KSAP VOL 3 MOD 1 UPDATE Flashcards
A 54-year-old man with ESRD is seen in follow-up. He performs home HD 4 times weekly using a machine that utilizes low dialysate volume.
His current prescription specifies a blood flow of 400 mL/min, dialysate flow of 160 mL/min, with a flow fraction of 40%. He uses 25 L of dialysate per treatment session. His residual creatinine clearance is 2.59 mL/min, a decline from 3 months ago. His standardized weekly Kt/V dialysis is 1.34, and his standardized weekly Kt/V renal is 0.56, for a total of 1.9. His treatment time has ranged from 115 to 162 minutes per session.
On exam, he appears well. His BP is 126/82 mm Hg and his heart rate is 84/min. There is no lower extremity edema.
Which of the following is the BEST strategy to improve his standardized weekly Kt/V dialysis?
Select one:
A. Increase flow fraction from 40% to 50%
B. Increase blood flow to 450 mL/min
C. Increase dialysate volume to 30 L per treatment
D. Decrease blood flow rate but maintain flow fraction of 40%
E. Reduce target weight to reduce his volume of distribution for urea
The correct answer is: C
Increase dialysate volume to 30 L per treatment
The best strategy to improve the standardized weekly Kt/V in this patient who is being treated with a low dialysate volume hemodialysis platform is to increase the dialysate volume per treatment.
Home HD with a low volume dialysate platform can be an attractive alternative to other strategies for dialysis. Unlike conventional HD, this method does not require special home electrical or plumbing modifications. Optimization of dialysis using this modality requires additional knowledge of the kinetics and the unique features of this platform.
Although current dialysis guidelines do not address the low dialysate volume approach, most caregivers target a standardized weekly Kt/V urea of 2.0 per week or 0.6 per treatment.
There are several components of the prescription for low volume dialysate approach to consider:
1. The volume of dialysate is the chief determinate of dialysis dose. The initial prescription begins with an estimate of the volume of distribution of urea in the patient, which is similar to the volume of distribution of water. This volume is multiplied by the target of 0.6 to provide an initial volume of dialysate, which it is assumed will achieve 100% urea saturation. Thus, rather than prescribing a treatment duration, a volume of dialysate is prescribed.
2. The dialysate can be either a prepackaged fluid, similar to that used for PD, or generated with a self-contained system. Lactate is used as the buffer because bicarbonate cannot be stored with calcium or magnesium due to precipitation.
3. The low volume dialysate approach depends on nearly complete saturation of the dialysate by urea. This is achieved by maintaining a low ratio of the dialysate flow rate (Qd) to blood flow rate (Qb). This ratio is called the flow fraction (FF), which is calculated as Qd/Qb. A decrease in the dialysate rate will lower the flow fraction but maintain the volume of dialysate. This would result in an increase in the time required to deliver the dialysis. However, it would not increase the clearance because the volume of dialysate, which is essentially 100% saturated, is fixed. This is analogous to PD, in which it is necessary to increase the effluent volume in order to increase the delivered dialysis. According to data from NxStage Medical, the company that manufactures and distributes the most widely used low dialysate platform in the United States, dialysate is 90% saturated at a FF of 40% and 95% saturated at a FF of 20%.
4. If the ultrafiltration (UF) is significant, the FF calculation is expanded to (Qd+UF)/Qb. Increases in UF will contribute to clearance, again analogous to PD, but this effect will not be as great as an increase in dialysate volume unless the UF increase is substantial.
5. Unlike conventional HD, the clearance of urea is dependent on dialysate total effluent volume (dialysate + UF) rather than Qb and dialysis time.
Applying these fundamental principles, only an increase in dialysate volume for each treatment will increase the Kt/V in this patient.
Decreasing the blood flow rate but maintaining the FF will slightly decrease the rate of dialysate consumption and increase the treatment time. This is a reasonable strategy for a patient with poor tolerance of UF because it also extends the time for fluid removal, which may be better tolerated hemodynamically. However, it does not substantially affect the clearance of urea because the dialysate saturation remains approximately 90% and the dialysate volume is unchanged, thus the net urea removal is unchanged.
An increase in FF will decrease the treatment time and decrease the saturation of dialysate, thereby decreasing the clearance of urea.
An increase in Qb will require a corresponding increase in Qd if the FF remains fixed. This will shorten treatment time, but will not substantially change the clearance because the total effluent volume and saturation are unchanged. Shorter treatment may be desirable if UF goals can be met but there is little knowledge of the impact of treatment time on clearance of substances other than urea.
Reducing the target weight can potentially impact the clearance of urea in two ways: it can reduce the volume of distribution for urea (V) and it can potentially increase the UF volume per treatment, which increases the effluent volume. However, the numerical impact of these effects is likely to be small unless a major change is undertaken. The target weight should be modified to maintain euvolemia, not to address clearance problems. This patient appears euvolemic on exam and has a normal BP; therefore, a change in target weight would be ill-advised.
A 26-year-old woman presents to the nephrology clinic for evaluation as a potential kidney donor to her father, who has ESRD due to autosomal dominant polycystic kidney disease (ADPKD). She is well and takes no medications. Her father began dialysis at age 49. A paternal cousin also carries the diagnosis of ADPKD and hypertension but has normal kidney function at age 35. No other family members are known to have ADPKD.
The potential donor appears healthy and has a normal physical examination, including BP. Serum creatinine is 0.8 mg/dL and the urinalysis is normal. Ultrasonography of the kidneys reveals one cyst in each kidney.
Which of the following is strategies is best regarding this prospective kidney donor and recipient pair?
Select one:
A.
Proceed with kidney donation
B.
The family should undergo genetic linkage analysis
C.
The father should undergo direct mutation analysis
D.
The daughter should undergo direct mutation analysis
The correct answer is: C
The father should undergo direct mutation analysis
For this prospective kidney donor with a family history of ADPKD, the best approach would be to perform direct mutation analysis for PKD1 and PKD2 mutations in her father. Depending on results, the prospective donor could then undergo direct mutation testing to see if she carries the same (identified) mutation. Linkage analysis for PKD mutations requires at least 3 affected family members across at least 2 generations, and would not be an option in this case.
A family history of ESRD before age 58 in at least one family member is highly predictive of a PKD1 genotype, whereas a family history of ESRD after the age of 68 is highly predictive of a PKD2 genotype. Thus, a PKD1 mutation is likely in this family. The kidney ultrasound finding of only 1 cyst in each kidney is not sufficient to exclude a diagnosis of ADPKD at this age because a negative ultrasound (no cysts) in people younger than 30 is only 94% sensitive for ADPKD due to a PKD1 mutation (and only 70% sensitive for a PKD2 mutation). Therefore, it would not be appropriate to proceed with further workup or donation until a more definitive conclusion can be made regarding the potential donor’s PKD status. Because there can be nonpathogenic mutations in PKD1 or PKD2, it would not make sense to test the patient without first testing her father for the presence of a mutation. If he has an identifiable mutation in either PKD1 or PKD2, the potential donor can be tested for that specific mutation. Finding the same mutation in the daughter would exclude her as a potential donor.
Note that an alternative strategy would be to perform either magnetic resonance imaging or computed tomography with contrast, both of which are more sensitive than ultrasound for the detection of small cysts in the kidneys and other organs. The presence of more than 10 cysts in both kidneys establishes the ADPKD diagnosis and would exclude donation, whereas the absence of any cysts appears to exclude the diagnosis. However, identification of fewer than 10 cysts would leave the diagnosis still in doubt. The use of cross-sectional imaging criteria in the evaluation of prospective donors is not well-established and genetic testing may be preferred if the initial screening ultrasound is not diagnostic.
A 70-year-old woman is admitted with multi-lobar pneumonia. She weighs 75 kg; her vital signs include temperature 38.4°C, BP 108/82 mm Hg, heart rate 96/min, and oxygen saturation of 94% on 2 L/min nasal oxygen. She has scattered coarse breath sounds and decreased air movement at both bases with dullness to percussion.
Laboratory data on presentation:
Result Reference Range
Leukocyte count 3,800 µL 4000–11,000
Hemoglobin 10 g/dL 12–16
Platelet count 140,000 µL 150,000–450,000
Sodium 125 mEq/L 136–145
Potassium 3.6 mEq/L 3.5–5.0
Chloride 100 mEq/L 98–106
Total CO2 23 mEq/L 23–30
BUN 15 mg/dL 8–20
Creatinine 1.1 mg/dL 0.5–1.1
Glucose 85 mg/dL 70–99 (fasting)
Calcium 10.2 mg/dL 8.6–10.2
Albumin 3.0 g/dL 3.5–5.5
Osmolality 296 mOsm/kg 275–295
Urine
Sodium 35 mEq/L Varies
Osmolality 350 mOsm/kg H2O 38–1400
Intravenous saline is administered at 200 mL/hour. She develops respiratory distress after 2 hours. A repeat chest x-ray demonstrates pulmonary congestion superimposed on pneumonia. An arterial blood gas (ABG) is obtained and a repeat sodium measurement on this specimen is 141 mmol/L.
What is the MOST likely cause of the rapid change in the sodium measurement?
Select one:
A. Overly rapid correction from normal saline
B. Metabolism of an osmolal gap secondary to an ingestion
C. Pseudohyponatremia on initial sample
D. Contamination from saline in ABG sample
The correct answer is: C
Pseudohyponatremia on initial sample
On presentation, this patient has a low serum sodium but the serum osmolality is in the normal range and higher than predicted based on calculation of the serum osmolality. This finding is consistent with pseudohyponatremia. The apparent increase in her sodium concentration occurs when her serum sodium is measured by a different technique, which eliminates the error.
The initial serum chemistries were measured using indirect potentiometry, the most common technique. With this method, a diluent is added to the serum to limit the amount of blood that is required for the measurement. Normally, serum contains a solid phase of approximately 7%, composed of proteins and lipids. If this solid phase is considerably larger, the liquid phase will be smaller. When the standard volume of diluent is added to a smaller aliquot of plasma (containing both liquid and solid phases), the components of the liquid phase will be relatively more diluted and the laboratory will report a falsely low serum sodium. In contrast, most laboratories use direct potentiometry for blood gas analysis, which eliminates this error. The serum osmolality is typically measured by freezing point depression and is not affected by changes in the solid phase.
Pseudohyponatremia can be caused by extreme elevation in plasma proteins (as with plasma cell dyscrasias), triglycerides (as with lipemic serum), or total cholesterol and lipoprotein X (as with obstructive jaundice). Note that an abnormality related to lipoprotein X does not result in lipemic serum. The patient may have occult multiple myeloma, as evidenced by her pancytopenia, low serum anion gap, and mild hypercalcemia (corrected calcium is 11 mg/dL). Multiple myeloma can result in hyperproteinemia and cause pseudohyponatremia.
Infusion of 400 mL of normal saline provides an additional 62 mEq of sodium, which would not be sufficient to cause a 16 mEq rise in serum sodium in a 75 kg woman. Although an osmolal gap and a normal anion gap are associated with isopropyl alcohol ingestion, this would not lead to either hyponatremia or pseudohyponatremia. Contamination of arterial blood samples can occur from the saline flush used for arterial line but not from the IV fluid. In addition, this would not explain the normal serum osmolality on the initial sample.
A 20-year-old woman with a history of systemic lupus erythematosus (SLE) since age 16 is referred for evaluation of hematuria and proteinuria. She is 10 weeks pregnant and has recently transferred from pediatric to adult care. She has no history of nephritis. Her current primary symptom is nausea, but she also has some joint aches. Hydroxychloroquine 200 mg daily, amlodipine 5 mg daily, and azathioprine 50 mg daily were all discontinued when her pregnancy was recognized 2 weeks previously. She remains on prednisone 10 mg daily and now also takes a daily prenatal vitamin.
Her BP is 140/90 mm Hg. She weighs 50 kg. Mild lower extremity edema is present.
Her urinalysis shows 300 mg/dL protein and moderate blood by dipstick. The urine sediment has occasional cellular casts and acanthocytes. The serum creatinine is 0.8 mg/dL. Her 24-hour urine protein is 5 g.
Which of the following is the MOST appropriate next step in the management of this patient?
Select one:
A.
Obtain an ultrasound-guided kidney biopsy
B.
Defer evaluation to the postpartum period
C.
Give pulse methylprednisolone and delay biopsy until later in pregnancy
D.
Increase prednisone to 50 mg daily
E.
Resume hydroxychloroquine and azathioprine
The correct answer is:A
Obtain an ultrasound-guided kidney biopsy.
This patient with underlying SLE, an active urinary sediment, and significant proteinuria should undergo an ultrasound-guided kidney biopsy to define her diagnosis and guide treatment. Indications for biopsy during pregnancy include new-onset glomerulonephritis (including lupus nephritis), severe nephrotic syndrome that requires therapy, and an acute decline in kidney function. Kidney biopsy can be safely undertaken during the first trimester. Biopsy can also be performed later in pregnancy, but the procedure may need to be performed with the patient lying in the lateral decubitus position rather than prone because of the gravid uterus. In addition, the risk for complications may be increased after mid-trimester. It would be inappropriate to defer the kidney biopsy when there is evidence of active nephritis that may adversely affect both the patient and the pregnancy if it is not treated.
In this case, the urinalysis is consistent with acute glomerulonephritis, and the patient’s history of SLE makes lupus nephritis of one form or another the most likely consideration. Serologic studies, including complement and anti-double-stranded DNA antibody levels, can be useful adjuncts, but cannot themselves classify glomerulonephritis adequately to guide therapy. If a severe, diffuse proliferative lesion were identified on biopsy, treatment would be warranted. This would also prompt difficult decisions in the context of the pregnancy. Both cyclophosphamide and mycophenolate mofetil are contraindicated during pregnancy.
Empirical pulse therapy would not be justified in the absence of AKI. Similarly, empiric increase in her prednisone to 50 mg would expose the patient (and fetus) to the side effects of high dose corticosteroids without any certainty of necessity or effectiveness, and potentially could hamper the ability to make a definitive diagnosis in the future if biopsy were eventually pursued.
Hydroxychloroquine should be continued during pregnancy and is considered safe. Azathioprine is potentially useful in the treatment of lupus during pregnancy and is considered reasonably safe in doses up to 2 mg/kg, but it would not be adequate treatment for severe lupus nephritis at the present dose. Mothers and families should be informed of reports of late developmental delay in some offspring of patients treated with azathioprine during pregnancy, though this association is not proven to be causal.
A 50-year-old man develops fevers, hypotension, and altered mentation. He has multiple myeloma and received a stem cell transplant 1 week ago. He remains pancytopenic. Urine and blood cultures have grown a gram-negative rod that has not yet been identified. He is transferred to the medical intensive care unit, where he is intubated and receives IV saline, vasopressin, and norepinephrine. A dose of gentamicin 240 mg IV is administered and piperacillin-tazobactam 3.375 g IV every 8 hours is ordered.
On examination, he is sedated and receiving mechanical ventilation. His BP is 90/60 mm Hg and his weight is 80 kg. There are coarse breath sounds that are decreased at the bases, and he has severe generalized edema.
Result Reference Range
Potassium 5 mEq/L 3.5–5.0
Total CO2 15 mEq/L 23–30
Blood urea nitrogen 30 mg/dL 8–20
Creatinine 2 mg/dL 0.7–1.3
Glucose 110 mg/dL 70–99 (fasting)
Lactate 5 mmol/L <0.7–2.1
Arterial blood gas
Fi02 50%, 5 cm H2O positive end-expiratory pressure
pH 7.35 7.38–7.44
PaCO2 30 mm Hg 38–42
PaO2 100 mm Hg 75–100
Chest x-ray reveals a right lower lobe opacity and bilateral pulmonary vascular congestion.
Continuous venovenous hemofiltration is begun utilizing 2.5 L/h of replacement solution, administered pre-filter. One day later, the gram-negative rod is identified as a Klebsiella species, sensitive to piperacillin-tazobactam, so further gentamicin therapy is not administered.
Which of the following options is the BEST strategy to optimize the pharmacodynamic properties of the piperacillin-tazobactam in this case?
Select one:
A.
Administer piperacillin-tazobactam as a prolonged infusion
B.
Administer piperacillin-tazobactam as a rapid bolus
C.
Give all replacement fluid post-filter
D.
Continue current piperacillin-tazobactam prescription
E.
Increase blood flow from 200 to 250 mL/h
The correct answer is: A
Administer piperacillin-tazobactam as a prolonged infusion
Target levels of antibiotics including piperacillin-tazobactam (piptazo) are associated with more effective bacterial killing and are more likely to be achieved with extended infusions (3 hours) during continuous renal replacement therapy (CRRT).
Inadequate antibiotic dosing for patients with sepsis may lead to adverse outcomes, and there is strong evidence that under-dosing of antibiotics is common among patients on CRRT.
Beta-lactam antibiotics, including piptazo, exhibit time-dependent killing and the drug concentration should exceed the minimal inhibitory concentration (MIC) for at least 50% of the dosing interval. Because of the potentially high clearance of antibiotics by CRRT, conventionally dosed antibiotics may fail to achieve this goal. Extension of infusion time increases the time at which the concentration of pip-tazo exceeds the MIC. This strategy has shown benefit for some patients with severe infections and sepsis.
Multiple factors affect drug clearance in CRRT, including residual renal function, modality, dose, drug properties, and volume of distribution.
The clearance of a drug (C) by CVVH can be estimated as follows:
C=effluent rate x sieving coefficient
For a patient receiving prefilter replacement fluid, the equation becomes:
C= effluent Rate x sieving coefficient x blood flow
blood flow + prefilter replacement
This equation demonstrates that giving all replacement fluid postfilter would increase the clearance, which would tend to reduce the piperacillin-tazobactam concentration.
Blood flow during CRRT does not influence drug clearance unless the replacement fluid is administered pre-filter, in which case a higher blood flow will increase the clearance and this will tend to reduce the time that the pip-tazo concentration exceeds the MIC.
Giving the piptazo as a bolus would achieve a higher peak level but the concentration would fall more rapidly below the target. This strategy may be more appropriate for drugs such as aminoglycosides that exhibit concentration-dependent rather than time-dependent killing.
A 43-year-old woman with a history of hypertension and bipolar disorder is admitted to the hospital after her husband noticed an alteration in her behavior. He states that she has had some vomiting and diarrhea in the last 24 hours and she has not been able to eat anything for the past 2 days. She has taken lithium for the last 20 years and has attempted suicide on two prior occasions.
Medications include lithium, hydrochlorothiazide, and a multivitamin.
On physical examination, she is somnolent but arousable. She is afebrile, her BP is 110/60 mm Hg, and her heart rate is 110/min. Her weight is 80 kg. She has no edema. The neurologic examination is notable for stuttering speech, tremulousness, and hyperreflexia.
Laboratory data is notable for blood urea nitrogen 35 mg/dL (reference range, 8–20) and creatinine 2.3 mg/dL (reference range, 0.5–1.1). Her lithium level is 3.5 mEq/L (therapeutic range, 0.6–1.2). There is no evidence of other ingestions.
In addition to volume expansion with IV fluid, which is the MOST appropriate initial treatment plan for this patient?
Select one:
A.
Initiate continuous venovenous hemofiltration and continue for 48 hours
B.
Recheck kidney function and lithium level in 4 hours
C.
Prescribe daily HD treatments for 4 hours at a blood flow of 350 mL/min
D.
Begin HD with first treatment 2.5 hours at a blood flow of 250 mL/min
E.
Prescribe HD for 6 hours with blood flow of 350 mL/min
The correct answer is: E
Prescribe HD for 6 hours with blood flow of 350 mL/min
This patient should receive HD for a minimum of 6 hours with a blood flow of 350 mL/min and treatments should be repeated until the serum lithium level is <1 mEq/L.
This patient manifests acute on chronic lithium toxicity evidenced by acute neurologic symptoms and an elevated lithium level superimposed on chronic lithium use. AKI and volume depletion can contribute to lithium poisoning among patients receiving chronic lithium therapy. In this case, the recent vomiting and diarrhea as well as her diuretic may have resulted in renal impairment which then led to lithium toxicity. Alternatively, the gastrointestinal symptoms may have been symptoms of emerging lithium toxicity, which then contributed to volume depletion and further lithium accumulation.
Although there are no randomized controlled trials that address the treatment of lithium toxicity, the mainstay of treatment involves volume resuscitation and prolonged dialytic therapy to achieve adequate removal.
Lithium is a monovalent cation, which distributes widely in the body and is not protein-bound. The volume of distribution is 0.5 L/kg; however, this can increase with chronic use to 0.7–0.9 L/kg. Lithium is freely filtered by the glomerulus but reabsorbed in the proximal tubules, loop of Henle, and the principal cells. The half-life of lithium varies widely from as short as 12 hours to nearly 60 hours depending on age, kidney function, and duration of therapy. Lithium has both acute and chronic toxicity. Acute toxicity includes AKI as well as neurologic and cardiac manifestations. Chronic lithium toxicity may lead to nephrogenic diabetes insipidus or CKD from chronic tubulointerstitial nephropathy. It can also lead to hyperparathyroidism, hypercalcemia, and hypocalciuria.
Indications for dialytic therapy include a serum lithium level >4 mEq/L among patients with AKI or CKD or the presence of altered mentation, seizures, or dysrhythmias regardless of lithium levels. For patients with acute on chronic lithium toxicity, plasma levels may not correlate with toxicity as closely as with acute toxicity. Because of more efficient (rapid) removal of lithium, intermittent HD is the preferred modality for extracorporeal treatment of lithium poisoning. The initial dialytic treatment should be extended until the lithium level is <1 mEq/L; a minimum treatment time of 6 hours is recommended if levels are not immediately available. Levels should be checked serially over the subsequent 12 hours to identify a rebound increase in levels that would require additional dialysis. Rebound of lithium levels can be caused by ongoing absorption from the gastrointestinal tract if an extended release formulation has been ingested. Redistribution from extravascular location to vascular space also contributes to level rebound. Continuous renal replacement appears to be less efficient at lithium removal but expert opinion suggests that it is a reasonable alternative if intermittent HD is not readily available, or if additional therapy is required after the initial conventional dialysis treatment.
A short dialysis treatment with low blood flow is appropriate for individuals who initiate dialysis for the treatment of uremia in the setting of CKD when rapid removal of uremic toxins could provoke dialysis disequilibrium syndrome.
Conservative management without dialysis is not appropriate for this patient with neurologic manifestations of lithium toxicity.
A 40-year-old man is referred for proteinuria and hematuria that was incidentally found on routine urinalysis. Review of systems is negative.
Examination is normal except for BP 140/85 mm Hg and trace pretibial edema. His hemoglobin is 13.5 g/dL (reference range, 14–18) and creatinine is 1.2 mg/dL (reference range, 0.7–1.3). Urinalysis shows 3+ protein and microscopy shows 4–10 RBC/HPF.
Twenty-four-hour urine shows 4.2 g protein.
A kidney biopsy is performed and a representative light microscopic image is shown.
Masani N, Jhaveri K, Fishbane S: Update on Membranoproliferative GN. Clin J Am Soc Nephrol 9(3):600—608, 2014
Light microscopy shows hypercellularity, hypersegmentation, thickened basement membranes and increased mesangial material in a membranoproliferative pattern of glomerular pathology.
Electron microscopy shows immune deposits in the mesangial, para-mesangial, and subendothelial regions. Occasional subepithelial deposits are also identified.
Immunofluorescence microscopy shows 4+ IgG, 2+ C3, 2+ C1q, 4+ kappa, and 1+ lambda granular fluorescence in the capillaries and mesangium, but is negative for IgM, IgA, fibrinogen, and albumin.
Which of the test below would be MOST helpful in determining the underlying etiology of this patient’s kidney disease?
Select one:
A. Serum protein electrophoresis
B. Antinuclear antibody
C. Factor H activity
D. Hepatitis C antibody
E. Blood cultures
The correct answer is: A
Serum protein electrophoresis
Serum protein electrophoresis is indicated for this patient with immune complex-mediated membranoproliferative glomerulonephritis (MPGN) with predominant kappa deposition.
Historically, MPGN was categorized based on pathologic features. However, the current classification of MPGN is based on the pathogenesis of the disease and whether it is mediated by immune complexes, complement, or endothelial dysfunction.
The immunofluorescence (IF) pattern of the biopsy provides clues to the pathogenesis and helps define the subtypes.
1. Immunoglobulin-positive, complement-positive (these can be monoclonal immunoglobulins as with a plasma cell dyscrasia, or polyclonal as with the case of hepatitis C)
2. Immunoglobulin-negative, complement-positive (disorders of complement, as with dense deposit disease or C3 glomerulonephritis)
3. Immunoglobulin-negative, complement-negative (as with a thrombotic microangiopathy)
Etiologies of immune complex MPGN include autoimmune disease such as lupus nephritis. Lupus nephritis, however, usually demonstrates IgA and C1q in addition to IgG, IgM, C3, kappa, and lambda by IF, often referred to as a “full house pattern.” MPGN related to hepatitis C (with or without cryoglobulins) is associated with the deposition of polyclonal immune complexes, and shows granular deposition of IgM, C3, and relatively equal kappa and lambda; IgG deposition is variable. MPGN related to chronic bacterial infection as with bacterial endocarditis would also produce polyclonal immune complex deposition, rather than a monoclonal pattern by IF. Deposition of a monoclonal immunoglobulin can also result in an immunoglobulin-positive, complement-positive MPGN-pattern of inflammation, as in this case.
C3 glomerulopathies are characterized by dysregulation of the alternative complement pathway and C3 deposition in the absence of significant immunoglobulin. Abnormal function of factor H, an inhibitor of the alternative pathway, can lead to unregulated complement activation, leading to C3 glomerulopathy. This disorder is characterized by C3 deposition without other significant immune deposition. Although C3 is present here, the additional immunoglobulin and monoclonal kappa deposition are not characteristic of C3 glomerulopathy and testing for factor H is not indicated.
A 44-year-old woman is evaluated for resistant hypertension. She feels well and is adherent to her antihypertensive regimen, which includes amlodipine 10 mg each night, carvedilol 25 mg twice daily, hydrochlorothiazide 25 mg daily, hydralazine 50 mg 3 times daily, and potassium chloride 20 mEq twice daily. She follows a 2 g sodium diet and consumes one glass of wine daily. She does not consume licorice or other herbal products. Her average BP by ambulatory monitor is 145/87 mm Hg. She has a family history of hypertension but details are not known to the patient.
On physical examination, she appears well. Her BP is 150/90 mm Hg, pulse is 70/min, and body mass index is 24 kg/m2. The remainder of the examination is normal.
Laboratory data (see table):
Which ONE of the following management strategies is the MOST appropriate for this patient?
Select one:
A. Replace hydralazine with lisinopril
B. Restrict alcohol intake to less than one drink daily
C. Replace hydrochlorothiazide with amiloride
D. Restrict sodium intake to 1 g daily
E. Replace hydrochlorothiazide with spironolactone
The correct answer is: C
Replace hydrochlorothiazide with amiloride
The presence of hypertension, hypokalemia, and metabolic alkalosis is consistent with hyperaldosteronism, yet here the renin level is suppressed and aldosterone level is not elevated. These findings are consistent with the diagnosis of Liddle syndrome, which is optimally treated with an epithelial sodium channel (ENaC) blocker such as amiloride.
This patient has resistant hypertension as defined by the failure to achieve BP control despite adequate doses of at least 3 antihypertensive medications including a diuretic. The ambulatory BP monitor excludes pseudo-resistance. The presence of resistant hypertension should prompt consideration of interfering substances and secondary causes. In this case, Liddle syndrome is the likely diagnosis based on the clinical and laboratory findings of spontaneous hypokalemia and metabolic alkalosis (before therapy is initiated) and the absence of elevation of renin, aldosterone, and cortisol.
Liddle syndrome is a rare, autosomal dominant cause of hypertension. It usually presents as early onset hypertension, but occasionally, this syndrome may escape detection until adulthood. Liddle syndrome results from an activating mutation of ENaC in the distal nephron. Increased ENaC activity results in increased sodium reabsorption. In addition, the increased luminal electronegativity leads to potassium secretion from the principal cells and favors H+ excretion via the H+ATPase at the apical membrane of the α-intercalated cells. Because of the resultant volume expansion, mineralocorticoid activity is suppressed. Thus, treatment with spironolactone is ineffective. Liddle’s syndrome is treated with blockade of ENaC by agents such as amiloride or triamterene.
Although it would be reasonable to consider substituting an angiotensin-converting enzyme inhibitor for hydralazine in a patient with hypertension and hypokalemia, it would not address the underlying issue in this case and is unlikely to be sufficient because renin is already suppressed.
Excessive sodium or alcohol intake may contribute to resistant hypertension, but this patient’s intake is already limited.
A 73-year-old woman with history of vaginal cancer that had been treated by hysterectomy and radiation therapy presents with constipation and abdominal pain. She is found to have a colonic stricture and undergoes resection and diverting colostomy.
Her medical history is notable for a kidney transplant 10 years ago, CKD stage G3a, and hypertension.
Her medications include aspirin, losartan, mycophenolate mofetil, and cyclosporine.
Her postoperative course is complicated by high-volume output from her colostomy.
Examination is significant for BP 100/58 mm Hg and pulse 100/min. The abdomen is soft and the ostomy is clean, dry, and intact with a healing stoma. The remainder of the examination is normal.
Lab data (see table):
Urinalysis: specific gravity 1.020, pH 5, negative blood, glucose and protein, and no cells or casts.
Which ONE of the following is the MOST likely cause of this patient’s metabolic acidosis?
Select one:
A. Calcineurin inhibitor
B. Chronic kidney disease
C. Type 1 (distal) renal tubular acidosis
D. Gastrointestinal losses
E. Type 4 renal tubular acidosis
Answer: D
Gastrointestinal losses
The patient has hypokalemia and a non-anion gap metabolic acidosis that is most likely caused by gastrointestinal losses.
A metabolic acidosis in which the fall in bicarbonate is matched by an equivalent rise in chloride is referred to as a non-anion gap metabolic acidosis (NAGMA) or a hyperchloremic metabolic acidosis. This can occur from a loss of bicarbonate from the gastrointestinal tract or the kidney, impaired net acid excretion, or intake of HCl or substances that are metabolized to HCl.
The history often provides key clues to the cause of a non-anion gap metabolic acidosis. For example, bicarbonate losses are expected from certain urinary diversions or the use of acetazolamide. In this case, there are multiple potential causes of a NAGMA, including gastrointestinal losses, CKD, and cyclosporine. Gastrointestinal losses can also cause extracellular volume depletion and hypokalemia, which can provoke additional superimposed metabolic abnormalities.
If the history, physical examination, and routine laboratory data do not fully explain the cause of the NAGMA, the next step is to assess renal acidification.
Although recent data suggest that direct measurement of urinary ammonium is much more accurate, and this analysis is becoming more widely available, renal acidification is traditionally assessed by using the urine anion gap, which compares the major ions that are easily measured in urine.
The urine anion gap is calculated by the following equation:
Urine anion gap = [Na+] + [K+] – [Cl-] = 46 + 20 – 106 = -40
In the setting of a metabolic acidosis, the expected, normal kidney response is to increase urinary excretion of ammonium with chloride, which results in urinary chloride levels that exceed the sum of urinary sodium and potassium levels. The urine anion gap among patients with metabolic acidosis from a non-renal source, therefore, is usually negative and in the -20 to -50 mEq/L range, as seen here. It should be noted, however, that ammonium excretion might be impaired among patients who have significant hypovolemia. Moreover, recent data suggest that direct measurement of urinary ammonium is considerably more accurate than estimation using the urine anion or osmolal gap.
Because this patient had a normal serum bicarbonate level on admission, it is unlikely that CKD is the cause of the acute metabolic acidosis. In addition, CKD would not explain the development of hypokalemia.
Type 1 (distal) renal tubular acidosis (RTA) also results in a hypokalemic non-anion gap metabolic acidosis because of the inability to excrete an acid load. In this situation, the urine pH would be >5.5 and the urine anion gap would be inappropriately high.
Type 4 RTA, defined as hyporeninemic hypoaldosteronism, is characterized by hyperkalemia, and the metabolic acidosis, if present, is typically mild. Calcineurin inhibitors can contribute to the development of a type 4-pattern RTA as well.
A 40-year-old man is referred to the nephrology clinic for evaluation of hematuria and proteinuria. He has a history of successfully treated hepatitis C (HCV) and well-compensated cirrhosis. His medications are tramadol, furosemide, and pantoprazole. His symptoms include arthralgias, a rash on his legs, and occasional numbness in his fingers.
On examination, his BP is 154/97 mm Hg and pulse is 76/min. There are multiple petechial lesions on his feet, legs, and back. The remainder of the examination is unremarkable.
Laboratory data (see table):
Which ONE of the following is the MOST likely cause of this patient’s hematuria and proteinuria?
Select one:
A. Focal and segmental glomerulosclerosis
B. Lupus nephritis
C. Henoch-Schönlein purpura
D. Membranous nephropathy
E. Cryoglobulinemic glomerulonephritis
The correct answer is: E
Cryoglobulinemic glomerulonephritis
Nephritic sediment in the presence of systemic manifestations, low complement, and high rheumatoid factor levels in a patient with a history of HCV infection, makes cryoglobulinemic glomerulonephritis the most likely cause of the hematuria and proteinuria.
Cryoglobulins are immunoglobulins that precipitate at a temperature lower than 37oC. There are 3 types of cryoglobulins, as shown below:
(see table)
Cryoglobulinemia can be asymptomatic or result in tissue damage from hyperviscosity (mainly with type I) or immune-complex mediated inflammation (mainly type II, strongly associated with HCV infection). Other associated conditions include infections, such as hepatitis B virus and HIV, and autoimmune disorders, such as Sjögren syndrome, systemic lupus erythematosus, and rheumatoid arthritis.
Renal manifestations of cryoglobulinemia may include hematuria, proteinuria, hypertension, and AKI. Hypocomplementemia, especially C4 depletion, and elevated rheumatoid factor are common. Blood cryoglobulin levels (sometimes referred to as the “cryocrit”) can be high, but reliable detection requires appropriate collection in pre-warmed syringes. The light microscopic appearance of a kidney biopsy specimen most commonly shows a membranoproliferative pattern, but may also show vasculitis, hyaline thrombi, and crescents. Immunofluorescence reveals deposition of immune complexes in the mesangium and subendothelium that are often IgM-dominant; electron microscopy may reveal substructure to the electron-dense deposits with a microtubular or fibrillary pattern. It is important to note that because of independent B-cell proliferation, cryoglobulins can persist even after HCV has been eradicated by antiviral therapy. Treatment for cryoglobulinemia that persists or appears after antiviral therapy may include steroids, rituximab, and plasma exchange in severe cases.
Although membranous nephropathy is sometimes associated with HCV, it does not explain the hypocomplementemia, high rheumatoid factor level, or this patient’s systemic signs and symptoms.
The presentation of lupus nephritis can be very similar to that of cryoglobulinemic glomerulonephritis, but lupus nephritis is unlikely in the setting of a low titer ANA and normal C3, as well as the absence of other auto-antibodies commonly found in lupus nephritis.
Pauci-immune glomerulonephritis may have systemic symptoms and can occasionally be ANCA- negative, but would not cause hypocomplementemia or an elevated rheumatoid factor.
Although complement activation is part of the pathophysiology of Henoch-Schönlein purpura, C3 and C4 levels are generally normal and rheumatoid factor is not be elevated in this condition.
A 27-year-old man is brought to the emergency room with altered mental status. He is known to have a history of depression but is unable to answer questions and further information is unobtainable.
His BP is 136/88 mm Hg. His temperature, heart rate, and pulse oximetry are normal. Skin turgor and capillary refill are also normal. His speech is slurred and is disoriented, but there are no other neurologic abnormalities and the remainder of his physical examination is unrevealing.
(see table)
In addition to administration of fomepizole, which of the following is the MOST appropriate next step in treatment?
Select one:
A. Isotonic saline
B. Activated charcoal
C. Continuous venovenous hemofiltration
D. Hemodialysis
E. Gastric lavage
The correct answer is: D
Hemodialysis
This patient should undergo HD urgently to treat a presumptive toxic alcohol ingestion. His presentation includes altered mentation in the presence of a severe anion gap metabolic acidosis and an elevated osmolal gap, all of which point to a toxic alcohol ingestion. The osmolal gap is determined by subtracting the calculated plasma osmolality from the measured plasma osmolality (Posm) as follows:
Calculated Posm = 2 × [Na] + glucose (mg/dL)/18 + BUN (mg/dL)/2.8 + ethanol (mg/dL)/3.7
Here, the calculated Posm = 2 × 145 + 118/18 + 8/2.8 + 0 = 299 mOsm/kg
The osmolal gap = 336 – 299 = 37 mOsm/kg. Normally, the osmolal gap is <10.
Many toxic ingestions are accompanied by co-ingestion of ethanol. If there is a measurable ethanol level, the serum ethanol level should also be included in calculated plasma osmolality after converting to mOsm/kg. Although the molecular weight of alcohol is 46 mg/mmol, in clinical practice, dividing the alcohol concentration measured in mg/dL by 3.7 rather than 4.6 appears to best account for the osmolal contribution of ethanol.
The combination of AKI, severe metabolic acidosis, an osmolal gap, and calcium oxalate crystals in the urine suggest that the patient ingested ethylene glycol (EG). EG is not directly toxic but generates toxic metabolites, including glycolic acid and oxalic acid.
Fomepizole is an alcohol dehydrogenase inhibitor and is used to attenuate the metabolism of alcohols. It has a 500–1000 times greater affinity for alcohol dehydrogenase than ethanol. It helps prevent the metabolism of ethylene glycol (or methanol) to its toxic byproducts. Administration of alkali to correct acidosis is often recommended, as it may promote renal excretion of metabolites. Pyridoxine and thiamine are given to promote further metabolism of glycolic acid to non-toxic derivatives. HD is effective at removing EG and its toxic metabolites and is recommended if there is severe metabolic acidosis (pH <7.25), AKI, ethylene glycol level >50 mg/dL, or glycolate level >10 mg/dL (if available). HD is generally continued until the EG level is <20 mg/dL. Continuous renal replacement therapy can be used but is less efficient than HD.
Gastric lavage and activated charcoal are unlikely to be effective unless given in the first 30–60 minutes after an ingestion. Volume expansion with isotonic saline might promote renal excretion but is not the best treatment for this patient with signs of severe intoxication.
Because of the high morbidity and mortality of toxic alcohol ingestions, it is important for clinicians to have a high index of suspicion for an ingestion.
A 59-year-old man returns for a scheduled follow-up appointment for management of immunosuppression. He has a history of anti-proteinase 3-(anti-PR3) positive ANCA vasculitis and pauci-immune glomerulonephritis. He feels well except for occasional heartburn.
ANCA vasculitis was diagnosed 8 months ago when he presented with dyspnea, wheezing, rash, AKI, and active urinary sediment. Serum creatinine at the time of his presentation was 2.3 mg/dL. Kidney biopsy demonstrated pauci-immune, crescentic glomerulonephritis and ATN.
Induction therapy consisted of pulse methylprednisolone 7 mg/kg intravenously for 3 days followed by oral prednisone at a dose of 1 mg/kg per day, which has been slowly tapered. Three doses of IV cyclophosphamide were given at monthly intervals. His rash and pulmonary symptoms rapidly improved. His physicians felt that he had achieved a complete remission, as he had a Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis (BVAS/GPA) score of 0. Around the time of his third dose of cyclophosphamide, he also received a dose of rituximab for maintenance of remission and his prednisone dose was reduced to 10 mg daily, and subsequently tapered to further to 5mg daily. Current medications also include calcium, trimethoprim-sulfamethoxazole, vitamin D, alendronate, and omeprazole.
On exam, he has moon facies and a prominent dorsocervical fat pad. His BMI is 31 kg/m2. His BP is 145/84 mm Hg and his heart rate is 76/min. He has no rash and the remainder of the examination is normal.
(See Lab data)
Which one of the following is the MOST appropriate next step in the treatment of this patient?
Select one:
A. Prescribe lisinopril
B. Discontinue omeprazole
C. Prescribe azathioprine
D. Discontinue prednisone
E. Prescribe glipizide
The correct answer is: D
Discontinue prednisone
Prednisone should be completely discontinued with a taper in this patient with ANCA vasculitis. He has achieved a complete remission based on the BVAS/GPA, a tool used to measure disease activity based on clinical symptoms and signs in 9 organ systems. Furthermore, he has evidence of long-term side effects of steroid use, including Cushingoid features.
In an observational study of nearly 150 patients with ANCA-associated disease, the length of glucocorticoid therapy after 6 months appeared to have no effect on time to relapse, relapse-free survival, ESRD, or death. Conversely, steroid therapy beyond 6 months was associated with a significantly greater risk of infections. Based on this study and other observational data, most experts recommend that clinicians begin to taper prednisone once the patient has achieved remission, with a goal of discontinuing the steroids after 4–8 months of therapy.
Although the patient is hyperglycemic on a random measurement of blood glucose, it would be premature to initiate drug therapy for diabetes mellitus (DM). Rather, the possibility of DM should be investigated with either a glucose tolerance test or measurement of hemoglobin A1c. Lifestyle interventions such as diet and exercise are likely to be indicated regardless of results, but if the DM diagnosis is established, additional therapy may be warranted. It is also possible that hyperglycemia will improve or resolve with discontinuation of prednisone.
Azathioprine is a reasonable choice for maintenance therapy to prevent relapse of ANCA-associated vasculitis, but it would be used as an alternative to rituximab, rather than in combination. This patient received rituximab 2 months ago and is within the expected window of activity for this long-acting agent.
Omeprazole and other proton-pump inhibitors are often prescribed prophylactically for patients treated with high-dose oral corticosteroids to reduce the risk of gastrointestinal bleeding. There is epidemiologic evidence that this class of medication is linked to CKD, but a causal relationship has not been established. It is reasonable to plan to stop the PPI when steroid therapy has been completed. However, it would be premature to discontinue this therapy for this patient who has dyspepsia without replacing it with an alternative medication or investigating the symptom further.
Angiotensin-converting enzyme inhibitors are considered first-line agents for the treatment of hypertension in patients with kidney disease and proteinuria. However, this patient also has mild hyperkalemia, which is a relative contraindication for this agent. In addition, his BP may improve when the prednisone is discontinued.
A 61-year-old man with a long-standing history of rheumatoid arthritis is referred for kidney biopsy when his serum creatinine was noted to be elevated and accompanied by proteinuria.
He had taken aspirin 6 days previously for a headache but otherwise had not taken any non-steroidal anti-inflammatory medications.
On examination, his BP is 144/86 mm Hg. His examination is notable for basilar rales and marked lower extremity edema. The hemoglobin is 12.5 g/dL (reference range, 14–18). His platelet count and coagulation studies are normal. His estimated GFR is 26 mL/min/1.73 m2.
The kidney biopsy is performed.
Six hours after the biopsy, he develops severe flank pain. A CT scan shows a large perinephric hematoma, and his repeat hemoglobin is 8 g/dL. His kidney biopsy reveals amyloidosis.
Which of the following factors is the MOST likely to have increased the risk of bleeding in this patient?
Select one:
A. Male sex
B. Aspirin use
C. Amyloidosis
D. Reduced kidney function
E. Hypertension
The correct answer is: D
Reduced kidney function
For this patient with multiple potential risk factors, reduced kidney function has the strongest association with kidney biopsy-related bleeding.
Percutaneous kidney biopsy is an essential tool for the diagnosis of various kidney diseases, but there are associated risks. Bleeding is the primary complication, likely related to the vascular nature of the renal parenchyma. The reported rate of kidney biopsy complications varies in the literature, ranging from 3–6%. Serious complications, such as bleeding requiring a transfusion, occur less frequently, in just 1–3% of cases. AKI and CKD have both been independently associated with an increased risk of bleeding after kidney biopsy. The risk increases with higher stages of CKD. This increased risk has been attributed to increased interstitial fibrosis and cortical thinning. In more advanced disease, uremic platelet dysfunction may also play a role. Desmopressin is recommended by some authorities to prevent bleeding for patients with an eGFR <30 mL/min/1.73 m2. However, trial data is lacking and a recent systematic review found insufficient evidence to support this practice. Interestingly, some studies have found that use of desmopressin in patients with relatively preserved renal function can increase the risk of bleeding. Prior studies have shown that older age and female sex are also associated with an increased risk of bleeding after biopsy.
A large meta-analysis including more than 9000 patients did not find a significant association between elevated BP prior to biopsy and the risk of bleeding requiring a transfusion, although half the studies included used a systolic BP cutoff of 130 mm Hg. Smaller studies have shown that a BP >160/100 mm Hg is associated with an increased risk of bleeding.
The role of aspirin as a risk factor for post-biopsy bleeding was examined in a large retrospective study of more than 1000 patients involving 2 centers, in 1 of which it was routine to hold aspirin prior to kidney biopsy. An increased risk of post-biopsy hematoma and a greater fall in hemoglobin following biopsy was found among aspirin-treated patients, but there was no increased risk of major bleeding complications, including the need for intervention or transfusion. Most guidelines continue to recommend cessation of anti-platelet agents 5–7 days prior to the biopsy. For this patient, aspirin exposure 6 days prior to biopsy would be unlikely to contribute significantly to the development of a post-biopsy hematoma.
Amyloidosis was not shown to be associated with an increased risk of post-biopsy bleeding complications in a large retrospective study. A previously described association was likely due to reporting bias.
A 77-year-old woman presents to the emergency department with hemoptysis. She has had several weeks of worsening dyspnea on exertion, progressive lower extremity edema, and dark urine. She reports a history of sinus congestion, but has never required antibiotics or experienced epistaxis. She has not had any rash or joint symptoms.
Past medical history is significant for hypertension and hypothyroidism. She has a 20 pack-year history of smoking.
On physical examination, she appears anxious and tachypneic. Her BP is 178/100 mm Hg, pulse is 60/min, temperature is 37°C, and oxygen saturation is 78% on ambient air. Cardiovascular exam reveals no murmurs or rubs. Coarse crackles are present bilaterally. She has 1+ lower extremity edema bilaterally. There is no rash or synovitis.
Laboratory data:
Chest x-ray reveals bilateral alveolar opacities.
She is admitted to the intensive care unit. Bronchoscopy shows evidence of diffuse alveolar hemorrhage.
Serologic studies for ANCA and anti-GBM antibodies are pending as are blood and urine cultures. Gram stain of a bronchoalveolar lavage specimen is negative for organisms.
In addition to supporting oxygenation, which one of the following is the most appropriate NEXT step in the management of this patient?
Select one:
A. Await diagnostic serologic data
B. Pulse methylprednisolone and plasma exchange
C. Broad spectrum antibiotics
D. Kidney biopsy
E. Rituximab
The correct answer is: B
Pulse methylprednisolone and plasma exchange
The initiation of therapy with pulse methylprednisolone and therapeutic plasma exchange (TPE) is the most appropriate next step in the management of the patient with diffuse alveolar hemorrhage and evidence of acute glomerulonephritis. Kidney biopsy and serologic evaluation should be pursued, but treatment for the possibility of an autoimmune pulmonary-renal syndrome should be initiated even before a diagnosis is established.
The role of TPE in the management of autoimmune disorders continues to evolve. A randomized trial (“PEXIVAS”) for ANCA-related vasculitis (AAV) that included patients with severe kidney impairment and pulmonary hemorrhage, but excluded patients with anti-GBM disease did not find that TPE conferred benefit beyond that of immunosuppression. However, as of 2019, guidelines from the American Society for Apheresis (ASA) lists AAV with severe renal involvement as a class I indication for TPE, as it does for pulmonary hemorrhage related to either anti-GBM or ANCA antibodies. In this patient, for whom the clinical suspicion of an autoimmune process is high, and in whom anti-GBM disease has not been excluded, empirical TPE and corticosteroids would be indicated. Either Rituxan or cyclophosphamide (or both) is often added once the diagnosis is established. Renal biopsy can often be deferred until a patient is stabilized without a loss of diagnostic utility. Serologic data can be sufficient in some circumstances. Renal replacement therapy should be initiated if complications of AKI ensue, but should not delay empirical corticosteroids and plasma exchange. Based on the results of the PEXIVAS trial, some clinicians would forgo continuing TPE if AAV was identified, but others would continue TPE due to the pulmonary hemorrhage. New guidelines from the ASA may add clarity.
A 61-year-old woman with a history of hypertension, hypothyroidism, and diabetes presents to her primary care physician with dysuria and is prescribed a 5-day course of trimethoprim-sulfamethoxazole. Her medications include lisinopril, metformin, and levothyroxine. Four days later, she presents to the emergency department with nausea, diaphoresis, and generalized muscle weakness.
Her BP is 135/50 mm Hg and pulse is 55/min and regular. She appears unwell, sweaty, and anxious. The examination is notable for generalized weakness.
Plasma Result Reference Range
Potassium 6.0 mEq/L 3.5–5.0
Total CO2 22 mEq/L 23–30
Anion gap 10 mEq/L 7–13
Creatinine 1.8 mg/dL (baseline 1.5) 0.5–1.1
Her 12-lead electrocardiogram shows sinus bradycardia with peaked T waves and mild prolongation of the PR and QRS intervals.
Which of the following BEST explains this patient’s hyperkalemia?
Select one:
A. Competitive inhibition of the aldosterone receptor in the collecting tubule
B. Decreased distal delivery of sodium due to relative volume depletion
C. Direct toxicity to adrenal zona glomerulosa cells reducing aldosterone secretion
D. Competitive inhibition of the epithelial sodium channel in the collecting tubule
E. Inhibition of angiotensin II-mediated aldosterone release
The correct answer is: D
Competitive inhibition of the epithelial sodium channel in the collecting tubule
Trimethoprim is structurally similar to amiloride, and competitively inhibits the luminal epithelial sodium channel in the collecting duct. This leads to impairment of distal potassium excretion and can provoke hyperkalemia. Hyperkalemia was first reported primarily in patients receiving high-dose trimethoprim therapy for Pneumocystis jiroveci pneumonia in the setting of AIDS. Although the occurrence of severe hyperkalemia in outpatients is rare, caution is warranted when other risk factors for hyperkalemia are present, such as angiotensin-converting enzyme (ACE) inhibitors, reduced kidney function, or type IV pattern renal tubular acidosis. Note that trimethoprim also inhibits tubular secretion of creatinine so it is common for the serum creatinine to rise without actual kidney injury or a change in GFR.
ACE inhibitors block angiotensin-mediated aldosterone release by preventing conversion of angiotensin I to angiotensin II, which normally stimulates the cells of the zona glomerulosa of the adrenal gland to secrete aldosterone. Hyperkalemia is an uncommon side effect of ACE inhibitors (or angiotensin receptor blockers) in the absence of additional risk factors such as diabetes, decreased kidney function, decompensated heart failure, or co-administration of potassium-sparing diuretics. In this case, addition of trimethoprim is the most likely cause of the acute rise in potassium.
Eplerenone and spironolactone competitively inhibit the aldosterone receptor in the collecting duct.
Heparin and low molecular weight heparins can lead to hyperkalemia due to direct toxicity to zona glomerulosa cells, leading to reduced aldosterone production.
Decreased distal sodium delivery leads to a reduction in potassium secretion in the setting of volume depletion. However, there is no evidence of hypovolemia, such as a clinical history of poor oral intake or physical examination findings consistent with volume depletion.
A 45-year-old woman is evaluated for hypercalcemia. She initially presented to the hospital with cough, weight loss, lethargy, and dyspnea. On chest x-ray, she has bilateral hilar lymphadenopathy. A radiograph of her kidneys, ureter, and bladder is notable for calcifications in both kidneys. A lymph node biopsy reveals noncaseating granulomas.
Result (Reference Range)
Creatinine 1.4 mg/dL
[0.9 mg/dL 3 months earlier] (0.5–1.1)
Calcium 12 mg/dL (8.6–10.2)
Phosphorus 4.8 mg/dL (3–4.5)
PTH 10 pg/mL (10–65)
PTH-related protein <1.5 pmol/L (<1.5)
25-hydroxyvitamin D 25 ng/mL (30–60)
1,25-dihydroxyvitamin D 72 pg/mL (15–60)
Which of the following is the MOST appropriate therapy to treat the cause of this patient’s hypercalcemia?
Select one:
A. Prednisone
B. Denosumab
C. Furosemide
D. Cinacalcet
E. Sevelamer
The correct answer is: A
Prednisone
The most appropriate treatment for this patient’s hypercalcemia is prednisone. Based on this patient’s history, laboratory results, and histology, the most likely diagnosis is sarcoidosis. Hypercalcemia, in this setting, is mediated by extra-renal production of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D] in granulomatous tissue. Corticosteroids are currently considered the best initial management for sarcoidosis and associated hypercalcemia. Corticosteroids reduce the 1-alpha hydroxylation that leads to 1,25-(OH)2D formation. By reducing 1,25-(OH)2D production, less calcium is absorbed or reabsorbed from the gastrointestinal tract, kidneys, and bone. Note that the patient’s elevated phosphorus is also partially due to 1,25-(OH)2D-mediated gastrointestinal phosphorus absorption.
Prednisone can be initiated at 0.3–0.5 mg/kg/day, with higher doses for more significant organ impairment. Steroid therapy may also be useful to treat interstitial nephritis and extra-renal manifestations of sarcoidosis as well. There are few studies that provide data on specific dosing and duration of steroids for the treatment of sarcoidosis. The disease often remits spontaneously, but relapses are common. Generally, a starting dose is maintained for at least 4 weeks with a gradual taper to a 5–10 mg maintenance dose for up to 12 months.
Other therapies that can reduce conversion of 25-(OH)D to 1,25-(OH)2D include ketoconazole and hydroxychloroquine. Azathioprine, mycophenolate mofetil, and tumor necrosis factor-α inhibitors such as infliximab can also be used in addition to, or in place of, corticosteroids for those patients who are intolerant of or do not respond to corticosteroids.
Patients should be counseled to stop any vitamin D supplements and to avoid sunlight exposure to avoid increased vitamin D substrate. While excessive calcium intake should be avoided, dietary calcium should not be strictly limited because osteopenia from bone resorption may ensue. Bisphosphonates may also help prevent osteoporosis in patients treated with corticosteroids (and possibly those not treated with steroids as well).
Isotonic saline can be used to treat acute hypercalcemia. This strategy improves intravascular volume depletion caused by high serum calcium levels and promotes urinary calcium excretion. Furosemide can be added to address volume overload that may occur with IV resuscitation. However, neither of these strategies would address the cause of hypercalcemia in this case nor prevent its recurrence.
Cinacalcet can improve hypercalcemia secondary to hyperparathyroidism by binding to the calcium-sensing receptor in the parathyroid glands. PTH in this patient is already appropriately suppressed.
Denosumab, an antibody that binds to the receptor activator of nuclear factor kappa-B ligand (RANK-L), is used to treat the hypercalcemia of malignancy (as well as osteoporosis).
Sevelamer is used to treat hyperphosphatemia in CKD. It could be used in this setting but would not improve the hypercalcemia. Reduction of 1,25-(OH)2D production would reduce phosphorus absorption without sevelamer.
A 60-year-old man with a history of severe chronic obstructive lung disease has been admitted to the intensive care unit (ICU) with respiratory failure. He is intubated, sedated, and receiving mechanical ventilation, corticosteroids, and antibiotics.
On day 2 of his ICU course, he remains sedated and ventilated. His BP is 88/50 mm Hg and pulse is 110/min. Diminished breath sounds are present on auscultation. There is no peripheral edema.
Chest x-ray demonstrates clear but hyperinflated lungs.
Which ONE of the following is the MOST appropriate treatment for this patient’s acid-base disorder?
Select one:
A. Dilute hydrochloric acid
B. Continuous renal replacement therapy
C. 0.45% sodium chloride
D. 0.9% sodium chloride
E. Acetazolamide
The correct answer is: D
0.9% sodium chloride
The patient has post-hypercapnic metabolic alkalosis and volume depletion, which are best treated with 0.9% sodium chloride infusion.
Patients with chronic respiratory acidosis, such as those with advanced chronic obstructive lung disease, develop a compensatory increase in bicarbonate, which raises the pH toward normal. The kidneys achieve this by increasing ammonia production and thereby net acid secretion, which results in the generation of “new bicarbonate” and loss of chloride with ammonium. The kidneys maintain the higher serum bicarbonate by increasing reabsorption of the greater filtered load of bicarbonate. This process begins immediately with retention of carbon dioxide, but it takes several days to achieve the maximal compensation. If the PaCO2 is rapidly lowered (corrected), which may occur when mechanical ventilation is applied, the retained bicarbonate results in an elevated pH, and is referred to as post-hypercapnic metabolic alkalosis.
If there is no stimulus to retain the high serum bicarbonate and kidney function is normal, the kidneys will begin to excrete the excess bicarbonate. In the setting of volume depletion or reduced kidney function, the elevated serum bicarbonate can persist. This patient has evidence of effective circulating volume depletion (hypotension and tachycardia)and should be treated with an infusion of 0.9% sodium chloride. Potassium chloride can also help correct the metabolic alkalosis and should be prescribed for this patient with hypokalemia.
The urine electrolytes in this case support the diagnosis; the urine chloride is low when metabolic alkalosis has resulted from chloride depletion as with vomiting, prior diuretics, or the chloride depletion from chronic respiratory acidosis. The urine sodium is low because of volume depletion and activation of the renin-angiotensin-aldosterone axis. However, urine sodium may be paradoxically high during the development of metabolic alkalosis when bicarbonaturia is occuring, mandating increased excretion of sodium as a counterion despite the presence of hypovolemia.
Acetazolamide is a good choice for patients with metabolic alkalosis who have evidence of total body volume overload but maintain a metabolic alkalosis because of reduced effective arterial blood volume (e.g, congestive heart failure).
Continuous renal replacement therapy can correct metabolic alkalosis but is rarely required. It can be used if this patient does not respond to volume expansion and develops additional electrolyte abnormalities and AKI with persistent hemodynamic instability.
Dilute hydrochloric acid has been used to treat severe metabolic alkalosis for patients with contraindications to either dialysis or infusion of saline or potassium chloride, but must be infused via a central line. Many hospitals no longer stock this medication.
In the setting of hypotension and no apparent free water deficit, isotonic 0.9% saline is preferred to hypotonic 0.45% sodium chloride.
In addition to infusion of 0.9% saline, adjustment in ventilator parameters to permit a degree of hypercapnia which more closely approximates the patient’s baseline may facilitate weaning from the ventilator when the acute illness resolves.
A 65-year-old woman with ESRD due to polycystic kidney disease has received HD for 3 months. She finds her appetite has improved since she started dialysis. Urine output has decreased slightly.
Medications include a renal vitamin daily, cholecalciferol 1000 IU daily, lisinopril 10 mg daily, and erythropoietin 5000 IU at each dialysis session.
Monthly blood work reveals:
Result Reference Range
Calcium 10.0 mg/dL (8.6–10.2)
Phosphorus 6.5 mg/dL (3–4.5)
PTH 500 pg/mL (10–65)
25-hydroxyvitamin D 28 ng/mL (30–60)
Which of the following is the BEST initial therapy for this patient’s CKD-MB?
Select one:
A. Initiate calcitriol 0.25 mcg by mouth 3 times per week at dialysis
B. Increase cholecalciferol to 2,000 international units by mouth daily
C. Initiate sevelamer carbonate 800 mg by mouth with each meal
D. Initiate cinacalcet 30 mg by mouth daily with dinner
E. Initiate calcium acetate 667 mg by mouth with each meal
The correct answer is: C
Initiate sevelamer carbonate 800 mg by mouth with each meal
The best initial therapy for this patient with metabolic abnormalities including secondary hyperparathyroidism and hyperphosphatemia is sevelamer carbonate with each meal.
Treatment of CKD-MBD is a routine but challenging task. As the name implies, this is not just a bone disorder but a constellation of mineral metabolism abnormalities that can have a major adverse effect on cardiovascular outcomes. Current treatment goals and therapies are largely opinion-based and not supported by data from large, well-controlled studies. In addition, treatment often places a heavy pill burden on the patient, making adherence difficult.
The optimal intact PTH level has not been defined. Various studies have found an association between elevated PTH levels and increased mortality at a cutoff ranging from 400–600 pg/mL. KDOQI guidelines target a broad intact PTH range of 2–9 times the upper limit of normal (a range of 130–585 pg/mL in most labs). In this case, although the intact PTH is within this range, it is relatively high and accompanied by hyperphosphatemia. Therefore, the optimal choice of therapy will lower the intact PTH level and improve (or at least not worsen) the other parameters. Hyperphosphatemia is associated even more strongly with poor cardiovascular outcomes for dialysis patients than is high PTH.
A physiologic approach is to address those metabolic abnormalities that enhance PTH secretion. These include high serum phosphorus, low serum calcium, and low 1,25-dihydroxyvitamin D. A phosphate binder is recommended as first-line therapy because it may lower the serum phosphorus and intact PTH level. There is an increasing array of choices for phosphate binders, which can be broadly divided into calcium-containing (calcium carbonate and calcium acetate) and non-calcium-containing (sevelamer carbonate, lanthanum carbonate, and emerging iron-based compounds). Data supporting the use of non-calcium-containing binders is accumulating. In this case, sevelamer is the preferred option because the serum calcium is already at the upper range of normal and hypercalcemia could result if a calcium-based binder were added.
Treatment with calcitriol (1,25-dihydroxyvitamin D3) may reduce the PTH. However, because it also enhances absorption of calcium and phosphorus from the gastrointestinal tract, it is contraindicated in the setting of hyperphosphatemia (and it can cause or worsen hypercalcemia). Calcitriol should not be prescribed until the phosphorus level is closer to normal (or ideally at least <5.5 mg/dL).
An increase in the cholecalciferol dose could potentially result in a reduction in the PTH level, but the 25-hydroxyvitamin D level is already normal, and it is uncertain that supplementation would result in more conversion to 1,25-dihydroxyvitamin D, which would then suppress PTH production. In addition, this conversion might also cause undesirable phosphorus and calcium absorption from the gut as described for calcitriol.
Cinacalcet, a calcimimetic agent that acts directly on the parathyroid glands to reduce parathyroid hormone secretion, is an effective means of lowering the intact PTH level. It is an appropriate option if initial adjustment of phosphorus, calcium, or vitamin D levels is not successful. With a brisk reduction in PTH, the patient may develop a mild “hungry bone syndrome” in which the phosphorus and calcium levels may both decrease significantly. If this occurs and the calcium level falls below 8.0 mg/dL and the phosphorus is less than 5.3 mg/dL, a change to a calcium-containing binder, such as calcium acetate or calcium carbonate, may be indicated.
A 34-year-old woman with no past medical history presents to the emergency department with weakness. She reports a 2-month history of unintentional weight loss and progressive fatigue with intermittent fevers. She denies diuretic or laxative use.
On physical examination, she is a thin woman who appears well. Her BP is 118/55 mm Hg and pulse is 72/min. Lungs are clear. Mucous membranes are dry and she has no lower extremity edema.
Result (Reference Range)
Sodium 135 mEq/L (136–145)
Potassium 3.0 mEq/L (3.5–5.0)
Chloride 113 mEq/L (98–106)
Total CO2 15 mEq/L (23–30)
Creatinine 0.85 mg/dL (0.5–1.1)
Albumin 3.7 g/dL (3.5–5.5)
Osmolality 299 mOsm/kg (275–295)
Venous blood gas
pH 7.27 (7.38–7.44)
PaCO2 33 mm Hg (38–42)
Urine
Sodium 74 mEq/L (Varies with intake)
Potassium 48 mEq/L (Varies with intake)
Chloride 86 mEq/L (Varies with intake)
Osmolality 374 mOsm/kg (38–1400)
Urine dipstick: pH 6.5 and 1+ protein
What is the MOST likely etiology of this patient’s electrolyte disorders?
Select one:
A. HIV infection
B. Paroxysmal nocturnal hemoglobinuria
C. Diabetes mellitus
D. Lead toxicity
E. Sjögren syndrome
The correct answer is: E
Sjögren syndrome
This patient most likely has Sjögren syndrome, which may cause a distal renal tubular acidosis (RTA).
This patient has a non-anion gap metabolic acidosis with hypokalemia. The normal kidney response to metabolic acidosis is to maximally acidify the urine by increasing urinary ammonium excretion. In this case, the relatively high urine pH of 6.5 points to a failure of this mechanism.
It is now possible to measure urinary ammonium concentration in many laboratories, but it remains most common to estimate urinary ammonium by calculating the urine anion gap (also called “net urine charge”). This calculation is useful to classify non-anion gap metabolic acidosis and distinguish between renal and non-renal causes. The urine anion gap calculation may not be reliable in the setting of significant bicarbonaturia, such as early proximal RTA, because it adds an additional unknown variable (urinary bicarbonate).
The urine anion gap is calculated by the following equation:
Urine anion gap = [Na+] + [K+] – [Cl-]
Because metabolic acidosis should result in increased urinary excretion of ammonium which is accompanied by chloride, urinary chloride levels are expected to exceed the sum of urinary sodium and potassium levels when metabolic acidosis is present. The urine anion gap, therefore, is usually negative and in the -20 to -60 mEq/L range among patients with acidosis if kidney function is normal. In this case, the urine anion gap is positive (urine anion gap = 74 + 48 – 86 = 36), implying a failure of the kidney to augment ammonium excretion.
It is also notable that the urinary potassium is elevated in the setting of hypokalemia. Spot urinary potassium measurements can be misleading, but a value greater than 40 mEq/L implies that urinary potassium wasting is present. Hypokalemia and inability to excrete ammonium are characteristics of a classic, distal RTA, also known as a type 1 RTA.
The most frequent causes of adult-onset hypokalemic distal RTA are autoimmune disease (most commonly Sjögren syndrome) and hypercalciuria. The prevalence of distal RTA in Sjögren’s syndrome is estimated at 25%.
HIV is not associated with a distal RTA; however, proximal tubular dysfunction associated with HIV infection has been described. In addition, proximal tubulopathy is a well-known complication of tenofovir disoproxil fumarate, a nucleotide reverse transcriptase inhibitor.
Paroxysmal nocturnal hemoglobinuria is a rare cause of proximal renal tubular acidosis. The kidney biopsy of affected individuals reveals hemosiderin deposition in proximal tubular cells.
Diabetes mellitus is associated with hyporeninemic hypoaldosteronism, also known as a type 4 RTA. This disorder is characterized by hyperkalemia and relatively mild metabolic acidosis.
Lead-related nephrotoxicity is typically associated with CKD, gout, hypertension, mild proteinuria, and hyperuricemia.
A 30-year-old woman presents for kidney donor evaluation. She is interested in donating to her brother, who has ESRD at age 30 secondary to Alport syndrome. She has no history of tobacco use, diabetes, or hypertension and takes no medications.
Her BP is 122/68 mm Hg, pulse 72/min, and BMI 24 kg/m2. Physical examination is normal.
Laboratory data reveal creatinine 0.9 mg/dL (reference range, 0.5–1.1) and estimated GFR 100 mL/min/1.73 m2. Urinalysis reveals no red blood cells and no protein. Kidney ultrasound is normal.
A skin biopsy reveals the segmental presence of the α5 chain of type 4 collagen along the epidermal basement membrane.
Which of the following is the MOST appropriate next step in the management of this prospective donor?
Select one:
A. Counsel against kidney donation
B. Measure anti-glomerular basement membrane (GMB) antibody titer
C. Obtain kidney biopsy
D. Obtain 24-hour urine for creatinine and total protein
E. Start an angiotensin-converting enzyme inhibitor
The correct answer is: A
Counsel against kidney donation
Based on the skin biopsy, this patient should be counseled against donation. This potential donor’s skin biopsy is consistent with mosaic expression of the α5 chain of type 4 collagen, indicating a heterozygous carrier state for the mutation. Although the clinical course is less severe than for affected males, females with X-linked Alport syndrome have a risk of ESRD approaching that of a patient with diabetes, reaching 30% by age 60 and 40% by age 80. For this reason, female carriers under age 45 are discouraged from kidney donation. This patient, as a heterozygous carrier, has a significantly higher lifetime risk of ESRD compared with the general population.
Skin biopsy is a less invasive diagnostic test for Alport syndrome, and kidney biopsy would only be necessary to confirm the diagnosis if the results revealed normal staining for the α5 chain of type 4 collagen along the epidermal basement membrane.
Anti-GBM disease is a potential post-transplant complication in kidney transplant recipients with Alport syndrome, but there is no role for measuring titers in the potential donor. Moreover, this test measures antibodies against the α3 chain of type 4 collagen, which occur in native anti-GBM disease. Anti-GBM disease in kidney transplant recipients with underlying Alport syndrome, is caused by antibodies to the α5 chain.
Angiotensin-converting enzyme inhibitor therapy is indicated for patients with Alport syndrome who have proteinuria, but there is no role for blockade of the renin-angiotensin-aldosterone system in the absence of proteinuria or hypertension.
Many kidney transplant programs require 24-hour urine collections to assure adequate kidney function if the estimated glomerular filtration rate is at the lower range of normal. In this case, the abnormal skin biopsy finding precludes kidney donation and therefore a 24-hour collection is unnecessary.
A 55-year-old man presents for follow-up of CKD. His medical history includes hypertension and type 2 diabetes mellitus that was diagnosed at age 31. Three months ago, he was placed on a low potassium diet to address serum potassium of 5.6 mEq/L. He reports that he is adhering to his diet. He feels well and has no additional concerns.
Medications include losartan, amlodipine, insulin glargine, and chlorthalidone.
On physical examination, he appears well. Blood pressure is 142/85 mm Hg, pulse is 85/min, and BMI is 36 kg/m2. Lungs are clear and cardiovascular examination is normal. There is no edema of the extremities.
Laboratory data:
Serum Result (Reference Range)
Sodium 138 mEq/L (136–145)
Potassium 5.5 mEq/L (3.5–5.0)
Total CO2 21 mEq/L (23–30)
Creatinine 1.5 mg/dL
(increased) (0.7–1.3)
Urine albumin-to-creatinine ratio 450 mg/g (<30)
Patiromer 8.4 g once daily is added at this visit.
In addition to a gradual reduction in serum potassium, which of the following is MOST likely following this change in his regimen?
Select one:
A. Increase in enteral magnesium absorption
B. Increase in enteral oxalate absorption
C. Increase in enteral sodium absorption
D. Increase in enteral calcium absorption
The correct answer is: D
Increase in enteral calcium absorption
Patiromer is a potassium binding polymer that utilizes calcium sorbitol as a counterion to exchange for potassium. It is associated with a modest increase in calcium absorption and also therefore urinary excretion.
Patiromer is an oral non-absorbable potassium binding agent approved for the treatment of chronic hyperkalemia and is expected to decrease the serum potassium by 0.5–1 mEq/L over the course of 3 days to 2 weeks. This agent has been studied in patients at risk for hyperkalemia associated with renin-angiotensin-aldosterone blockade and allows for the potential continuation of this blockade in settings where hyperkalemia may otherwise limit or prohibit this strategy.
Patiromer has been studied at varying doses based on baseline serum potassium. Mean serum potassium decrease is 0.73 mEq/L, with more accentuated decrease among patients starting with higher potassium levels. Patiromer carries a black box warning against use for immediate treatment of life-threatening hyperkalemia, given that decrease in serum potassium is not immediate.
Patiromer releases calcium when it binds potassium. Recent studies demonstrate a moderate increase in calcium excretion among normal subjects receiving patiromer. So far, there are no recognized effects of patiromer on oxalate absorption.
One of the most commonly reported adverse effects of patiromer is a reduction in serum magnesium as stool losses of magnesium are increased. This may be particularly important among patients taking proton-pump inhibitors chronically, who commonly have hypomagnesemia because the subsequent change in gastric pH appears to limit magnesium absorption by enterocytes.
Sodium polystyrene sulfonate is associated with enhanced enteric sodium absorption because sodium is exchanged for potassium.
A 37-year-old woman with stage 2 CKD due to autosomal dominant polycystic kidney disease (ADPKD) is referred for management of an intracranial aneurysm (ICA). Her father has also been diagnosed with ADPKD, but there is no family history of ICA or subarachnoid hemorrhage (SAH). The patient does not smoke. She works as a bus driver. Because of her occupation, she underwent MRI and angiography of the brain (MRI/MRA) 5 years ago, which revealed a 3-mm anterior circulation ICA. She currently feels well and denies headache, visual changes, or vomiting.
On physical examination, blood pressure is 130/84 mm Hg and heart rate is 72/min. She has no edema, and heart and lung findings are normal. Neurologic examination is normal.
Her serum creatinine is 1.0 mg/dL (reference range, 0.5–1.1) and urinary albumin is 56 mg/g creatinine (reference range, <30).
Which one of the following is the MOST appropriate next step in management of ICA?
Select one:
A. Lisinopril
B. Repeat MRI/MRA
C. Angiography and endovascular intervention
D. Surgical clip of aneurysm
E. No further evaluation
The correct answer is: B
Repeat MRI/MRA
The most appropriate next step in management of this patient with ADPKD and an ICA is to repeat the MRI/MRA.
The prevalence of ICA among patients with ADPKD is high compared with the general population (9–12% versus 2–3%) and is believed to result from polycystin dysfunction in the arterial endothelium and vascular smooth muscle. Risk factors for the development of ICA include smoking, hypertension, and family history of ICA or SAH.
Although ICA rupture may be catastrophic, not all ICA have a high risk of rupture, and screening is not required for all patients with ADPKD. Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend ICA screening only for patients without limited life expectancy who have a family history of ICA or SAH, are employed in high-risk occupations (e.g., airline pilots or bus drivers), or those who request screening. Patients with family history as their only risk factor are advised to have MRI/MRA every 5–10 years. Patients who have known aneurysms <7 mm in diameter, engage in high-risk occupations, or are planning conception, transplantation, or other major surgery are advised to have MRI/MRA every 1–5 years. ICA >10 mm in diameter have a relatively high risk of rupture and, if feasible, should be repaired by surgical clipping or endovascular intervention such as deployment of a coil.
Patients with ADPKD who have an anterior circulation ICA <7 mm in diameter, such as this one, have a low risk of rupture (0.5%), so MRI/MRA every 1–5 years would be appropriate.
In the HALT-PKD trial, lisinopril to target blood pressure 95–110/60–75, compared with 120–130/70–80, conferred a slower increase in kidney volume and improved left ventricular mass index and urine albumin excretion among patients with ADPKD and eGFR ≥60 mL/min/1.73 m2 at 5 years. However, risk of ICA rupture was not assessed in this trial, and there is no evidence that aggressive blood pressure control affects the natural history of ICA.
Cerebral angiography is invasive and not recommended for screening. Prophylactic repair of a small ICA is unnecessary and is associated with procedural risk. Conversely, it would not be appropriate to forego periodic screening in a patient with ADPKD with a known ICA
A 56-year-old man with diabetes mellitus is admitted to the vascular surgery service for management of a chronic diabetic foot ulcer. Wound cultures have grown Enterococcus and Klebsiella. Antibiotics and wound care are initiated and revascularization is planned. His usual medications, which include insulin, metformin, amlodipine, aspirin, atorvastatin, and metoprolol, are continued. In addition, he is treated with piperacillin-tazobactam and subcutaneous heparin.
His medical history includes myocardial infarction, hypertension, and deep vein thrombosis.
On physical examination, he appears well. His blood pressure is 169/85 mm Hg and pulse is 85/min. Body mass index is 35 kg/m2. The lungs are clear and the heart is normal. The left lower extremity is wrapped with a dressing over the left heel. There is bilateral mild pretibial edema. A post-void residual bladder volume by bladder scan is 100 mL. Kidney ultrasonography demonstrates normal kidney size and contour without hydronephrosis.
Which of the following options is the BEST management of this patient’s hyperkalemia?
Select one:
A. Add furosemide
B. Discontinue heparin
C. Discontinue metoprolol
D. Insert a urinary catheter
E. Add oral potassium binder
The correct answer is: A
Add furosemide
The best management for this patient’s hyperkalemia is the addition of a diuretic such as furosemide.
The findings of hyperkalemia and mild hyperchloremic metabolic acidosis are consistent with a type 4 renal tubular acidosis (RTA) and is commonly identified in patients with diabetic nephropathy. Hyperkalemia is a result of hyporeninemic hypoaldosteronism, leading to impaired potassium excretion in the distal nephron. Metabolic acidosis, if present, is typically mild and has been attributed to impaired ammonium production secondary to intracellular alkalosis induced by hyperkalemia.
First-line treatment includes the addition of a kaliuretic diuretic. Both thiazide and loop diuretics can be effective, but loop diuretics may be more potent for patients with CKD. In addition to inducing natriuresis and kaliuresis, diuretics improve volume overload and correct the metabolic acidosis. In a volume-neutral or volume-depleted patient, oral sodium bicarbonate can be added to address the metabolic acidosis and provide a source of sodium so that diuretic therapy does not result in symptomatic volume contraction.
Aldosterone production by the zona glomerulosa cells of the adrenal cortex may be suppressed by heparin. This may result in hyperkalemia, but this patient’s hyperkalemia predated the exposure to heparin. Furthermore, this patient is at high risk of venous thrombosis, so discontinuation of heparin prophylaxis would be considered only if other strategies were unsuccessful.
Non-selective beta-blockers can contribute to hyperkalemia by interfering with the β2-adrenergic facilitation of potassium entry into cells. This effect is typically mild unless other factors are present. Metoprolol is β1-selective, so discontinuation is unlikely to affect the hyperkalemia. Further, the history of myocardial infarction and stable angina are strong indications to continue beta-blockade.
Although the post-void residual is abnormal, the degree of urinary retention is less than that normally associated with a need for intervention. It would be premature to insert a urinary catheter with the attendant risk of infection. It would be reasonable to consider stopping medications, such as amitriptyline, which may impair bladder function.
Sodium polystyrene sulfonate (SPS) resin has been used to manage both acute and chronic hyperkalemia, but the effectiveness and safety have been questioned. The exchange of sodium for potassium can aggravate volume overload. This strategy would be considered only if the hyperkalemia could not be managed with other methods. Alternative potassium binding medications, including patiromer and sodium zirconium cyclosilicate, appear to be safer and more effective than SPS, but diuretic therapy is the first approach to a type IV RTA, particularly in patients such as this who also have hypertension and edema.
A 56-year-old man with a history of CKD attributed to type 2 diabetes presents to the clinic for a routine follow-up visit. Diabetic complications include retinopathy, neuropathy, and albuminuria.
Medications include amlodipine, metoprolol, atorvastatin, and metformin.
On physical examination, his blood pressure is 134/78 mm Hg and heart rate is 82/min. There is mild lower extremity edema, and heart and lung exams are normal.
Result Reference Range
Creatinine 1.4 mg/dL 0.7–1.3
Hemoglobin A1c 7.7% 4–5.6
Urine albumin-to-creatinine ratio 510 mg/g <30
Two weeks ago, the patient’s endocrinologist prescribed empagliflozin 10 mg daily to improve glycemic control.
Which of this patient’s medications is associated with a reduction in hyperfiltration and delayed progression of diabetic nephropathy in this patient?
Select one:
A. Empagliflozin
B. Metformin
C. Metoprolol
D. Atorvastatin
E. Amlodipine
The correct answer is: A
Empagliflozin
The sodium-glucose transporter (SGLT2) inhibitor class of medications decreases glomerular hyperfiltration and the risk of progression of diabetic nephropathy.
This patient has evidence of increased glomerular capillary pressure based on the elevated urinary albumin. Persistently elevated glomerular capillary pressures are felt to contribute to glomerular damage secondary to diabetic nephropathy. Recent studies suggest that this process can be mitigated by inhibitors of the low affinity, high capacity Na+-glucose cotransporter (SGLT2). A major factor in this process appears to be the increase in distal tubule NaCl delivery seen with initiation of empagliflozin.
Under normal circumstances, most filtered glucose (90%) is reabsorbed in the proximal tubule by SGLT2. Early in the course of diabetic nephropathy, the proximal tubule cells undergo hyperplasia and hypertrophy to absorb the higher glucose load present in the filtrate. Enhanced glucose reabsorption proximally is matched by increased Na+ reabsorption (and paracellular Cl- absorption). Thus, less Na+ and Cl- are delivered to the macula densa. This can inhibit tubuloglomerular feedback, which leads to afferent arteriolar vasodilation. Intraglomerular pressure rises and leads to hyperfiltration, albuminuria, and ultimately sclerosis. SGLT2 inhibitors appear to normalize distal tubule NaCl delivery, and in Akita diabetic mice, decrease albuminuria, kidney weight, and glomerular size. Proximal tubule hypertrophy does not increase with SGLT2 inhibitors.
The Empagliflozin, Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients enrolled 7020 patients with type 2 diabetes (hemoglobin A1c 7–10%) and high cardiovascular risk. Patients randomly assigned to empagliflozin, compared with those receiving placebo, had lower risks of all-cause mortality (32%), cardiovascular mortality (38%), and hospitalization for heart failure (35%). A prespecified subgroup of patients with CKD (estimated GFR <60 mL/min/1.73 m2) experienced these benefits, as well as a lower risk of renal endpoints (doubling of creatinine, worsening nephropathy, ESRD, or renal death). Other agents in this class have also been shown to reduce cardiovascular and renal risk in patients with type 2 diabetes and use of this class in renal impairment has been expanded to include patients with eGFR not less than 30 mL/min/1.73 m2. More recent trials with similar medications, including Canagliflozin and Renal Outcomes in Type 2 Diabetes and Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction, found these benefits extend to diabetic patients with eGFR as low as 30 mL/min/1.73 m2 as well as congestive heart failure patients, with or without diabetes.
Control of blood pressure is an important strategy to reduce progression of diabetic nephropathy (and CKD in general), but neither metoprolol nor amlodipine has been reported to act specifically to reduce hyperfiltration.
Metformin may retard progression of diabetic nephropathy by facilitating glycemic control, which may indirectly reduce hyperfiltration, but a direct effect has not been reported.
Statins are indicated to reduce the risk of cardiovascular events among patients with diabetes and CKD, but a direct effect on hyperfiltration has not been reported. The effect of statins on the progression of CKD and proteinuria is the subject of ongoing investigation; there is some evidence of benefit, although the mechanism is not known.
A 28-year-old man with type 1 diabetes is brought to the emergency department following a syncopal episode. He notes that he has been nonadherent to his insulin regimen. He has been diabetic for several years but has not had recognized complications. He reports feeling lightheaded, thirsty, and weak. Until yesterday, he was urinating frequently and drinking copiously, but urine output has become scant in the past day.
On physical exam, blood pressure and heart rate are 108/62 mm Hg and 88/min (seated) and 88/50 mm Hg and 116/min (standing), and weight is 72 kg. There is no edema, and heart and lung exams are normal with the exception of orthostatic tachycardia. Mucous membranes are dry and skin turgor is decreased.
Result (Reference Range)
Sodium 140 mEq/L (136–145)
Potassium 3.2 mEq/L (3.5–5.0)
Creatinine 2.8 mg/dL (0.7–1.3)
Glucose 750 mg/dL (70–99 (fasting))
Osmolality 350 mOsm/kg (275–295)
Urinalysis is significant for 3+ glucose, 3+ ketones, and specific gravity 1.015
Which one of the following is the MOST closely approximates this patient’s water balance on presentation?
Select one:
A. 3 L deficit
B. 1.5 L gain
C. 1.5 L deficit
D. 0 L (no deficit)
E. 3 L gain
The correct answer is: A
3 L deficit
This patient has developed a 3 L water deficit related to his uncontrolled diabetes and osmotic diuresis with inadequate fluid intake despite his thirst.
Severe hyperglycemia is commonly associated with significant volume depletion, and both hyponatremia and hypernatremia can occur depending on water intake compared with losses. Sodium, other electrolytes, and water are lost in the urine during the osmotic diuresis, but the net loss is unpredictable and may depend on the duration and severity of the hyperglycemia, underlying kidney function, and intake during the episode. Relatively more water loss than sodium loss results in hypernatremia that may be masked by the translocation of intracellular water to the extracellular space due to the osmotic effect of the hyperglycemia. To manage patients effectively, it is crucial to determine a corrected serum sodium concentration and use that value to estimate the relative loss or gain of water.
In this case, the normal serum sodium might suggest there is no water deficit, but this unlikely given the elevated glucose and serum osmolality.
To estimate the water deficit, it is necessary to first estimate the serum sodium, which requires correction for the effect of the elevated glucose. The most commonly cited correction factor for the serum sodium concentration is 1.6 mmol/L for every 100 mg/dL increase in glucose concentration above normal. In this case, the increase in glucose is 750 – 100 = 650 mg/dL. The corrected sodium is thus 140 + (6.5 × 1.6) = 150.4 mmol/L.
Free water deficit (FWD) may then be estimated by the following equation:
FWD = 0.6 × weight (kg) × ([serum Na / 140] – 1) = 0.6 × 72 × ([150.4/140] – 1) = 3.2 L
Thus, the closest approximation of this patient’s free water balance is a deficit of 3 L.
The management of diabetic ketoacidosis involves correction of volume depletion with IV fluid as well, as suppression of ketogenesis and correction of hyperglycemia with insulin. Potassium deficits are also common, and severe hypokalemia may result if potassium is not supplemented before insulin is given. Although the initial therapy should include isotonic crystalloid to restore extracellular volume, hypotonic fluids may also be required to address a water deficit, as in this case. The rate of correction of both the hyperglycemia and the hyperosmolality should be gradual to avoid cerebral edema.
Note that the sodium correction factor of 1.6 mmol/L per 100 mg/dL increase in glucose concentration is controversial. Alternative formulas have been suggested, including one that endorses a higher correction factor if the serum glucose is greater than 400 mg/dL. Application of this formula results in a corrected sodium of 159 mEq/L and a water deficit of 6 L. Whichever formula is used, the crucial concept is that correction of the serum sodium concentration is important in the setting of hyperglycemia, and allows the clinician to recognize an abnormality in water balance that may otherwise be masked. Therapy can be initiated with this in mind and modified as laboratory parameters change during treatment.
A 46-year-old woman with stage 3 CKD is referred to the outpatient clinic for evaluation of hypercalcemia. She has a history of bipolar disorder, which has been successfully treated with lithium carbonate for the past 13 years. She has no history of acute lithium toxicity, AKI, or proteinuria, and the etiology of CKD has not been defined. Although lithium discontinuation has been considered, her bipolar disorder was poorly controlled before treatment with lithium and she and her psychiatrist are reticent to stop this agent. The patient takes no other medications or supplements.
On physical examination, her blood pressure is 112/56 mm Hg and heart rate is 82/min. There is no edema, and heart and lung exams are normal.
Bone densitometry is normal.
Result Reference Range
Creatinine 1.4 mg/dL (stable) 0.5–1.1
Calcium 11.2 mg/dL 8.6–10.2
Ionized calcium 1.46 mmol/L 1.12–1.23
Phosphorus 3 mg/dL 3–4.5
PTH 266 pg/mL 10–65
Lithium 1 mEq/L therapeutic range, 0.6–1.2
Which one of the following is the MOST appropriate next step in treatment?
Select one:
A. Furosemide
B. Alendronate
C. Cinacalcet
D. Amiloride
E. Magnesium
The correct answer is: C
Cinacalcet
The most appropriate next step in treatment of this patient would be the addition of cinacalcet, a calcimimetic drug capable of suppressing parathyroid hormone.
The association between lithium and altered calcium homeostasis has been known for more than 50 years. Lithium may increase absorption of calcium from renal tubules and the gastrointestinal tract. In addition, lithium appears to decrease parathyroid gland sensitivity to calcium by inhibiting the calcium sensing receptor (CaSR), which results in an increase in PTH, a response analogous to that seen with familial hypocalciuric hypercalcemia. The result is typically a mild increase in serum calcium and PTH, but more significant increases can occur, perhaps by causing or exacerbating primary hyperparathyroidism (PHPT). Indeed, hyperplasia of all 4 glands and adenomas have been observed.
PHPT-mediated hypercalcemia may also be aggravated by lithium inhibition of CaSR activity in the loop of Henle. Normally, hypercalcemia activates the CaSR in the loop, which results in inhibition of the renal outer medullary K (ROMK) channel, leading to a decrease in potassium substrate for the sodium-potassium-chloride co-transporter on the luminal membrane, and a decrease in paracellular calcium reabsorption. Instead, lithium inhibits the CaSR and calcium reabsorption continues.
If lithium can be safely discontinued, mild hypercalcemia often resolves. Because altered calcium sensing appears to explain the pathogenesis of lithium-induced hyperparathyroidism, cinacalcet, which increases the sensitivity of the CaSR to calcium, would be expected to address this issue and help avoid surgical intervention. This was demonstrated in a case report describing 3 patients with lithium-mediated hypercalcemia who received cinacalcet 30–120 mg daily with subsequent normalization of calcium and PTH.
Amiloride has been used to treat lithium-induced nephrogenic diabetes insipidus but not PHPT; in fact, by blocking sodium entry into the principal cells, amiloride causes membrane hyperpolarization in the distal nephron and increases calcium reabsorption. Furosemide increases calcium excretion by blocking paracellular transport in the loop of Henle but has also been associated with secondary hyperparathyroidism. Stimulation of both calcium resorption from bone as well as calcium excretion in the urine could lead to total body calcium depletion. Additionally, furosemide may cause hypovolemia.
Magnesium levels in tissue, but not plasma, increase in response to high doses of lithium in rodent experiments, but there is no evidence that magnesium supplementation would affect lithium-mediated PHPT.
Alendronate (and other bisphosphonates) have been shown to improve bone mineral density among patients with primary hyperparathyroidism, but there is no information on the use of these agents specifically in lithium-mediated PHPT. The safety and efficacy of this class of medicines in CKD remains an area of controversy. In this case, because bone mineral density is normal, there would be no indication for this class of medication.
A 76-year-old man is referred for evaluation for kidney transplantation. He has had a progressive decline in kidney function over recent years attributed to diabetes and hypertension. His most recent estimated GFR was 16 mL/min/1.73 m2. He reports limited mobility due to back pain. His spouse notes that he has been more tired than usual. He smokes ½–1 packages of cigarettes per week. He does not have any chest pain, shortness of breath, lower extremity swelling, or claudication. He is interested in kidney transplantation to avoid dialysis and improve his energy level.
In addition to diabetes mellitus and hypertension, his medical history is notable for prostate cancer (Gleason 7), which was treated by prostatectomy 1 year ago. He currently has no evidence of disease.
His blood pressure (BP) has ranged from 150–170/80–90 mm Hg on amlodipine and furosemide.
Physical examination reveals BP 160/80 mm Hg, pulse 80/min, and body mass index (BMI) 38 kg/m2. Other than abdominal obesity and elevated BP, there are no abnormal findings.
Laboratory data shows:
Result Reference Range
Potassium 4.9 mEq/L 3.5–5.0
Total CO2 18 mEq/L 23–30
Creatinine 3.2 mg/dL 0.7–1.3
Hemoglobin A1c 6.5% 4–5.6
Prostate specific antigen undetectable No specific normal or abnormal level
Which one of the following is an ABSOLUTE contraindication to kidney transplantation for this patient?
Select one:
A. History of prostate cancer
B. BMI above 35 kg/m2
C. Current smoking
D. Uncontrolled hypertension
E. Age above 75
The correct answer is: A
History of prostate cancer
Recent history of prostate cancer is an absolute contraindication to kidney transplantation at this time. It is recommended that potential kidney transplant candidates with a history of cancer should have a waiting period free of recurrence of 2– 5 years, depending on the type and extent of malignancy. For prostate cancer, at least 2 years is generally recommended to minimize the risk of recurrence because of the potential presence of micrometastases that might expand once immunosuppression is introduced. For other cancers, such as myeloma, breast cancer, and melanoma, the waiting period is 5 years. Therefore, this patient should wait at least another year before being considered for kidney transplantation. It is worth noting that there are no strong data to support these exact waiting periods, although they are widely recommended by transplant guidelines.
There is no absolute age cut-off for potential recipients, and current data indicate that older transplant recipients, even those who are older than 75, have improved mortality compared with similarly aged candidates who remain on the waiting list. This survival benefit, however, is not realized until approximately 2 years after transplantation. Transplantation of a kidney from a living donor may confer benefit sooner. Although smoking is associated with worse kidney transplant outcomes, and some programs decline to transplant active smokers. However, it is not considered an absolute contraindication to kidney transplantation. Most programs strongly encourage patients to stop smoking prior to transplantation.
Uncontrolled hypertension is not an absolute contraindication to transplantation. Adherence (“compliance”) can influence candidacy and control of blood pressure and blood sugar are sometimes used to gauge this aspect.
Obesity is a relative contraindication to transplantation, although the mortality follows a J-shaped curve, which means that both very low and very high BMI carry increased risk of graft loss and patient death. In general, a BMI >40 kg/m2 is considered an absolute contraindication because of higher risk of mortality. Therefore, this patient with BMI 35 should be acceptable.
A 77-year-old man with stage 4 CKD due to type 2 diabetes is admitted to the hospital with a non-ST elevation myocardial infarction. Last week, he began taking ibuprofen daily for intermittent chest pain, which subsequently worsened. Today, he presented to the emergency department with substernal chest pain and received nitroglycerin, morphine, aspirin, oxygen, and clopidogrel with symptomatic improvement. Other home medications include atorvastatin, furosemide, metformin, lisinopril, and metoprolol.
On physical examination, his blood pressure is 112/64 mm Hg, heart rate is 88/min, arterial oxygen saturation is 100% with nasal cannula at 2 L/min, and pain is 0 on a scale of 0–10. There is no peripheral edema; jugular venous pressure is normal, and heart and lung exams are normal.
Result Reference Range
Hemoglobin 10 g/dL 14–18
Blood urea nitrogen 34 mg/dL 8–20
Creatinine 2.2 mg/dL
(baseline) 0.7–1.3
Estimated GFR 28 mL/min/1.73 m2 >60
Troponin I 4 ng/mL <0.04
Diagnostic coronary angiography with possible percutaneous coronary intervention (PCI) is scheduled.
Which one of the following medications is MOST appropriate to continue?
Select one:
A. Ibuprofen
B. Atorvastatin
C. Lisinopril
D. Furosemide
E. Metformin
The correct answer is: B
Atorvastatin
Atorvastatin is the most appropriate medication to continue for this patient at risk of AKI due to exposure to radiocontrast (contrast nephropathy, CN).
The true incidence and impact of CN has become controversial and many experts now feel it is much less common than previously thought. However, arterial procedures are higher risk than venous procedures and underlying CKD is an important risk factor. Multiple pathophysiologic events may contribute to CN including endothelial and tubular cytotoxicity related to reactive oxygen species and vasoconstriction. In addition, medullary hypoxia is believed to occur from the high viscosity of iodinated contrast and the tendency to cause sludging in the vasa recta.
A risk prediction tool for CN has been validated in the setting of percutaneous coronary intervention (PCI). Points are given for hypotension (systolic BP <80 mm Hg for ≥1 h), use of intra-aortic balloon pump, congestive heart failure, age >75, anemia (hematocrit <39% for men, <36% for women), diabetes, volume of contrast, and serum creatinine >1.5 mg/dL. This patient, with points given for age, anemia, diabetes, and serum creatinine, would have a score of at least 14, which confers a 26% risk of CN and approximately 1% risk of dialysis.
According to cardiology guidelines, statins should be started during hospitalization for acute coronary syndrome (ACS). In addition, 2 clinical trials of patients with CKD and ACS found that rosuvastatin was associated with a reduction in the incidence of CN and major adverse cardiovascular events.
Conversely, although furosemide has been theorized to protect against CN by blocking ATP depletion in the nephron, clinical trials have shown an increased risk of CN. Loop diuretics should be avoided in the absence of signs and symptoms of fluid overload.
Metformin, traditionally discontinued at time of contrast administration, is now permitted per the 2015 American College of Radiology Manual on Contrast Media for patients with estimated GFR ≥30 mL/min/1.73 m2. However, the guidelines continue to advise that metformin should be held for at least 48 hours post-procedure for patients with eGFR <30 mL/min/1.73 m2.
Continuation of angiotensin-converting enzyme inhibitors at time of contrast administration is controversial, but a recent meta-analysis suggested evidence of harm.
Ibuprofen may both block the cardiovascular benefits of aspirin and worsen the risk of AKI; it should be discontinued.
A 44-year-old man with obstructive sleep apnea is referred for evaluation of possible hypertension.
He has been treated with continuous positive airway pressure (CPAP) for the past 6 years. He had a sleep study performed 2 months ago that confirmed appropriate treatment of his sleep apnea. He recently underwent a 24-hour ambulatory blood pressure monitoring (ABPM) study for evaluation as part of a research study.
He has never been diagnosed with hypertension in the past and his blood pressure has ranged from 120–130/70–80 mm Hg at multiple physicians’ office visits.
His ABPM are below (see attachment):
His medical history is remarkable for a knee injury that required surgery in his teens, depression, and hyperlipidemia. Medications include simvastatin 20 mg daily and fluoxetine 10 mg daily. He does not use non-steroidal anti-inflammatory drugs (NSAIDs), tobacco, alcohol, or illicit substances. He does not add salt to his food and tries to eat 5 servings of fruit or vegetables daily. His mother has hypertension and had a stroke in her late 60s. His father has had hypertension since age 50 and has coronary artery disease.
On examination, he appears well. His blood pressure is 126/ 76 mm Hg, pulse is 84/min, weight is 80 kg, and body mass index (BMI) is 25 kg/m2. Arteriovenous nicking is present on fundoscopy. No abdominal bruit is heard. The remainder of the exam is normal.
Laboratory data:
Result Reference Range
Sodium 138 mEq/L 136–145
Potassium 4.2 mEq/L 3.5–5.0
Chloride 100 mEq/L 98–106
Total CO2 28 mEq/L 23–30
Blood urea nitrogen 16 mg/dL 8–20
Creatinine 0.9 mg/dL 0.7–1.3
Urine albumin-to-creatinine rati 68 mg/g <30
An echocardiogram demonstrates mild left ventricular hypertrophy.
Which of the following is the APPROPRIATE management for this patient?
Select one:
A. Repeat office BP in 4–8 weeks
B. Reassurance
C. Repeat ambulatory BP in 4–8 weeks
D. Initiate lisinopril
E. Repeat sleep study
The correct answer is: D
Initiate lisinopril
This patient has masked uncontrolled hypertension and antihypertensive therapy should be initiated.
Masked hypertension, defined as normal office blood pressure (BP) but elevated BP by home or ambulatory monitor, is a common finding and has been documented in as many as 10–40% of patients with low or satisfactory office blood pressure measurements. Masked hypertension may be particularly common among patients with worse cardiovascular risk factor profiles.
Ambulatory blood pressure monitoring is not always available in clinical practice but can be a useful adjunct in the diagnosis and management of hypertension. When this procedure is performed, experts recommend that there are at least 20 daytime measurements and 7 nighttime measurements. Day and night intervals are defined by the patient’s diary card. Practitioners should review the average 24-hour blood pressure and the average values during each interval and determine whether a fall (“dipping”) in blood pressure was present during sleep. Conservative thresholds for the diagnosis of hypertension are as follows:
Measurement Threshold for diagnosis of hypertension
24-hour average ≥130/80 mm Hg
Awake (or daytime) average ≥135/80 mm Hg
Asleep (or nighttime) average ≥120/70 mm Hg
Nocturnal “dipping” <10% (“non-dipper”)
This patient has elevated 24-hour, awake, and asleep blood pressure, but there was evidence of dipping later in the night. The nocturnal phenomenon of dipping is believed to improve risk stratification, but it is not clear whether this also applies when the mean asleep values are high.
In this patient, there is evidence of target organ damage with left ventricular hypertrophy, albuminuria, and early hypertensive retinopathy, as well as a family history of cardiovascular disease. His sleep apnea has recently been re-evaluated and his treatment regimen confirmed. There is little to be gained by delaying treatment to repeat either office BP measurement (consistently normal over multiple visits) or the ambulatory monitor (data quality appears good with over 80% of readings in hypertensive range). Note that lifestyle modification and elimination of contributing or interfering substances is always worthwhile
A 68-year-old man with no significant medical history is referred for evaluation of nephrotic syndrome. He has gained 20 kg over the last 6 months and has severe lower extremity edema. He also reports generalized diffuse bone pain particularly in his spine, pelvis, and knees. The pain is dull and worse with activity.
On examination he appears unwell. His blood pressure is 102/66 mm Hg, pulse is 84/min, and temperature is 37.1°C
He has conjunctival pallor and macroglossia. There is dullness to percussion with decreased air entry at his lung bases. Heart sounds are soft and there is a grade I/VI systolic ejection murmur. Abdomen is soft and nontender. Edema is 4+ extending from the feet to the sacrum. There is no focal bony tenderness. There are no joint effusions or joint tenderness.
(see attached lab data)
Furosemide is prescribed and kidney biopsy is scheduled.
Which of the following is the MOST likely cause of this patient’s generalized bone pain?
Select one:
A. Metastases to bone
B. Hypocalcemia
C. Lytic bone lesions
D. Renal osteodystrophy
E. Vitamin D deficiency
The correct answer is: E
Vitamin D deficiency
The most likely cause of this patient’s generalized bone pain is severe vitamin D deficiency and osteomalacia. This patient has severe nephrotic syndrome, which is likely due to AL amyloidosis, although a kidney biopsy would be required to confirm this. This diagnosis is suggested by the combination of macroglossia, severe nephrotic syndrome, and the small M-spike.
Patients with nephrotic syndrome can develop significant vitamin D deficiency because of urinary losses of vitamin D bound to vitamin D-binding protein. Prolonged, severe vitamin D deficiency with serum values <10 ng/mL results in secondary hyperparathyroidism and osteomalacia. In this setting, patients may complain of bone pain and tenderness, and muscle weakness. The spine, pelvis, and lower extremities are most commonly involved.
It would be difficult to exclude either lytic bone lesions related to myeloma without imaging or bone marrow biopsy, but diffuse bone pain would be less likely than pain localized to the site of the lesion. Although some myelomas are non-secretory, the faint monoclonal band favors amyloidosis over widespread myeloma. Destructive bone lesions have been reported with primary amyloidosis but this occurrence is rare, tends to involve the long bones, and would likely result in localized rather than diffuse pain.
Metastatic lesions can cause bone pain, but pain would be expected to localize to the lesion(s).
Renal osteodystrophy with prolonged hyperparathyroidism can cause bone pain but does not typically occur in the absence of advanced CKD or ESRD.
Hypocalcemia is not known to cause bone pain; instead, this can cause muscle cramping and signs of latent tetany on exam with a positive Chvostek or Trousseau sign.
A 72-year-old woman with rheumatoid arthritis and stage 4 CKD attributed to diabetic nephropathy is hospitalized with confusion. Despite significant chronic pain from her rheumatoid arthritis and diabetic neuropathy, she remains active and continues to work as a teacher’s aide. Two days ago, she became ill with acute symptoms of gastroenteritis, including nausea, diarrhea, poor intake, and low-grade fever. On the day of admission, her husband had difficulty waking her and found her to be confused and lethargic. Her fingerstick blood sugar was 180 mg/dL (reference range, 70–99 [fasting]).
Her medical history is also significant for hypertension, gout, postherpetic neuralgia, and carpal tunnel syndrome.
Medications include insulin, oxycodone 5 mg three times daily as needed, aspirin 81 mg daily, tramadol 100 mg twice daily, gabapentin 300 mg three times daily, lisinopril 20 mg daily, and chlorthalidone 25 mg daily.
On examination, she is confused and inattentive. Her BP is 96/ 76 mm Hg, pulse is 74/min, and temperature is 37°C. She has decreased tissue turgor and has prominent myoclonic twitching of her upper and lower extremities, but exam is otherwise normal.
Laboratory data (attachment):
Which of the following is the MOST likely cause of her symptoms?
Select one:
A. Uremia
B. Salicylate
C. Oxycodone
D. Tramadol
E. Gabapentin
The correct answer is: E
Gabapentin
Gabapentin is the most likely cause of the symptoms in this patient. Gabapentin is cleared entirely by renal excretion and therefore accumulates when kidney function declines, as in this patient who developed AKI in the setting of volume depletion from a gastrointestinal illness. At baseline, her dose of 300 mg thrice daily was already higher than recommended for a patient with stage 4 CKD (300 mg twice daily would have been more appropriate) and resulted in toxicity when her kidney function declined. Myoclonus is a typical symptom of gabapentin toxicity. Gabapentin is cleared by HD, which can be used for treatment.
Myoclonic jerks have been reported to occur with opioids, but the propensity for this side effect varies with the specific metabolism and activity of the parent compound and its metabolites. There are only rare reports of oxycodone causing myoclonus, and in some of these cases, other agents (such as methadone), were co-administered. Only a small fraction of oxycodone is excreted unchanged in the urine, but the half-life of this agent and its metabolites are prolonged when kidney function is severely reduced. Thus, while oxycodone may certainly contribute to the altered mental status observed in this case, it is not the best explanation for the myoclonus.
Myoclonus can be seen with uremia; however, this would be a diagnosis of exclusion after gabapentin toxicity was addressed.
Tramadol is also largely renally cleared; 30% is excreted unchanged. Labeling recommendations suggest that the dosing should be 50–100 mg daily, but some experts favor the lower end of this scale. Expected side effects include sedation and confusion but not myoclonus.
Salicylate toxicity is a multiphasic syndrome that is consistent with some features in this case, including nausea, altered mental status, and an acid-base disorder. However, this patient’s dose of 81 mg daily is too low to cause toxicity and there is no reason to suspect an intentional or accidental overdose. Salicylate toxicity that is sufficiently severe to cause altered mental status typically leads to an anion gap metabolic acidosis and a respiratory alkalosis. This patient has only a small anion gap and also has hyperphosphatemia, which may contribute to the anion gap. Measurement of the pH would be helpful to clarify the acid-base disorder, but because the anion gap is relatively small and the bicarbonate is only mildly decreased, it is unlikely that a severe acid-base disorder is present. Rare cases of falsely normal anion gap have been reported with salicylate toxicity. However, in these instances, the chloride was falsely elevated secondary to interference from high concentrations of salicylate, and the bicarbonate values were still low.
A 35-year-old Tanzanian man who moved to the United States one year ago is evaluated for nausea, fever, and flu-like symptoms approximately 2 weeks after starting therapy for suspected pulmonary tuberculosis. He had initially presented with a protracted cough, mild weight loss, and upper lobe consolidation on chest x-ray. Sputum was obtained for culture and an anti-tuberculous regimen consisting of isoniazid, rifampin, pyrazinamide, and ethambutol was initiated. Three days after starting these medications, he began to experience nausea, fever, and body aches. Examination at that time revealed a very thin man with low-grade fever, abnormal breath sounds in the lung apices and bilateral upper abdomen and flank tenderness. Laboratory investigation was notable only for a mild increase in liver aminotransferase levels. A viral syndrome was suspected, and he was advised to return in one week if symptoms did not improve.
His medical history is notable for prior treatment for tuberculosis more than 5 years ago, but additional details are not available. His only medications are his anti-tuberculous agents.
Examination is unchanged from 10 days ago; low-grade fever and bilateral abdominal and flank tenderness persist.
Laboratory data are as follows (attachment):
Urinalysis: specific gravity 1.014, 1+ protein, 1+ glucose; microscopy: 1–4 RBC/HPF and 1–4 WBC/HPF.
Which of the following is the BEST explanation for the patient’s AKI ?
Select one:
A. Renal tuberculosis
B. Isoniazid-related hepatic and kidney toxicity
C. Rifampin-related acute interstitial nephritis
D. Pyrazinamide-related urate nephropathy
E. Hepatorenal syndrome
The correct answer is: C
Rifampin-related acute interstitial nephritis
This patient with AKI most likely has rifampin-related acute interstitial nephritis.
Of the commonly prescribed anti-tuberculosis (anti-TB) agents, rifampin is the most likely to cause AKI. This is estimated to occur in <2% of patients. The pathogenesis of AKI from rifampin is likely from anti-rifampin antibodies, which may explain the observation that the syndrome develops rapidly after a second exposure. Patients tend to present with nausea, vomiting, abdominal pain, fever, and flu-like symptoms. Only a fraction of patients with a clinical diagnosis of AKI related to rifampin have had kidney biopsies. When kidney biopsy has been performed, the histopathologic findings reported include acute interstitial nephritis, acute tubular necrosis, or both. Although the AKI can be severe and dialysis may be needed, recovery is the rule, occurring in >90% of patients when the drug is discontinued. Abnormalities of aminotransferases, anemia, thrombocytopenia, and hemolysis are often observed.
Isoniazid (INH) and pyrazinamide (PZA) are the most frequent causes of hepatotoxicity among common anti-TB agents, and INH is usually implicated in the most severe cases. PZA is also associated with hyperuricemia and gout. Hyperuricemia is a well-recognized component of tumor lysis syndrome, and there is emerging concern that uric acid can contribute to AKI in other scenarios. In this case, the uric acid is not sufficiently elevated to likely have a direct role in causing AKI.
Hepatorenal syndrome is a form of AKI that occurs in the setting of advanced chronic liver disease with complications of cirrhosis including ascites or severe acute liver failure, neither of which is present in this case.
The genitourinary tract, including the kidneys, represent the most frequent site of extrapulmonary TB in many series. AKI is uncommon, but when it does occur, it is usually attributable to inflammation and obstruction of the urothelium. Pyuria and hematuria are often prominent. Although an ultrasound examination or alternative imaging of the kidneys and bladder would be reasonable, renal TB is not the most likely explanation for this patient’s clinical presentation.
A 48-year-old woman presents for evaluation of an abnormal ultrasound finding. A few weeks ago, she experienced abdominal pain and went to a local emergency department where an abdominal ultrasound was performed. Her pain subsequently resolved, but the ultrasound of the abdomen revealed an abnormality of both kidneys prompting referral.
One year ago, the diagnosis of primary hyperparathyroidism was established on the basis of an elevated PTH, persistently elevated serum calcium ranging from 10.3 to 10.9 mg/dL (reference range, 8.4–10.2), and 24-hour urinary calcium of 609 mg (reference range, <250). She was found to have a parathyroid adenoma. Additional investigations at that time included normal electrolyte levels, urinalysis findings, and chest x-ray.
Six months ago, she had a parathyroidectomy of the right inferior parathyroid gland resulting in normalization of her serum calcium and PTH levels.
On examination, she appears well, her BP is normal, and physical examination is unremarkable.
The sagittal view of the right kidney is shown below:
Which of the following options BEST explains the findings present on this ultrasound image?
Select one:
A. Polycystic kidney disease
B. Acquire kidney cysts
C. Nephrolithiasis
D. Nephrocalcinosis
E. Hydronephrosis
The correct answer is: D Nephrocalcinosis
The ultrasound image demonstrates a bright, hyperechoic medullary interstitium with acoustic shadowing characteristic of nephrocalcinosis. In this case, it is related to previous long-standing primary hyperparathyroidism.
Nephrocalcinosis is defined as the parenchymal deposition of either calcium oxalate or calcium phosphate in contradistinction to luminal deposition, which is referred to as nephrolithiasis. Both conditions can coexist because they share predisposing factors. In this case, several small, punctate examples of nephrolithiases are identified by ultrasound, in addition to the diffuse parenchymal calcification. The distribution of nephrocalcinosis is most often medullary. Cortical nephrocalcinosis is unusual and may develop from severe AKI such as cortical necrosis. Nephrolithiasis appears most often as a bright, echogenic focus with shadowing. Hydronephrosis would appear as echo-lucent dilatation of the collecting system. Both acquired kidney cysts and polycystic kidney disease would demonstrate variable numbers of round, echo-lucent cortical lesions. In this case, there is a fluid-filled echo-lucent structure but it is extra-renal in location.
There are many possible causes of nephrocalcinosis, but in this patient, who had primary hyperparathyroidism and documented hypercalciuria, there is no reason to invoke an alternative cause. The otherwise normal preoperative electrolyte levels and chest x-ray, coupled with the prompt normalization of her serum calcium and PTH postoperatively, clearly identify primary hyperparathyroidism as the underlying etiology.
Any inherited or acquired condition that results in hypercalciuria can provoke nephrocalcinosis. Patients with a classic distal renal tubular acidosis can develop nephrocalcinosis. The chronic systemic metabolic acidosis leads to buffering of acid by bone and release of calcium and phosphate, which can precipitate in the tubules. This is exacerbated by the fact that patients with distal renal tubular acidosis cannot maximally acidify the urine, so calcium phosphate precipitation is favored. Chronic sarcoidosis can lead to hypercalcemia and hypercalciuria with nephrocalcinosis.
Nephrocalcinosis may be clinically silent and discovered incidentally when abdominal imaging is performed for some other purpose. Although it may improve with time, it would not be expected to resolve within 1 month and may in fact persist indefinitely. Advanced nephrocalcinosis is visible on plain radiography, but CT and ultrasound are more sensitive imaging techniques. Nephrocalcinosis is typically asymptomatic unless it is associated with other conditions such as nephrolithiasis
A 53-year-old man developed ESRD from diabetic nephropathy and started in-center HD 4 years ago. He no longer makes urine. He is 180 cm tall and his target weight is 100 kg. He gains 3.5–5.5 L between treatments. He has a radial arteriovenous fistula that is working well. His current dialysis prescription is blood flow 400 mL/min, dialysate flow 600 mL/min, and a dialyzer with a mass transfer-area coefficient (KoA) of urea 1170 mL/min. During his last session, he dialyzed for 215 min, and his Kt/V was 1.14.
Which of the following would lead to the LARGEST increase in his single-pool Kt/V (spKt/V)?
Select one:
A. Increasing his dialyzer KoA from 1170 to 1480 mL/min
B. Increasing his dialysate flow rate from 600 to 800 mL/min
C. Decreasing his ultrafiltration volume from 4 to 3 L per session
D. Increasing his treatment time from 215 to 240 min
E. Increasing his blood flow rate from 400 to 500 mL/min
The correct answer is: D
Increasing his treatment time from 215 to 240 min
Increasing the dialysate flow, the blood flow, or the KoA of the dialyzer will all increase the clearance (K) during the treatment and therefore increase single-pool Kt/V (spKt/V). Increasing the treatment time will also increase the spKt/V. The relative effect of each change is shown in the table. The estimated spKt/V is calculated using a V of roughly 50 L from the Watson anthropometric equation.
Ultrafiltration (UF) will increase clearance because urea is removed through both diffusion and convection. Decreasing the UF goal will therefore decrease clearance (K) and decrease the spKt/V, but by a relatively modest amount. Increasing his target weight will also decrease his spKt/V, because the V will be larger. Note that all the treatment times needed to achieve an estimated spKt/V of 1.4 are longer than 4 hours, even with a very large KoA dialyzer. A treatment time extending beyond 4 hours would also be appropriate to keep the UF rate <10 mL/kg per hour, which is associated with less intradialytic hypotension and lower all-cause mortality.
A 60-year-old woman with locally invasive pancreatic cancer is evaluated for AKI. She was diagnosed with pancreatic cancer 9 months ago and underwent proximal pancreaticoduodenectomy with excision of 2 positive lymph nodes. Six months ago, she began a chemotherapy protocol that included cisplatin and gemcitabine every 28 days.
She was doing well until 2 weeks ago when she presented with a headache, and her BP was noted to be 190/110 mm Hg. She began taking amlodipine.
One week ago, she was admitted to the hospital with shortness of breath and edema. Her BP was 200/100 mm Hg, and she had evidence of volume overload. She was treated with diuretics and discharged. Laboratory test results from that admission revealed a creatinine level of 1.3 mg/dL, increased from a baseline of 0.7 mg/dL (reference range, 0.5–1.1).
At the time of nephrology consultation, she complained of fatigue. Her most recent chemotherapy treatment was 30 days ago. Her current medications are amlodipine 5 mg daily and furosemide 20 mg twice daily. Examination was significant for BP 160/90 mm Hg. She had pallor and mild tachycardia, but findings were otherwise unrevealing.
Laboratory data are as follows:
1 month ago Current result Reference range
Hemoglobin 10 g/dL 7 12–16
Platelets 230,000/µL 100,000 150,000–450,000
Creatinine 1.3 mg/dL 1.6 0.5–1.1
Lactate dehydrogenase (LDH) 484 U/L 80–225
Urinalysis shows 100 mg/dL of protein and 5–10 RBC/HPF.
A kidney biopsy yields 12 glomeruli, many with global endothelial cell swelling, and occasional microthrombi are seen within the capillary lumens. Two interlobular arteries show intraluminal obliteration by fibrin clot. The tubular interstitial compartment has mild acute tubular necrosis and interstitial fibrosis.
Image, silver stain x 400: CJASN 13(2): 300–317, 2018 (image attached)
Which is the most appropriate next step to address this patient’s AKI?
Select one:
A. Stop cisplatin
B. Start prednisone
C. Start heparin
D. Stop gemcitabine
E. Increase amlodipine
The correct answer is: D
Stop gemcitabine
The most appropriate next step for this patient with evidence of AKI due to a thrombotic microangiopathy (TMA) is to discontinue gemcitabine.
Gemcitabine is a nucleoside analog that has activity against pancreatic, breast, and lung cancer. This agent is one of several anti-neoplastic drugs that can cause a TMA. Mitomycin C and vascular endothelial growth factor inhibitors can also have this adverse effect.
This patient demonstrates the clinical features of gemcitabine-associated TMA (gTMA), which is seen in 0.4–5% of patients receiving this drug. It can occur at any time after exposure to gemcitabine, but most commonly presents after a median exposure time of 7 months or a cumulative dose of 20,000 mg/m2. Clinical symptoms can be insidious and slowly progressive. Patients will most commonly present with hypertension, edema, and AKI. Non-nephrotic proteinuria and hematuria are frequently present as well. Hematologic findings of TMA include anemia, thrombocytopenia, high LDH, and low haptoglobin. Diagnosis can be made by kidney biopsy or by peripheral smear if there are findings consistent with a TMA such as fragmented red blood cells and schistocytes. The mechanism of gTMA is not entirely clear but may be related to direct drug toxicity to endothelial cells. There is no standard treatment for gTMA. Recognition of the clinical entity and discontinuation of the drug is most important. If kidney dysfunction does not improve with discontinuation of the gemcitabine, then options include plasmapheresis, steroids, and eculizumab, which have been used with varying degrees of success.
Cisplatin is nephrotoxic but causes tubular toxicity, rather than TMA; discontinuation of this agent in the setting of AKI is important, but this would not address the TMA. Increasing amlodipine may improve BP slightly but would likewise would not address the underlying pathology. Anticoagulation, with heparin or other agents, does not appear to have a role in the treatment of this disorder.
A 76-year-old man receiving maintenance HD for longer than 1 year seeks advice regarding his advanced directive.
He has been admitted to the hospital to undergo revision of his arteriovenous fistula. Except for difficulties with his arteriovenous fistula, his course on dialysis has been uneventful. His medical history includes congestive heart failure. He is ambulatory within his home but uses a wheelchair when he goes out. He is currently living in his home with his wife but has previously required skilled nursing facility support when recuperating from an exacerbation of congestive heart failure. Although he is content with his current functional status, he is uncertain whether a return to a skilled nursing facility would be acceptable.
In the event of a cardiopulmonary arrest during this hospitalization, what is the MOST likely outcome for this patient?
Select one:
A. Prolonged hospitalization
B. Unsuccessful resuscitation
C. Discharge to a skilled nursing facility
D. Discharge to home
The correct answer is: B
Unsuccessful resuscitation
The most likely outcome of a cardiopulmonary arrest in this patient is unsuccessful resuscitation.
A recent study of outcomes for in-hospital cardiopulmonary resuscitation (CPR) found a significantly greater risk of mortality among patients with ESRD compared with those without, although the risk of death was extremely high in both patient populations. Almost 3/4 of all patients who underwent CPR experienced in-hospital mortality. In addition, patients with ESRD were less likely to be discharged home after in-hospital CPR than those without ESRD. This study, which examined the outcome of in-hospital CPR in more than 50,000 patients with ESRD compared with more than 300,000 patients without ESRD, also found greater length of stay (LOS) among patients with ESRD who survived (mean 12 days versus 7). Patients with ESRD were younger than those without ESRD but had more comorbid conditions. Note that, although the odds ratios for in-hospital mortality and nursing home discharge for ESRD-CPR patients were statistically significant at 1.24 and 1.13, respectively, the absolute differences in risk were small, as shown below.
The following table is adapted from the study:
It is important for nephrologists to have discussions with their patients regarding goals of care and advanced directives, and to counsel patients regarding the risk of adverse outcomes in patients who require CPR. Based on a desire to avoid future care in a skilled nursing facility, some patients may choose to avoid CPR in the event of a cardiopulmonary arrest; alternatively, some would choose to accept CPR and make a decision about nursing home care if/when the issue arises. It may also be useful to point out to dialysis patients that over 10% survive CPR and return to their home.
A 48-year-old man receiving maintenance HD complains of painful nodules in his left lower abdomen. He has been receiving dialysis for 8 years for ESRD due to diabetic nephropathy. He recently had osteomyelitis of his left great toe. Evaluation at that time included magnetic resonance imaging with gadolinium and a bone biopsy.
Medications include labetalol, cinacalcet, calcitriol, renal vitamin, insulin, and ciprofloxacin.
The patient is in visible discomfort. His BP is 170/95 mm Hg, heart rate 80/min, temperature 36.8°C, and body mass index 45 kg/m2.
Abdominal examination reveals 2 firm, exquisitely tender, subcutaneous plaques of approximately 8 cm diameter with an overlying violaceous hue.
The patient’s symptoms are managed with analgesics. One month later, one of the lesions ulcerates and forms a black eschar. A punch biopsy is performed at the margin of the lesion, which subsequently heals poorly. Histopathologic findings include calcification of dermal arterioles and surrounding fat necrosis.
Laboratory data include the following:
Result Reference Range
PTH 400 pg/mL 130–585 (dialysis patients only)
Calcium 9.5 mg/dL 8.6–10.2
Phosphorus 6 mg/dL 3–4.5
Albumin 3.2 g/dL 3.5–5.5
Which of the following is a RISK factor for the etiology of these abdominal lesions?
Select one:
A. Gadolinium
B. Cinacalcet
C. Male sex
D. Ciprofloxacin
E. Calcitriol
The correct answer is: E
Calcitriol
These abdominal lesions are caused by calciphylaxis, for which calcitriol has been identified as a risk factor.
Calciphylaxis is also known as calcific uremic arteriolopathy (CUA). This condition has been reported in 1% of patients with ESRD and rarely in patients with CKD or without kidney disease. The disease is characterized by extremely painful, violaceous plaques or nodules involving the skin and subcutaneous fat, which typically ulcerate and form eschars. There may be purpuric lesions that radiate from the areas of the nodules. Poor healing after biopsy is also a notorious feature. Historically, distal calcification of the toes and fingers leading to digital gangrene or acral involvement of the nose or penis was commonly observed. In recent years, it is more common to observe involvement of more central areas of adiposity including the abdomen, buttocks, breasts, and thighs.
Often the diagnosis can be established on clinical grounds. When performed, biopsies of the plaques show calcification (calcium deposition, usually composed of calcium and phosphorus) in the media and intima of small- and medium-sized blood vessels that lie within the subcutaneous fat and dermis. Inflammation of the surrounding fat (panniculitis) and fat necrosis can also be seen. The calcium deposition in small arteries and arterioles is often followed by intimal hyperplasia with endothelial fibrosis that can narrow the vessel lumen leading to ischemia in more severe lesions. Although the pathogenesis is not well understood, one potential cause may be the stimulation by uremic toxins of vascular smooth muscle cells causing differentiation into osteoblast-like (bone) cells that deposit bone matrix.
Because calciphylaxis is a rare disease, well-designed studies addressing risk factors and treatment are lacking. Factors associated with development of the lesions include obesity, female sex, long dialysis vintage, diabetes mellitus, insulin injections, hypercoagulable states (especially with warfarin use), autoimmune diseases, liver disease, and malignancy. Mineral metabolism disorders such as high levels of serum calcium, phosphate, and PTH have been implicated as well as an elevated calcium-phosphorus product, low serum albumin, and elevated alkaline phosphate levels. Medications associated with development of CUA include corticosteroids, warfarin, calcitriol, calcium-containing supplements and phosphate binders, and IV iron. CUA may be present without any of these laboratory abnormalities or risk factors.
Cinacalcet has not been implicated and is often used to reduce PTH levels and improve mineral metabolism. First generation gadolinium contrast agents, such as gadodiamide, were occasionally associated with nephrogenic systemic fibrosis (NSF), a skin condition characterized by thickened skin, brawny plaques, and pain. In this condition, there is fibrosis on skin biopsy but no arteriolar calcification. Newer formulations of gadolinium, such as gadoteric acid, appear to have minimal risk for inciting NSF. Ciprofloxacin and other antibiotics have not been implicated in CUA.
A 58-year-old man presents for evaluation of a 6-week history of fever, weight loss, abdominal pain, and rash. His medical history is significant for hypertension and hyperlipidemia. Current medications are lisinopril 20 mg daily and atorvastatin 20 mg daily.
Physical examination reveals BP 162/97 mm Hg, mild peripheral edema, and palpable purpura affecting the lower limbs.
Laboratory data include the following (attached):
Renal arteriogram demonstrates microaneurysms and segmental occlusion in small renal arteries.
Which ONE of the following is MOST appropriate initial treatment for this patient?
Select one:
A. Prednisone and cyclophosphamide
B. Prednisone and tenofovir
C. Prednisone and methotrexate
D. Prednisone and plasma exchange
E. Pulse methylprednisolone and prednisone taper
The correct answer is: A
Prednisone and cyclophosphamide
The preferred initial therapy for polyarteritis nodosa (PAN) is the combination of cyclophosphamide and corticosteroids.
PAN is a rare systemic vasculitis involving medium-sized arteries and results in aneurysms, stenosis, occlusion, and potentially rupture of the involved vessel and distal ischemia. The diagnosis is established by the clinical findings and characteristic imaging abnormalities. Arteriography is considered the gold standard for imaging, but CT and MRI may also be useful. Complement levels are typically normal and anti-neutrophil cytoplasmic antibody (ANCA) is usually negative (in contrast, ANCA testing is often positive in cases of small vessel vasculitis). PAN may be associated with hepatitis B or C infection or hairy cell leukemia and is considered secondary if these conditions are present. Most cases in the United States are primary and are seen in middle-aged or older adults with a slight male predominance. If PAN is associated with hepatitis B or C infection, antiviral therapy is indicated. In this case, there is no evidence of a viral hepatitis. Furthermore, tenofovir disoproxil fumarate is contraindicated in the presence of AKI or advanced CKD. Because it is potentially less nephrotoxic, tenofovir alafenamide could be considered for viral hepatitis associated PAN, but would still not be first-line treatment in the setting of AKI.
PAN may affect any organ; skin, kidney, and neurologic involvement are particularly common. Skin manifestations are diverse and may include painful nodules, purpura, bullae, vesicles, or livedo reticularis. Because of the “preglomerular” location of the kidney lesion, kidney involvement is manifested by hypertension and reduced filtration. The urine sediment may be surprisingly bland without nephritic or nephrotic features. Mononeuritis multiplex occurs in up to 70% of patients, affecting both motor and sensory nerves. Patients can also have central nervous system involvement, including stroke, hemorrhage, and seizures.
Untreated PAN is associated with a high mortality, with AKI and gastrointestinal, cardiac, and cerebrovascular complications being among the most common causes of death in these patients. Treatment with corticosteroids alone is satisfactory for a mild presentation with only skin involvement. The combination of cyclophosphamide and corticosteroid therapy is recommended for more severe presentations that include AKI and is associated with a higher rate of remission and improved survival. Relapse is relatively uncommon after remission, but maintenance therapy is often provided for up to 18 months.
Plasma exchange has been used in hepatitis B-associated cases but has not been shown to be effective for primary PAN. Azathioprine and methotrexate have both been used for maintenance of remission, but neither is preferred for induction therapy; in addition, methotrexate is contraindicated in AKI.
