessment of its effect difficult, although results of growth from this centre are good.
Essential aminoacid (EAA) supplements
Serum EAAs, carnitine and total protein levels have been demonstrated to be low in CRF, particularly in patients on PD [98]. It has been suggested, therefore, that a low protein diet supplemented with EAAs might benefit growth by ensuring adequate AA intake without protein toxicity. However, results have been inconclusive. No improvement in growth was seen in seven children with severe CRF who were given half the protein RDA for height age as EAAs for 6–8 months [99]. Ten children with CRF managed for 3 years using a strict low protein diet supplemented by a mixture of the keto and amino forms of the EAAs and histidine showed a significant increase in height and weight velocity [100]. HtSDS improved from −1.93 to −1.37 over 30 months in 20 patients with a GFR <50 ml/min/1.73 m2 on a diet of 0.6 g/kg of protein supplemented with ketoacids [101]. Ten children on HD given AA supplementation (0.25 g/kg body weight i.v.) with and without carnitine (25 mg/kg body weight i.v.) had no overall improvement in AA levels [102].
Amino acid-containing peritoneal dialysis solutions
Excessive glucose absorption and dialysate AA and protein losses contribute to malnutrition in children on PD. It has been suggested, therefore, that using an AA dialysate might both decrease glucose load and replace AA losses. AAs are absorbed in proportion to the concentration difference between dialysate and plasma; after a 1% AA exchange in seven children on CAPD, the rise in plasma levels of AAs correlated with the ratio of the amount of AA in the bag to the basal plasma concentration. The amount of AA absorbed was 66% after 1 h, and 86% after 4 h and 6 h [103, 104].
However, there is no evidence for any long-term nutritional benefit: eight children on CAPD who had a first morning exchange of 1% AA dialysate instead of dextrose for 12–18 months had no improvement in any plasma or anthropometric parameter of nutrition; plasma urea increased. Plasma EAAs, which had been low, improved but the intracellular pool of free AAs, measured in polymorphonuclear leucocytes did not improve [105]. Two randomised prospective cross-over studies of 3 months AA or dextrose dialysate for three months have been performed, both in seven growth-retarded children either on CAPD [106] or continuous cycling PD (CCPD) [107]. In the children on CAPD there was no nutritional benefit from the AA dialysis [106]. The children on CCPD received dextrose dialysate overnight, plus a single daytime dwell of either AA dialysate or dextrose dialysate. Appetite, calorie and protein intake improved and total body nitrogen increased in half the children during AA dialysis. However, total plasma protein and albumin did not change and fasting AAs after 3 months of AA dialysis were comparable to baseline; plasma urea concentrations were higher [107]. High plasma urea may be due to inadequate protein synthesis in the absence of glucose. Ten children underwent overnight CCPD using a 3:1 ratio of glucose to AA solutions simultaneously during the night. Glucose absorption was 33.7% and AA absorption was 55.2% of the infused amount, and although plasma AA levels were high for the entire ambulatory PD (APD) treatment the plasma urea levels did not increase suggesting that the AAs were being used for protein synthesis with this regimen [108].
Disadvantages compared with glucose include cost, and reports of fluid removal are variable. However, equal amounts of urea and creatinine are removed, normoglycaemia is maintained and there are no reported adverse clinical or biochemical effects, other than a slight increase in plasma urea [106, 107, 109].
Intradialytic parenteral nutrition (IDPN)
There are only four studies of IDPN during HD in children so it is difficult to draw conclusions about its effectiveness. Losses of AAs occur into the dialysate during HD and depend on their plasma concentrations and molecular weights. AAs were added to the dialysate of three children in increasing concentrations. Plasma nonessential AAs were not affected, but EAAs improved [110]. Four malnourished children on HD were given IDPN as AAs (8.5% solution), glucose (10% to 15% dextrose), and 20% fat emulsion at every dialysis session (three times a week) for 7–12 weeks. Oral intake improved and, although weight did not improve during treatment, it did so subsequently. Albumin did not change [111]. The weights of three children improved after 6 weeks of IDPN; again, albumin did not improve [112]. Nine patients who on HD had a >10% weight loss and were <90th percentile of ideal body weight received thrice weekly IDPN. In six, BMI increased in the first 5 months and PCR increased, whereas serum albumin did not change; those who did not gain weight were considered to have psychosocial causes for their malnutrition [113].
Nutritional causes of poor growth not related to energy and protein
Sodium
Requirements for sodium vary according to the type of renal disease. Congenital structural abnormalities often result in an obligatory urinary loss of salt and water. Such children may become chronically salt- and water-depleted and need sodium supplementation and free access to water as salt wasting impairs growth [83]. On the other hand, children with glomerular disease need to restrict their sodium intake. Young children on PD may need sodium supplementation as considerable sodium losses can occur in dialysate.
Acidosis
Acidosis is associated with a catabolic state, suggesting that acidosis-related protein wasting could contribute to growth retardation [114, 115]. Correction of acidosis improves serum albumin, catabolic rate and growth [83, 116, 117].
Anaemia
Anaemia is a well recognised cause of poor appetite. However, studies that include blinded, placebo-controlled trials have found that despite subjective increases in appetite, there were no consistent improvements in dietary intake or anthropometric measures observed during rhuEPO treatment [118–122].
Vitamin D
The dose of calcitriol prescribed to control hyperparathyroidism must be balanced against its potential to depress the activity of chondrocytes causing adynamic bone disease. Large doses impair growth, even if intermittent [123, 124], but the frequency of administration does not affect growth if small doses are used [125, 126].
Growth hormone
There may be cases when, despite at least 6 months of adequate nutrition, growth continues to be poor. GH may be offered in these circumstances.
The effect of dialysis adequacy on nutrition
Several studies have looked to see whether increasing dialysis dose benefits appetite, protein intake, nutrition and growth. Twenty-one children on CCPD showed an improvement in HtSDS when aiming for a Kt/V of >2 and a creatinine clearance of >60 l/week/1.73 m2 compared with 1.7 and 40 l/week/1.73 m2 [127].
However, in some, but not all studies, there would appear to be a ceiling above which no further benefit occurs. The nPCR and serum albumin were assessed according to Kt/V in 15 patients on HD. Serum albumin levels were normal. The nPCR was lowest in patients with a Kt/V <1.3, but increasing over 1.6 did not improve nPCR further, suggesting that although adequate dialysis needs to be achieved in order to ensure good protein intake, high dialysis doses are of no further benefit [128]. However, in 12 children taking 90.6% and 155.9% of their requirements for energy and protein, respectively, and receiving HD with a Kt/V of 2.00 and a urea reduction ratio of 84.7%, there was an improvement in HtSDS of +0.31 SD/year and pubertal growth was normal, suggesting that for HD, increasing dialysis dose does improve growth [129].
In PD, but not HD, there was an inverse relationship between albumin level and Kt/V, suggesting that increasing PD dose may reach a point of no further benefit due to increasing albumin losses in PD fluid [130]. PD causes an influx of glucose which can contribute to obesity. High transporter status was associated negatively with HtSDS and positively with BMI SDS in 51 children on PD. Large dialysate volumes also affected BMISDS [131].
Improving dialysis dose can be achieved by the addition of an icodextrin daytime dwell to overnight PD. A cross-over study in eight children of overnight PD with or without addition of a daytime dwell with 1,100 ml/m2 icodextrin for a week showed an improvement in weekly dialysis creatinine clearance from 35 to 65 l/week/1.73 m2 and Kt/V from 1.99 to 2.54. However, protein and calorie intake did not improve and peritoneal albumin loss and serum albumin did not change, but there was increased loss of AAs, although plasma AA levels did not change [132].
Residual renal function (RRF) has an important positive effect on clearance and growth. Mean HtSDS improved from −1.78 to −1.64 over a year of PD in 12 patients with RRF, but declined from −1.37 to −1.90 in 12 patients without. Weekly Kt/V was not different, and only the native kidney Kt/V and creatinine clearance correlated with growth, suggesting that clearance obtained by PD cannot be equated with that obtained by native kidneys [133]. Eleven of 20 patients on PD with a minimum total Kt/V of 2.1, daily protein intake of 3.25 g/kg/day and HtSDS of −2.3 improved their HtSDS by 0.55, while in nine it declined by −0.50. Variables affecting growth were nitrogen balance and residual Kt/V [134].
The role of nutrition in the outcome of children with CRF
Malnutrition is associated with increased mortality. The association with plasma albumin levels has already been discussed [12]. Of 2,306 children, those with a HtSDS less than −2.5 at the start of dialysis had a twofold higher risk of death [135]. In 1,949 children with ESRF, each decrease in height by 1 SD was associated with a 14% increase in risk for death, and there was a U-shaped association between BMI and death [4]. Part of this may be due to an increased risk of infection in malnourished patients [136].
In conclusion, commencement of careful nutritional support early in the course of disease may improve not only growth but also mortality in children of all ages with CRF.
Multiple choice questions
(Answers appear following the reference list)
For each question answer true or false:
During the phases of growth
Rate of growth is highest during prenatal life50% of final height is achieved by the age of 2 yearsThe infantile phase of growth is principally dependent on growth hormoneGrowth rate stays the same throughout the childhood phase of growthA pubertal growth spurt can occur without the development of secondary sexual characteristicsAssessment of nutritional status in CRF and on dialysis
It may be more appropriate to express measures of growth according to height age rather than chronological ageThe height standard deviation score (HtSDS) is the number of standard deviations from the mean for a normal population of the same age and sexThe BMI is the Ht/Wt2 and indicates the proportion of fat mass to fat free massLow serum albumin is always an indication of malnutritionPeritonealprotein losses in dialysate are twofold greater in relation to body surface area in infants than in those >50 kg in weightNutritional requirements
The estimated protein requirement for a normal healthy 30-week-old girl weighing 6.0 kg (0.4th centile) and 59.0 cm in length (<0.4th centile) is >2.1 g/kg/dayHer estimated energy requirement is 150 cal/kg/dayThe prescribed dietary protein intake for the same child on PD would be 2.8–3.0 g/kg/dayChildren with CRF or on dialysis need a calorie intake that exceeds the EAR for height ageSupplements of vitamin A are necessary in children on dialysisAppetite and metabolic rate
Abnormal taste sensation can occur in CRF and on dialysisLeptin is produced by adipocytes and levels are high in CRF and on dialysisHigh leptin levels cause an increase in food intake and metabolic rateGH levels are normal or high and IGF-1 levels are low in CRFGH levels are normal or high and IGF-1 levels are low in malnutritionDietary supplementation
Salt restriction is important in all children with CRFNutritional supplementation has not been shown to benefit children over two years of ageIncreasing dialysis dose in PD may increase peritoneal dialysate protein losses and contribute to obesitySodium supplementation may be necessary in children on PDGastrostomy placement is preferable before PD commences

nutrition
dialysis
growth
chronic renal failure


Doppler waveforms of the ureteric jet: an overview and implications for the presence of a functional sphincter at the vesicoureteric junction

This paper is a comprehensive review of the Doppler waveform appearance of ureteric jets. Six jet waveform patterns have been identified: monophasic, biphasic, triphasic, polyphasic, square and continuous. Details of the physical properties of jet patterns and their changes under various physiological conditions are illustrated. The immature monophasic ureteric jet pattern is common in infancy and early childhood up to around 4 years of age. This pattern is also noted to have a high incidence in older children with urinary tract infection/vesicoureteric reflux, nocturnal enuresis and in other special physiological conditions such as in children undergoing general anaesthesia, in women during pregnancy, and in patients who have had ureteric transplantation. A hypothesis of dual myogenic and neurogenic components is proposed to explain the mode of action of the vesicoureteric junction (VUJ). The implication of this hypothesis is that it alters the scientific basis of the understanding of the VUJ. Furthermore, the application of colour Doppler US to ureteric jets may provide a non-invasive technique to study the physiology or pathophysiology of the VUJ in humans. This might shed light on new novel approaches to the monitoring and treatment of diseases related to VUJ function.
Introduction
When the bolus of urine being transmitted through the ureter reaches the terminal portion, it is ejected forcefully into the bladder through the vesicoureteric junction (VUJ). This creates a jet of urine that can be seen within the urinary bladder during cystoscopy and grey-scale ultrasonography (US). Ureteric jets are also occasionally visible during intravenous urography (IVU) and voiding cystourethrography (VCU).
In 2-D, grey-scale real-time US imaging the jet can be visualized as a stream or burst of low-intensity echoes emerging from the ureteric orifice. Each ureteric jet usually lasts for few seconds and is fast enough to produce a frequency shift; therefore the ureteric jet can be demonstrated by colour Doppler US. Colour Doppler US is in fact the easiest method for demonstrating the jet. It is also amenable to further characterization using a pulse-wave Doppler waveform. The US appearance of the jet has been documented in a number of studies and the jet can be consistently demonstrated in both humans [1, 2] and animals such as the dog [3].
This review is based on a number of previous studies that involve US scanning of a total of 2,128 subjects, which include a normal population of 1,341 subjects. The characteristics of ureteric jets in a normal population of 1,341 subjects are described and the effect of age, gender and bladder-filling (based on a subgroup of 102 normal adult females) are discussed. A summary of jet patterns seen in children with urinary tract infection/vesicoureteric reflux (VUR) (n = 98) [4] and nocturnal enuresis (n = 511) [5] is also presented. Special groups, including pregnant women (n = 107) [6], anaesthetized children (n = 16) [7] and subjects with ureteric transplantation (n = 55) [8] are also discussed to look at changes of ureteric jet patterns under specific physiological conditions. Overall the observations suggest a possible correlation of different jet patterns with functional sphincteric action of the VUJ. A hypothesis of dual myogenic and neurogenic components is proposed to explain the mode of action of the VUJ.
Discussion
Basic ureteric jet patterns on Doppler US
Jequier et al. [9] were the first to describe the ureteric jet. In their study of children, they demonstrated that ureteric jets had both crescendo and decrescendo forms. The jet waveforms ranged from a single to as many as four “humps”. Cox et al. [2] noted that the number of peaks (the “humps” of Jequier et al.) in the ureteric jet varied from one to four while Wu et al. [10] found only two or three peaks. Both the latter studies involved only adults. To the best of our knowledge, ours is the only group that has studied in detail ureteric jet patterns in a cohort of subjects with a wide age range, including a large paediatric population.
Six basic patterns have been identified according to the number of peaks within a single ureteric jet: monophasic, biphasic, triphasic, polyphasic, square and continuous [11] (Fig. 1). Among these, the square and continuous waveforms represent modified waveforms under the state of forced diuresis and they are deliberately avoided in most of the study analysis. The biphasic, triphasic and polyphasic waveforms are grouped under the category of mature complex jets while the monophasic jet is classified as the immature jet. We have shown that the majority of the population have a complex mature waveform of the ureteric jet while the immature monophasic waveform has a significantly higher incidence in young children. This is discussed in more detail below.
Fig. 1Six patterns of the ureteric jet: a monophasic, b biphasic, c triphasic, d polyphasic, e square, and f continuous
The initial slope, duration and maximum velocity (peak velocity) of the strongest jet are measured on every Doppler waveform for quantification purposes. Significant differences have been found in the above physical parameters among the four jet patterns monophasic, biphasic, triphasic and polyphasic. The monophasic jet has the shortest duration, lowest velocity and smallest initial slope [11].
Occasional modification features of the ureteric jet
Some interesting features have been observed in the jet patterns of some normal subjects. These features include (a) the presence of breaks, (b) a multispike pattern, and (c) change of angle of the jet between the beginning and the end. The number of cases with the above features is too small for statistical analysis; however, we sought to describe them in detail for completeness of the whole spectrum of ureteric jet patterns. These features also provide indirect supportive evidence for the hypothesis of functional sphincteric action at the VUJ and are discussed further in the final section.
Breaks
The presence of break is defined as the total absence of Doppler signal between peaks within a single ureteric jet waveform (Fig. 2). Breaks were identified in 5.7% (149/2,629 ureters) of the study population. Comparing different groups of subjects, it has been found that most breaks occur in adult females when their bladder is at maximum capacity, i.e. when the subjects experience an urgent desire to micturate (33.3% of adult females, P<0.05, chi squared test).
Fig. 2Break within a ureteric jet
Multispike pattern
A multispike pattern is defined as the pulsations noted within a single jet waveform as the result of pulsation transmitted from adjacent arteries (Fig. 3). The incidence of a multispike pattern was found to be 1.9% (50/2,629) in the normal population and is more commonly observed when the bladder is extremely full (forced diuresis).
Fig. 3A multispike pattern of a ureteric jet
Change in angle of the jet
A change in the angle within a single jet waveform is illustrated given in Fig. 4. The incidence of change in angle of the ureteric jet in the whole normal population was 4.3% (113/2,629).
Fig. 4Change in angle of the ureteric jet (a) at the beginning and (b) at the end of the ureteric waveform
Ureteric jet pattern and physical properties of jets in normal subjects
General properties
Direction of flow Dubbins et al. [1] and Elejalde and de Elejalde [12] have found on both US and MRI that the ureteric jet is usually directed anteriorly or anteromedially (with or without crossing of the jets), while others have found ureteric jets directed in a more vertical direction or perpendicular to the bladder base [2, 9, 13–16]. Our US findings are in agreement with the above on the ureteric jet direction of flow.
Mean jet velocity In our studies, the mean velocity of ureteric jets in children was found to be 34.03 cm/s for the monophasic pattern and 61.82 cm/s for the complex pattern (Tables 1 and 2). These values are higher than those reported previously. The mean jet velocity previously reported in children aged from 26 days to 17 years varies between 18 and 31.6 cm/s [9, 17, 18]. The discrepancy between the findings of our study and those of previous studies can be explained by different proportions of children of different ages. The mean velocity in adults in our cohort was found to be 57.65 cm/s for the monophasic pattern and 78.89 cm/s for the complex pattern. These values are similar to those reported previously [2, 18, 19].
Table 1Mean values of jet parameters in children and adults with the monophasic pattern Right sideLeft sideChildrenAdultsP valueChildrenAdultsP valueNumber of ureteric jets83188018Initial slope (cm s−2)211.82195.540.60256.55281.100.87Velocity (cm s−1)34.0357.65<0.0138.6663.93<0.01Duration (s)1.171.91<0.011.171.90<0.01Table 2Mean values of jet parameters in children and adults with the complex pattern Right sideLeft sideChildrenAdultsP valueChildrenAdultsP valueNumber of ureteric jets293910296892Initial slope (cm s−2)293.32271.210.09264.48309.130.13Velocity (cm s−1)61.8279.89<0.0161.9773.83<0.01Duration (s)5.266.92<0.015.157.03<0.01
Mean jet duration In our studies, the mean jet duration in children was 1.17 s for the monophasic pattern and 5.26 s for the complex pattern. In adults, the mean jet duration was 1.91 s for the monophasic pattern and 6.9 s for the complex pattern (Tables 1 and 2). These values are similar to those reported previously. In adults, previously reported jet durations range from 3.5 to 15 s [2, 16, 18, 20], while in children previously reported mean jet durations in two different series were 2.77±1.53 s [9] and 1.8±0.2 s [18].
Laterality difference in ureteric jets In general, there are no significant differences in waveform pattern, initial slope, velocity and duration of ureteric jets between the right and left sides in both children and adults. This is in agreement with the study of Matsuda and Saitoh [18]. There were two exceptions in our cohort, which might not have clinical significance. Boys were found to have a higher incidence of the monophasic waveform in jets on the left side compared with girls (P<0.01, chi-squared test; Table 3), while adult males have a lower velocity on the left than the right (P<0.01, paired sample T-test) (Table 4).
Table 3Waveform patterns in children and adults in relation to sex (total of 2,629 ureteric jets in 1,341 subjects) ChildrenAdultsFemaleMaleFemaleMaleRightLeftRightLeftRightLeftRightLeftNumber of ureteric jets166164211215567560373373PatternMonophasic28 (16.9%)19 (11.6%)55 (26.1%)61 (28.4%)14 (2.5%)12 (2.1%)4 (1.1%)6 (1.6%)Biphasic54 (32.5%)53 (32.3%)59 (28.0%)63 (30.2%)219 (38.6%)224 (40%)110 (29.5%)89 (23.9%)Triphasic54 (32.5%)53 (32.3%)57 (27.0%)54 (25.1%)207 (36.5%)183 (32.7%)134 (35.9%)122 (32.7%)Polyphasic29 (17.5%)37 (22.6%)40 (19.0%)34 (15.8%)120 (21.2%)126 (22.5%)120 (32.2%)148 (39.7%)Square1 (0.6%)1 (0.6%)0 (0%)0 (0%)5 (0.9%)13 (2.3%)2 (0.5%)1 (0.3%)Continuous0 (0%)1 (0.6%)0 (0%)1 (0.5%)2 (0.4%)2 (0.4%)3 (0.8%)7 (1.9%)Table 4Mean values of jet parameters in children and adults in relation to sex ChildrenAdultsFemaleMaleFemaleMaleRightLeftRightLeftRightLeftRightLeftNumber of ureteric jets165162211214560545368365Initial slope (cm s−2)290.73261.06264.22264.31268.12274.72271.93234.07Velocity (cm s−1)56.3157.0255.7257.6069.9468.8494.0180.82Duration (s)4.644.564.214.206.376.437.527.69
Effect of age on ureteric jets
The distribution of the four basic patterns (monophasic, biphasic, triphasic, polyphasic) among children and adults has been previously described by our group. We have found a strikingly larger proportion of monophasic waveforms in children than in adults in a population of 1,010 subjects [11].
In this review, the above finding is substantiated after expanding the study population to 1,341 normal subjects. Children are found to have a higher incidence of the immature pattern than adults. The incidences of the monophasic waveform in children and adults are 22% and 1.9% on the right side, and 21.1% and 1.9 % on the left side, respectively (P<0.01, chi-squared test; Table 5). This immature pattern occurs constantly in the first 6 months of life [4]. In our previously reported cohort, the immature monophasic pattern in children changed to a mature complex pattern at a mean age of 4.54 years, which probably reflects the mean age of VUJ maturity in general. There is no significant gender difference for the mean age of VUJ maturity in children: boys show VUJ maturity at a mean age of 4.88 years and girls at a mean age of 4.34 years (P>0.05, simple Z test) [21].
Adults have higher velocity (P<0.01, independent sample t test) and longer duration of the ureteric jet (P<0.01, independent sample t test) than children in both the monophasic and complex patterns. This finding has also been reported by Matsuda and Saitoh [18], suggesting that the stroke volume of urine in children is less than that in adults. The initial slope of the ureteric jet, however, shows no significant difference between children and adults (all P>0.05, independent sample t test; Tables 1 and 2).
Effect of gender on ureteric jets
In the adult population, males have a higher incidence of the polyphasic waveform than females (P<0.01 for both right and left sides, chi-squared test; Table 3). Male subjects also have a higher velocity (P<0.01 for both sides, independent sample t test) and longer duration of the ureteric jet than females (P<0.01 for both sides, independent sample t test; Table 4). In children, however, no significant differences in velocity, duration, initial slope or number of peaks within a single jet was observed between boys and girls (all P>0.05, chi-squared and independent sample t test; Tables 4 and 5).
Table 5Incidence of monophasic jet in children and adults (total of 2,629 ureteric jets in 1,341 subjects). Note that the total number of ureteric jets is less than double the number of subjects as jets in some subjects could not be satisfactorily demonstrated on both sides by Doppler US Right sideLeft sideChildrenAdultsP valueChildrenAdultsP valueNumber of ureteric jets377940379933Monophasic pattern83 (22%)18 (1.9%)0.0180 (21.1%)18 (1.9%)0.01
Effect of bladder filling status on ureteric jets
In a subgroup of 102 adult females we demonstrated how jet patterns are affected by different bladder filling status. Jet characteristics are compared between two different time intervals: (1) when bladder volume was small and rate of diuresis was low, and (2) when bladder volume was large and rate of diuresis more active. We found that 42.2% of the subjects showed no change in the number of peaks within a single jet waveform, 28.9% showed a decrease and 26.5% showed an increase, and 2.4% had square and continuous jet patterns when the bladder was very full [11]. Among the group with changes in the number of peaks, 3.4% showed a change from a monophasic to a complex pattern and 3.9% showed a change from a complex to a monophasic pattern. In all subjects, the initial slope, velocity and duration of the jet were not affected by different stages of bladder filling (all P>0.05, paired sample t test; Table 6). Even though bladder filling was shown to have little effect on whether the subjects had an immature or complex pattern, we standardized the protocol of bladder filling in all our subsequent Doppler US studies of ureteric jets. Scanning was started in most subjects 20 min after water intake because the jet frequency is reasonably high at that time while the bladder is not yet too distended to make the subject feel uncomfortable.
Table 6Mean values of jet parameters in 102 subjects under different stages of bladder filling. Only the jet on the right side is shown for comparison as there was no significant difference between the two sidesJet parameterBladder statusP valueNot fullMaximally fullInitial slope (cm s−2)245.27209.440.39Velocity (cm s−1)62.8158.300.37Duration (s)6.246.230.81
Characteristics of ureteric jet under specific physiological conditions
Pregnancy (physiological)
A total of 107 pregnant women and 375 non-pregnant women were investigated. The occurrence of the monophasic waveform was significantly higher in the pregnant women than in the non-pregnant women (18.7%, 41.1% and 1.6% at 20 weeks’ gestation, 32 weeks’ gestation, and 3 months postpartum, respectively, vs. 1.9% in the non-pregnant women) [6].
General anaesthesia (pharmacological)
Our previous study has documented loss of the complex jet pattern after general anaesthesia. A total of 16 children undergoing surgery under general anaesthesia were recruited. Before anaesthesia, 14 of them showed a complex pattern and two showed a monophasic pattern. After anaesthesia, all showed a monophasic waveform [7].
Ureteric transplantation following renal transplantation
Our previous study has shown that transplanted ureters do not have the normal regulatory function at the VUJ, but inherent peristalsis is retained [8]. From a comparison of 55 transplant patients and 817 healthy subjects, we found that the Doppler waveforms of transplanted ureters are distinctly different from those of healthy adult ureters. Basically, only two patterns were identified from transplanted ureters: more commonly a short monophasic waveform (66.1% vs. 2.6% in the health ureters), and less commonly a longer multiphase pattern that does not resemble the patterns of the healthy ureter.
Ureteric jet characteristics in paediatric conditions
Literature review
Previous studies have attempted to relate the ureteric jet seen during IVU in UTI, VUR and bladder neck obstruction. The studies of Kalmon et al. [22] and Nevin et al. [23] have suggested that identification of ureteric jets in IVU studies do not exclude VUR, but Kuhns et al. [24] found an association between the jet sign and absence of VUR. They postulated that the jet sign is produced by peristalsis through the ureteric sphincter. There might be an abnormal increase in the intravesical volume and pressure in the presence of reflux, thus preventing ureteric peristalsis so that no jet can be seen. Eklöf and Johanson [25], however, disagreed with this hypothesis, finding a lower incidence of visible jet in subjects without radiological proof of VUR (5.7% compared with 32% in the study of Kuhns et al.). Although infrequent, significant ipsilateral VUR is observed even when a ureteric jet is detected (10.7% [25] vs. 5.3% [24]). Eklöf and Johanson [25] concluded, therefore, that the low rate of bilateral jets detected on IVU restricts the potential clinical value of jet detection on IVU as an indicator of the absence of gross VUR and that voiding cystourethrography is necessary in the radiological work-up of children with UTI.
Marshall et al. [17] agreed with the view of Kuhns et al. [24] that visualization of a ureteric jet on IVU should not exclude VUR. In addition, they found a strong correlation between relatively lateral positioning of the orifice and the presence of VUR. The mean velocity of the ureteric jet is not related to VUR. A midline-to-orifice distance of >7 mm has been proposed as the cut-off for predicting VUR. The more laterally positioned the ureteric orifice, the more likely it is that reflux will occur [17].
Subsequent studies largely agree with the concept that the ureteric jet is just a normal physiological phenomenon. Gothlin [26] found that the ureteric jet can be identified in subjects with and without UTI. Neither sex nor age has an effect on jet visualization. He therefore concluded that the jet is just a physiological phenomenon and the roentgenographic finding is normal.
There are a number of previous studies evaluating characteristics of the ureteric jet based on Doppler US. Jequier et al. [9] found that the Doppler waveform parameters of jet direction, duration, frequency, velocity and shape do not help in predicting VUR. A lateral ureteric orifice is not seen in normal patients, but is identified in subjects with VUR and other urinary tract disorders.
Gudinchet et al. [27] found no difference between refluxing and non-refluxing ureters with regard to ureteric jet length, angle, and midline-to-orifice distance. They concluded that these parameters cannot be used to predict recurrence of reflux in children after endoscopic subureteric collagen injection (SCIN) for the treatment of VUR.
In two recent studies carried out by our group, we found a high correlation between the immature monophasic jet pattern in children with specific urinary disease entities. The details are discussed in the following sections.
Children with VUR and UTI
Ureteric jets of 241 healthy children and 98 children with UTI were studied. The incidence of monophasic jet (immature pattern) was 29% in healthy children overall, but varied greatly according to age. The immature pattern was universal in the first 6 months of life, but was markedly reduced to below 15% in late childhood. This immature pattern was more commonly seen in children with UTI (73.5%) and VUR (90.5%) than in healthy controls of the same age [4].
Children with nocturnal enuresis
A comparison was made between 511 children presenting with primary nocturnal enuresis and 266 age-matched normal controls. The incidence of immature monophasic jet was significantly greater in enuretic children (19.2% in both sides) than in normal children (6.4% on the right side and 8.3% on the left side). Furthermore, the immature waveform was more commonly seen in the enuretic group with a markedly thickened bladder wall and multiple urodynamic abnormalities [5].
Taking all the observations together, we postulate a hypothesis concerning the mode of action of the VUJ as illustrated in the last section.
Hypothesis of an active sphincter at the VUJ
There has been controversy regarding the anatomy and function of the VUJ for a long time. There are three schools of thought for the antireflux mechanism at the VUJ. In the first theory the VUJ is thought to be governed by a passive valve mechanism dependent on the length and obliquity of the intravesical ureter [28, 29]. In the second theory the VUJ is considered to possess mixed active and passive valvular action. In addition to the anatomical factors, the distal ureter also shows antireflux ureteric peristaltic activity so that contraction of the ureter can prevent retrograde leakage of the intraluminal contents [30–32]. In the third theory the VUJ is considered to be able to act as a sphincter. Noordzij and Dabhoiwala [33] have proposed a sphincteric function for the VUJ which might be activated by the intrinsic muscular meshwork of the trigonal region of the bladder complementing a purely passive antireflux mechanism.
Taking into consideration all the features observed in previous Doppler US studies of the ureteric jet, we postulate that the human VUJ can act as a functional sphincter. Only a monophasic ureteric peristaltic wave is demonstrated by M-mode study of the ureter [11] while the waveform of the ureteric jet emanating from the VUJ becomes more complex in pattern. Because the waveform of the ureteric jet is modified, an active sphincter mechanism is probably present at the VUJ [11]. Because the VUJ shows sphincteric activity, different patterns of ureteric jet can be identified under different physiological and pathological conditions with occasional modifications.
We hypothesize that dual components are present regarding the mode of action in the active functional sphincter. The first component is the “myogenic” (primary or “immature”) and the second component is “neural” (secondary or “mature”). The distal ureteric muscle and possibly part of the detrusor muscle may contribute to the functional sphincteric action at the VUJ. We postulate that the monophasic jet pattern is the result of contraction caused by the myogenic component of the VUJ, while the complex pattern is the result of modulation of the myogenic component of the jet by the neural component in response to the distal intraureteric pressure. The mode of the functional sphincteric action of the VUJ and the subsequent ureteric jet waveform vary depending upon whether or not the neural component is active.
In normal adults and in children reaching a certain age of maturity, the neural component modulates the myogenic component and complex patterns can thus be seen. When the neural component is absent, for example in a small immature child, under general anaesthesia or in certain pathological conditions, only the myogenic component is functioning, and thus the jet pattern reverses to the monophasic pattern.
In renal transplantation patients with ureteric reimplantation, the normal VUJ mechanism in the transplanted ureter is completely lost and the ureteric jet patterns observed are completely different from the patterns obtained from the native VUJ in normal subjects [8]. These distinct patterns could be explained by loss of both the normal myogenic and the neural components of the sphincter action.
Although the neural component governing the ureteric jet pattern is either present (resulting in a complex pattern) or absent (resulting in a monophasic pattern), the characteristics (initial slope, velocity, and duration) of the monophasic and complex pattern within the same age group remain distinct. Although there is a trend for a longer duration and higher peak velocity of the ureteric jet with increasing age, this could be explained by a larger bolus of urine in each jet in adults than in smaller children.
The neural component governing the sphincteric action of the VUJ appears to be affected under various physiological and pathological conditions. We have observed a marked increase in the incidence of a monophasic jet pattern in pregnant women. However, for those pregnant women who retain the complex jet pattern, the characteristics of the complex waveform remain similar to those seen in non-pregnant women [6]. The above observation suggests that the neural mechanism of the VUJ is lost in some pregnant women, but the underlying reason remains obscure.
In subjects undergoing general anaesthesia, the ureteric jet waveforms revert to the monophasic pattern with no difference in initial slope, velocity, and duration of the waveform when compared with the normal population [7]. This suggests that the ureteric jet in anaesthetized subjects is under myogenic influence solely, while the neurogenic influence is temporarily suspended. Histochemical study of the VUJ [34] has shown the muscular components of the VUJ to be innervated by both adrenergic and cholinergic nerves. However, because several drugs were simultaneously administered during general anaesthesia in our small cohort, the exact pharmacological action of these drugs on the neurogenic pathway could not be clearly determined.
The presence of VUR is highly correlated with the immature monophasic waveform [4]. This observation suggests that the complex jet pattern is associated with a more efficient antireflux mechanism than the simple monophasic waveform that is more primitive or immature. In those children with UTI, but without VUR, a high correlation with the immature monophasic pattern is still observed. It is not clear whether the monophasic pattern is a risk factor for or the consequence of UTI. However, the association of the monophasic jet waveform with VUR and UTI might partially explain why pregnant women with a higher incidence of the monophasic jet pattern are also more prone to VUR and UTI [4]. A higher incidence of the immature jet pattern is also found in children with nocturnal enuresis [5]. This suggests that there is a lower level of maturity of the VUJ in a proportion of enuretic children. This group of children also has more deranged parameters on urodynamic studies.
The hypothesis of dual components in the sphincteric action of the VUJ might also help explain some of the jet phenomena that we have described previously. The multispike pattern in the ureteric jet resulting from pulsations transmitted from adjacent arteries could probably be explained by premature relaxation of the VUJ that precedes the ureteric jet proper so that the transmitted arterial pulse becomes dominant. Premature relaxation of the VUJ is also likely to be governed by the neural mechanism seen in forced diuresis.
The modification involving breaks in the jet is predominantly observed when the bladder is maximally full. Under these circumstances the intravesical pressure would be very high, which might impose a countering effect on the pressure wave of the ureteric jet emitted from the VUJ. Breaks might therefore appear within the jet waveform when the jet velocity drops significantly to zero flow on entering the bladder.
In summary, based on all the above observations, we postulate that the human VUJ can act as a functional sphincter with two possible components: (1) a myogenic component which has a simple “open and close” action that gives rise to the monophasic jet pattern, and (2) a neural component that modulates the monophasic waveform into a more complex pattern. Further anatomical study to determine the exact nature of the sphincteric muscle governing VUJ function is warranted. The major implication of this overview of ureteric jet patterns is a change of concept for the human VUJ. Rather than being a passive valve, the VUJ functions as an active sphincter. This might lead to a novel approach to the management of VUR, UTI and enuresis in children which could replace traditional treatment.
Conclusion
This review has provided a comprehensive understanding of the physiological pattern of ureteric jets and contributes to our knowledge of the pathophysiology of urinary dysfunction in disease entities such as UTI, VUR and primary enuresis. The application of this technique in future studies might lead to novel approaches to the monitoring and prognosis of these conditions and more evidence-based treatment of related diseases.

doppler
ureteric jet
vesicoureteric junction
children
ultrasound