“Paediatric chronic kidney disease”

Rajiv Sinha, Stephen D Marks*. 

Department of Paediatric Nephrology
Great Ormond Street Hospital for Children NHS Trust
Great Ormond Street
London, WC1N 3JH, UK.

 

 

 

 

INTRODUCTION
Chronic kidney disease (CKD) is the term used for irreversible kidney damage that can lead to a progressive decrease in kidney function. The term CKD has replaced the earlier terms of chronic renal failure (CRF) or chronic renal insufficiency (CRI) as it more clearly defines renal dysfunction as a continuum, rather than a discrete change.

DEFINITIONS AND CLASSIFICATIONS 
The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) definition and classification has become internationally accepted.
The K/DOQI workgroup defined CKD as either

  1. The presence of markers of kidney damage for at least three months, as defined by structural or functional abnormalities of the kidney with or without a decreased glomerular filtration rate (GFR) that is manifested by either pathological abnormalities or other markers of kidney damage, including abnormalities in the blood, urine, or in imaging tests.

or

  1. GFR below 60 mls/min/1.73m2 for at least three months, with or without kidney damage.

The K/DOQI has also developed a classification system for the severity of CKD based on GFR and independent of primary renal diagnosis (Table 1). GFR is equal to the sum of the filtration rates in all of the functioning nephrons and therefore, can give an estimate of renal function. Interpretation requires a clear understanding that GFR varies according to age, gender, and body size. The normal GFR is much lower in infancy and reaches adult values after one year of age. Despite this, a calculated GFR based upon serum creatinine can be compared to normative age-appropriate values to detect renal impairment even in toddlers and infants with CKD. As actual determination of the glomerular filtration rate (GFR) is cumbersome an alternative is estimating GFR by using serum creatinine, height, and in adolescents, the gender of the patient (Table 2). However in patients with an unusual dietary intake (eg, vegetarian diet or creatinine supplements) or in those with decreased muscle mass (eg, amputation, malnutrition, or muscle wasting), the estimated GFR might not be accurate and the formal GFR calculation may be more advisable.

EPIDEMIOLOGY
There are limited data on the epidemiology of CKD in children. The most comprehensive report is from the prospective, population-based registry, ItalKid project, which included all Italian paediatric cases of CKD defined as a creatinine clearance (CrCl) less than 75mls/min/1.73m2 between 1990 and 2000. The mean annual incidence and prevalence of CKD were 12.1 and 74.7 cases per million children and adolescents below 20 years of age, respectively.
Larger registry based data are available primarily on children with end stage renal disease (ESRD) requiring renal replacement therapy. Based on these the estimated incidences for ESRD in children from United States, New Zealand, and Austria are 14.8, 13.6, and 12.4 per million children whereas it is lower at 4 per million in Japan. The difference in incidence of ESRD around the world can be attributed to various reasons including presence of screening programmes and easy availability of renal replacement therapies.
The commonest primary diagnosis for CKD in childhood is congenital anomalies of the kidney and urinary tract (CAKUT), including renal dysplasia, renal hypoplasia as well as obstructed uropathies including those secondary to posterior urethral valves. A male preponderance is often observed primarily because of the higher incidence of CAKUT among boys.
In the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) database, which includes patients below 21 years of age with a CrCl less than 70 mls/min/1.73m2, the age distribution at presentation were as follows:

AETIOLOGY
 Congenital renal anomalies and glomerular disease accounted for 57% and 17% respectively of over 7000 children with CKD in the largest database provided by NAPRTCS.  Congenital renal anomalies such as renal dysplasia with or without vesico-ureteric reflux / with or without posterior urethral valves; were commoner among younger children. Glomerular disease was common in older children, accounting for approximately 45% of cases in patients older than 12 years of age. The commonest glomerular disorder was focal and segmental glomerulosclerosis (FSGS), which occurred in 9% of all CKD cases. African-American children were three times more likely to develop FSGS than Caucasian patients (18% versus 6%), and FSGS was the cause of CKD in one-third of African-American adolescent patients. It is important to note that in 18% of all cases of CKD, the underlying primary diagnosis was not identified (15%) or was unknown (3%).
A similar distribution of aetiologies was also reported by the Italian registry (ItalKid project) with the leading cause being renal hypoplasia/dysplasia, which occurred with and without urinary tract anomalies in 54% and 14% of patients, respectively.

NATURAL HISTORY AND PROGRESSION OF CKD
Children with established CKD can show a continued progression of renal disease leading to end stage renal disease (ESRD). This has been well demonstrated by the NAPRTCS database which showed 86% of children registered progressed to ESRD (although this may be skewed as most of those registered in NAPRTCS were having advanced CKD).  
The persistent deterioration of renal function may be a result of repeated and chronic insults to the renal parenchyma leading to permanent damage and/or to the adaptive hyperfiltration response of the kidney, which compensates for the loss of nephrons from the initial injury. The adaptive hyperfiltration process increases the filtration rate in the remaining nephrons by increasing glomerular pressure and flow. Although this can initially maintain normal or near-normal glomerular filtration rate and serum creatinine in patients with mild impairment; with time the enhanced trans-glomerular ultra filtration and glomerular pressure leads to glomerular damage and interstitial inflammation and fibrosis.
Deterioration of renal function among children with CKD is particularly common during infancy and puberty as during these two periods of rapid growth the sudden increase in body mass results in a rise in the filtration demands on the remaining nephrons. Therefore, children with CKD should be closely monitored during these two periods.
The rate of progression to ESRD is primarily influenced by the underlying diagnosis and the baseline CrCl at presentation. In addition to this a number of other factors also influence disease progression such as hypertension, proteinuria, obesity, dyslipidaemia, anaemia, intra-renal precipitation of calcium and phosphate and metabolic acidosis. Genetic, familial, or ethnic predisposition may also influence the rate of renal decline as seen by the faster rate of progression among African-Americans.
Many of these factors are modifiable with early interventions. The initial report from the CKiD study (an ongoing prospective study following up more than 580 children with CKD) linked proteinuria, a modifiable factor, with decreased GFR. Similarly the ESCAPE trial showed definite benefit of strict blood pressure control in slowing the progress of CKD.

CLINICAL PRESENTATION
In view of the wide heterogeneity of the underlying cause of kidney injury the presentation of CKD also varies widely. Antenatal ultrasound screening can now identify many foetuses with CAKUT. Those detected in early stages of CKD are likely to be asymptomatic and are often detected on routine examination or work up for some other medical problem. In contrast, children in advanced stages of renal failure are more likely to be symptomatic.
Glomerular diseases are more likely to present with nephritic and/or nephrotic syndrome (with oedema, hypertension, discoloured urine and or decreased urine output (oliguria)). In contrast to adults, where oliguria is a common finding among patients with CKD, polyuria (increased urine output) may be the presenting finding for many congenital anomalies of the kidney and urinary tract (eg, dysplastic kidneys), inherited disorders (eg- nephronophthisis), and tubulointerstitial disorders as they are associated with reduced concentrating ability. It is important to be aware of this presentation as impairment in renal concentration and the resulting polyuria generally precedes a significant reduction in GFR and if detected early can provide a window period wherein one can initiate measures to slow the rate of progression of CKD. 
Incidental detection of CKD is also not uncommon. This can happen during routine blood or urine checks for unrelated or related conditions, such as poor growth, which is a common manifestation of CKD in children when the underlying kidney disorder is often detected late. In addition, with the greater availability of ultrasound scans incidental detection of renal anomalies is also increasing.
Symptoms and/or signs of severe renal impairment usually begin to appear by Stage III CKD. These symptoms (referred to as symptoms of uraemia) include anorexia, vomiting, weakness and easy fatiguability. Other findings attributable to the uraemic state include pericarditis, deficits in neurocognitive function and renal osteodystrophy. Apart from these, specific signs and symptoms of the underlying aetiology (such as lupus nephritis or vasculitis) may be present and should always be searched.

COMPLICATIONS OF CKD 
As CKD progress to Stage 3 onwards, a number of complications are manifested due to impairment of the multiple functions performed by the kidneys. These include disorders of fluid and electrolytes, renal osteodystrophy, anaemia, hypertension, dyslipidaemia, endocrine abnormalities, growth impairment, and decreased clearance of toxic substances.
In the largest single centre study (366 children) of children with CKD, the majority of whom were in Stage I CKD (57%), the overall prevalence of complications like hypertension, anaemia, renal osteodystrophy, growth failure and significant electrolyte disturbances were 70%, 37%, 17% 12% and 9% respectively.
Fluid and electrolyte imbalance
Fluid and electrolyte disturbances usually present when the GFR falls below 10 to 15mls/min/1.73m2. As the GFR becomes severely impaired (Late Stage IV and V CKD), decreased urine output leads to water retention which may result in volume overload as well as hypertension and hyponatremia.
Of the electrolyte complications, hyperkalaemia is the most dangerous and usually occurs at the latter Stage V CKD. Although  hyperkalaemia occurs due to inadequate potassium excretion from reduced GFR, it is also due to decreased delivery of sodium to distal tubules secondary to reduced GFR which results in reduced exchange rate of potassium and therefore, inadequate potassium excretion. Other contributory factors for hyperkalaemia include increased tissue breakdown due to hypercatabolic state, metabolic acidosis, type IV renal tubular acidosis in some patients with obstructive uropathy, hypoaldosteronism (in some cases due to the administration of an angiotensin converting enzyme inhibitor or angiotensin receptor blocker).
Metabolic acidosis
Metabolic acidosis is another common complication usually manifesting when the GFR decreases to below 40 to 50mls/min/1.73m2. This is usually due to fewer functioning nephrons to maintain the degree of ammonia excretion required for acid base equilibrium. The net effect is retention of hydrogen ions resulting in metabolic acidosis. The anion gap is usually increased in this setting, but may be normal due to the concomitant retention of anions such as phosphate, sulphate, urate, and hippurate. The presence of acidosis has a negative impact on growth, as the body utilises bone to buffer the excess hydrogen ions and it has been demonstrated that treatment of bone disorders associated with CKD is better if the acidosis is corrected. In addition, recent research has also shown a correlation between correction of acidosis and slowing of the progression of CKD.

Bone disease
The bone disease of CKD, referred to as renal osteodystrophy or more recently described as CKD-Mineral bone disorder (CKD-MBD) can have subtle biochemical manifestation from Stage II CKD disease. The pathogenesis of CKD-MBD is complex and its understanding is still evolving. It is believed that decreased renal clearance of phosphorus with resultant increase of serum parathyroid hormone (PTH) in response to phosphate retention is a key step. Decreased production of calcitriol (also referred to as 1,25-dihydroxy-vitamin D) secondary to renal dysfunction is also thought to be an important contributory factor. In addition, recent evidence also indicates an increased prevalence of generalised vitamin D deficiency in children with CKD and this also might contribute to CKD-MBD. Subtle signs of bone disease begin to appear in patients with Stage III disease. Patients with more advanced renal osteodystrophy have bone pain, difficulty in walking, and/or skeletal deformities
Anaemia
Anaemia is the other major complication and is due to reduced erythropoietin which is primarily produced in the kidneys. It usually develops when eGFR falls below 60mls/min/1.73m2. Anaemia of CKD is normally normocytic, normochromic and a microcytic picture suggests concomitant iron deficiency or aluminum excess, while macrocytic picture suggests vitamin B12 or folate deficiency. Anaemia in children with CKD has been associated with fatigue, weakness, decreased attentiveness, increased somnolence and poor exercise tolerance.
Hypertension
Hypertension is among the commonest complication in children with CKD, ranging from 54 to 70% of patients. It is usually due to volume expansion although it can also be secondary to excess renin from damaged kidneys or iatrogenic such as use of corticosteroids or ciclosporin or tacrolimus for treatment of any underlying renal disease.
Unlike many of the complications of CKD, hypertension can present in the earlier stages of CKD, although the prevalence does increase with progressive decline in GFR. This was shown in the Canadian case series, which demonstrated that the prevalence of hypertension increased from 63% in Stage I CKD to 80% among those with Stage IV and V CKD. Detection rate for hypertension does increase with 24 hour ambulatory blood pressure monitoring as confirmed by preliminary reports from CKiD where 18%  had confirmed hypertension (both elevated ambulatory and office blood pressures) and an additional 34% had masked hypertension (normal office but elevated ambulatory BP).
Left ventricular hypertrophy (LVH) is also a common finding and can be of concentric LVH type secondary to the presence of hypertension or eccentric LVH secondary to associated volume overload and anaemia. In its preliminary report, the CKiD study found LVH detected by echocardiography in 17% of cases (with 11% eccentric LVH and 6% concentric LVH). LVH was more common in children with confirmed and masked hypertension compared to those with normal BP measurements (34, 20 and 8%, respectively).

Dyslipidaemia
Abnormal lipid metabolism is common in patients with CKD and adds to the risk for cardiovascular disease (CVD) along with hypertension. Young adults aged 25 to 34 years with CKD have at least a 100-fold higher risk for CVD related mortality and/or morbidity compared to the general population. This has led to the American Heart Association identifying CKD as one of eight diseases associated with an increased risk for coronary artery disease.
Endocrine dysfunction 
Thyroid hormones: CKD states are often associated with "sick euthyroid syndrome" with low total and free T4 and T3, a normal thyroid stimulating hormone (TSH) level, and normal or decreased thyroid hormone-binding globulin levels or thyrotropin-releasing hormone (TRH).
Gonadal hormones: Abnormalities in gonadal hormones are seen in two-thirds of adolescents with ESRD and can result in delayed puberty. The average pubertal delay in children with CKD is 2.5 years. Whereas males have reduced levels of serum free testosterone, dihydrotestosterone, adrenal androgens, and increased level of serum luteinising hormone (LH) and follicle stimulating hormone (FSH), post-pubertal females with CKD have reduced serum oestrogen, elevated LH and FSH, and loss of the LH pulsatile pattern.
Growth impairment: The aetiology of growth failure, a common complication of childhood CKD, is multifactorial and includes metabolic acidosis, decreased caloric intake, renal osteodystrophy, and alterations in the function of the growth hormone and insulin-like growth factor (IGF-1) axes. In particular, poor linear growth is primarily due to increased levels of insulin growth factor binding proteins, which promotes a growth hormone resistant state resulting in short stature.
Uraemia
As the kidney failure enters Stage V CKD, a constellation of symptoms and signs referred to as uraemia is usually manifested. This includes anorexia, nausea, vomiting, growth retardation, peripheral neuropathy, and central nervous system abnormalities ranging from loss of concentration and lethargy to seizures, coma, and death. Patients who are uraemic also have an increased tendency to bleed secondary to abnormal platelet adhesion and aggregation properties. They can also have pericardial disease (pericarditis and pericardial effusion) which by itself is an indication to institute dialysis in children with CKD.
Neurodevelopment: Uraemia is associated with alterations of cognitive development in children. The neurologic findings can range from seizures and severe intellectual disability and developmental delay to subtle deficits resulting in poor school performance. The neurodevelopment outcome has shown steady improvement with the avoidance of aluminium as a phosphate binder, and optimisation of dialysis, nutrition and anaemia management. Recent studies have shown an overall optimistic outcome among children started on long term dialysis as well as after renal transplantation.

Sleep and fatigue: Daytime sleepiness and fatigue are commonly seen in children with CKD and increases with decreasing renal function. Sleep disorders (including restless leg syndrome / paroxysmal leg movements, sleep-disordered breathing, excessive daytime sleepiness, and insomnia) are also common in children with Stage I to IV CKD as well as in those on dialysis.

EVALUATION
The evaluation of a child with CKD begins with a clinical evaluation, including history and physical examination. Imaging and laboratory evaluations are useful adjuncts in not only establishing an underlying cause but also in determining the severity of renal impairment and identifying any associated complications.
Clinical evaluation
The history should include documentation of the age at onset of symptoms, duration of symptoms, and the presence of symptoms due to uraemia (weakness, fatigue, anorexia, or vomiting), any underlying systemic diseases (fever, rash, or arthralgia / arthritis), or specific renal disorders (eg, glomerulonephritis) that may present with nephrotic and/or nephritic syndrome. One should also try to elicit any relevant history such as neonatal, past medical, drug (nephro-toxicity as well as idiosyncratic reactions) and family history.  Particular emphasis on growth failure, polyuria, polydipsia, enuresis, antenatal detection of any renal anomalies, spinal abnormalities or recurrent urinary tract infection should be sought.
Physical examination
The physical examination of any child suspected of having CKD should include:

Imaging 
Ultrasonography (US) is the most widely used modality and has the advantage of being non-invasive. It can be used to assess renal structure for any underlying structural abnormalities like CAKUT (including obstructive pathology), including cystic kidney diseases. It is equally useful for measuring the length of the kidneys which can be compared with normative age-appropriate values. Kidneys that are smaller than normal indicate a decrease in renal mass due to congenital maldevelopment (such as renal hypoplasia), poor growth, or loss of nephrons due to an underlying disorder or injury. In addition, serial follow up of renal growth can also be accomplished through US. In children with a solitary kidney, renal length is generally in the upper range of length for normal paired kidneys and often greater than the 95th centile due to compensatory renal hypertrophy when the child has normal renal function. It is better to correlate the kidney size with height in children with CKD as correlating with age can lead to over-reporting of small kidneys among children with poor growth.
Nuclear scans have specific uses such as demonstrating scars (DMSA scan) or demonstrating any obstruction in drainage of the urine (DTPA scan). In addition, they can also give a good estimate of the overall as well as individual renal functions.
Other imaging studies are used less often with their use restricted for cases where US fails to give proper resolution or visualisation (computed tomography and magnetic resonance imaging (MRI)) or definite answers like the presence of vesicoureteric reflux (such as from a micturating cystourethogram).
Ionic and non-ionic contrast agents used for radiographic procedures and imaging studies may be nephrotoxic and can cause acute renal dysfunction. Gadolinium-based contrast agents for Magnetic Resonance Imaging (MRI) and MR angiography have been associated with nephrogenic fibrosing dermopathy and sometimes fatal nephrogenic systemic fibrosis in both children and adults with Stages III, IV and V CKD.  Therefore, contrast agents should be used with caution in patients with CKD.

Laboratory testing
Depending on the type of kidney disease, blood and urine studies are often used to support the diagnosis of CKD. Laboratory testing is useful for identifying as well as monitoring various complications of CKD. In addition, serum creatinine can give a basic estimate of the degree of renal dysfunction and the estimated GFR a more reliable estimation of renal function.
In children, estimated GFR (eGFR) is usually calculated by the Schwartz formula which was developed in 1970. It was based upon serum creatinine determined by the Jaffe method, height, and an aged based constant k that varied with age (and in adolescents the gender of the patient)
  GFR = k x height (cm) / Serum creatinine [mg/dl (Jaffe method)]
The constant k is directly proportional to the muscle component of body, and varies with age. The value for k is 0.33 in premature infants through the first year of life, 0.45 for term infants through the first year of life, 0.55 in children and adolescent girls, and 0.7 in adolescent boys.
In contrast to the older Jaffe method, currently creatinine is usually estimated by the enzymatic method which results in a lower value of creatinine leading to overestimating of GFR calculated by the Schwartz formula. A bedside formula based upon serum creatinine measured by the enzymatic method derived from data collected from 349 children enrolled in CKiD study has been recently suggested to have a better correlation with the enzymatic method of creatinine estimation.
GFR = 0.413 x height (cm) / Serum creatinine (enzymatic method)
As stated earlier, eGFR can be used to classify the severity of CKD (K/DOQI classification) as well as follow up the progression of renal dysfunction.
Urinalysis is a useful screening test for abnormalities of the kidney and urinary tract, and as an aid in identifying the underlying cause of CKD. The urinary dipstick makes it possible to detect proteinuria, pH, concentrating ability, glycosuria, haematuria, and pyuria which can serve as an initial guide for the possible underlying aetiology of CKD. Significant proteinuria along with haematuria is an indicator of underlying glomerular disease. Proteinuria can also be present in tubular dysfunction and has been shown to be an important biomarker of CKD progression. The severity of renal disease is generally associated with the amount and duration of proteinuria. Therefore, persistent high-grade proteinuria (2+ proteinuria or greater) usually warrants a prompt evaluation for other signs of renal dysfunction. The presence of persistent proteinuria by dipstick evaluation should be quantified by determination of early morning urine protein or albumin to creatinine ratio.

Additional laboratory tests:
Electrolytes estimation is routinely required to detect abnormalities such as hyperkalemia and metabolic acidosis (with low serum bicarbonate). Serum calcium, phosphate, 25-hydroxyvitamin D, and parathyroid hormone level are performed to detect any abnormalities in bone mineral metabolism.
Full blood count (FBC) is performed to detect anaemia which is a common complication of CKD. As per K/DOQI guidelines it is defined by haemoglobin (haematocrit) below the 5th centile of normal when adjusted for age and sex. An initial reticulocyte count will not only rule out any underlying haemolysis (atypical haemolytic uremic syndrome) but will also aid in follow up of the results of any intervention. The red blood cell indices can identify an underlying iron deficiency (microcytic anemia) or vitamin B12 or folic acid deficiency (megaloblastic anemia). Iron deficiency should be quantified by determination of iron status (serum iron, total iron binding capacity, percentage transferrin saturation). In refractory anaemia, any source of blood loss should be investigated including testing the stool for occult blood.
Fasting lipid profile is indicated to detect presence of dyslipidaemia which is not uncommon among children with CKD.
Kidney biopsy is rarely helpful in establishing the underlying aetiology of CKD and has increased risks.  It is unlikely to help in guiding therapeutic choices. However, the biopsy result may provide information about disease severity, including whether any abnormalities may be reversible and the degree of renal scarring.

FOLLOW-UP EVALUATION
CKD is generally progressive, and therefore, children with CKD require ongoing monitoring of their renal function, and screening for complications associated with CKD.
Recommendations for frequency of clinical, lab and nutritional monitoring of children with CKD are published in KDOQI Clinical Practice Guideline for Children with Chronic Kidney Disease. More frequent assessments are recommended in younger children, and children with severe impairment regardless of age (such as Stage IV and V CKD).
The follow up of children with CKD should ideally be performed in a multidisciplinary setting (paediatric nephrologist, renal dietician, renal nurse and pharmacist). Inputs from other specialties are also often required. During follow up growth, blood pressure, nutritional status should be monitored along with laboratory parameters (serum creatinine, electrolytes, calcium and phosphate, haemoglobin, fasting lipid profile, 25-hydroxyvitamin D, and parathyroid hormone level).

MANAGEMENT
Basic principles:
The overall management includes some basic principles:

  1. Treat any reversible condition
  2. Prevent or slow the progression of kidney disease targeting hypertension and proteinuria
  3. Anticipate and prevent the complications of CKD
  4. Treat the complications as and when they are detected
  5. Identify and adequately prepare the child and family in whom renal replacement therapy will be required

The sequence of implementation of the above principles will obviously be influenced by the stages of CKD.
In the early stages of CKD, the focus should be on identification of any reversible insult and preventing or slowing the progression of kidney disease. Ideally this period should also be used to educate the child and family about CKD, highlighting awareness of risk factors that can aggravate kidney failure (such as avoidance of nephrotoxic drugs, recurrent infections, dehydration) and of measures that may slow the progression of kidney failure (such as blood pressure control).
CKD-associated complications begin to appear as CKD progresses into Stage 3 where the focus changes to anticipation, early identification and management of the various complications. Patients who will require renal replacement therapy (RRT) should be identified well in advance of the time that RRT is required so that adequate preparation and education can be provided to both the patient and family. The gold standard is to prepare for where possible pre-emptive living related renal transplantation.
REVERSIBLE KIDNEY DYSFUNCTION 
The most common conditions with potentially recoverable kidney function are primarily due to decreased kidney perfusion or the administration of nephrotoxic agents.
Kidney hypoperfusion is usually due to hypotension secondary to shock or volume depletion from diarrhoea and vomiting. Perfusion to kidneys can also be hampered by drugs like non-steroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors (ACEI), and angiotensin II receptor blockers (ARBs). Children with CKD often have concomitant tubulopathy with disorders in water and salt retention. They are unable to mount an appropriate response and are more prone to hypovolaemia which can further aggravate the renal function. If significant hypovolaemia is accompanied by a reduction of GFR, a judicious trial of fluid repletion may result in the return of kidney function to the previous baseline.

SLOWING CKD PROGRESSION 
In patients with CKD, progressive long-term kidney damage is in part due to adaptive hyperfiltration with increased intra-glomerular perfusion and pressure. The progression of CKD is greatest during the two periods of rapid growth: infancy and puberty. Although reversal of the process of CKD is not possible a few interventions have been identified to help slow the progression of CKD.

MANAGEMENT OF SPECIFIC COMPLICATIONS

Some children with obstructive uropathy and/or dysplastic kidneys have poor urinary concentrating capacity and exhibit urinary sodium wasting, resulting in a propensity for hypovolaemia and hyponatraemia. These children may continue to have substantial urine output despite water losses and require ongoing fluid and sodium replacement.

Management of hypertension among CKD population includes adoption of both non-pharmacologic as well as pharmacologic therapy. Non pharmacologic intervention includes weight reduction, exercise, and dietary salt reduction (noting that the recommended daily sodium intake is 1.2 g/day for four to eight year olds and 1.5 g/day for older children). ACE inhibitors or ARBs are often the preferred agent as they have a dual action on reducing proteinuria which has been linked to CKD progression. In addition they have anti-fibrotic activity which may also contribute to the slowing of CKD progression.
Both ACE inhibitors and ARBs should be used cautiously if the GFR is less than 60mls/min/1.73m2. Since the decline in GFR induced by an ACE inhibitor typically occurs within the first few days after the onset of therapy, the serum creatinine and potassium concentrations should be rechecked within a week after the institution of therapy to ensure that the therapy has not adversely affected the GFR resulting in elevation of serum creatinine and/or hyperkalemia. In view of the teratogenic potential of these drugs, post pubertal females should be counselled regarding pregnancy.
In addition to ACE inhibition and ARB, diuretics are also often used in situations of fluid overload. Although a thiazide can be used in early CKD it becomes less effective in advanced CKD when loop diuretics prove to be more effective. 

Initial investigation should at least include:

If any underlying contributing factors are identified it should be treated. Iron deficiency is often the most common underlying contributing factor. Iron therapy (elemental iron 3 - 6 mg/kg per day) should be initiated if iron deficiency is detected. Iron supplementation is targeted to maintain a TSAT above 20% and serum ferritin above 100 ng/dl among children with CKD. In addition to iron supplementation, children with CKD often require addition of erythropoiesis stimulating agent (ESA) on account of the diminished erythropoietin secretion from the damaged kidneys. Commonly used ESA are recombinant human eythropoeitin (rHuEPO) or the longer acting darbepoetin alfa. Once iron status is normalised, it should be monitored at least every three months or monthly following the initiation of and/or increase in ESA dosing. Increasing the haemoglobin into an acceptable range in patients with anaemia may ameliorate anaemia-induced symptoms (such as fatigue and exercise intolerance), result in cardiovascular improvement, and possibly decreased mortality. The target haemoglobin for children with CKD is unclear. Limited data suggest that children with CKD having haemoglobin less than 9.9 g/dl are at increased risk for mortality, left ventricular hypertrophy, and/or decreased exercise capacity. In addition, quality of life and neurocognitive function improved in patients treated with rHuEPO who experienced a significant increase in haemoglobin compared to baseline haemoglobin, which was below 9g/dl. K/DOQI has based its recommendation on expert opinion and has recommended target haemoglobin levels between 11 and 12 g/dl. Recent publications of major studies in adults like CHOIR & TREAT have questioned the practice of targeting high haemoglobin which has been found to increase risk of cardiovascular adverse effects, and there is a trend towards accepting lower haemoglobin targets of 10g/dl as adequate.
The initial rHuEPO dose in older children not receiving dialysis is 80 to 120 Units/kg/ week. Children younger than five years of age or children receiving dialysis frequently require higher doses (300Units/kg/week). The response to rHuEPO is monitored by haemoglobin measurement every one to two weeks following the initiation of treatment or following a dose change until stable target haemoglobin and a stable rHuEPO dose has been achieved by which time, it should then be monitored every four weeks.
Failure to mount a good haemoglobin response to ESA is usually iron deficiency. But if the iron level is adequate other factors like persistent infection or inflammation, severe hyperparathyroidism, chronic blood loss, malnutrition, folate or vitamin B12 deficiency need to be ruled out. In addition, one should exclude presence of haemogloinopathies.
  1. Dyslipidaemia: K/DOQI, the American Heart Association (AHA) and the American Academy of Pediatrics (AAP) recommend that all adolescents with CKD should be evaluated for dyslipidaemia which should include total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides at presentation, and annually thereafter or two to three months following a change in treatment or subsequent to the presentation of another condition known to cause dyslipidaemia. Although intervention for dyslipidaemia is of proven benefit among adults with CKD, no such evidence exists for paediatric CKD patients. In absence of any such proven intervention, any recommendation is based only on expert opinion.
  2. Nutrition: malnutrition is often seen in children with CKD. A number of factors can be attributed. These include poor appetite, decreased intestinal absorption of nutrients due to altered transit time, and metabolic acidosis. Attention to nutrition is critical as it affects both the physical growth and neurocognitive development of children.

As per the K/DOQI paediatric guidelines for nutrition the nutritional status of children with CKD should be evaluated on a periodic basis. The frequency should be greater in infancy where early dietary intervention has been shown to definitely improve growth outcome.
Nutritional therapy based upon growth parameters should be developed for each child with CKD and ideally be coordinated by a dietician with expertise in paediatric and renal nutrition. Nutritional management should address the energy, protein, vitamin, mineral and electrolyte needs of the individual patient.
The initial prescribed energy (calories) for children with CKD is based upon the estimated energy requirement (EER) for chronological age. Further supplementation should be considered when the initial intake fails to meet the child's energy requirements and he/she is not achieving expected rates of weight gain and/or growth. Although supplementation by the oral route is preferred, one may have to resort to tube feedings with a nasogastric tube, transpyloric tube, or gastrostomy to ensure adequate energy intake. Protein intake should be between 100 to 140% of the Dietary Reference Intake (DRI) based upon age and gender for children with Stage III CKD and between 100 and 120% for those with Stages IV and V CKD. Protein restriction is not recommended in children as it has not been shown to influence the decrease in kidney function in children with CKD. Children with CKD should receive 100% of the DRIs for the vitamins, thiamine (B1), riboflavin (B2), pyridoxine (B6), vitamin B12, A, C, E, K, and folic acid, and the minerals, copper and zinc. It has to be remembered that children with advanced Stage V CKD might be at an increased risk of developing hypervitaminosis A due to loss of renal clearance of vitamin A metabolites.

The criteria for initiating rHuGH in children with CKD include all of the following:

 rHuGH is continued until the child reaches the 50th centile for mid-parental height, achieves a final adult height with closed epiphyses, or receives a renal transplant
The initial dose of rHuGH in children with CKD is currently 0.05mg/kg per day (corresponds to 4IU/day/ m2 body surface area or 1IU/kg/week); rHuGH is given daily via subcutaneous injections.

If neurodevelopment impairment is identified interventions should include steps such as review of the general CKD management including correction of anaemia, checking the adequacy of the dialysis if the child is on dialysis and ensuring educational support at home and school.

Pre-emptive living-related renal transplantation is often the preferred modality in children as it avoids the problems associated with dialysis. When parents can donate they are a half haplotype match. In these situations, the paediatric nephrologist can prepare the patient and their family for transplantation.
When pre-emptive transplantation is not an option, the choice between the two forms of dialysis is generally dictated by technical, social, concordance issues, and family preference. Peritoneal dialysis is much more common in infants and younger children in large part due to problems of vascular access; haemodialysis becomes more common in older adolescents who have failing peritoneum. Peritoneal dialysis can be performed by parents at home and can be performed overnight with a cycling machine. The use of a cycler potentially allows the least disruption of home life, school, and work attendance, when compared to ambulatory peritoneal dialysis, which often requires a peritoneal dialysis exchange procedure to be conducted during the daytime, or haemodialysis, which usually requires three weekly visits to a haemodialysis centre for at least three to four hours (not counting travel time). In addition, access to a nearby haemodialysis centre may not be readily available to patients and their families or the centre personnel may not be trained to care for children, especially prepubertal children and infants.  However, home haemodialysis programmes are increasing in paediatric practice.

QUALITY OF LIFE 
CKD -as is true for any chronic condition, impacts on the quality of life for both the child and family. A survey of 402 families of 2 to 16 year old children with mild to moderate CKD (median GFR 42.5mls/min/1.73m2) of median duration of seven years found an overall low health related quality of life in children with CKD. They scored lower compared to their healthy peers in all of the four domains tested: physical, school, emotional, and social.
In particular, psychological and social stresses are found in children with CKD and their families. The prospect of a lifetime with renal replacement therapy (dialysis and/or transplant) and the potential for catastrophic complications and/or death makes it difficult to achieve normal childhood and adolescent developmental goals.
Even for those children who progress to adulthood it is usually an uphill task. Studies have shown that compared to age-matched population normative data, these patients are twice as likely to be unemployed (19 versus 11%), and those who were employed are often at a lower occupational level.
The negative impact of chronic disease on the emotional status of the patient's siblings is also well recognised. The siblings frequently feel "neglected" because the parents must provide substantial physical and psychological support to the sick child. Furthermore, the well child may simultaneously feel jealous of the attention provided to the sick child, as well as guilty about being well while the sibling is severely ill.
Optimal comprehensive management of these issues involves a multidisciplinary approach that proactively addresses these concerns.

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Table 1: (KDOQI staging)


Stage

GFR (mL/min/1.73 m2)

I

Kidney damage with normal or ↑ GFR ≥90

II

Kidney damage with mild ↓ GFR 60-89

III

Kidney damage with moderate ↓ GFR 30-59

IV

Kidney damage with severe ↓ GFR 15-29

V

Kidney failure <15 (or on dialysis)

 

 

 

Table 2: Normal GFR in children and young adults


Age (gender)

Schwartz equation
Length in cm & Cr in mg/dl

Mean GFR ± SD mL/min/1.73m2

1 week (males and females)

GFR=0.33*(Length/SCr) in Preterm
GFR=0.45*(Length/SCr) in Term

40.6±14.8

2-8 weeks (males and females)

GFR=0.45*(Length/SCr)

65.8±24.8

>8 weeks (males and females)

GFR=0.45*(Length/SCr)

95.7±21.7

2-12 years (males and females)

GFR=0.55*(Length/SCr)

133.0±27.0

13-21 years (males)

GFR=0.70*(Length/SCr)

140.0±30.0

13-21 years (females)

GFR=0.55*(Length/SCr)

126.0±22.0