Hypertension 347

renovascular hypertension. Renal artery stenosis and renal aneurysm are often
cured by revascularization procedures. In selected cases, percutaneous trans-
luminal angioplasty or stenting of renal arteries may be feasible.

Antihypertensive Drug Therapy

Children with symptomatic and/or secondary hypertension, and those with
features of target organ damage require therapy with antihypertensive
medications. Patients showing persistent hypertension despite nonpharmacologic
measures also need similar treatment.
The Fourth Report on Hypertension in Children recommends a stepped-care
approach to reduce BP. Various classes of medications are used to treat hyper-
tension: angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor
blockers (ARB), calcium channel blockers, -adrenergic blockers, -adrenergic
blockers, diuretics and their combinations. In the absence of underlying
contraindications, ACEI and calcium channel blockers are considered first-line
therapy. As a next step, usually a -adrenergic blocker, -adrenergic blockers
or diuretics are added.

Angiotensin Converting Enzyme Inhibitors (ACEI)

ACEI (enalapril, lisinopril, ramipril, fisinopril) have been demonstrated to be
safe and effective in lowering blood pressure. They are well tolerated by most
patients and do not have any metabolic side effects. The most common adverse
effect is a dry, persistent cough. Hyperkalemia and a reduction in the glomerular
filtration rate (indicated by elevated blood level of urea and creatinine) may occur.
Blood levels of electrolytes and creatinine should be measured 10-14 days
after initiation of therapy. A rare side effect is angioedema. ACEI should be
prescribed cautiously to patients with impaired renal function, and their use
avoided in those with bilateral stenosis of the renal arteries. ACEI are not
recommended during any trimester of pregnancy, since their use may be
associated with fetal and neonatal death, renal tubular dysgenesis and defects
in skeletal developmental.

Angiotensin Receptor Blockers (ARB)

Blockade of the angiotensin II receptor achieves more specific lowering of BP
without production of substance P, and associated side effects, e.g. cough. The
indications, contraindications and guidelines for monitoring are similar to those
advised for ACEI. Although ARB have been less extensively studied in children,
there is published data on the efficacy and safety of losartan, valsartan, irbesartan
and olmesartan in children.
348 Pediatric Nephrology

Calcium Channel Blockers

There are three major groups of calcium channel blockers with distinct properties:
phenylalkylamines (verapamil), dihydropyridines (nifedipine, nicardipine,
amlodipine) and benzothiazepines (diltiazem). Dihydropyridines have relative
selectivity for arteriolar smooth muscle and are most widely used in treatment
of hypertension. Availability of sustained release preparations permits once or
twice daily administration.
Calcium channel blockers are safe and effective in lowering blood pressure.
Side effects include tachycardia, headache and flushing (especially with the fast-
acting dihydropyridines), ankle edema and constipation (with verapamil). These
agents do not have adverse metabolic effects. Amlodipine is a lipophilic
dihydropyridine with a longer duration of action. The tablets can be crushed
or placed in suspension. Children seem to require higher doses of amplodipine
on a per kilogram body weight basis, and twice-a-day regimen of administration
is more effective.

-Adrenoceptor Blockers
-blockers are safe and effective antihypertensive agents, which are widely used
in children. A variety of -blockers are available. Some are cardioselective
(atenolol, metoprolol), while others demonstrate intrinsic sympathomimetic
activity (pindolol) or have -blocking and vasodilator properties (labetalol).
Common side effects of this class of drugs include bradycardia, syncope,
irritability, lethargy, weakness and depression. These drugs are contraindicated
in patients with asthma, diabetes mellitus, congestive heart failure, Raynaud
phenomena and atrioventricular conduction defects.

-Adrenoceptor Blockers
-Adrenoceptor blocking agents (prazosin, phenoxybenzamine, phentolamine)
are effective in lowering blood pressure. Prazosin antagonizes peripheral 1-
adrenergic receptors resulting in dilatation of arteriolar resistance and venous
capacitance vessels. Pediatric experience with this drug is limited. Phenoxy-
benzamine and phentolamine are used exclusively in the treatment of
pheochromocytoma. The main side effect of -blockers is postural hypotension
that may occur after the first dose.

Diuretics
Diuretics are widely used as the first line antihypertensive agents in adults.
Compared to loop diuretics, thiazides (chlorthiazide, hydrochlorthiazide,
chlorthalidone) provide a sustained but less vigorous diuresis. Thiazides are
 Hypertension 349

ineffective in patients with GFR <30 ml/min/1.73 m2. Loop diuretics remain
relatively effective in patients with low GFR and are thus valuable in patients
with chronic renal failure. In large doses, diuretics may cause multiple metabolic
effects, such as hypokalemia, metabolic alkalosis, hyperuricemia and impaired
glucose tolerance. Prolonged therapy with thiazide diuretics has an adverse effect
on the lipid profile.
These drugs are particularly valuable as ancillary treatment to enhance the
effectiveness of other antihypertensive drugs. A combination of diuretics with
potassium sparing drugs or ACEI prevents potassium depletion. Diuretics are
also inexpensive.

Other Drugs
Direct vasodilators, such as hydralazine and minoxidil, are effective in lowering
blood pressure, but some of their side effects (tachycardia, headache and salt
and water retention) make it difficult to use them as monotherapy. Concurrent
use of -blockers or diuretics is usually needed.
Clonidine and methyldopa inhibit central sympathetic output (through
stimulation of 2-adrenergic receptors). Rebound hypertension may occur in
patients who suddenly discontinue using clonidine. Other side effects include
dry mouth, depression, sedation and hallucinations.

Combination of Drugs
The management of children with sustained hypertension starts with low doses
of one drug and titration of the dose to therapeutically effective levels. The initial
drug is usually a -adrenergic or calcium channel blocker, or an ACEI. If one
of the initial medications is ineffective in lowering blood pressure, it is necessary
to use a drug from a different class. If therapy with a single drug is only partly
effective, it is preferable to add a small dose of a drug from another class rather
than increase the dose of a single drug. This permits the addition of different
primary actions while minimizing the homeostatic compensations (in response
to administration of individual drugs) that limit the fall in blood pressure.
Combination therapy also reduces side effects by encouraging the use of drugs
in moderate doses.
An additive effect has been shown when combining a diuretic with a -blocker,
ACEI or a dihydropyridine calcium antagonist. A similar effect is seen when
a -blocker is combined with a -blocker. In difficult situations (chronic GN,
post-transplantation), other drugs including hydralazine, clonidine, prazosin or
minoxidil may be used to lower the blood pressure.
350 Pediatric Nephrology

Administration of multiple drugs in a small child is difficult but compliance

must be ensured. Single agent therapy with an ACEI (enalapril, ramipril) or a
calcium channel blocker (nifedipine, amlodepine) may be sufficient to control
moderate hypertension. Stepwise reduction of antihypertensive medication may
be possible in some patients after blood pressure has remained in the normal
range for 8-12 months. A list of common antihypertensive drugs and dosage
is given in Table 17.6.

HYPERTENSIVE EMERGENCIES
Blood pressure levels 5-10 mm above the 99th centile or diastolic blood pressure
more than 110 mm Hg are considered ‘severe’. Patients with severe hypertension
are likely to manifest clinical features of end organ involvement and need urgent
attention. The condition can be life threatening with serious sequelae if therapy
is inadequate. Over enthusiastic therapy with precipitous decline of blood pressure
(particularly in patients with long standing hypertension) should be avoided.

Clinical Features
Hypertensive emergencies are typically associated with a rapid rise in blood
pressure. Chronic elevations of blood pressure are usually well tolerated with
few symptoms. The child may present with features of encephalopathy. Thus,
there may be headache, vomiting, ataxia, sensorial disturbances, stupor and
seizures. Focal neurological deficits such as hemiparesis, blurring and transient
loss of vision may be present.

Key points: Pharmacologic therapy

• Indications for therapy include secondary hypertension, features of end organ
damage and unsatisfactory response of hypertension to lifestyle modifications
• Dosing recommendations for many medications are now available for children
• Initial therapy should be with a single drug
• The goal for antihypertensive treatment should be reduction of pressures
below the 90th percentile
• Severe symptomatic hypertension should be treated with intravenous
antihypertensive drugs.

Management
The immediate aim is to bring the blood pressure down to safe (yet still
hypertensive) values followed by a gradual reduction to normal over the next
48 hours. At the same time, supportive measures are instituted to manage various
complications that may be present, such as seizures, heart failure and airway
obstruction.
 Hypertension 351

Table 17.6: Drugs for long-term treatment of hypertension

Drug Initial dose Maximum dose Divided daily
(per kg/day) (per kg/day) doses
Vasodilators
Hydralazine 1-2 mg 5-8 mg 3-4
Minoxidil1 0.1-0.2 mg 1 mg 1-2
Prazosin 50-100 μg 500 μg 2-3
Central alpha-agonist
Clonidine2 5-7 μg 25 μg 3
Adrenergic blockers
Atenolol3 1 mg 2 mg 1
Propranolol 1-2 mg 4 mg 3
Metoprolol 1-2 mg 6 mg 2
Labetalol 1-3 mg 10-12 mg 2
Phenoxybenzamine 0.2 mg 1-2 mg 2
Calcium channel blockers
Nifedipine4 (slow release) 0.25 mg 3 mg 1-2
Amlodepine 0.05-0.2 mg 0.6 mg 1-2
Angiotensin converting enzyme inhibitors (ACEI)5
Captopril 0.3 mg 5 mg 3
Enalapril 0.1 mg 0.5-1 mg 1-2
Lisinopril 0.05 mg 0.6 mg 1
Ramipril 5-6 mg/m2 per day
Angiotensin receptor blockers (ARB)5
Losartan 0.5-0.6 mg 1 mg 1
Irbesartan (total dose)
6-12 years 75-150 mg/day 1
> 3 years 150-300 mg/day 1
Valsartan (more than 6 years) 1.3 mg 2.7 mg 1
Diuretics
Hydrochlorthiazide6 0.5-1 mg 2-4 mg 2
Chlorthalidone 0.25 mg 2 mg 1
Frusemide 0.5 mg 5-6 mg 1-2
Spironolactone7 1 mg 3 mg 1-2

ACE inhibitors and atenolol are dialyzable

The maximum recommended adult dose should not be exceeded in routine clinical practice.
1
Powerful vasodilator; balance side effects against benefit; usually reserved for patients with
hypertension resistant to multiple drugs
2
Risk of rebound hypertension on abrupt discontinuation
3
Decrease dose by 50% at GFR <50 ml/min/1.73 m2; give on alternate day at GFR <10 ml/min/
1.73 m2
4
Extended release nifedipine must be swallowed whole, without crushing
5
Lower doses are used in neonates
5
ACEI and ARB are useful in treatment of renal parenchymal hypertension. Renal artery stenosis
is a relative contraindication
5
Caution when GFR <30 ml/min/1.73 m2; monitor serum potassium and creatinine periodically
6
Thiazides not effective at GFR <30-40 ml/min/1.73 m2
7
Potassium sparing diuretics may cause severe hyperkalemia, especially when used in combination
with ACE inhibitors or ARB
352 Pediatric Nephrology

Potent agents (Table 17.7) are available that decrease the blood pressure within
a few minutes. Reduction of blood pressure should, however, be achieved slowly,
since a precipitous fall in blood pressure can lead to neurological sequelae.
Patients with long standing hypertension, renovascular disease or those having
neurological symptoms and signs are particularly susceptible to develop such
complications. The patient must be closely monitored during treatment to detect
hypotension. The neurological status and pupillary reaction should be frequently
examined.
Approximately a third of the desired reduction should be made over the first
8 hours, with gradual normalizing the blood pressure over 26-48 hours. The target
blood pressure level is the 95th centile of the systolic value for the age and sex.
It is preferable to administer the antihypertensive drug by constant infusion with
careful regulation of the dose to achieve a controlled fall in blood pressure. The
risk of hypotension is greater with sublingual administration of nifedipine.

Sodium Nitroprusside
Blood pressure and pulse rate is monitored continuously and the changes in the
rate of infusion are made after constant readings of blood pressure are obtained.
The infusion of sodium nitroprusside is gradually tapered once the blood pressure
has been reduced to safe levels. Sodium nitroprusside is not stable when exposed
to sunlight. The bottle and the infusion line should be wrapped in an aluminum
foil. The drug should be used with caution in severe renal or hepatic dysfunction
and impaired cerebral circulation. Thiocyanate toxicity may occur if the drug
is used for more than 72 hours.

Labetalol
Constant infusion of labetalol is the method of choice for the treatment of
hypertensive emergency. Unfortunately, the IV preparation is not easily available
in this country. The dose is 1 to 3 mg/kg/hour, titrated by incremental infusion
according to the level of blood pressure. The same precautions as during the
infusion of sodium nitroprusside are observed. No dosage reduction is required
in renal or hepatic impairment.

Nifedipine
This drug is given at a dose of 0.25 mg/kg/dose orally or sublingually; little
absorption takes place by the latter route. The drug must be removed from the
capsule or the patient bites through the capsule. Lowering of blood pressure is
observed within a few minutes. The absorption of nifedipine is erratic and the
response unpredictable. The dose can be repeated, if necessary, twice at 10-minute
 Table 17.7: Treatment of hypertensive emergencies
Drug Dosage Side effects Onset of action Duration
Sodium 0.5-8 μg/kg/min IV infusion Nausea, muscle twitching, headache, Immediate Short half life
nitroprusside1,2 tachycardia; cyanide toxicity (especially
if used for >72 hours or in renal failure)
Labetalol3 Infusion: 0.5-3 mg/kg per hour, or Transient nausea, pallor, bradycardia 2-10 min 2-3 hours
Bolus: 0.2-1 mg/kg bolus IV Avoid in patients with asthma, congestive
heart failure
Nifedipine 0.25-0.5 mg/kg oral or sublingual Increased cerebral blood flow: flushing, 5-30 min Up to 6 hours
(bite and swallow); maximum headache, syncope; unpredictable
single dose 5-10 mg hypotension
Nicardipine 1-3 μg/kg/min IV infusion Flushing, reflex tachycardia; increase 1-2 min 10-15 min
cyclosporin levels
Hydralazine 0.1-0.5 mg/kg/dose slow IV; Tachycardia, palpitations, flushing, 5-20 min 4-12 hours
can be repeated after 4 hours headache, fluid retention

1
Sodium nitroprusside is reconstituted in 5 percent dextrose to achieve a final concentration of 50 to 200 mg/ml. In fluid restricted patients, an infusion
concentration of 1 mg/ml may be used at the rate of 0.5 to 8 mg/kg/IV in incremental amounts, starting with the lower dose hours
2
In case the blood pressure falls too rapidly or below the desired level, a bolus of 50 ml of 0.9 percent saline may be administered hours
3
The drug is diluted in 5 percent glucose and given slowly.
Hypertension
353
354 Pediatric Nephrology

intervals. Nifedipine is available in 5 and 10 mg capsules. The medication is

very sensitive to light. Capsule contents or the crushed tablet should be used
immediately to avoid significant loss in potency of the drug.
Children with long standing hypertension show impaired cerebral
autoregulation of blood flow and are at high risk of neurologic sequelae following
rapid lowering of blood pressure. It is prudent to avoid nifedipine in these
circumstances. Oral nifedipine can be safely used for treatment of acute severe
hypertension. Patients having seizures, loss of consciousness, pulmonary edema
or congestive cardiac failure should preferably receive IV nitroprusside or
labetalol.
Children with severe hypertension may be salt depleted on presentation and
routine administration of diuretics is not recommended, since volume contraction
and severe hypotension may ensue. However, if there is evidence of salt and
fluid overload (e.g. in acute glomerulonephritis) and renal function is adequate,
frusemide should be administered intravenously.

Risk of Hypotension
Occasionally, a rapid fall in blood pressure may cause permanent neurological
sequelae. The risk of such complications is particularly greater in patients with
chronic, severe hypertension with end organ damage such as retinopathy and
left ventricular enlargement. In such cases there is a loss of relative vascular
elasticity and narrowing of lumina. Such vessels cannot readily react to changes
in blood flow, especially due to hypotension. In the brain there is loss of
autoregulation, and rapid hypotension may lead to ischemic injury especially
to the visual cortex and the optic nerve.
Careful administration of appropriate medications and close monitoring are
important to balance the risks of cerebral hemorrhage (due to hypertension and
ischemic complications from hypotension. Caution must be exercised and a
precipitous fall in blood pressure corrected with rapid administration of 0.9
percent saline.

Subsequent Care
Once the blood pressure has been brought down to safe levels, maintenance oral
treatment is introduced gradually, keeping in mind the underlying cause of
hypertension. Medications such as nifedipine (in a slow-release form), ACEI
and -blockers are highly effective. Other agents such as hydralazine, clonidine,
prazosin may also be required. Appropriate evaluation should be carried out to
determine the cause of hypertension.
 Hypertension 355

ESSENTIAL (PRIMARY) HYPERTENSION

Mild asymptomatic hypertension is occasionally detected on incidental
examination of an older child or adolescent. There may be a family history of
hypertension. Genetic factors play a role in hypertension independent of diet
and habitus. An association between low birth weight (with reduced number
of nephrons in the kidneys) and hypertension later in life has also been suggested.

Obesity and Hypertension: The Metabolic Syndrome

Obesity is in children and adolescents rapidly becoming a major health concern
not only in USA, Europe and Japan, but also in urban affluent communities in
developing countries. The association between obesity and hypertension is well
recognized. Obesity, in particular upper body obesity, is an independent risk
factor for hypertension in children and adolescents. Both prehypertension and
hypertension are commonly detected in obese children. The mechanisms include
insulin resistance leading to salt and water retention, activation of the renin-
angiotensin system, secretion of leptin by adipocytes leading to increased
sympathetic outflow and altered vascular reactivity in obese children. Weight
loss is associated with improved BP in children and adolescents with
hypertension.

Tracking
A child’s blood pressure tends to remain in the same centile as he grows. Thus
a 7-year-old boy with blood pressure at the 90th percentile for height is likely
to have blood pressure at the same percentile at the age of 15 years. Children
with blood pressure consistently in the higher percentiles are at greater risk for
complications of hypertension.

Treatment
A diagnosis of essential hypertension is rarely made below the age of ten years.
Careful clinical and laboratory evaluation is required in each case. The goal of
treatment is to lower the blood pressure below the 90th percentile. Treatment
is particularly important in children with a family history of early complications
of hypertension (heart disease, cerebral vascular complications, renal failure).
Nonpharmacological measures and changes in life style are initially advised.
Reducing body fat is very effective in lowering blood pressure in children. Other
measures include stoppage of smoking, regular physical exercise (30-60 minutes
a day, 3 days per week) and reduction of dietary sodium to 1 mEq/kg/day.
If hypertension persists or there is evidence of left ventricular hypertrophy,
small doses of beta-adrenergic blocking agents (atenolol or propranolol), ACEI
356 Pediatric Nephrology

(enalapril), or calcium channel blockers (nifedipine) may be used. Regular follow-

up visits are required to assess control of hypertension. After 6 to 12 months
of treatment, antihypertensive drugs may be reduced and blood measurements
obtained frequently. It may be possible to discontinue treatment in some patients.

Key points: Primary hypertension

• Primary hypertension is identifiable in children and adolescents, often in
association with obesity
• Weight reduction and regular physical activity are important components of
therapy
• Dietary modifications should be strongly encouraged
• The presence of target organ damage (chiefly left ventricular hypertrophy)
is an indication to initiate or intensify pharmacologic therapy.

Exercise in Hypertensive Children

Children and adolescents who have systemic hypertension are at risk for
complications when certain exercises cause their blood pressures to rise even
higher. Hypertensive children should avoid highly static (isometric) exercises
like weight and power lifting, gymnastics and body building. Children with no
evidence of target organ involvement can participate in all sports once their high
blood pressure is controlled.

RARE CAUSES OF HYPERTENSION

When there is no obvious cause for hypertension, several rare conditions
should be considered (Table 17.8). Some of these are amenable to specific
treatment.

Table 17.8: Monogenic forms of hypertension

Condition Inheritance Gene locus Gene product
Liddle syndrome AD 16p Epithelial sodium
channel, ENAC
Syndrome of apparent AR 16q 11 -hydroxysteroid
mineralocorticoid excess dehydrogenase type II
Glucocorticoid remediable AD 8q Aldosterone synthase
aldosteronism CYP11B2
Gordon syndrome AD 12p WNK1
17q WNK4
Congenital adrenal AR 8q 11 -hydroxylase
hyperplasia AR 10q 17 -hydroxylase

AR—autosomal recessive; AD—autosomal dominant

 Hypertension 357

Syndromes with Hypertension, Hypokalemia and

Metabolic Alkalosis
In normal conditions, aldosterone is the chief mineralocorticoid regulating
electrolyte and water balance through its effects on distal tubules and cortical
collecting ducts. Following its binding to a nuclear mineralocorticoid receptor,
aldosterone increases synthesis of various proteins, chiefly Na-K ATPase on the
basolateral surface and epithelial sodium channels (ENaC) on the apical surface
(Chapter 1). These proteins increase sodium reabsorption and potassium secretion
in the distal tubules. Cortisol is also a ligand for the mineralocorticoid receptor
and shows potent salt retaining activity. Cortisol is, however, normally metabolized
by 11 -hydroxysteroid dehydrogenase to cortisone, which lacks such an action.

Liddle Syndrome (Pseudohyperaldosteronism)

Liddle syndrome is an autosomal dominant condition that occurs due to
constitutive overactivity of the ENaC resulting in features akin to hyperaldo-
steronism. Enhanced Na+ reabsorption in the distal nephron leads to volume
expansion, hypertension and suppressed renin and aldosterone secretion.
Functional coupling of Na+ reabsorption to K+ and H+ secretion in the distal
nephron leads to hypokalemic alkalosis.
Liddle syndrome predominantly manifests in teenage children with variable
polyuria, increased thirst, failure to thrive and hypertension. Patients are at risk
of cerebral hemorrhage and cardiovascular disease. Hypokalemic metabolic
alkalosis with low blood levels of renin and aldosterone are characteristic. Levels
of urinary mineralocorticoids are within normal limits. Salt restriction or K+
supplements do not increase aldosterone secretion. No improvement is seen after
administration of the mineralocorticoid receptor blocker, spironolactone.
Liddle syndrome should be distinguished from primary hyperaldosteronism,
syndrome of apparent mineralocorticoid excess, glucocorticoid-remediable
aldosteronism and deficiency of 11 -hydroxylase or 17 -hydroxylase enzymes.
Therapy consists of restriction of salt intake and administration of K +
supplements. Triamterene (2-4; up to 6 mg/kg/d; maximum dose 300 mg daily)
directly inhibits ENaC, resulting in increased urinary Na+ and decreased K+
excretion and resolution of hypertension. Amiloride (0.1-0.2 mg/kg q12 h,
maximum dose 10 mg daily) may also be used.

Apparent Mineralocorticoid Excess (AME)

This is an autosomal recessive condition due to deficiency of the renal isoform
of the enzyme 11 -hydroxysteroid dehydrogenase. Deficiency of this enzyme
results in high intrarenal levels of cortisol, which binds to mineralocorticoid
358 Pediatric Nephrology

receptors resulting in Na+ retention and urinary K+ loss. Carbenoxolone or

glycyrrhizinic acid (found in licorice compounds) are potent inhibitors of this
enzyme. Consumption of these agents may therefore be associated with features
similar to AME.
Clinical features of this condition closely mimic those of Liddle syndrome
and include polyuria, increased thirst, failure to thrive and early-onset hyper-
tension. There is history of intrauterine growth retardation. Marked hypokalemia
and metabolic alkalosis is present. Plasma renin and aldosterone levels are low.
The diagnosis of AME is made by detecting elevated urinary levels of hydro-
genated metabolites of cortisol to cortisone (tetrahydrocortisol + allotetrahy-
drocortisol: tetrahydrocortisone).
Treatment with oral dexamethasone (10-30 μg/kg daily) suppresses cortisol
secretion resulting in reduced Na+ reabsorption and amelioration of hypertension
and hypokalemia. Patients also respond to treatment with potassium supplements
combined with spironolactone, triamterene or amiloride.

Glucocorticoid Remediable Aldosteronism (GRA)

This condition is characterized by increased expression of a chimeric gene
regulating production of aldosterone synthase that results in increased synthesis
of aldosterone, and moderate to severe hypertension. The risk of hemorrhagic
stroke and ruptured intracranial aneurysms is high. Hypokalemia is characteristic,
but serum K+ may be normal.
Levels of plasma renin activity are reduced. Though the mean aldosterone
levels are high, determination of serum aldosterone has poor sensitivity as a
screening test. Hyperaldosteronism is increased by administration of
corticotrophin and reduced by glucocorticoids. Following dexamethasone
suppression, an aldosterone level of <4 ng/dl is strongly suggestive of GRA.
Increased urinary excretion of 18-oxocortisol and 18-hydroxycortisol is
characteristic. Treatment with low-dose dexamethasone is useful in reducing
blood pressure and correcting electrolyte disturbances.

Adrenal Enzymatic Disorders

Inherited deficiency of 11 -hydroxylase or 17 -hydroxylase cause mineralo-
corticoid excess with hypertension and hypokalemic metabolic alkalosis.
Replacement with corticosteroids is beneficial.

Gordon Syndrome
This autosomal dominant disorder is characterized by hypertension, hyperkalemia
and hyperchloremic metabolic acidosis with normal GFR. Hyperkalemia may
 Hypertension 359

be present from birth, but as in GRA, hypertension may not develop until later
in life. Some patients may have short stature, intellectual impairment, muscle
weakness, hypercalciuria and renal stones. Plasma renin and aldosterone are
reduced. Treatment with hydrochlorthiazide (1-2 mg/kg/d) or frusemide (1-2 mg/
kg/d) results in reversal of clinical and biochemical abnormalities. Sodium
bicarbonate may be required to correct acidosis.

BIBLIOGRAPHY
1. Adelman RD, Coppo R, Dillon MJ. The emergency management of severe hypertension.
Pediatr Nephrol 2000;14:422-27.
2. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure:
The JNC 7 Report. JAMA 2003;289:2560-72.
3. Dillon MJ. The diagnosis of renovascular disease. Pediatr Nephrol 1997;11:366-72.
4. Flynn JT. Pediatric hypertension update. Curr Opinion Nephrol Hypertension 2010;
19:292-97.
5. Goble MM. Hypertension in infancy. Pediatr Clin North Am 1993;40:105-22.
6. Goonasekera CD, Dillon MJ. Measurement and interpretation of blood pressure. Arch
Dis Child 2000;82:261-65.
7. Hari P, Bagga A, Srivastava RN. Hypertension in children. Indian Pediatr 2000;37:
268-74.
8. Hiner LB, Falkner B. Renovascular hypertension in children. Pediatr Clin North Am
1993;40:123-40.
9. Sorof JM, Cardwell G, Franco K, Portman RJ. Ambulatory blood pressure and left
ventricular mass index in hypertensive children. Hypertension 2002; 39:903-08.
10. Sorof JM. Systolic hypertension in children: Benign or beware? Pediatr Nephrol 2001;
16:517-25.
11. The Fourth Report on the Diagnosis, Evaluation and Treatment of High Blood Pressure
in Children and Adolescents. Pediatrics 2004;114:555-76.
360 Pediatric Nephrology

18 Chronic Kidney
Disease
Aditi Sinha

Chronic renal failure (CRF) implies irreversible loss of renal function that
eventually requires renal replacement therapy. The underlying etiology includes
a variety of conditions, congenital and acquired. The decline in function is often
mild but slowly progressive. Early detection and appropriate management of
various conditions, which have a potential to cause increasing kidney damage,
can retard the decline of renal function and delay the development of end stage
renal disease (ESRD). The terms CRF and chronic renal insufficiency have now
been replaced by the more appropriate and useful title of “chronic kidney disease”
(CKD). This term was proposed by the National Kidney Foundation-Kidney
Disease and Outcome Quality Initiative (NKF-KDOQI) group to classify any
patient who has kidney damage lasting for at least 3 months with or without
a decreased glomerular filtration rate (GFR), or any patient who has a GFR of
less than 60 ml/min per 1.73 m2 lasting for 3 months with or without kidney
damage. The severity of CKD has been graded on the basis of GFR.

STAGES OF CHRONIC KIDNEY DISEASE

CKD can be divided in 5 stages, based on the level of GFR, which is estimated
in children from the level of serum creatinine and height, using the Schwartz
formula (Table 18.1). This classification, proposed by the NKF-KDOQI, is useful
to standardize definitions and allow categorization of patients worldwide. The
nomenclature is popular since it assists both physicians and parents in
understanding disease severity, anticipating comorbidities and planning therapy.
The CKD classification is criticized in two respects: stages 1 and 2 are defined
better by the associated abnormalities (e.g. proteinuria, hematuria, structural
anomalies) than by the estimated GFR; secondly, GFR varies with age, gender,
and body size, increasing with renal maturation from infancy to reach adult values
at 2 years of age. Hence, the GFR ranges defining the CKD stages apply only
to children >2-year-old.
Previously, the terms chronic renal insufficiency and chronic renal failure
(CRF) have been used to signify GFR levels between 50 and 25 percent and
 Chronic Kidney Disease 361

Table 18.1: Stages of chronic kidney disease

Stage GFR, ml/min/1.73 m2 Description
1 90 Kidney damage with normal or increased GFR
2 60-89 Kidney damage with mild reduction of GFR
3 30-59 Moderate reduction of GFR
4 15-29 Severe reduction of GFR
5 <15 Kidney failure
5D <15, on dialysis Kidney failure, dialysis dependent
GFR: Glomerular filtration rate

<25 percent of normal respectively. The GFR is even lower (6-8%) in patients
with end stage renal disease (ESRD); these patients show life-threatening
biochemical abnormalities that persist despite medical management and can be
corrected only by maintenance dialysis or transplantation. The term CKD with
the qualifying grades (1 to 5) is now widely accepted.

EPIDEMIOLOGY
The prevalence of CKD among children, <16-year-old, is 1.5-3.0 per 1,000,000
child population. Estimates of occurrence of preterminal CKD from registry data
from the United States, Europe, Italy, Australia and New Zealand and Japan
suggest an incidence of 4-12 cases per year per million of the age-related
population (MARP) and a point prevalence of 21-82 cases per MARP. The
incidence and prevalence rates for ESRD are greater for boys, for older children,
and in African-Americans. Information on the prevalence, stages and management
of childhood CKD within our country is limited; in two reports from North India,
12% and 50% of patients presenting to pediatric nephrology services had ESRD.

Etiology
Important conditions causing CKD are shown in Table 18.2. In our country,
glomerulonephritis is reported as the main cause of CRF responsible for more
than a third of all cases. Reflux nephropathy, congenital renal anomalies, obstructive
uropathy and hereditary nephropathies account for the remainder. During neonatal
period and infancy important causes include obstructive uropathy, renal cortical
necrosis, infantile polycystic kidney disease and renal hypoplasia.
In developed countries where CKD is diagnosed earlier, congenital causes
are responsible for most cases of end stage renal disease. According to the data
from the North American Pediatric Renal Trial and Collaborative Studies
(NAPRTCS), structural causes (obstructive uropathy and aplasia/hypoplasia/
dysplasia contribute 16% each), with focal segmental glomerulosclerosis (12%),
362 Pediatric Nephrology

Table 18.2: Causes of chronic renal failure

Glomerulonephritis
Idiopathic
Associated with multisystem diseases: SLE, polyarteritis nodosa,
Henoch-Schönlein purpura, microscopic polyarteritis
Familial nephropathy
Nephronophthisis, Alport syndrome, congenital nephrotic syndrome
Amyloidosis
Hemolytic uremic syndrome
Congenital anomalies
Bilateral renal dysplasia, hypoplasia, polycystic kidney disease
Reflux nephropathy
Obstructive uropathy
Pelviureteric or ureterovesical junction obstruction
Posterior urethral valve, calculi
Miscellaneous
Bilateral Wilms tumor
Renal cortical necrosis

reflux nephropathy (5%) and glomerulonephritis (3%), accounting for the

remainder. Though the literature from developing countries in scant, chronic
glomerulonephritis and infection associated glomerular diseases are considered
important contributors to the burden of pediatric CKD. Disorders that put children
at risk for CKD are listed in Table 18.3.

ASSESSMENT AND FOLLOW-UP

Careful urine examination should be periodically carried out. Those with 1+ or
more proteinuria should have a quantitative test (protein/creatinine ratio on spot

Table 18.3: Risk factors for chronic kidney disease

• VUR associated with recurrent urinary infections and renal scarring

• Obstructive uropathy
• Prior history of acute nephritis or nephrotic syndrome
• Children with history of renal failure in perinatal period
• Family history of polycystic kidneys or genetic renal conditions
• Renal dysplasia or hypoplasia
• Low birth weight infants
• Prior history of Henoch-Schönlein purpura
• Presence of diabetes, hypertension
• Systemic lupus erythematosus, vasculitis.
 Chronic Kidney Disease 363

urine or measurement in a timed collection). Detailed evaluation should be

performed in patients with persistent proteinuria. Other markers of kidney damage
include active urinary sediment (WBCs, RBCs and RBC casts) and imaging
abnormalities. Early diagnosis and appropriate treatment and other therapeutic
interventions aimed at delaying the progression of renal damage and management
of comorbidities can be instituted.

Key points: Diagnosis and staging of

chronic kidney disease
• The term ‘chronic kidney disease’ is preferable to ‘chronic renal failure’.
• Any structural abnormality or functional impairment of kidney(s) that persists
for 3 months is termed chronic kidney disease, regardless of severity
• Chronic kidney disease is staged according to estimated GFR, from normal
renal function (stage 1) to severe kidney disease, previously termed end stage
renal disease (stage 5)
• The terminology is applicable to children above 2 years of age
• The GFR is estimated by the Schwartz or modified Schwartz formulae
• Glomerulonephritis, congenital renal and urological anomalies and reflux
nephropathy account for majority of pediatric CKD burden
• Children with history of acute kidney injury, recurrent urinary tract infections,
corrected obstructive uropathy, and unilateral or bilateral structural
abnormalities require follow-up in view of risk of development of renal
impairment in future.

RENAL RESPONSE TO NEPHRON LOSS

The kidneys have the ability to maintain chemical homeostasis in spite of the
loss of a large proportion of nephrons. This adaptation involves changes in the
remnant glomerular and tubular function and structure.

Functional Changes
Increase in Single Nephron GFR (SNGFR)
Loss of nephrons is associated with an increase in glomerular blood flow in the
remaining normal nephrons. There is dilatation of the afferent and the efferent
arterioles, the afferent dilating more than the efferent. This enhances the
transcapillary hydraulic pressure and increases the GFR. Thus, the whole kidney
GFR is augmented.

Maintenance of Tubuloglomerular Balance

Increased filtration in normal glomeruli is matched by a proportionate increase
in reabsorption in the corresponding tubules. For example, a child with a body
364 Pediatric Nephrology

surface area of 1 m2 and a GFR of 70 ml/min has a 24 hours-GFR of 70 × 60 × 24,

approximately 100 liters. About 99 percent of the filtered water is reabsorbed
and the daily urine volume is 1 liter. A decrease in the number of nephrons by
25 percent is followed by a proportionate increase in the SNGFR of the remaining
nephrons to maintain the whole kidney GFR at 100 liters/day. If the rate of
reabsorption by each tubule had remained unchanged, the total reabsorption
would decrease by 25 percent (since there are 25% less tubules) and the urine
volume would increase to 25 liters/day. However, the tubular absorption increases
in parallel with the increased filtration so that 99 percent of the filtered water
is still reabsorbed by 75 percent of the nephrons, and the urine output remains
at 1 liter.
The absorption of sodium, glucose and amino acids is adjusted similarly. The
tubular handling of substances that are excreted wholly or partly by secretion,
such as potassium and fixed acids, is also modified to keep pace with the decline
in the number of tubules.

Structural Changes
There is an increase in glomerular volume secondary to the hemodynamically
mediated increase in capillary lumen volume and hypertrophy of cellular and
matrix constitutents of the glomerulus. There is also an increase in the size and
volume of the tubules involving predominantly the proximal tubules.

PROGRESSION OF RENAL DAMAGE

Regardless of the etiology of CKD, once there is a critical loss of nephron mass,
the renal failure is progressive. As a significant proportion of nephrons are
damaged, the remaining compensate for the loss of renal function. These nephrons
undergo progressive hyperperfusion and hyperfiltration that gradually causes
increasing glomerular injury and sclerosis (Fig. 18.1).
As GFR decreases, there is an increase in serum creatinine. Without major
intervention or additional renal damage, the reciprocal of serum creatinine
decreases with time in a relatively linear manner. The rate of decline in GFR,
however, varies in different individuals and diseases.

Risk Factors Associated with Disease Progression

A reduction in GFR is a risk factor for renal progression, with studies in children
showing that a higher CKD stage is associated with faster progression to renal
failure. It is also proposed that renal function does not deteriorate linearly but
declines rather sharply during puberty.
 Chronic Kidney Disease 365

Fig. 18.1: Progression of chronic kidney disease

Proteinuria and hypertension are important and independent risk factors for
progression to end stage renal disease. Progression of CKD is therefore faster
in patients with heavy proteinuria. Results from the multinational ESCAPE trial
(Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of
Chronic Renal Failure in Pediatric Patients) suggest that the amount of residual
proteinuria after ACE inhibition correlates with rate of GFR decline. Multiple
studies in adults and children confirm that hypertension is an important risk factor
for progressive kidney disease. Additionally, absence of the normal nocturnal
fall in blood pressure (non-dipping), a characteristic of renovascular hypertension,
is associated with progression of kidney disease in adults.
Systemic hypertension is associated with loss of glomerular autoregulation,
leading to intraglomerular hypertension that causes increased filtration pressure,
glomerular injury and proteinuria. Proteinuria triggers vasoactive signaling with
release of angiotensin-II, aldosterone and endothelin-I, as well as
proinflammatory signaling mediated through RANTES, NFkB and MCP-1. The
latter mediates macrophage invasion and epithelial mesenchymal transformation,
promoting inflammation and fibrosis. Vasoactive signaling causes decrease in
tissue protease activity through increase in tissue inhibitors of metalloproteinases
and plasminogen activator inhibitor. Both pathways promote increased synthesis
of transforming growth factor (TGF) , which promotes collagen and matrix
protein synthesis, leading to tissue fibrosis and reduction in nephron mass. These
pathways provide potential targets for interventions aimed at retarding progression
of CKD. Other factors contributing to scarring and glomerulosclerosis include
366 Pediatric Nephrology

platelet derived growth factor, fibroblast growth factor, insulin like growth factor-
1, growth hormone, interleukin (IL)-1, IL-6 and tumor necrosis factor.
Other factors that are associated with CKD progression include anemia,
dyslipidemia, metabolic acidosis and hyperuricemia. Infants who are small for
gestational age are believed to have a paucity of nephrons and develop
hypertension in addition to type II diabetes, dyslipidemia and obesity as adults.
The metabolic syndrome with insulin resistance was linked to a risk for CKD
and microalbuminuria in non-diabetic adults.

SYSTEMIC FEATURES
The clinical features in patients with advanced CKD (stage 3-5) include anorexia,
failure to thrive, growth retardation, fatigue, anemia, hypertension and bone
disease. The late features, with extreme reduction of GFR, are itching, severe
acidosis, hyperkalemia, left ventricular failure and pulmonary edema, pericarditis
and altered sensorium. The possibility of CKD should be considered when one
or more of these manifestations are present without an obvious cause.

Growth Retardation
During the first 2 years of life growth is chiefly nutrition dependent, during
childhood it is under the influence of growth hormone, while gonadal hormones
play a major role during puberty. Growth impairment and retardation of sexual
development are common and important consequences of chronic renal failure
in children. Linear growth slows or stops. Skeletal maturation is also retarded,
so both the height and bone age lag behind the chronological age. The slowing
of linear growth leads to particularly severe height loss in infants, since children
with normal renal function achieve one-third of their final adult height during
the first 2 years after birth. In the 2 to 3 years prior to puberty the height velocity
again decreases disproportionately. The onset of pubertal growth spurt is delayed
although it occurs at the appropriate bone age. Thus, the height reduction in
CKD mainly results from suppression of growth during two periods, infancy
and puberty.
The causes of growth failure include poor nutrition, metabolic acidosis, bone
disease and anemia. In children with obstructive uropathy and renal dysplasia,
salt wasting and recurrent dehydration are also important. Plasma growth hormone
(GH) levels are normal or high but levels of insulin like growth factor (IGF)-
1 are reduced. Resistance to actions of GH may be mediated by reduced
concentrations of GH receptors and by upregulation of intracellular inhibitors,
which alter phosphorylation of these receptors. Levels of hormones important
for pubertal growth, e.g. luteinizing hormone and testosterone are reduced.
 Chronic Kidney Disease 367

Malnutrition
Children with CKD usually have multiple nutritional deficiencies. The causes
for malnutrition include anorexia, nausea and vomiting from uremic gastritis,
an abnormal sense of taste, and imposition of a variety of appropriate or
inappropriate dietary restrictions. Restriction of the normally recommended
protein intake is not required, as there is no evidence that protein restriction
slows the progression of renal disease in children. Children with advanced CKD
are often advised dietary salt, phosphate and/or potassium restriction. Salt
restriction makes food unpalatable for already anorexic children, while other
restrictions limit food choices. Patients on maintenance dialysis lose protein,
vitamins and essential minerals. Protein losses are particularly high in those on
chronic peritoneal dialysis.

Anemia
Anemia is a major and predictable consequence of CKD, which develops once
the renal function decreases to less than 50%. It may often be the first clue to
a kidney disease. Anemia is the chief cause of fatigability and reduced exercise
tolerance and left ventricular hypertrophy. The peripheral blood shows
normocytic normochromic red cells but features of superadded iron deficiency
might also be present. The bone marrow morphology shows a slightly decreased
or normal erythroid-myeloid ratio.
The chief cause of anemia is the lack of erythropoietin production by the
peritubular interstitial cells of inner cortex and outer medulla of the kidney. Other
contributory factors include uremic suppression of the bone marrow, decreased
RBC lifespan, poor appetite causing iron and folate deficiency, myelofibrosis
secondary to hyperparathyroidism, and blood losses and increased red blood cell
destruction once the patient begins dialysis, particularly hemodialysis. Decreased
appetite often limits the dietary intake of iron. Folate deficiency is likely to occur
in patients on maintenance dialysis, since folic acid is dialyzable. Gastrointestinal
blood loss can also contribute to anemia. The bleeding tendency is aggravated
by platelet dysfunction. Aluminum toxicity, from absorption of aluminum
containing antacids, is an important cause of anemia in patients on maintenance
dialysis.
Anemia reduces physical capacity and neurocognitive function and worsens
quality of life, both in predialysis and dialysis patients. Anemia also induces
adaptive cardiovascular mechanisms, which result in left ventricular hypertrophy
and dilatation, and myocardial ischemia, which are risk factors for cardiovascular
morbidity and progressive kidney disease. Improvement of anemia is likely to
reverse some of these risks.
368 Pediatric Nephrology

Renal Osteodystrophy (Mineral and Bone Disorder)

Normal kidneys participate in the homeostasis of calcium, phosphorus and
magnesium. Hypocalcemia, release of parathormone (PTH) and decreased dietary
intake of phosphate are stimuli for kidneys to convert 25-dihydroxyvitamin D3
into 1, 25-dihydroxyvitamin D3. The latter promotes intestinal calcium absorption,
renal calcium and phosphorus reabsorption and bone mineralization. Additionally,
kidneys degrade and excrete PTH and excrete phosphorus.
In patients with CKD, the production of 1, 25-dihydroxyvitamin D3 decreases,
leading to hypocalcemia. Reduced excretion of phosphorus results in
hyperphosphatemia. Both events stimulate PTH formation and release, which
is expected to promote renal phosphorus excretion and resolve hypocalcemia
by increasing its bone resorption and formation of 1, 25-dihydroxyvitamin D3.
However, there is resistance to PTH action because of downregulation of PTH
receptors as well as the inability of kidneys to synthesize 1,25-dihydroxyvitamin
D3 and excrete the phosphate load.
Secondary hyperparathyroidism results in osteitis fibrosa cystica, bone
resorption, fractures and deformities. Alterations in the growth plate cartilage,
due to abnormal bone mineralization, results in failure of linear growth.
Additionally, the deficiency of 1,25-dihydroxyvitamin D3 leads to rickets/
osteomalacia. Metabolic acidosis also contributes to impaired bone minerali-
zation. Adynamic lesions (low turnover disease) are common following excessive
use of aluminum containing phosphate binders or oversuppression of PTH by
treatment with 1,25-dihydroxyvitamin D3. The syndrome of clinical, metabolic
and imaging (bony) deformities in CKD is termed the ‘chronic kidney disease-
mineral and bone disorder’ (CKD-MBD). The term ‘osteodystrophy’ should be
restricted to the description of histological features on bone biopsy.
The clinical manifestations of CKD-MBD depend on the age of the patient
and duration of the disease. Infants show features of rickets such as rachitic
rosary, widened metaphyses and Harrison sulcus. Hypotonia and delayed motor
development are often present. In older children, genu valgum may be seen.
Scoliosis, compression fractures of vertebrae, thoracic deformities and pathologic
fractures of long bones are features of advanced MBD. Hyperphosphatemia is
observed at GFR of 50-80 ml/min/1.73 m2.

Metabolic Acidosis and Dyselectrolytemia

Metabolic acidosis results from decreased bicarbonate reabsorption, reduced renal
ammonia synthesis, decreased acidification of tubular fluid, and low titratable
acid excretion. Bicarbonaturia begins once the GFR declines to below 50% of
normal. In patients with obstructive uropathy and in those with predominant
tubulointerstitial lesions, acidosis develops early and its severity is out of
proportion to the fall in GFR. Systemic acidosis causes protein degradation and
 Chronic Kidney Disease 369

efflux of calcium from bone, worsening growth failure. Catabolic states and
infections further aggravate the acidosis.
Hyperkalemia is a complication of advanced CKD. Normally, potassium
reabsorption occurs in the proximal tubules and the loop of Henle, and up to
90% of the daily intake of potassium is secreted in the distal tubules. As renal
disease progresses, the distal tubular capacity to secrete potassium is impaired.
Aldosterone increases in order to enhance potassium secretion by stimulating
sodium-potassium exchange in kidneys and the colon. In advanced CKD,
hyperkalemia occurs if the potassium intake overwhelms the excretory capacity
of the kidneys, or with use of medications that alter potassium secretion
(spironolactone, amiloride, or angiotensin converting enzyme inhibitors).

Hypertension
Hypertension is noted in 20-80% of children with chronic kidney disease stage
2 or higher. Renal parenchymal disease is the most common cause of hypertension
in children. Hypertension is diagnosed on detecting elevated blood pressures
(>95th percentile of systolic or diastolic blood pressure) on two or more clinic
visits at least 1 week apart. The diagnosis is based on the child’s age, sex and
height percentile, using internationally accepted standards; hypertension is graded
for severity (Chapter 17).

Neurological Abnormalities
The developing brain is susceptible to the effects of azotemia, and infants and
young children with moderate CKD are at risk for encephalopathy. Children show
hypotonia, delayed motor development, seizures (secondary to hypertension,
hypocalcemia, hyponatremia or azotemia), truncal ataxia and other signs of
cerebellar dysfunction. Older children may show these features and uremic
neuropathy. Severe proximal muscle weakness is occasionally present.

Miscellaneous
Anorexia, lack of energy, increased sleep, poor school performance, platelet
dysfunction and depressed cell mediated immunity are seen in patients with CKD
stage 3-5. Gastric ulceration, severe itching and pericarditis are late features.

Key points: Presenting features of chronic renal failure

• Growth retardation; failure to thrive
• Malnutrition
• Anemia
• Hypertension; congestive heart failure
• Metabolic bone disease: renal osteodystrophy and refractory rickets
• Rapid breathing; acidosis
• Encephalopathy.
370 Pediatric Nephrology

DIAGNOSTIC EVALUATION
A detailed history should be taken for features that suggest renal disease.
Obstructive uropathy and tubulointerstitial disorders such as nephronophthisis
are characterized by early onset of polyuria and polydipsia. A history of renal
disease in the family should be obtained. Clinical examination should include
measurement of blood pressure and evaluation of growth, pubertal developmental
and nutritional status. Anemia and features of rickets should be looked for and
psychological and intellectual functions assessed.
Several methods have been proposed for estimation of GFR in children. The
measurement of creatinine clearance, using a timed urine collection is
inconvenient, variable and often inaccurate. While accurate measurement of GFR
is possible using plasma clearance of DTPA, EDTA or iohexol, such precise
determinations are not necessary. The commonly used method for estimation
of GFR is by the Schwartz formula, as follows:

k × height (in cm )
Glomerular filtration rate = serum creatinine mg/dl
( )
Where, k = 0.34 for low birth weight infants, 0.45 for term appropriate for
gestational age infants, 0.55 for children and adolescent females, and 0.70 for
adolescent males. This formula is criticized for its tendency to overestimate the
GFR, especially in presence of malnutrition and at lower levels of GFR.
Furthermore, the ability to estimate true plasma creatinine more accurately (e.g.
using modified Jaffe’s method; ELISA; HPLC) has lead to suggestions that the
value of the constant (k) should be lower, based on the technique utilized for
estimating plasma creatinine. A recent Chronic Kidney Disease in Children
(CKD) study has proposed a new formula for determining GFR.

eGFR= 39.1 [Ht(m)/SCr]0.516 ×[1.8/CysC]0.294 ×[30/BUN]0.169 ×[1.099male] ×[Ht/1.4]0.188

The CKD study also proposed a simpler bedside formula whereby the GFR
might be determined using the Schwartz formula, but with a lower value of k
= 0.413. These formulae have been validated for GFR between 15 and 75 ml/
min/1.73 m2.
Laboratory investigations include urinalysis, measurement of levels of blood
urea, electrolytes, creatinine, calcium, phosphate, alkaline phosphatase and
proteins. Fasting blood levels of triglycerides, cholesterol, PTH and iron studies
may be required. There is limited role for routine skeletal survey for detecting
radiological features of CKD-MBD. Various investigations to determine the cause
of CKD include imaging, radionuclide studies and renal histological examination.
 Chronic Kidney Disease 371

However, nuclear imaging has limited role when GFR falls to below 20-30 ml/
min/1.73 m2. Similarly, renal histology provides little information as only
extensive scarring is expected to accompany chronic severe renal insufficiency.

Key points: Diagnosis and assessment of severity

• Ultrasonography is useful for examining renal size, anomalies and obstruction
• Radionuclide imaging is usually not helpful if GFR <20-30 ml/min/1.73 m2
• Glomerular disorders are suggested by proteinuria, hematuria and casts
• Blood levels of urea, creatinine, electrolytes, and appropriate tests to evaluate
anemia, bone disease and acid-base status are necessary.

MANAGEMENT
Adequate management of early stages of CKD retards the decline in renal
function. In some of the underlying conditions, particularly those not associated
with heavy proteinuria, the progression of renal damage is slow and the child
may remain in a stable condition for prolonged periods. The treatment is aimed
at maintaining the well-being and quality of life. Normal physical activity and
schooling should be encouraged. Family counseling and emotional support to
the child is important. A multidisciplinary approach including help of a
nutritionist is necessary for comprehensive management.

Retarding the Progression of CKD

Once a critical fraction of renal function has been lost, renal function
progressively worsens independent of the underlying disorder. The most
important independent risk factors for renal disease progression are hypertension
and proteinuria; hence, current therapeutic strategies to prevent progression aim
at optimizing blood pressure control and reducing urinary protein excretion.
Intensified blood pressure control, aiming for a target blood pressure between
50-75th percentile, exerts a renoprotective effect. Numerous studies in adults
have noted a linear relationship between the level of blood pressure achieved
and the rate of decline of renal function.
Trials on proteinuria reduction have demonstrated renoprotective effects when
targeting a reduction in proteinuria by 1 g/day or more. Hence, it is recommended
that the goal of any antiproteinuric strategy should be to reduce proteinuria to
<300 mg/m2/day. While large studies have shown that blood pressure control,
by itself, decreases proteinuria, blockade of the renin-angiotensin system (RAS)
by angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor
blockers (ARBs) is considered the renoprotective strategy of choice in patients
with CKD. RAS inhibition is associated with antiproteinuric as well as anti-
hypertensive effects. These effects are mediated through decrease in glomerular
vascular tone that decreases intraglomerular pressure, proteinuria and local release