9/23- Pediatric Nephrology, Pharmacology, and Polycystic Kidneys Flashcards
What are 5 pharmacologic properties affected in kidney disease?
- Bioavailability
- Drug storage
- Volume of distribution
- Drug metabolism affected by uremic molecules and P450 system
- Renal excretion affecting pharmacodynamics
How is bioavailability affected by kidney function?
F = AUCoral/AUCiv
Clinical correlate (CC):
- CKD and metabolic acidosis
- Nephrosis and bowel edema
How is drug storage affected by kidney disease?
- Generally storage is in plasma proteins
CC:
- Uremic molecules may displace drug
- Hypoalbuminemia may increase drug levels
How is volume of distribution affected by kidney disease?
Vd = dose/plasma concentration
CC:
- Volume increases in CKD due to salt and water retention
How is drug metabolism affected by kidney disease?
- Delayed phase I metabolism results in toxic levels of drug (metabolism affected by uremic mcls and P450 system)
How is renal excretion affected by kidney disease?
- Changes in GFR or tubular secretion: Follow drug dosing guidelines!
CC:
- Higher/lower dose of drug may be required in CKD (diuretics, insulin…)
Pharm calculations: How do you determine creatinine clearance?
The best clinical estimate that we can use in the steady state is a 24-hour urine collection for creatinine clearance.
Most of the time, we estimate clearance for drug dosing with the Cockroft-Gault formula, calculated as:
What drug properties should be modified for change in GFR?
- Frequency
- Dose
- Both
T/F: The loading dose of the drug should be reduced for patients with low GFR
False
- Typically not adjusted in CKD; need to reach steady state in therapeutic window fast
- Drug levels can be measured as a guide to drug therapy; Loading doses may predispose patients with CKD to toxicity
Practice Problem
- What is the creatinine clearance for a fit 25-year old male patient with a serum Cr of 1 mg/dL and a body weight of 80 kg?
Practice Problem
- What is the maintenance dose for a drug that is 75% excreted through the kidney in a patient with a creatinine clearance of 10 ml/min?
- Assume a normal creatinine clearance of 100 ml/min. Give answer as percent of dose that would be given in a patient with normal kidneys
ANSWER (step-wise approach)
- 10% of normal renal clearance remains (10ml/min / 100 ml/min)
- Assume other routes of clearance are normal (feces, etc.): 25%
- 25% + (10% of 75%) = 25% + 7.5% = 32.5%
ANSWER: The dose should be 32.5% due to the reduced capacity of this patients’ kidneys to clear the drug
Practice Problem
- A 34-year old 110 lb female patient is to be given tobramycin for sepsis.
- The usual dose of tobramycin is 150 mg twice a day by IV injection.
- The creatinine clearance in this patient is stable at 50 ml/min.
- Assume a normal creatinine clearance of 100 ml/min. 90% of each dose of tobramycin is excreted by the kidney.
- Calculate the appropriate maintenance dose of tobramycin.
- 90% of tobramycin is cleared by kidneys
- 50% of renal clearance is intact
- 50% of 90% = 45% renal clearance of Tobramycin.
- 10% is cleared by other routes (Think: 100% - 90% = 10%)
- Total drug needed for maintenance: 55% of usual dose
- 55% of 150 mgs = 83 mgs. Adjust the dose accordingly.
- Remember, the loading dose is the same!
- This is the maintenance dose only.
Practice Problem
- The normal dose of flecainide (for ventricular arrhythmias) is 100 mg every 12 hours.
- You need to administer it to a patient with a stable creatinine clearance of 20 ml/min. The drug monograph states that flecainide is 30% eliminated by the kidney.
- What is the adjusted maintenance dose to be given every 12h?
- Assume normal non-renal clearance. Normal dose 100 mg.
- 30% of 20% (20 ml/min / 100 ml/min) is 6%
- 6% of 100 mg = 6 mg
- Add to this normal non-renal clearance of 70% (70 mg) = 76 mgs
Answer: 76 mg every 12 hours.
Practice Problem (Too complicated for an exam)
- A 73 year old adult male weighs 65 kg and has diabetes mellitus and ESRD on hemodialysis. His residual creatinine clearance is 5 ml/min. The patient is given tobramycin at 1 mg/kg IV bolus injection.
- Tobramycin is 90% excreted unchanged in the urine, is less than 10% bound to plasma proteins and has an elimination half-life of approximately 2.2 hours in patients with normal renal function.
- In ESRD, tobramycin has an elimination half-life of 50 hours during the intra-dialysis period and an elimination half-life of 8 hours during the dialysis treatment.
- The volume of distribution for tobramycin is about 0.33 L/kg (given from the drug monograph)
Q1: What is the expected drug concentration after the first dose of tobramycin
Q2: What will be the drug concentration prior to the start of his next hemodialysis?
- Assume he gets dialysis 48 hours after the initial tobramycin loading dose AND the drug was given to him at the completion of his last dialysis.
Q3: Let us assume the patient accidentally gets the drug at the start of dialysis. WHAT is the drug concentration and drug amount at the completion of a 4 hour hemodialysis treatment?
Q4: Now, how much tobramycin should you give after dialysis to restore the plasma concentration to our target of 3 mg/L
Q1:
- Total drug given:
1 mg / kg x 65 kg = 65 mgs;
- Vd of the drug: 0.33L / kg x 65 kg = 21.45 L
- So… 65 mg in 21.45 liters ~ 3 mg / L (expected drug level if we measured it)
Q2:
- 48 hrs is ~ one half-life; so, half the drug will be metabolized.
- Answer: 1.5 mg / L
Q3:
- After 4 hours of dialysis, 50% of the drug remains -
Answer: 0.75 mg / L
- 0.75 mg / L x 21.5 L (VD) = 16 mg total
Q4:
- Answer: 49 mg
- 16 mgs remaining; total 65 mgs needed; 49 mg to be added
In clinical practice:
- Drug levels take hours to days to be reported and may or may not correlate with therapy
- Patients are often under or over-dosed with a drug, exacerbated in patients with organ failure.
- Drug monograms provide reference so that these calculations are rarely done.
Fun fact
Question:
- Your patient is given 100 mg of a new diuretic X. She has a GFR of 50 ml/min. Lets assume a normal GFR of 100 ml/min.
- Drug X is 100% excreted through the kidney. After the initial loading dose, you wish to give a maintenance dose and the half life is 12 hours.
What is the appropriate dose?
A. 100 mg q12h
B. 50mg q12h
C. 10mg q12h
What is the appropriate dose?
A. 100 mg q12h
B. 50mg q12h
C. 10mg q12h
Question:
- Your patient has an estimated GFR of 10 ml/min. He is not yet on dialysis. His laboratories suggest metabolic acidosis, and on examination, he has 1+ pitting edema bilaterally.
- He is enrolled in a clinical trial and is to randomized to receive Drug Y.
Which of the following pharmacokinetic characteristics must be accounted during the study design?
A. Changes in drug storage (due to uremic mcls)
B. Delayed renal excretion
C. Increased volume of distribution
D. All of the above
Which of the following pharmacokinetic characteristics must be accounted during the study design?
A. Changes in drug storage (due to uremic mcls)
B. Delayed renal excretion
C. Increased volume of distribution
D. All of the above
What are some Renal Cystic Diseases?
Kidney cysts are very common
- Autosomal Dominant Polycystic Kidney Disease**
- Autosomal Recessive Polycystic Kidney Disease
- Acquired Renal Cystic Disease
- Medullary Cystic Disease/ Nephronophthisis
- Medullary Sponge Kidney
- Tuberous Sclerosis Complex
Describe AD Polycystic Kidney Disease
- Prevalence
- Genetic inheritance
- 400,000 people in US annually (1800 begin dialysis each year) Genetics
- Highly variable gene expression and course; about 50% w/ gene mutation develop kidney dz
- Genes: PKD1 and 2
PKD1:
- 85-90% of clinically detected cases
- Chrom 16
- Encode for polycystin 1
PKD2:
- Chrom 4
- Encode for polycystin 2
What is the pathogenesis of ADPKD?
Disruption of the polycystin proteins leads to
- epithelial dedifferentiation, unregulated proliferation and apoptosis, AND
- altered cell polarity, disorganization of surrounding extracellular matrix, AND
- excessive fluid secretion (vasopressin mediated via apical aquaporin channels) through apical chloride and aquaporin channels, and abnormal expression of several genes, including some that encode growth factors. As abnormal cells proliferate, out pouching develops which seals off and forms a cyst. Renal cysts originate from any tubule in the nephron (ADPKD)`
What are the clinical manifestations of ADPKD?
Diagnosis typ made by radiographic findings:
- US or CT scan
- > 4 cysts/kidney if age > 60
Kidney size increases with age:
- Each can weigh 10-15 kg (normal = 0.2 kg!)
Renal Manifestations:
- Cyst hemorrhage, hematuria, and pain are common
- 60-75% develop HTN (commonly presenting Sx)
- UTIs and kidney stones are more than gen pop
What are extra-renal manifestations of ADPKD?
- Polycystin protein found elsewhere…
- Liver cysts are the most common finding.
- Synthetic liver function usually preserved
- Cysts may present in other organs like pancreas, spleen, ovaries and testes.
- 25 % patients have mitral valve prolapse.
- Colonic diverticulosis
- Abdominal hernias.
- 5% patients have intra-cranial (berry) aneurysms.
What is the most feared ADPKD association?
- Percent affected
- Genetics
Intracranial “Berry” anuerysms
- 5% of all ADPKD pts
- Positive FHx increases incidence 10-20%
What are the treatment options for ADPKD?
- No targeted therapy for underlying genetic disease
- HTN control with a target BP of 130/80 mmHg or less. Usually RAS blockers.
- Possible UTI? Certain antimicrobials, like fluoroquinolones, have better cyst penetration if suspect an infected cyst
- Aggressive water hydration is one theoretical treatment (suppresses vasopressin mediated cyst growth)
- Tolvaptan (ADH antagonist) has been tried with some success; limited by cost and ASEs
- Kidney Transplant is treatment of choice if necessary (does not recur!)
Describe ARPKD
- Inheritance
- Age of diagnosis
- Prevalence
- Exam findings
AR Polycystic Kidney Disease
- Autosomal recessive
- Most Dx in infancy; sometimes young children/young adults - Rare; affects 1/20-50K
- Large palpable kidneys on exam
Describe Henoch Schonlein Purpura (HSP) in pediatrics
- Age affected
Symptoms:
- Skin
- MSK
- GI
- GU
Also:
- Prognosis
- Appearance on biopsy
- Younger age, under 10 yo
Symptoms:
- SKIN: Purpuric rash (palpable), especially lower extremities
- MSK: Arthritis/arthralgias
- GI: Abd pain, bloody diarrhea, intusussception
- GU: Nephritis with gross or microscopic hematuria
Prognosis:
- Poor if nephrotic syndrome or HTN;
- Rarely progresses to ESRD Renal biopsy
- Looks just like IgA nephropathy
- “HSP is systemic IgA nephropathy”
What is renal dysplasia?
Altered differentiation of metanephric tissue with persistence of primitive structures
- Unilateral or bilateral; most common cause of congenitally small kidney
- Primitive glomeruli and tubules in varying numbers
- Fibromuscular tissue present with or without foci of primitive cartilage
- Cysts frequent; if large cysts, called “cystic dysplasia
What is Multicystic dysplastic kidney?
Dysplastic kidney with multiple large cysts, no functioning renal tissue, absent or rudimentary ureter
- Almost always unilateral; may confuse with hydronephrosis on renal ultrasound
- Incidence: 1 in 2000 live births; most frequent cause of palpable abdominal mass in newborn infant
- High incidence of obstruction or VU reflux in opposite kidney
What are common sites of obstructive uropathy in pediatrics?
- Uretero-pelvic junction (UPJ) obstruction
- Uretero-vesical junction (UVJ) obstruction (vesico-ureteral reflux)
- Posterior urethral valves (PUV)
- persistent tissue in posterior prostatic urethra of male
- bilateral hydronephrosis + vesico-ureteral reflux
What is shown here?
Voiding Cysto-UrethroGram (VCUG): Place catheter in bladder, instill contrast, watch for reflux. Allow patient to drink. Observe urination. Watch for reflux.
What is Prune Belly Syndrome?
Includes:
- LUTO: Ureteral dilatation/poor musculature, poor peristalsis & stagnant urine, hydronephrosis
- Absent abdominal muscules (“wrinkled prune in newborn”- appearance improves with age);
- Undescended testicles
- Occurs in males
What is Wilm’s Tumor?
- Most common malignancy of the urinary tract in child
- Abnormal proliferation of metanephric blastema
- 90% present before 7 y.o. (peak 3-4 y.o.): “painless abdominal tumor”
- Bilateral in 4-8% cases
- Genetics: Wilm’s tumor genes
- WT1 at chromosome 11p13
- deletion one copy associated with WAGR (Wilm’s tumor, aniridia, genitourinary malformations, mental retardation)
- point mutation associated with Denys-Drash syndrome
- WT2 at chromosome 11p15
- associated with Beckwith Wiedemann syndrome (hemi-hypertrophy, enlarged tongue, medullary sponge kidney)
Overall survival > 85% with combination therapy
Describe HUS in Pediatrics
- Triad for diagnosis
- Typical
- Atypical
Triad for diagnosis
- Microangiopathic hemolytic anemia
- Thrombocytopenia
- Uremia
Typical (Diarrhea +) = bloody diarrheal pro-drome
- Shiga-toxin in E.coli O157, Shigella, etc.
- Acute kidney injury; 10-20% of these cases are irreversible
Atypical (Diarrhea -) = Factor H or I deficiency
- Classified as Thrombotic Microangiopathy (TMA)
- Treatment is complex; must turn off complement system
- You are a pediatric nephrologist and your next patient is a sweet 6-year old girl with hematuria. On examination, you find palpable purpura on her buttocks and she gives a history of occasional ‘upset stomach’ with diarrhea
- You perform a renal biopsy and the immunofluorescence is shown below.
What is the most likely diagnosis?
A. Hemolytic Uremic Sydnrome
B. Minimal Change Disease
C. Henoch Schonlein Purpura
D. IgA Nephropathy
What is the most likely diagnosis?
A. Hemolytic Uremic Sydnrome
B. Minimal Change Disease
C. Henoch Schonlein Purpura
D. IgA Nephropathy
