It may be possible for patients with renal insufficiency, including those with end-stage kidney disease (ESKD), to undergo MRI using potentially safer preparations of gadolinium-based contrast agents (GBCAs) with “very low, if any” risk of the feared nephrogenic systemic sclerosis (NSF). 1
In contrast to the so called “linear” chelates of gadolinium (eg, gadodiamide, gadopentetate), “cyclic” GBCA’s (eg, gadoteridol) have not been clearly associated with NSF. 2 A Veterans Administration study involving gadoteridol identified no cases of NSF among the 141 patients on hemodialysis following 198 exposures. 2 In fact, the 2017 American College of Radiology (ACR) Manual on Contrast Media reports the risk of NSF with cyclic chelates as “very low, if any”. 1 Even when a cyclic GBCA is used in patients with ESKD, however, hemodialysis is recommended as soon as possible after MRI. 3
GBCAs are chelates with 2 major components: gadolinium and either a linear or cyclic ligand. Cyclic ligands bind to gadolinium more avidly, resulting in lower probability of circulating renally-cleared free gadolinium which when deposited in tissue is thought to potentially trigger NSF.2
Although NSF is characterized by progressive fibrosis of skin and soft tissue, it may involve multiple organs with an estimated 30% mortality rate. 4
Bonus Pearl: Did you know NSF is really a new disease, with no evidence of its existence before 1997?
- “Nephrogenic Systemic Fibrosis”. In ACR Manual on Contrast Media; Version 10.3; May 31, 2017. https://www.acr.org/-/media/ACR/Files/Clinical-Resources/Contrast_Media.pdf
- Reilly RF. Risk for nephrogenic systemic fibrosis with gadoteridol (ProHance) in patients who are on long-term hemodialysis. Clin J Am Soc Nephrol 2008;3:747-51. https://www.ncbi.nlm.nih.gov/pubmed/18287249
- Wang Y, Alkasab TK, Nari O, et al. Incidence of nephrogenic systemic fibrosis after adoption of restrictive gadolinium-based contrast agent guidelines. Radiology 2011;260:105-111. https://www.ncbi.nlm.nih.gov/pubmed/21586680
- Schlaudecker JD, Bernheisel CR. Gadolinium-associated nephrogenic systemic fibrosis. Am Fam Physician 2009;80:711-14. https://www.aafp.org/afp/2009/1001/p711.pdf
Contributed by Richard Newcomb, MD, Mass General Hospital, Boston, MA.
Depends on how high the serum levels are! Although the clearance of both amylase and lipase appears to be impaired in patients with significant renal insufficiency (eg, creatinine clearance <50ml/min), serum levels greater than 2-4 times the upper limits of normal for these enzymes are still considered suggestive of pancreatitis in these patients1-3.
Interestingly, in hemodialysis patients, elevation of lipase may also be due to the lipolytic effect of heparin during this procedure. That’s why obtaining serum lipase levels before, not after, hemodialysis has been recommended4
Also fascinating is that most of the elevation of serum amylase in patients with significant renal insufficiency appears to be related to the elevation of salivary, not pancreatic, isoenzyme of amylase4.
Final fun fact: Did you know that at one time the diagnosis of pancreatitis was based on the activity of serum on starch (for amylase) and olive oil (for lipase)? 5
- Levitt MD, Rapoport M, Cooperband SR. The renal clearance of amylase in renal insufficiency, acute pancreatitis, and macroamylasemia. Ann Intern Med 1969;71:920-25. http://annals.org/aim/article/683643/renal-clearance-amylase-renal-insufficiency-acute-pancreatitis-macroamylasemia
- Collen MJ, Ansher AF, Chapman AB, et al. Serum amylase in patients with renal insufficiency and renal failure. Am J Gastroenterol 1990;85:1377-80. https://www.ncbi.nlm.nih.gov/pubmed/1699413
- Royce VL, Jensen DM, Corwin HL. Pancreatic enzymes in chronic renal failure. Arch Intern Med 1987;147:537-39. https://www.ncbi.nlm.nih.gov/pubmed/2435254
- Vaziri ND, Change D, Malekpour A, et al. Pancreatic enzymes in patients with end-stage renal disease maintained on hemodialysis. Am J Gastroenterol 1988;83:410-12. https://www.ncbi.nlm.nih.gov/pubmed/2450453
- Editorial. Pancreatic enzymes. N Engl J Med 1963;268:901-2. http://www.nejm.org/doi/pdf/10.1056/NEJM196304182681613
Not as strong as one might expect with an increasing number of investigators questioning the causative role of IV contrast in precipitating CIN.
A 2013 meta-analysis involving observational—mostly retrospective— studies concluded that the risks of AKI, death, and dialysis were similar between IV contrast and non-contrast patients, including those with diabetes or underlying renal insufficiency1.
Two retrospective studies2,3 designed to control for a variety of factors that may affect the risk of AKI by propensity matching found divergent results with the larger and better designed study finding no significant difference in AKI between the 2 groups3. A 2017 retrospective cohort analysis of emergency department patients utilizing a similar propensity-score analysis also failed to find a difference in post-CT AKI between those receiving and not receiving IV contrast4.
Further shedding doubt on the role of IV contrast in causing AKI, a study involving patients with chronic kidney disease found no difference in the rates of excretion of 2 biomarkers of AKI (neutrophil gelatinase-associated lipocalin-NGAL, and kidney injury molecule-1-KIM-1) between patients with and without presumed CIN5. Some have even criticized experimental animal studies supporting the existence of CIN due to their poor applicability to human renal disease1.
This is not to say that IV CIN does not exist. Rather, we should keep an open mind about the pathophysiology and epidemiology of CIN. Stay tuned!
Fun pearl: Did you know that the first case of CIN was described in a patient with multiple myeloma undergoing IV pyelography (before the CT era)?
- McDonald JS, McDonald RJ, Comin J, et al. Frequency of acute kidney injury following intravenous contrast medium administration: a systematic review and meta-analysis. Radiology. 2013;267(1):119-128. https://www.ncbi.nlm.nih.gov/pubmed/23319662
- Davenport MS, Khalatbari S, Dillman JR, et al. Contrast material-induced nephrotoxicity and intravenous low-osmolality iodinated contrast material. Radiology. 2013;267(1):94-105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606541/pdf/121394.pdf
- McDonald RJ, McDonald JS, Bida JP, et al. Intravenous contrast material-induced nephropathy: causal or coincident phenomenon? Radiology 2013;267:106-18. https://www.ncbi.nlm.nih.gov/pubmed/23360742
- Hinson JS, Ehmann MR, Fine DM, et al. Risk of acute kidney injury after intravenous contrast media administration. Ann Emerg Med 2017; 69:577-586. https://www.ncbi.nlm.nih.gov/pubmed/28131489
- Kooiman J, van de Peppel WR, Sijpkens YWJ, et al. No increase in kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion following intravenous contrast enhanced-CT. Eur Radio 2015;25:1926-34. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457910/pdf/330_2015_Article_3624.pdf
Contributed by Ginger Jiang, Medical Student, Harvard Medical School
There is no firm evidence either for or against the use of systemic anticoagulants (ACs) in patients with asymptomatic pulmonary embolism (PE) following hemodialysis vascular access declotting (HVAD).
However, despite the common occurrence of asymptomatic PE following HVAD procedures (~40%), symptomatic PE—at times fatal—has also been reported in these patients1,2.
In the absence of hard data and any contraindications, anticoagulation can be justified in our patient for the following reasons:
- Asymptomatic segmental PE is commonly treated as symptomatic PE irrespective of setting2,3
- Hemodialysis patients are often considered hypercoagulable due to a variety of factors eg, platelet activation due to extracorporeal circulation, anti-cardiolipin antibody, lupus anticoagulant, decreased protein C or S activity, and/or reduced anti-thrombin III activity4-7
- Overall, chronic dialysis patients have higher incidence of PE compared to the general population8
- There is no evidence that asymptomatic PE following HVAD has a more benign course compared to that in other settings
- Untreated PE may be associated with repeated latent thrombosis or progression of thrombosis in the pulmonary artery5
- Calderon K, Jhaveri KD, Mossey R. Pulmonary embolism following thrombolysis of dialysis access: Is anticoagulation really necessary? Semin Dial 2010:23:522-25. https://www.ncbi.nlm.nih.gov/pubmed/21039878
- Sadjadi SA, Sharif-Hassanabadi M. Fatal pulmonary embolism after hemodialysis vascular access declotting. Am J Case Rep 2014;15:172-75. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004792/pdf/amjcaserep-15-172.pdf
- Chiu V, O’Connell C. Management of the incidental pulmonary embolism. AJR 2017;208:485-88. http://www.ajronline.org/doi/pdf/10.2214/AJR.16.17201
- Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: Chest guideline and expert panel report. CHEST 2016;149:315-52. http://journal.chestnet.org/article/S0012-3692(15)00335-9/fulltext
- Yamasaki K, Haruyama N, Taniguchi M, et al. Subacute pulmonary embolism in a hemodialysis patient, successfully treated with surgical thrombectomy. CEN Case Rep 2016;5:74-77 https://link.springer.com/article/10.1007/s13730-015-0195-9
- Nampoory MR, Das KC, Johny KV, et al. Hypercoagulability, a serious problem in patients with ESRD on maintenance hemodialysis, and its correction after kidney transplantation. Am J Kidney Dis 2003;42:797-805. https://www.ncbi.nlm.nih.gov/pubmed/14520631
- O’Shea SI, Lawson JH, Reddan D, et al. Hypercoagulable states and antithrombotic strategies in recurrent vascular access site thrombosis. J Vasc Surg 2003;38: 541-48. http://www.jvascsurg.org/article/S0741-5214(03)00321-5/pdf
- Tveit DP, Hypolite IO, Hshieh P, et al. Chronic dialysis patients have high risk for pulmonary embolism. Am J Kidney Dis 2002;39:1011-17. https://www.ncbi.nlm.nih.gov/pubmed/11979344
Nephrotoxicity associated with piperacillin-tazobactam (PT) combined with vancomycin (V) has been increasingly reported1,2, with some recommending that an alternative to V be used when PT is also on board 2. However, there are several reasons why the nephrotoxic potential of PT either alone or with antibiotics other than V also deserves further study before such recommendations can be widely embraced3.
First, most studies of VPT combination do not include comparative V or PT alone arms making it difficult to assess the relative contribution of these 2 antibiotics to kidney injury when used in combination. A small study that did include a PT-only arm reported a similar rate of acute kidney injury (AKI) in PT and VPT arms ( 15.4% and 18.8% , respectively), both significantly higher that than of V-only group (4%).4
Other reasons not to readily dismiss PT as a cause of nephrototoxicity include the lack of association between higher V trough levels and AKI in patients receiving VPT2, the association of PT with lower rates of renal function recovery in critically ill patients when compared to other selected β-lactams5, and higher magnesium and potassium renal tubular loss with the use of PT compared to selected cephalosporins and ciprofloxacin6. As with other penicillins, PT-associated acute interstitial nephritis may also occur7-8.
In short, even in the absence of V, nephrotoxic potential of PT should not be automatically dismissed.
Disclosure: Ref 3 was also authored by the creator of this pearl.
- Hammond DA, Smith MN, Chenghui Li, et al. Systematic review and meta-analysis of acute kidney injury associated with concomitant vancomycin and piperacillin/tazobactam. Clin Infect Dis 2017;64:666-74.
- Navalkele B, Pogue JM, Karino S, et al. Risk of acute kidney injury in patients on concomitant vancomycin and piperacillin-tazobactam compared to those on vancomycin and cefepime. Clin Infect Dis 2017;64:116-123.
- Manian FA. Should we revisit the nephrotoxic potential of piperacillin-tazobactam as well? Clin Infect Dis 2017; https://doi.org/10.1093/cid/cix321
- Kim T, Kandiah S, Patel M, et al. Risk factors for kidney injury during vancomycin and piperacillin/tazobactam administration, including increased odds of injury with combination therapy. BMC Res Notes 2015;8:579.
- Jensen J-U S, Hein L, Lundgren B, et al. Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomized trial. BMJ Open 2012;2:e000635. http://bmjopen.bmj.com/content/2/2/e000635
- Polderman KH, Girbes ARJ. Piperacillin-induced magnesium and potassium loss in intensive care unit patients. Intensive Care Med 2002;28:530-522.
- Muriithi AK, Leung N, Valeri AM, et al. Clinical characteristics, causes and outcomes of acute interstitial nephritis in the elderly. Kidney International 2015;87:458-464.
- Soto J, Bosch JM, Alsar Ortiz MJ, et al. Piperacillin-induced acute interstitial nephritis. Nephron 1993;65:154-155.
Cryoglobulins (CGs) are immunoglobulins that precipitate in the blood under cold conditions (<37◦ C) and redissolve upon warming1. The term “cryoglobulinemia” is commonly used to describe patients with a systemic inflammatory syndrome that is often associated with small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. Although some patients with cryoglobulinemia may be asymptomatic, most present with a range of diseases characterized by fatigue, arthralgia, skin rashes or necrosis, purpura, neuropathy, bowel wall ischemia and/or glomerulonephritis and kidney failure.
Wintrobe and Buell are credited for first describing cryglobulinemia in 1933 when assessing a patient who ultimately was found to have multiple myeloma2. Since then the spectrum of diseases associated with CG has expanded to also include seemingly disparate conditions such as hepatitis C, autoimmune disorders and monoclonal gammopathy of undetermined significance (MGUS). A commonly cited classification scheme for CG is shown (Table)3. It should be emphasized that some CGs may not fit neatly into this scheme.
In our patient, the positive CG serum test should be interpreted in the clinical context in which it was obtained while searching for risk factors as well as signs and symptoms that may be associated with cryoglobulinemia.
Table. Classification of cryoglobulinemia
||Isolated monoclonal immunoglobulin, either IgM or IgG (less commonly IgA or free immunoglobulin light chains
||Multiple myeloma, Waldenström’s macroglobulinemia, monoclonal gammopathy of undetermined significance (MGUS)
||Mixture of monoclonal IgM and polyclonal IgG
||Hepatitis C, HIV, other viral infections
||Polyclonal mixture IgM and IgG
||Autoimmune disorders, hepatitis C
- Takada S, Shimizu T, Hadano Y, et al. Cryoglobulinemia (review). Mol Med Rep 2012;6:3-8
- Wintrobe MM, Buell MV. Hyperproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp 52: 156-165, 1933
- Brouet JC, Clauvel JP, Danon F, et al. Biological and clinical significance of cryoglobulins. Am J Med 1974; 57:775-88.
Contributed by Kirstin Scott, Medical Student, Harvard Medical School
Polyuria is considered a classic symptom of hypercalcemia and was one of the symptoms described in the first published case of hyperparathyroidism (1). Several potential mechanisms may explain this phenomenon.
The calcium sensing receptors (CaSRs) found in the kidney play a major role in volume status due to their expression in the thick ascending loop (TAL) of Henle and the collecting duct. Interestingly, hypercalcemia activates the CaSR in the medullary portion of TAL, causing inhibition of the same cotransporter (Na-K-2Cl) inhibited by furosemide and other loop diuretics (2-4)! Hypercalcemia also inhibits vasopressin action ( therefore urine concentration) by activating CaSR in the collecting duct (5). Lastly, inhibition of Na+-K+ ATPase in the proximal convoluted tubule may further contribute to natriuresis and subsequent polyuria.
Thus, hypercalcemia may lead to polyuria by interfering with the absorption of sodium as well as inhibiting the action of vasopressin. One can’t help but compare its effect to that of a patient with diabetes insipidus taking a loop diuretic! No wonder these patient may suffer from polyuria!
- Goldfarb S, Agus ZS. Mechanism of the polyuria of hypercalcemia. Am J Nephrol. 1984;4:69-76.
- Quamme GA. Effect of hypercalcemia on renal tubular handling of calcium and magnesium. Can J Physiol Pharmacol. 1982;60:1275-80.
- Peterson LN. Vitamin D-induced chronic hypercalcemia inhibits thick ascending limb NaCl reabsorption in vivo. Am J Physiol. 1990;259:122-9.
- Riccardi D, Brown EM. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol. 2010;298:485-99.
- Toka HR, Pollak MR, Houillier P. Calcium sensing in the renal tubule. Physiology (Bethesda). 2015;30:317-26.
Contributed by Michael Hughes, Medical Student, Harvard Medical School