Acute Renal Failure Adapted From UpToDate “Clinical Presentation Evaluation

acute renal failure adapted from up-to-date “clinical presentation, evaluation and diagnosis of acute renal failure in children” and “preven

acute renal failure
Adapted from Up-To-Date “Clinical presentation, evaluation and
diagnosis of acute renal failure in children” and “Prevention and
management of acute renal failure in children”
Introduction — Defined by a rapid decline in GFR, resulting in
disturbance of renal physiological functions including:
*
Impairment of nitrogenous waste product excretion
*
Loss of water and electrolyte regulation
*
Loss of acid-base regulation
Pathogenesis and Etiology — The causes of acute renal disease can be
related to renal anatomy:
*
Vascular — Blood from the renal arteries is delivered to the
glomeruli.
*
Glomeruli — Ultrafiltration occurs at glomeruli forming an
ultrafiltrate, which subsequently flows into renal tubules
*
Renal tubule — Reabsorption and secretion of solute and/or water
from the ultrafiltrate occurs within the tubules.
*
Urinary tract — The final tubular fluid (urine) leaves the kidney,
draining sequentially into the renal pelvis, ureter, and bladder,
from which it is excreted through the urethra.
*
Any process that interferes with any of these structures and/or
functions can cause renal disease.
The causes of ARF can therefore be categorized as Prerenal, Renal, or
Postrenal

Prerenal — Prerenal azotemia results from either:
*
Volume depletion due to bleeding (surgery, trauma,
gastrointestinal bleeding), gastrointestinal (vomiting, diarrhea),
urinary (diuretics, diabetes insipidus), or cutaneous losses
(burns).
*
Decreased effective arterial pressure and/or effective circulating
volume seen in heart failure, shock, or cirrhosis.
Intrinsic renal disorders — involve renal vascular, glomerular, and/or
tubular/interstitial pathology.
*
Vascular — Causes include thrombosis (arterial and venous),
hemolytic-uremic syndrome, malignant HTN, vasculitis.
*
Glomerular — Principal cause is postinfectious GN. ARF can be
observed with most GNs that can occur in childhood.
*
Tubular and interstitial disease — Acute tubular necrosis (ATN)
results from ischemia due to decreased renal perfusion or injury
from tubular nephrotoxins. All causes of prerenal azotemia can
progress to ATN if renal perfusion is not restored and/or
nephrotoxic insults are not withdrawn The administration of
nephrotoxic agents, (aminoglycosides, amphotericin B, contrast
agents) is a common cause of tubular disease. ARF can also be
induced by the release of heme pigments, as with myoglobinuria due
to rhabdomyolysis and hemoglobinuria due to intravascular
hemolysis. In children, acute interstitial nephritis most commonly
results from a hypersensitive reaction to a drug.
Postrenal — Postrenal ARF is due to bilateral urinary tract
obstruction unless there is a solitary kidney. In neonates, urinary
tract obstruction, due to posterior urethral valves is the most common
cause of postrenal failure. Children with chronic obstructive
uropathies are also at significant increased risk of ARF from ischemic
and toxic insults.
Evaluation and Diagnosis
Serum creatinine concentration — Estimation of the glomerular
filtration rate (GFR), usually by serum creatinine is used clinically
to assess the degree of renal impairment and to follow the course of
the disease. Due to maternal contributions in the newborn and
increased muscle mass with age, the normal range of creatinine varies
by age:
Newborn - 0.3 to 1.0 mg/dL (27 to 88 µmol/L)
Infant - 0.2 to 0.5 mg/dL (18 to 35 µmol/L)
Child - 0.3 to 0.7 mg/dL (27 to 62 µmol/L)
Adolescent - 0.5 to 1.0 mg/dL (44 to 88 µmol/L)
Serum BUN/creatinine ratio — In adults and older children, serum
BUN/Cr ratio is normal at 10-15:1 in ATN, and may be > 20:1 in
prerenal disease due to increase in passive reabsorption of urea that
follows enhanced proximal transport of sodium and water. Thus, a high
ratio is highly suggestive of prerenal disease. This ratio is not
useful in infants and smaller children as their serum creatinine
levels are much lower.
Urinalysis — The urinalysis is the most important noninvasive test in
the diagnostic evaluation, since characteristic findings on
microscopic examination of the urine sediment strongly suggest certain
diagnoses

Urine sodium excretion — Measurement of urine Na+ concentration is
helpful in distinguishing ATN from prerenal ARF due to effective
volume depletion. The urine Na+ concentration is usually >30-40 mEq/L
in ATN and < 10 mEq/L in prerenal ARF. Newborns have decreased ability
to conserve Na+, so prerenal disease is usually associated with
somewhat increased urine Na+ concentrations (< 20-30 mEq/L).
However, since the urinary sodium concentration is influenced by the
urine output, there is substantial overlap between ATN and prerenal
disease. As an example, a given rate of sodium excretion will be
associated with a lower urine sodium concentration by dilution in
patients who have a high urine output.

Fractional excretion of sodium (FENa)
UNa x PCr
FENa (%) = ————————— x 100
PNa x UCr
UCr and PCr = urine and serum Cr, respectively; UNa and PNa = urine
and serum Na+, respectively.
The FENa is a screening test that differentiates between prerenal ARF
and ATN in children.
*
<1% suggests prerenal dz, where reabsorption of almost all
filtered Na+ represents response to ↓renal perfusion.
*
A value between 1-2 % may be seen with either disorder.
*
> 2 % usually indicates ATN.
*
In newborns, prerenal disease and ATN are associated with FENa
values of less than 2.5 percent and greater than 2.5 to 3.5
percent, respectively, because of their decreased ability to
reabsorb sodium.
The FENa is most useful in patients with severe renal failure and low
urine output (oliguria). It is less accurate in those with a normal or
moderately reduced GFR because the value determining a prerenal state
changes continuously with the GFR. FENa may also be elevated after the
administration of either a distal or loop diuretic due to the increase
in urine sodium excretion.
A low FENa is not unique to prerenal dz, as it can occur in disorders
assoc with normal tubular function but low GFR (e.g. acute GN,
vasculitis, acute urinary tract obstruction) or when ATN is
superimposed upon chronic Na+-retaining state.
Urine osmolality — Loss of concentrating ability is an early and
almost universal finding in ATN with the urine osmolality usually
being below 350 mosmol/kg. However, lower values similar to those in
ATN may be seen in prerenal disease and are therefore of little
diagnostic help. In contrast, a urine osmolality > 500 mosmol/kg is
highly suggestive of prerenal disease.
Urine volume — The urine volume is typically, but not always, low
(oliguria) in prerenal disease due to the combination of sodium and
water avidity. In comparison, patients with ATN may be either oliguric
or nonoliguric.
Response to volume repletion — Unless contraindicated, a child with a
clinical history consistent with fluid loss (vomiting, diarrhea), a
physical examination consistent with hypovolemia (hypotension,
tachycardia), and/or oliguria should be administered IV fluid therapy.
This fluid challenge attempts to identify prerenal failure that can
progress to ATN if not treated promptly. However, such fluid infusion
is contraindicated in those with obvious volume overload or heart
failure.
Commonly used fluids are crystalloid solutions, such as NS (20 mL/kg)
over 20 to 30 minutes, which may be repeated. Restoration of adequate
urine flow and improvement in renal function with fluid resuscitation
is consistent with prerenal disease. However, if urine output does not
increase and renal function fails to improve with the restoration of
intravascular volume, invasive monitoring may be required to
adequately assess the child's fluid status and help guide further
therapy.
Additional laboratory measurements
Complete blood count — Severe microangiopathic hemolytic anemia
associated with thrombocytopenia in the setting of ARF confirms the
diagnosis of HUS. Severe hemolysis, whether drug-induced or secondary
to hemoglobinopathies, may also result in ATN due to massive
hemoglobinuria.
Other abnormalities —
*
Hyperkalemia - ability to maintain K+ excretion at near normal
levels is generally maintained in patients with renal disease as
long as both aldosterone secretion and distal flow are maintained.
Hyperkalemia generally develops in the patient who is oliguric or
who has an additional problem, such as a high K+ diet and
increased tissue breakdown.
*
Hyperphosphatemia - Once GFR falls below threshold, renal
excretion of phosphorus ↓, resulting in ↑ phosphate.
*
Hypocalcemia. Hypocalcemia can result from hyperphosphatemia,
decreased calcium absorption in the gastrointestinal tract (due to
inadequate renal production 1,25–vitamin D), and/or skeletal
resistance to parathyroid hormone (PTH).
*
Acid-base balance is normally maintained by renal excretion of the
daily acid load (~ 1 mEq/kg/day, derived mostly from the
generation of sulfuric acid during the metabolism of
sulfur-containing amino acids). Elimination of this acid load is
achieved by the urinary excretion of hydrogen ions. A metabolic
acidosis may therefore ensue with ARF.
*
Anti-neutrophil cytoplasmic Abs (ANCA), anti-nuclear Abs (ANA),
anti-glomerular basement membrane (GBM) Abs, antistreptococcal
Abs, and/or hypocomplementemia is associated with certain
inflammatory disorders.
*
Elevated serum levels of aminoglycosides are associated with ATN.
*
Eosinophilia and/or urine eosinophiluria may be present in some
cases of interstitial nephritis.
*
Markedly elevated uric acid levels may also induce ARF. Thus,
tumor lysis syndrome secondary to chemotherapy treatment of
childhood leukemia or lymphoma may result in ARF due to urate
nephropathy
Renal imaging — Renal ultrasonography should be performed in all
children with ARF of unclear etiology. It can document the presence of
one or two kidneys, delineate renal size, and help survey renal
parenchyma. It is particularly useful in diagnosing urinary tract
obstruction or occlusion of the major renal vessels.
Renal biopsy — Obtained when noninvasive evaluation has been unable to
establish the correct diagnosis
ARF Management
The basic principles of the general management of the child with acute
renal failure include:
Maintenance of electrolyte and fluid balance
Adequate nutritional support
Avoidance of life-threatening complications
Treatment of the underlying cause
Hyperkalemia —The gradient of K + across the cell membrane is the
major determinant of the resting membrane potential, which is the
basis for the action potential that is essential for neuronal and
muscular function. As the extracellular K + levels increase, gradient
and membrane potential are affected, resulting in clinical signs of
muscle weakness and cardiac arrhythmias.
EKG findings: peaked T waves, flattened P waves, increased PR
interval, and widening of the QRS.

Treatment:
*
Remove K+ from all IVF
*
Stabilization of cardiac membrane with IV calcium (10% Ca
gluconate - 0.5 to 1.0 mL/kg IV over 5-15 min)
*
Promotion of K + movement from the extracellular fluid (ECF) into
the cells via three different therapies:
1.
IV glucose and insulin (0.5-1 g of glucose/kg over 30 min
and 0.1 unit of insulin/kg IV or SQ)
2.
IV sodium bicarbonate (1-2 mEq/kg over 30 to 60 min)
3.
β agonists, such as albuterol via neb (2.5 mg if the child
weighs below 25 kg or 5 mg if above)
*
Kayexalate, an ion exchange resin, is used for net
elimination of K + (1 gm/kg PO or PR)
*
Diuretics can be given to patients with continued urine
output.
*
Renal replacement therapy should be considered if
medical correction fails to improve hyperkalemia.
Acidosis — In children with ARF, not only is acid excretion impaired,
acid production is frequently increased due to underlying co-morbid
conditions (shock, sepsis). Respiratory compensation provides some
correction of the acidosis.
Administration of sodium bicarbonate should be done only in
life-threatening situations in which maximal respiratory compensation
is inadequate, and/or acidosis is contributing to hyperkalemia. In
cases of severe or progressive acidosis following shock, serious
infections or other hypercatabolic states, supplemental bicarbonate
may be required to correct and maintain arterial pH above 7.2 until
underlying disease is controlled.
Although the administration of oral or parenteral sodium bicarbonate
may provide temporary benefit in children with concurrent hyperkalemia
or maximal respiratory compensation, it should be used cautiously b/c
it ↑intravascular volume and may further lower the amount of ionized
calcium, with the latter possibly precipitating tetany or seizures.
Ongoing administration of sodium bicarbonate can also result in
hypernatremia and hyperosmolality.
Intravascular volume — Appropriate immediate fluid management is
crucial in children with ARF. Based upon the underlying cause,
comorbid conditions, and possible previous therapy, the child with ARF
may be hypovolemic, euvolemic, or hypervolemic (including pulmonary
edema and heart failure).
Hypovolemic patients require immediate IVF therapy in an attempt to
restore renal function and perhaps prevent ischemic renal injury.
Commonly used fluids are crystalloid solutions, such as NS (20 mL/kg)
administered over 20-30o 30 min, which may be repeated. If urine
output does not increase and renal function fails to improve with the
restoration of intravascular volume, invasive monitoring may be
required to adequately assess the child's fluid status and help guide
further therapy.
By comparison, an edematous hypertensive child with a history of
oliguria, and/or signs of heart failure may require immediate fluid
removal and/or fluid restriction. A trial of furosemide (2 to 5 mg/kg
per dose) may be attempted to induce a diuresis and convert oliguric
to non-oliguric renal failure. However, diuretics should not be
continued in an unresponsive child. If a diuresis does not ensue
and/or the patient has evidence of fluid overload with pulmonary
edema, renal replacement therapy should be initiated.
Once euvolemia has been obtained, pay careful attention to ongoing
fluid losses (insensible water loss of approximately 300 to 500
mL/m2/day in addition to replacement of urine and GI losses) and gains
(fluid administered for nutritional and medical requirements). In
addition to invasive intravascular monitoring, ongoing fluid balance
evaluation is aided by daily weights, accurate records of fluid inputs
and outputs, and findings on physical examination.
Hyperphosphatemia and hypocalcemia — Oral phosphate binders and
dietary restriction of phosphorus are commonly used to decrease
intestinal absorption of phosphorus. Intravenous administration of
calcium gluconate should be considered if hypocalcemia is severe
and/or if bicarbonate therapy is required for severe acidosis and
hyperkalemia.
Hypertension — Although peripheral vasoconstriction can be a
contributing factor, hypertension in ARF is most likely secondary to
fluid overload. The absolute degree of hypertension, clinical
presentation, and response to initial therapy (such as diuretics) will
determine the choice of antihypertensive therapy.
Nutrition — ARF is associated with marked catabolism, and inadequate
nutrition can delay recovery of the patient's renal function. Children
should receive at least maintenance calories or higher.
Hyperalimentation can be considered if enteral feeding is not
possible. If the child is oliguric or anuric, and sufficient calories
cannot be achieved while maintaining appropriate fluid balance, renal
replacement therapy should be started.
Renal replacement therapy — Renal replacement therapy in children with
ARF should be initiated for the following:
*
Uremic symptoms - pericarditis, neuropathy or an unexplained
decline in mental status
*
Azotemia (BUN greater than 80 to 100 mg/dL [29 to 36 mmol/L]
*
Severe fluid overload as manifested by HTN, pulmonary edema or
heart failure refractory to medical therapy.
*
Severe electrolyte abnormalities - ↑K+, ↑Na+or ↓Na+, and acidosis
refractory to supportive medical therapy.
*
Need for intensive nutritional support in a child with oliguria or
anuria.
The choice of renal replacement modality is influenced by the clinical
presentation of the child, the presence or absence of multi-organ
system failure, and the indication for renal replacement therapy
*
Hemodialysis —most rapidly changes plasma solute composition and
removes excessive body water compared to the other modalities.
However, this may not be tolerated by hemodynamically unstable
patients.
*
Peritoneal dialysis —less efficient in altering blood solute
composition and fluid removal, but it can be applied continuously.
Well tolerated by hemodynamically unstable patients. It is the
simplest of the modalities to apply
*
Continuous renal replacement therapy (CRRT) — Includes several
modalities (continuous arteriovenous hemofiltration, continuous
venovenous hemofiltration, continuous arteriovenous hemodialysis
and continuous venovenous hemodialysis. Rate of fluid and solute
removal is slow and continuous. As a result, CRRT is better
tolerated than hemodialysis in patients who are hemodynamically
unstable. The removal of solutes over the course of 24 to 48 hours
is as efficient as conventional hemodialysis. In addition, some
prefer this technique in patients with sepsis or multiorgan system
failure, since it may enhance the removal of cytokines
Prognosis — The prognosis of ARF depends upon the etiology, age of the
patient, clinical presentation and status of the patient. Hypotension
and the need for inotropic support during renal replacement therapy
are significant poor predictors for patient survival.
Adapted from Up-To-Date: “Clinical presentation, evaluation and
diagnosis of acute renal failure in children” and “Prevention and
Management of Acute Renal Failure in Children”
Tumor Lysis Syndrome
Definition: A syndrome resulting from cytotoxic therapy, occurring
generally in aggressive, rapidly proliferating lymphoproliferative
disorders. It is characterized by combinations of hyperuricemia,
lactic acidosis, hyperkalemia, hyperphosphatemia with secondary
hypocalcemia. These can subsequently lead to renal failure.
Hyperuricemia
Uric acid is the end product of the digestion of purines from tumor
cells and is normally eliminated through urine. Uric acid is soluble
at physiologic pH, but can precipitate in the acidic environment of
renal tubules, causing obstructive uropathy and kidney failure.
(*xanthine oxidase converts hypoxanthine to xanthine & xanthine to
uric acid)

Hyperkalemia
May cause irregular cardiac rhythms and neuromuscular dysfunction
EKG findings:
1.
Early changes - peaked T waves, shortened QT interval, ST segment
depression
2.
Later changes - widened QRS complex, increased PR interval,
decreased P wave amplitude
3.
Without treatment, the P wave eventually disappears and the QRS
morphology widens to resemble a sine wave which ultimately leads
to ventricular fibrillation or asystole
Hyperphosphatemia
Elevated levels of phosphate can cause hypocalcemia. Complexes of
phosphates and calcium can form and deposit in the renal tubules,
leading to kidney failure. Calcium phosphate crystals precipitate in
the microvasculature and renal tubules when [PO42-]x[Ca2++] > 60 mg/dL.
Hypocalemia
May result in severe cardiovascular effects and neurological
dysfunction (e.g. seizures, hallucinations, tetany).
Management
Prevention:
• Hydration at 2-4x maintenance D5 ¼ NS + 40 mEq/L NaHCO3 (= ½ NS; No
K+ in IVFs!)
• Adjust bicarb to keep urine pH 7.0-7.5 (alkanize with 30-50 mEq/L
NaHCO3)
- too low pH precipitates urate crystals; too high pH precipitates
limestone, xanthine, hypoxanthine
• Allopurinol: inhibits xanthine oxidase and decreases uric acid
formation
< 6yo: 50 mg PO TID
6-10 yo: 100 mg PO TID
> 10yo: 200 mg PO TID
• Rasburicase: recombinant form of urate oxidase, an enzyme that
converts uric acid to allantoin
• Amphogel (phosphate binder) if high tumor burden (e.g. WBC>100K,
Burkitt’s lymphoma)
• Check lysis labs every 4-6 hours (Chem 10, LDH, uric acid)
• If the patient becomes puffy, use diuretics to increase urine flow
-do not decrease the IV infusion rate
Treatment
• Hyperuricemia: hydration to promote uric acid excretion,
alkalinization, decrease uric acid production w/allopurinol (xanthine
oxidase inhibitor) & rasburicase (oxidizes uric acid to allantoin)
• Hyperkalemia: calcium, bicarbonate, insulin/glucose, kayexalate,
?albuterol, dialysis
• Hyperphosphatemia: phosphate binders (amphogel/alternagel),
diuretics
• Hypocalcemia: replace calcium if symptomatic, diuretics to promote
excretion of phosphates in the urine
• Dialysis indications: uncontrolled hyperkalemia, worsening
hyperuricemia, symptomatic hypocalemia/hyperphos, acidosis, HTN, fluid
overload, rapidly rising BUN/Cr)
• Supportive Care
chronic Renal Failure/Chronic Kidney Disease
Adapted from Up-To-Date Overview of the management of chronic kidney
disease in children
Introduction - The gradual decline in function with CKD is initially
asymptomatic. However, different signs/symptoms may be observed with
advanced renal dysfunction, including volume overload, ↑K+, metabolic
acidosis, HTN, anemia, and bone disease. The onset of end-stage renal
disease results in a constellation of signs and symptoms referred to
as uremia.
Manifestations of the uremic state include anorexia, nausea, vomiting,
growth retardation, peripheral neuropathy, and CNS abnormalities
ranging from loss of concentration and lethargy to seizures, coma, and
death. Kidney function < 5 % of normal is believed to be insufficient
to sustain life. ESRD is defined as either a GFR of < 15
mL/min/1.73m2, which is accompanied in most cases by signs and
symptoms of uremia, or a need for the initiation of kidney replacement
therapy (dialysis or transplantation) for the treatment of
complications from a decreased GFR.
Definitions and Classifications
Within pediatric nephrology community, Chronic Renal Insufficiency has
been characterized by GFR < 75 mL/min/1.73 m2. In contrast, the K/DOQI
workgroup defined CKD in adults and children older than 2 years of age
as:
*
Kidney damage for greater than 3 months OR
*
GFR < 60 mL/min/1.73 m2 for 3 months, with or without
kidney damage.
CKD has been classically staged as renal failure that is:
*
Mild (GFR of 50-80 % of normal)
*
Moderate (GFR of 25-50 % of normal)
*
Severe (GFR < 25 % of normal)
*
End-stage (ESRD) (GFR < 10 % of normal).
K/DOQI developed a formal staging system based on level of kidney
function, independent of primary renal diagnosis:
*
Stage 1 disease is defined by a normal GFR ( 90 mL/min per
1.73 m2)
*
Stage 2 disease is a GFR between 60 to 89 mL/min per 1.73 m2
*
Stage 3 disease is a GFR between 30 and 59 mL/min per 1.73 m2 
start to become symptomatic at Stage 3
*
Stage 4 disease is a GFR between 15 and 29 mL/min per 1.73 m2
*
Stage 5 disease is a GFR of less than 15 mL/min per 1.73 m2 or
ESRD
Management OF CKD
1. Disorders of Fluid and Electrolyte Balance
A. Sodium and Intravascular Volume Balance
B. Potassium Homeostasis
C. Metabolic Acidosis
2. Renal Osteodystrophy
3. Calcium and Phosphate Mtabolism
4. Hypertension
5. Anemia
6. Dyslipidemia
7. Malnutrition
8. Hormonal Abnormalities
9. Neurocognitive Dvelopment
10. Uremic Complications
11. Renal Replacement Therapy
1. Disorders of Fluid and Electrolyte Balance
A. Sodium and Intravascular Volume Balance
Although sodium homeostasis is usually well-maintained, failing
kidneys eventually lose the capacity to rapidly adapt to a Na+ load or
restriction. There also exists an obligatory Na+ loss that can be
severe in children with obstructive uropathy and/or cystic kidneys,
thereby leading to volume contraction, poor growth, and need for Na+
supplementation.
Children with CKD may develop a fixed urine output dependent upon the
osmolar load. Although they may continue to have an adequate osmolar
clearance, they cannot adapt rapidly to an acute water load or
restriction. As a result, they can develop volume overload. This
generally responds to dietary Na+ restriction and diuretic therapy.
The current daily recommendation for Na+ intake is 1.2 g/day for 4-8
yo and 1.5 g/day for older kids (This amount is substantially lower
than the average current intake of a child). At LPCH we often restrict
Na+ intake to about 1 to 2 g/day.
B. Potassium Homeostasis
Hyperkalemia generally develops in children with decreased sodium
delivery to the distal tubule because of a low GFR, a high dietary K+
intake, increased tissue breakdown, metabolic acidosis,
hypoaldosteronism (due in some cases to administration of an ACE
inhibitor) or impaired cellular uptake of potassium. Management
consists of a low K+ diet and/or loop diuretic to increase urinary K+
loss or PO sodium bicarbonate to correct acidosis. Infant formula can
be mixed with kayexalate and decanted to decrease K+ content of
formula prior to feeding.
Hypokalemia is uncommon in children with CKD. However, it can be
observed in children in the early stages of CKD associated with
Fanconi syndrome, renal tubular acidosis, or from excessive diuretic
therapy.
C. Metabolic acidosis
Kidneys play a critical role in acid-base homeostasis by excreting an
acid load (produced by cellular metabolism and skeletal growth in
children) and preventing bicarbonate loss in the urine. There is an
increasing tendency to retain hydrogen ions among patients with
chronic renal disease, eventually leading to a progressive metabolic
acidosis
.
In children, overt acidosis is characteristically present when GFR <
30 mL/min/1.73 m2 and can be associated with an increased or normal
anion gap. Acidosis is associated with increased protein degradation
and oxidation of branched chain amino acids. Thus, its correction is
associated with an increase in serum albumin, the plasma concentration
of branched chain amino acids and total essential amino acids, and a
decrease in protein degradation rate.
The presence of acidosis also has the potential of having a negative
impact on growth as the body utilizes bone to buffer some of the
excess hydrogen ions. This is well-exemplified by children with renal
tubular acidosis in whom there is a return of normal growth parameters
following normalization of the serum bicarbonate level. Calcitriol
therapy is also more effective in the treatment of renal
osteodystrophy, if the acidosis has been corrected.
Current guidelines are to maintain the serum bicarbonate level
22 mmol/L. Sodium bicarbonate therapy may be started at 1 to 2 mEq/kg
per day in 2-3 divided doses, and the dose is titrated to the clinical
target. Be cautious with citrate preparations, as these may enhance
aluminum absorption from gut and increase risk of aluminum toxicity.
2. Renal osteodystrophy
Changes in mineral metabolism and bone structure are an almost
universal finding with progressive renal failure. These changes are
linked to abnormalities in the metabolism of calcium, phosphate, and
vitamin D, and increases PTH levels. Principal types of disease:
osteitis fibrosa, adynamic bone disease, and osteomalacia.
*
Osteitis Fibrosa and Secondary Hyperparathyroidism — Osteitis
fibrosa results from secondary hyperparathyroidism, with features
on bone biopsy being an increase in bone turnover activity and
defective mineralization. The principal goal of therapy is to
control elevated PTH levels. The major factors stimulating
parathyroid function include hypocalcemia, diminished
1,25-dihydroxyvitamin D levels, and hyperphosphatemia. Combination
of dietary phosphate restriction, phosphate binders l, and active
vitamin D therapy is required to maintain a normal serum phosphate
level and an intact PTH level no more than two to four times
normal. In severe cases of secondary hyperparathyroidism, although
rare in children, parathyroidectomy may have to be considered.
*
Adynamic Bone Disease — Adynamic bone disease is characterized by
low osteoblastic activity and bone formation rates. It has become
increasingly frequent, particularly among dialysis patients, since
it is now possible to suppress PTH with calcium-containing
phosphate binders and potent vitamin D analogues. The relatively
inert, adynamic bone does not modulate calcium and phosphate
levels appropriately. With this regulatory function impaired,
calcium is neither released from nor taken up by the bone normally
and the dialysis patient typically maintains a low intact PTH
level (eg, <100 pg/mL), which is frequently accompanied by an
elevated serum calcium level.
Adynamic renal osteodystrophy is not benign as it increases risk for
fractures and metastatic calcification seen more frequently in adults
than children. Best treated by allowing intact PTH level to rise to
increase bone turnover by decreasing or discontinuing the dosage of
the calcium-based phosphate binders and/or vitamin D therapy. Adynamic
bone disease is uncommon among pre-dialysis patients, but can occur
with aggressive therapy in dialysis patients.
*
Osteomalacia — Another low turnover bone lesion, osteomalacia, is
also uncommon among predialysis patients. Previously, this
disorder resulted from aluminum toxicity due to
aluminum-containing phosphate binders (no longer used). Among
children, the inadequate intake of calcium, phosphate, or vitamin
D also may result in osteomalacia.
Assessment and monitoring — Other factors that may impact renal
osteodystrophy include corticosteroids, metabolic acidosis,
hypophosphatemia from aggressive P restriction or excessive use of
phosphate binders, age, race, nutritional vitamin D deficiency, meds
that interfere vitamin D metabolism (eg, anticonvulsants), and
prolonged immobilization. Monitor for evidence of bone disease by
physical examination, with particular attention to muscle pain,
weakness, and bony changes such as varus and valgus deformities of the
long bones, and following iPTH and serum calcium levels.
3. Calcium and Phosphate Metabolism
A. Hyperphosphatemia
Phosphate levels are maintained within a normal range in early stages
of renal failure, at the cost of elevated PTH. This adaptation is
initially "appropriate", since elevated PTH levels enhance phosphate
excretion from kidneys. However, it eventually leads to renal
osteodystrophy. Thus, iPTH level may be an excellent marker to base
the need for dietary phosphate restriction early in the course of CKD,
which is a time when serum phosphate levels are still normal.
Dietary phosphate should be restricted to age-appropriate recommended
daily value. At LPCH, we tend to restrict to 800 mmol/day. Compliance
in children is poor as most of their favorite foods are rich in
phosphate. Thus, phosphate binders (taken 10-15 min before or during
meal) are often necessary to prevent phosphate absorption from GI
tract.
*
Good choices include Ca carbonate, Ca acetate, Ca gluconate, and
Ca ketoglutarate.
*
Ca citrate should not be administered, since it markedly increases
intestinal aluminum absorption.
*
If hypercalcemic, instead use sevelamer (Renagel®) alone or
together with a Ca-containing phosphate binder.
*
Irrespective of agent used, phosphate binders have a limited
phosphate-binding capacity: 1 g of Ca carbonate binds 39 mg P, 1 g
of Ca acetate binds 45 mg P and 400 mg of sevelamer HCl only binds
32 mg P. Thus, effective only if the dietary restrictions for
phosphate are continued simultaneously.
Phosphate binders that should be avoided in children with CKD:
*
Aluminum hydroxide, the previous standard, because of the gradual
induction of aluminum toxicity
*
Magnesium-containing antacids (such as magnesium hydroxide),
because risk hypermagnesemia and diarrhea
*
As previously mentioned, calcium citrate, since it markedly
increases intestinal aluminum absorption
B. Vitamin D supplementation

Calcitriol- The final step in vitamin D metabolism is 1-hydroxylation
of calcidiol in the kidney to produce calcitriol. This reaction is
stimulated by PTH and hypophosphatemia and inhibited by calcium and
phosphate. In patients with renal failure, calcitriol production is
low, due mostly to loss of the enzyme but also to hyperphosphatemia.
Calcitriol is believed to suppress PTH secretion by direct suppression
of parathyroid gland activity. It also helps correct the abnormal
shift in the "set point" for calcium and may decrease pre pro–PTH mRNA
synthesis in a dose-dependent manner. Thus, calcitriol deficiency may
help initiate secondary hyperparathyroidism even in the absence of
overt hypocalcemia.
Calcitriol (10-20 ng/kg/day) should be prescribed to children who have
an ↑iPTH level ↓Ca that persists despite correction of
hyperphosphatemia and vitamin D deficiency. The serum levels of
calcium, phosphate, and PTH should be monitored closely and subsequent
adjustments of calcitriol therapy should be based on these levels.
Dose should be held or decreased if hypercalcemia or hyperphosphatemia
develops/persists, or if iPTH is below target range for the stage of
CKD.
C. Calcium metabolism — Hypocalcemia and secondary hyperparathyroidism
is one of the hallmarks of bone disease among children. As previously
mentioned, hyperphosphatemia and decreased calcitriol levels develop
with progressive loss of kidney function, thereby contributing to low
calcium levels. Therapy should be instituted with calcium
supplementation such as oral calcium carbonate, calcium acetate, or
calcium gluconate; or parenteral calcium chloride.
D. Soft tissue calcification — The incidence of soft tissue
calcification is high when the calcium phosphate product (each in
mg/dL) exceeds 70. Soft tissue calcification can be divided into the
following:
Vascular calcification - involves media of the arteries
Ocular calcification - involves conjunctiva and cornea
Visceral calcification - deposits of calcium may be found in
lungs, stomach, myocardium, skeletal muscles, kidney
Periarticular calcification
Cutaneous calcification
Calciphylaxis
E. Aluminum in chronic kidney disease — Aluminum-related disorders in
CKD, although now extremely rare, can present with the findings of
hypercalcemia, osteomalacia, microcytic anemia, and dialysis
encephalopathy. Administration of aluminum, historically provided most
commonly in the form of phosphate binders, should be avoided and, in
hemodialysis patients, the dialysate concentration of aluminum should
be <10 mcg/L Patients who are ingesting aluminum-containing phosphate
binders or meds such as sucralfate that contain aluminum should not
receive citrate simultaneously as the latter med enhances GI
absorption of aluminum. Serum aluminum levels should be measured
yearly in patients with Stage 5 CKD, and the baseline level of serum
aluminum should be <20 mcg/L. A deferoxamine (DFO) test should be
performed if there are elevated serum aluminum levels (>60 mcg/L) or
clinical signs and symptoms of aluminum toxicity, or prior to
parathyroid surgery if the patient has had aluminum exposure.
4. Hypertension — The prevalence of hypertension in patients with CKD
is high, even when the GFR is only mildly reduced and increases
further with a decline in GFR. Treatment of hypertension should
include specification of target blood pressure levels, conservative
measures such as weight reduction, exercise, and dietary salt
reduction, and specific antihypertensive agents with the aim that
blood pressure control may help prevent the progression of CKD and the
development of cardiovascular disease.
5. Anemia — The anemia of CKD, which is due to the reduced production
of erythropoietin by the kidney, is principally normocytic and
normochromic. By comparison, the finding of microcytosis may reflect
iron deficiency, aluminum excess, or certain hemoglobinopathies, while
macrocytosis may be associated with vitamin B12 or folate deficiency.
Evaluation of patients with anemia should include an assessment of at
least the following:
Red blood cell indices
Reticulocyte count
Iron parameters (serum iron, total iron binding capacity,
percent transferrin saturation [TSAT] and serum ferritin)
Test for occult blood in stool
Work-up should be done prior to initiation of recombinant human
erythropoietin (rHuEPO) therapy. Whereas iron deficiency in the
general population is indicated by a TSAT of 16 % and/or a
serum ferritin 12 ng/mL, the recommended TSAT is 20 %
and serum ferritin 100 ng/dL (100-800) in patients with CKD
who are also receiving rHuEPO.
If the baseline iron studies are subnormal, iron therapy (elemental
iron 3-4 mg/kg/day) should be initiated; in addition, all patients
receiving rHuEPO require iron to prevent the development of iron
deficiency. Once iron status is normal, should be monitored q3-6
months, or monthly following initiation and/or increase of rHuEPO
dose. The expected increase in Hct after initiation of rHuEPO therapy
or after a dose change is between 2-8 % over a 2-4 week period.
Ddx Epogen Resistance
*
#1 Iron deficiency • ACE inhibitors • Aluminum toxicity • 2
HypoPTH
*
Infection/Inflammation • Carnitine Deficiency • Hemoglobinopathies
• Copper Deficiency
*
Chronic blood loss • Zinc Deficiency • Folate or B12 deficiency •
Hepatic failure
*
Osteitis fibrosa • Vitamin D Deficiency • Malnutiriton •
Malnutirion
*
Hemolysis • Multiple Myeloma
6. Dyslipidemia — Abnormal lipid metabolism is common in patients with
CKD and adds risk for cardiovascular disease.
The K/DOQI guidelines on dyslipidemias recommend that all children as
well as adults with CKD should be evaluated for dyslipidemia. The
patients should be evaluated with a complete fasting lipid profile to
include total cholesterol, LDL, HDL, and triglycerides at
presentation, and annually thereafter or two to three months after a
change in treatment or other conditions known to cause dyslipidemia.
Elevated triglyceride levels should initially be treated with
therapeutic life changes alone, as fibrates and nicotinic acid,
medications traditionally used for adults, have not been adequately
studied in children. On the other hand, a limited number of small
randomized controlled trials in children and adolescents from the
general population have found that statins (atorvastatin is US
FDA-approved in children) are safe and effective in lowering LDL
cholesterol. Patients receiving statin therapy should be closely
monitored for adverse effects on muscles and liver, and for drug
interactions with commonly used medications. In children who do not
achieve the desired target lipid levels with statin therapy, the
addition of bile acid sequestrants such as cholestyramine, colestipol,
and colesevelam hydrochloride, as well as the use of nicotinic acid,
can be considered. A common concern pertaining to the use of bile acid
sequestrants is their tendency to be associated with an increase in
the serum triglyceride level that can lead to deficiencies of vitamin
A, E, and folic acid.
7. Malnutrition — Malnutrition is common in children with CKD because
of poor appetite, decreased intestinal absorption of nutrients, and
metabolic acidosis. Children should be provided with 100 % of the RDA
for protein, as these diets are safe and palatable for the child and
avoid the problems associated with an excessive protein intake.
Protein restriction is not recommended in children as it has not been
shown to influence the decrease in renal function in children with
CKD.
Supplemental nutritional support may be needed in a child who is not
growing appropriately, is markedly malnourished, or fails to consume
the RDA for protein and/or calories. Although supplementation by the
oral route is preferred, one may have to resort to tube feedings with
a nasogastric tube, transpyloric tube, or gastrostomy.
The child should also receive 100 % of the dietary reference intakes
for water-soluble vitamins such as thiamine (B1), riboflavin (B2),
pyridoxine (B6), vitamin B12, and folic acid. An intake of 100 percent
of the RDA should be the goal for vitamins A, C, E, K, and copper and
zinc. A precautionary note should be made for vitamin A as the loss of
clearance of vitamin A metabolites by the normal kidney places
children with advanced CKD at risk for symptoms of hypervitaminosis A.
This should be considered when selecting a multivitamin that contains
a combination of water- and fat-soluble vitamins.
8. Hormonal Abnormalities — The kidney normally plays an important
role in the metabolism, secretion, degradation, and excretion of a
number of hormones, their associated receptors, and binding proteins.
This leads to either increased or decreased hormone levels, disturbed
activation of pro-hormones, altered bioactivity, altered hormone
binding to carrier proteins, and/or altered tissue sensitivity at the
receptor and post-receptor level.
*
Somatotropic: Abnormalities in somatotropic hormone axis consist
of "growth hormone insensitivity", manifested by normal or
elevated levels of GH, normal or ↓levels of total insulin-like
growth factor-1 (IGF-1), decreased GH receptor activity, increased
levels of insulin-like growth factor-1 binding protein -1
(IGFBP-1), IGFBP-2, IGFBP-4, and IGFBP-6 (with a resultant
decreased free IGF-1 level), and accumulation of various small- to
medium-sized molecules from CKD that can inhibit the somatotropic
axis.
*
The following is the current acceptable criteria for
initiating Growth Hormone in children with CKD:
*
Height for chronological age < SDS or height velocity SDS
for chronological age that is < -2
*
Growth potential that is documented by open epiphyses
*
There are no other contraindications for rHuGH.
The use of rHuGH is continued until the child reaches the 50th
percentile for mid-parental height, achieves a final adult height with
closed epiphyses, or receives a kidney transplant. Continued close
monitoring of growth should occur once rHuGH is discontinued, with the
potential for its reinstitution if "catch down" growth occurs.
*
Gonadotropic: Abnormalities detected in the gonadotropic hormone
axis in advanced CKD are characterized as a "compensated state of
hypergonadotropic hypogonadism" manifested by normal or elevated
levels of the gonadotropic hormones, FSH and LH, and the loss of
the LH pulsatile pattern. Thus, puberty is frequently delayed in
children with CKD. Onset is delayed by an average 2.5 years and
delayed puberty is present in 2/3 of adolescents with ESRD. The
average time for menarche in adolescent females is 15-16 years
compared to 13 years in normal healthy girls.
*
Thyroid: Abnormalities detected in the thyroid hormone axis are
characterized by low total and free T4 and T3, with normal TSH,
normal or decreased thyroid hormone-binding globulin and normal or
decreased TRH test; this is similar to "sick euthyroid syndrome"
seen in other chronic diseases. A normal or low reverse T3 in CKD
helps differentiate it from the sick euthyroid state of other
chronic diseases in which the reverse T3 is elevated.
*
Adrenal: The abnormalities detected in the adrenal hormone axis in
CKD are complex. A high index of suspicion is needed to help
diagnose adrenal disease in children with CKD.The findings of
hypertension, osteopenia, proximal muscle weakness and glucose
intolerance can be seen in both Cushing's syndrome and advanced
CKD. The findings of adrenal insufficiency of hypotension,
weakness, and hyperkalemia can be easily masked by renal
insufficiency.
9. Neurocognitive Development — Uremia is associated with alterations
in cognitive development in children.
Previously, the neurodevelopmental outcomes of infants and small
children with CKD were dismal, in large part as a result of
malnutrition and aluminum exposure. Subsequently, with improvement in
nutritional management, avoidance of aluminum, and optimization of
dialysis and anemia management, the neurodevelopmental outcome has
been more encouraging.
10. Uremic Complications
A. Uremic bleeding — An increased tendency to bleeding is present in
some patients with CKD in association with prolongation of the
bleeding time, due primarily to an acquired platelet dysfunction that
results in abnormal adhesion and aggregation. No specific therapy is
required in asymptomatic patients.
However, correction of platelet dysfunction is desirable if actively
bleeding or to undergo procedure (e.g.renal biopsy):
pRBCs, as an improved hematocrit is believed to facilitate
increased interaction between platelets and blood vessels
DDAVP (0.3 µg/kg intravenously or subcutaneously), the effect
of which is transient and lasts for six to eight hours
Cryoprecipitate (1 to 2 units/10 kg), the effect lasts for
24-36 hrs but increases risk of transmitting infectious diseases
Estrogen (0.6 mg/kg per day for 5 days), the onset of effect
is over 6 to 24 hours, but effect lasts for two to three weeks.
B. Uremic pericarditis — Uremic pericardial disease (pericarditis and
pericardial effusion) is seen only in late stages of CKD and is an
indication to institute dialysis. The patient presents with fever,
pleuritic chest pain, and a pericardial rub. The characteristic
feature of uremic pericarditis which differentiates it from other
inflammatory pericarditis, is that the electrocardiogram does not
usually show the typical diffuse ST elevation. Therefore, pericarditis
in a patient with mild to moderate renal failure or with an ST
elevation should suggest some other cause for pericarditis. Uremic
pericarditis, although not common in children, should be considered in
a patient presenting with the characteristic clinical features,
especially in children who have an associated primary collagen
vascular disease.
11. Renal replacement therapy — Once the estimated GFR declines to
less than 30 mL/min per 1.73 m2 and the child is in Stage 4 CKD, it is
time to start preparing the child and the family for renal replacement
therapy. The family should be provided with information related to
preemptive kidney transplantation, peritoneal dialysis, and
hemodialysis.
As in adults, some form of renal replacement therapy will be needed
when the weekly renal Kt/Vurea falls below 2.0, which approximates a
creatinine clearance between 9 to 14 mL/min/1.73 m2. However, renal
replacement therapy is often initiated before children reach these
levels for the following reasons:
Limitations of total calorie intake resulting in failure to
thrive
Clinical symptoms attributable to uremia
Delay in psychomotor development and/or educational issues
from progressive CKD.
Choice of renal therapy —Choices include peritoneal dialysis,
hemodialysis, renal transplantation
*
Peritoneal dialysis is more common in younger children, in large
part due to vascular access issues, and hemodialysis becomes more
common in older adolescents (but hemodialysis can be performed in
very young children as well)
*
Children who are to receive hemodialysis will need evaluation of
their vasculature for placement of an arterio-venous (AV) fistula,
arterio-venous graft, or cuffed double lumen catheter. The use of
AV fistula, the recommended type of vascular access in adults, is
limited in children due to the size of their vessels.
Adapted from UpToDate “Overview of the management of chronic kidney
disease in children”
Some Notes on Blood Products
Always remember to Gann Act the patient first!
Blood units are tested for HIV/HCV, West Nile Virus (IND 7/1/03),
anti-HIV-1 & -2, HIV p24 antigen, anti-HTLV-I/II, anti-HCV, anti-HBc,
HBsAg and syphilis. Current estimates of the risk of transmitting
viral infections per unit administered (Busch, JAMA 2003; 289: 959):
Hepatitis B
1 in 220,000
Hepatitis C
1 in 1.6 million
HIV
1 in 1.8 million
HTLV-I/II
1 in 641,000
Risks for other infections - babesiosis, malaria, syphilis,
trypanosomiasis, yersiniosis - are <1:1,000,000.
Packed red blood cells
One unit is roughly 200-300ml. Give 10ml/kg over 2-4 hrs to raise Hb
by 1-3g/dl.
*
Type and Screen – Screens for major antibodies, ABO, Rh
*
Type and Cross – Crossmatches additional antigens (patient serum
and donor RBCs are mixed to assess compatibility) and reserves
desired amount of blood.
If you think your patient might need blood, order 2 units to be
readily available for emergency purposes.
If blood cannot be typed and crossmatched quickly in an emergency
Universal donor: O negative
Universal recipient: AB positive
Platelets
One pheresed unit is roughly 250 mL. Give pheresed plts over ½ -1 hr
to raise plts by ~40,000-50,000.
Give ½ unit platelets if patient <20 kg
Give 1 unit platelets if patient >20 kg
Use non-packed platelets (unless volume is an issue)
Plasma (FFP)
One unit is 200-300ml. Has lots of factors, basically everything
except platelets. Give 10-15 mL/kg. Indications: DIC, TTP, to reverse
effects of warfarin, protein C and S disease.
Cryoprecipitate
One unit is 30ml. Give 10 ml/kg. Factors included: I (Fibrinogen),
VIII, vWF, XIII. Don’t use in Factor 9 Deficiency.
Note: For our Oncology kids, we need special blood handling:
*
All blood products should be CMV negative (to prevent transfusion
related infection)
*
All blood products should be irradiated (to kill T lymphocytes and
to reduce GVHD)
*
All blood products should be leukodepleted (removes WBC’s from
platelets and pRBC’s. Helps prevent febrile nonhemolytic
reactions, HLA sensitization and CMV exposure.)
Some of our kids require pre-medication:
Benadryl - to prevent urticarial reaction
Tylenol - to decrease febrile non hemolytic reaction from proteins
Use washed cells for pts w/ hx severe allergic transfusion reactions,
IgA deficiency to help remove extra plasma containing antigens and
cytokines
Transfusion Reactions
Class
Clinical Symptoms
Likely Cause
I
Urticaria, hives
Alloantibodies agst plasma protein antigens
II
Fever, chills, nausea
Alloantibodies agst leukocyte antigens
III
Delayed ↓Hct, increasing bilirubin, fever
Alloantibodies agst specific red cell antigens post transfusion
(delayed transfusion rxn)
IV
Oliguria, bleeding, hemoglobinuria, shock
Antibodies against specific red cell antigens
Anaphylaxis
Anti-IgA antibodies
Acute pulmonary insufficiency, edema, infiltrates
Anti-WBC antibody
Transfusion reaction workup
Stop transfusion!
Send untransfused blood product and patient sample to blood bank for
analysis
Obtain u/a to r/o hemoglobinuria
Support patient as needed (Benadryl, Tylenol)
Class III/IV may require PICU support
68