Should I be concerned about piperacillin-tazobactam nephrotoxicity in the absence of vancomycin?

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.

References

  1. 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.
  2. 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.
  3. Manian FA. Should we revisit the nephrotoxic potential of piperacillin-tazobactam as well? Clin Infect Dis 2017; https://doi.org/10.1093/cid/cix321
  4. 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.
  5. 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
  6. Polderman KH, Girbes ARJ. Piperacillin-induced magnesium and potassium loss in intensive care unit patients. Intensive Care Med 2002;28:530-522.
  7. 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.
  8. Soto J, Bosch JM, Alsar Ortiz MJ, et al. Piperacillin-induced acute interstitial nephritis. Nephron 1993;65:154-155. 
Should I be concerned about piperacillin-tazobactam nephrotoxicity in the absence of vancomycin?

How should I interpret a positive result for serum cryoglobulins?

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

Category Description Examples
Type I 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)
Type II Mixture of monoclonal IgM and polyclonal IgG Hepatitis C, HIV, other viral infections
Type III Polyclonal mixture IgM and IgG Autoimmune disorders, hepatitis C

References

  1. Takada S, Shimizu T, Hadano Y, et al. Cryoglobulinemia (review). Mol Med Rep 2012;6:3-8
  2. Wintrobe MM, Buell MV. Hyperproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp 52: 156-165, 1933
  3. 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

How should I interpret a positive result for serum cryoglobulins?

My patient with hypercalcemia complains of polyuria. What is the mechanism of hypercalcemia-associated polyuria?

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!

 

REFERENCES

  1. Goldfarb S, Agus ZS. Mechanism of the polyuria of hypercalcemia. Am J Nephrol. 1984;4:69-76.
  2. Quamme GA. Effect of hypercalcemia on renal tubular handling of calcium and magnesium. Can J Physiol Pharmacol. 1982;60:1275-80.
  3. Peterson LN. Vitamin D-induced chronic hypercalcemia inhibits thick ascending limb NaCl reabsorption in vivo. Am J Physiol. 1990;259:122-9.
  4. Riccardi D, Brown EM. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol. 2010;298:485-99.
  5. 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

 

My patient with hypercalcemia complains of polyuria. What is the mechanism of hypercalcemia-associated polyuria?

The serum creatinine of my patient originally admitted for management of tense ascites is slowly rising. How concerned should I be?

Although the causes of increasing serum creatinine (SCr) in patients with cirrhosis are legion (eg, sepsis, acute tubular injury, and intravascular volume depletion due to over-diuresis, gastrointestinal bleed, or other causes), the most feared cause is often hepatorenal syndrome (HRS). HRS is a functional renal impairment that reflects the final pathophysiological stages of systemic circulatory impairment1, and significantly contributes to a worsening prognosis in patients with cirrhosis2. For example, without treatment, in patients whose SCr doubles in less than 2 weeks (type I HRS) the median survival is less than 2 weeks , while in those who develop a more gradual renal impairment (type II HRS) the median survival is 6 months3.

Physiologically, HRS is a culmination of significant vasodilation in the splanchnic arteries which, in time, leads to reduced organ perfusion due to a drop in the cardiac output. The associated increase in the activity of the renin-angiotensin-aldosterone and the sympathetic nervous systems contributes to sodium and water retention, and further exacerbates intra-renal vasoconstriction and ascites3.

The primary goal in the medical management of HRS is to increase splanchnic vascular resistance4, often by administering a combination of IV albumin, octreotide and other vasoconstricting agents (eg, midodrine, norepinephrine, or terlipressin [unavailable in US and Canada]).  Of interest, in addition to expanding the circulating plasma volume, albumin may have a vasoconstricting effect by binding to endotoxins, nitric oxide, bilirubin and fatty acids4!

 

References

  1. Arroyo V, Fernandez J, Gines P. Pathogenesis and treatment of hepatorenal syndrome. Semin Liver Dis 2008;28:81-95.
  2. Salerno F, Gerbes A, Ginès P, et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007 Sep;56(9):1310-8.
  3. Cardenas A, Gines P. A Patient with cirrhosis and increasing creatinine Level: What Is It and what to do? Clin Gatroenterol Hepatol 2009;7:1287–1291. 
  4. Baraldi O, Valentini C, Donati G, et al. Hepatorenal syndrome: Update on diagnosis and treatment. World J Nephrol. 2015;4:511-20.

Contributed by Alireza Sameie, Medical Student, Harvard Medical School

The serum creatinine of my patient originally admitted for management of tense ascites is slowly rising. How concerned should I be?

When should I consider bicarbonate (BC) replacement in my patient with renal insufficiency?

Metabolic acidosis is one of the earliest complications of chronic kidney disease (CKD), with a direct correlation between the decline in glomerular filtration rate (GFR) and reduction in serum BC1.

Epidemiologic studies in patients with CKD have reported an independent association between serum BC (<22 meq/L considered low) and adverse renal outcomes and mortality1. Limited data from small interventional trials of alkali therapy supplementation and dietary interventions (eg, increased fruit and vegetable intake) have shown the benefits of raising serum BC. Specifically, 1 study involving patients with CKD stages 4 and 5 and another involving CKD stage 2 hypertensive nephropathy reported slower decline in creatinine clearance/eGFR in patients receiving BC replacement2,3.  

Less is known on the potential benefit of BC replacement in patients with acute kidney injury with a recent Cochrane review finding no randomized controlled trials4 and national guidelines not recommending either for or against its use in this setting5. Of note, BC therapy has also been associated with sodium and fluid overload, an increase in lactate and PCO2, and a decrease in serum ionized calcium6.

References

  1. Dobre M, Rahman M, Hostetter TH. Current status of bicarbonate in CKD. J Am Soc Nephrol 2015;26:515-523.
  2. de Brito-Ashurst I, Varagunam M, Raftery MJ, et al. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol 2009; 20: 2075–2084.
  3. Mahajan A, Simoni J, Sheather SJ, et al. Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy. Kidney Int 2010;78: 303–309.
  4. Hewitt J, Uniacke M, Hansi NK, et al. Sodium bicarbonate supplements for treating acute kidney injury. Cochrane Database of Systematic Reviews 2012; Jun 13; (6):CD009204. doi: 10.1002/14651858.
  5. Palevsky PM, Liu KD, Brophy PD, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis 2013;61:649-72.
  6. Sabatini S, Kurtzman NA. Bicarbonate therapy in severe metabolic acidosis. J Am Soc Nephrol 2009;20:692-695.

 

Contributed in part by Cynthia Cooper, MD, Mass General Hospital, Boston, MA.

When should I consider bicarbonate (BC) replacement in my patient with renal insufficiency?

Is the combination of piperacillin-tazobactam and vancomycin (PT-V) nephrotoxic?

Despite its widespread use for over 20 years, PT-V has only recently been linked to higher risk of AKI when compared to vancomycin+/- other β-lactams, particularly cefepime1,2.  A 2016 meta-analysis of 14 observational studies reported an AKI incidence ranging from 11%-48.8% for PT-V (used for ≥48 h in most studies), with an adjusted O.R. of 3.11 (95% C.I. 1.77-5.47) when compared to other vancomycin treatment groups1.  Of note, nephrotoxicity associated with PT-V appears to occur earlier than the comparative groups (median 3 days vs 5 days of therapy, respectively), with the highest daily incidence observed on days 4 and 52.

Although the exact mechanism(s) of nephrotoxicity in patients receiving PT-V is unknown, both piperacillin and vancomycin have been implicated in acute renal tubular dysfunction/necrosis and acute interstitial nephritis3-5.

Collectively, these findings are only a reminder to be more judicious in the selection and duration of treatment of even “safe” antibiotics.

 

References

  1. 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 2016 ciw811.doi:10.1093cid/ciw811.
  2. Navalkele B, Pogue JM, Karino S, et al. Risk of acute kidney injury in patients on concomitant vancomycin an dpiperacillin-tazobactam compared to those on vancomycin and cefepime. Clin Infect Dis 2017;64:116-123.
  3. Hayashi T, Watanabe Y, Kumano K, et al. Pharmacokinetic studies on the concomitant administration of piperacillin and cefazolin, and piperacillin and cefoperazone in rabbits. J Antibiotics 1986; 34:699-712.
  4. Polderman KH, Girbes ARJ. Piperacillin-induced magnesium and potassium loss in intensive care unit patients. Intensive Care Med 2002;28:530-522.
  5. Htike NL, Santoro J, Gilbert B, et al. Biopsy-proven vancomycin-associated interstitial nephritis and acute tubular necrosis. Clin Exp Nephrol 2012;16:320-324.
Is the combination of piperacillin-tazobactam and vancomycin (PT-V) nephrotoxic?

What are the potential pitfalls in reliance on serum creatinine levels or urine output in sepsis-associated acute kidney injury (SA-AKI)?

Although serum creatinine and urine output are usually easily measured, several limitations in their interpretation in patients suspected of having sepsis and AKI are worth emphasizing1.

First, there is an inherent lag of hours between a drop in glomerular filtration rate (GFR) and a rise in serum creatinine concentration. Second, in critically ill hypotensive patients with sepsis receiving aggressive fluid resuscitation, hemodilution may mask serum creatinine rise and delay the diagnosis of AKI by a day. Third, sepsis itself may reduce muscular production of creatinine, even in the absence of weight loss, as demonstrated in animal studies2.  Fourth, patients receiving diuretics may fail to meet criteria for AKI diagnosis based on reduced urine output alone because of increased urine output.  

Lastly, as renal function deteriorates, the half-life of serum creatinine increases from several hours to several days3, prolonging the time needed to achieve a new steady-state that may be more reflective of the concurrent GFR.

 References

  1. Godlin M, Murray P, Mehta. Clinical approach to the patient with AKI and sepsis. Semin Nephrol 2015;35:12-22.
  2. Doi K, Yuen PST, Eisner C, et al. Reduced production of creatinine limits its use as marker of kidney injury in sepsis. J Am Soc Nephrol 2009;20:1217-21.
  3. Chiou WL, Hsu FH. Pharmacokinetics of creatinine in man and its implications in the monitoring of renal function and in dosage regimen modifications in patients with renal insufficiency. J Clin Pharmacol. 1975; 15(5-6):427-34.
What are the potential pitfalls in reliance on serum creatinine levels or urine output in sepsis-associated acute kidney injury (SA-AKI)?