Setting: office
CC: “Why are my legs swollen?”
VS: BP: 112/70 mm Hg; P: 92 beats/minute; T: 98°F; R:12 breaths/minute
HPI: A 34-year-old man comes to see you at your office for swelling of both of his legs developing slowly over several months. He has seen another physician who gave him a diuretic to decrease the swelling, but there was no improvement.
PMHX:
Hyperlipidemia for 3 years
Medications:
Simvastatin
ROS:
Several colds and sinus infections over the past year
Anxiety about swelling
Denies pain, dyspnea
PE:
General: emotionally distressed
Chest: clear to auscultation
Cardiovascular: no murmurs, no gallops
Extremities: bilateral lower extremity edema to the knees
Head, Ears, Eyes, Nose, Throat (HEENT): mild periorbital edema
Initial Orders:
UA
Echocardiogram
Comprehensive metabolic panel (CHEM-20)
Liver function tests
Lipid panel
Periorbital edema is a main clue to low albumin as etiology.
Move the clock forward just enough to get the results. The patient is described as visibly anxious and you need to discuss the results with him as soon as possible.
Report:
Urinalysis: 4+ protein, oval fat bodies
Echocardiogram: normal
CHEM-20: albumin 2.1 mg/dL
Liver function tests: normal
Low-density lipoprotein (LDL) 145 mg/dL; triglycerides 500 mg/dL (elevated)
What is the best way to tell whether a patient’s albumin level is low from liver disease or another cause?
a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
b. Lactate dehydrogenase (LDH)
c. Prothrombin time (PT)
d. Liver sonogram
e. Alkaline phosphatase and gamma-glutamyl transferase (GGTP)
Answer c. Prothrombin time (PT)
If the albumin level is low, but the PT is normal, the liver is definitely not the cause of the low albumin level. It is impossible for the liver to be synthetically normal enough to make clotting factors but not normal enough to make albumin. The liver does not selectively fail to produce one protein such as albumin, but still make other proteins such as clotting factors. The AST and ALT can be normal when the liver is nearly dead. You have to have live cells to make transaminases. Dead livers do not shed AST/ALT. Bald people do not shed hair.
A liver sonogram tells nothing about the synthetic capacity of liver. Alkaline phosphatase and GGTP assess the biliary system. Obstruction elevates the levels of both.
Binge drinking elevates GGTP first.
The world’s best test of liver synthetic function is PT!
UA in hyperlipidemia
• Oval fat bodies
• Maltese crosses
Nephrotic Syndrome =
• Hyperalbuminuria +
• Hypoalbuminemia +
• Edema +
• Hyperlipidemia
The patient is actually quite relieved to hear the results of the tests. He feels this explains why, as a young man, he had hard-to-control hyperlipidemia.
Edema = Low Oncotic Pressure + Increased Sodium Absorption
Why does this patient have frequent respiratory infections?
a. The function of the neutrophils is decreased.
b. IgG is lost in urine.
c. Antibodies are not made when the albumin level is low.
d. Lipids inactivate lymphocytes.
Answer b. IgG is lost in urine.
The precise etiology of infections in nephrotic syndrome is not entirely clear, but likely reflects loss of immunoglobulins in urine.
Keep BP under 130/80 mm Hg in nephrotic syndrome.
You tell the patient to increase the dose of his statin medication and to return to check his BP. Although nephrotic syndrome is not a coronary artery disease equivalent, the lower the triglycerides and LDL are, the better it will be for his nutritional status.
Orders:
Urine protein-to-creatinine ratio
Nephrology evaluation
Nutrition evaluation
Low sodium diet
ACE inhibitors
Urine protein-to-creatinine ratio = 24-hour urine collection
• Ratio of 3:1 = 3 g/24 h excreted
• Ratio of 5:1 = 5 g/24 h excreted
Which of these medications should you ask the patient about having used?
a. Nonsteroidal antiinflammatory drugs (NSAIDs)
b. Lamotrigine
c. Proton pump inhibitors
d. Quinolone
Answer a. Nonsteroidal antiinflammatory drugs (NSAIDs)
NSAIDs have a clear association with the development of membranous glomerulonephritis and nephrotic syndrome. The other medications listed cause allergic interstitial nephritis, not nephrotic syndrome.
Cancer, especially lymphoma, causes nephrotic syndrome.
The patient comes back in 2 weeks. The swelling is worse in one leg than the other. Lower extremity Doppler ultrasound shows a deep venous thrombosis (DVT). The patient is started on enoxaparin and warfarin. His urine protein-to-creatinine ratio is 7:1.
Urine Protein-to-Creatinine Ratio >3.5 = Nephrotic Syndrome
>3.5 g of protein/24 h = Nephrotic Syndrome
Renal function varies with posture.
Matching protein with creatinine corrects for the alteration in renal function during the day.
What is the mechanism of DVT in nephrotic syndrome?
a. Urine loss of clotting factors (II, VII, IX, X).
b. Overproduction of clotting factors.
c. Urine loss of protein C, S, and antithrombin.
d. Low albumin level leading to stasis.
Answer c. Urine loss of protein C, S, and antithrombin.
Together with all the protein lost as albumin is also the loss of natural anticoagulants. Nephrotic syndrome is a hypercoagulable state. Protein C, protein S, and antithrombin are lost in the same way that albumin is lost. In addition, there is iron, zinc, and copper deficiency because the carrier proteins for these metals are lost as well.
Carrier protein loss leads to deficiency of
• Iron (transferrin)
• Copper (ceruloplasmin)
• Zinc
The patient declines a kidney biopsy that you order. The note says, “Patient declines biopsy because he does not understand what difference it will make in therapy.”
Orders:
Antinuclear antibody (ANA), hepatitis B and C serology
human immunodeficiency virus (HIV)
Antineutrophil cytoplasmic autoantibody (ANCA)
Cryoglobulins
Chronic hepatitis causes vasculitis that can involve the kidney.
Hepatitis C causes cryoglobulins.
Treat with interferon, ribavirin, and either telaprevir or boceprevir.
(Three drugs for hepatitis C)
In 2 weeks, the patient’s edema has only worsened. All the results of the tests ordered are normal. He agrees to kidney biopsy.
The loss of high density lipoproteins in the urine signals very low density lipoprotein (VLDL) and chylomicrons to increase lipid levels. Lipoprotein signals prompt the clearance of lipids from blood. Without lipoproteins, lipids build up.
The renal biopsy shows membranous glomerulonephropathy. The patient is placed on prednisone orally and returns every month, but after 3 months there is no improvement in urine protein excretion or serum albumin levels.
What should you add to therapy?
a. Add cyclophosphamide.
b. Add cyclosporine.
c. Add rituximab.
d. Add tacrolimus.
e. All are viable options.
Answer e. All are viable options.
It is not precisely clear as to which therapy to use. Although cyclophosphamide has been used for a long time, there is also significant risk of adverse effects.
Mechanism of Action
• Cyclosporine: calcineurin inhibition inactivating T cells
• Tacrolimus: calcineurin inhibition
• Rituximab: anti-CD20 antibody
Over the next several months, the nephrotic syndrome improves. It is not possible to give a definite answer as to which of these therapies is better than the other. All have fairly good efficacy. Many cases of nephrotic syndrome spontaneously resolve over time. ACE inhibitors and lipid-lowering therapy should be continued until that happens.