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  • Brian Rifkin MD & Vidhya Gunasekaran MD

Evolution of Vancomycin-Associated Nephrotoxicity

Internal Medicine PGY-2

Merit Health Wesley Medical Center


Department of Nephrology

Hattiesburg Clinic


Illustrations & infographics by: Corina Teodosiu, MD & Brian Rifkin, MD


AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.



Introduction

Vancomycin is a glycopeptide antibiotic that has been extensively utilized to treat severe bacterial infections for more than 60 years. Vancomycin was isolated in 1957 from a fungus, Streptomyces orientalis, found in the soil of Borneo. The name Vancomycin was originally derived from the word “vanquish”. Its clinical application as an antibacterial agent, however, was hampered by the development of allergic reactions (red-man syndrome), bone marrow suppression, vestibular and renal toxicity. Even though modern, more purified compounds are considered safer, the incidence of vancomycin-associated nephrotoxicity (VAN) remains high in some studies. It remains uncertain to what extent vancomycin is directly responsible for kidney injury, as numerous factors co-exists during bacteremia and sepsis (endotoxins, hypotension, capillary leak syndrome, etc) that may also cause kidney injury. Over time, there has been a growing interest in understanding the mechanisms and risk factors associated with VAN and discovering ways to mitigate side-effects. VAN can be severe, ultimately restricting the clinical use of this essential antibiotic, and unfortunately leading to significant patient harm.


Clinical Presentation

The onset of VAN can vary widely, with symptoms typically occurring a few days to several weeks after initiation of therapy. Patients may present with nonspecific symptoms such as fever, chills, nausea, vomiting, and fatigue. These symptoms can be challenging to attribute to vancomycin since they are common in patients with infectious diseases as well. Monitoring of serum creatinine levels is important during vancomycin therapy to detect early signs of nephrotoxicity. Some patients, especially those with critical illness, may not experience full renal function recovery even after medication discontinuation. VAN is associated with prolonged hospitalization, increased hospital readmission rates, and patient mortality. Other signs of VAN include proteinuria (typically non-nephrotic range), hematuria, and leukocyturia, signaling possible renal inflammation. Repeat exposure to vancomycin may also contribute to the development of chronic kidney disease from recurrent AKI.


Risk Factors

Vancomycin is a bacteriostatic antibiotic commonly used in combination with other medications to treat severe gram positive bacterial infections including methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin has been plagued with concerns about nephrotoxicity since its approval in 1958. Initial preparations were termed “Mississippi mud” and had significant impurities considered to be the major contributor to adverse events. Through improved purification processes, current preparations contain ∼90–95% vancomycin B (the active moiety), but nephrotoxicity persists.


First, there remains conflicting evidence as to the direct nephrotoxicity of vancomycin in various clinic settings. Several randomized clinical trials have found that vancomycin was associated with a higher AKI risk than other antibiotics. A meta-analysis of 4033 patients in 2016 by Ray et al found that vancomycin administration led to a 2.5-fold increased AKI risk versus non-glycopeptide antibiotics. A subsequent cohort study in 2020 by Gaggl et al found no increased nephrotoxicity with vancomycin with an adjusted hazard ratio for vancomycin versus all other comparators of 0.74 (95% CI 0.45-1.21), although the authors admit residual confounding might remain. VAN may represent a “multi-hit” model and the confounding variables of a complex clinical scenario may contribute to the development of AKI.


Next, the incidence of VAN reporting varies widely, ranging from 5% to 50% and is also influenced by the presence of risk factors. Various studies have identified a higher incidence of VAN associated with prolonged exposure to the medication. In fact, therapy durations ≥7 days increased the odds ratio of VAN by 4-12% for each additional day of therapy. Next, infectious disease experts often recommend a trough level of 15-20 mcg/mL, particularly for complicated infections including pneumonia, endocarditis, osteomyelitis and bacteremia. It has been noted that trough dosing may lead to higher incidences of AKI versus calculations for Area Under the Curve (AUC) guided dosing. AUC is somewhat cumbersome to calculate in clinical context, and thus trough levels are frequently used as a surrogate. However, studies utilizing AUC formula dosing have shown a lower incidence of nephrotoxicity. It has also been noted that vancomycin troughs tend to rise, due to incorrect dosing or declining creatinine clearance, after 1 week of treatment. Longer, more intense dosing might be a cause for the ongoing higher incidence of VAN despite better compounding.


In addition to drug dosing and duration, clinical factors including advanced age, pre-existing chronic kidney disease, hypotension, and severe illness may increase a patient’s risk of nephrotoxicity. Obesity may also be a risk factor for VAN due to supratherapeutic exposure from dose calculations based upon actual weight versus ideal weight. Individual patient genetics may also influence the risk of vancomycin-associated nephrotoxicity. Polymorphisms in the genes encoding drug transporters and metabolizing enzymes may influence the pharmacokinetics of vancomycin, increasing the risk of nephrotoxicity.


Risk factors for vancomycin-associated nephrotoxicity
Risk factors for vancomycin-associated nephrotoxicity

Finally, the uncertain incidence of VAN is likely driven by inconsistent study definitions of what constitutes nephrotoxicity. It is crucial to note that VAN criteria can vary among studies and may include increases in serum creatinine, decreases in urine output, or the need for renal replacement therapy. Also, some patients may experience transient changes in renal function that do not meet the criteria for nephrotoxicity, but may still require monitoring and adjustment of vancomycin dosing. Lastly, not all patients who receive vancomycin will develop nephrotoxicity, and the presence of risk factors does not necessarily mean that vancomycin should be avoided. The decision to use vancomycin should be based on a careful assessment of the potential benefits and risks, taking into account the individual patient's clinical situation and the available alternatives.


Mechanism of Nephrotoxicity

The exact mechanisms underlying VAN are not fully understood, but several causes have been proposed. When patients with VAN are biopsied, the most common findings are acute tubular necrosis (ATN) followed by acute interstitial nephritis (AIN). One proposed mechanism of vancomycin nephrotoxicity is direct tubular toxicity. Vancomycin has been shown to directly damage proximal renal tubular cells, leading to cell death and impaired renal function. The mechanism of direct toxicity is thought to involve mitochondrial dysfunction, oxidative stress, and disruption of intracellular calcium homeostasis. Another proposed mechanism of vancomycin-associated nephrotoxicity is intracellular accumulation of vancomycin. Vancomycin is a large and highly charged molecule that does not readily penetrate cell membranes. However, once inside renal tubular cells, vancomycin can accumulate in the lysosomes and interfere with normal lysosomal function. Lysosomes laden with vancomycin may rupture, leading to apoptosis and cell death.


A recent study analyzed the relationship between vancomycin-associated tubular casts (VATC) and VAN. The study found that the incidence of VATCs in people on vancomycin therapy was 15%, while the incidence of vancomycin-associated nephrotoxicity was slightly higher at 24%. The presence of VATCs was associated with a higher risk of vancomycin-associated nephrotoxicity, and patients with VATCs had a longer length of hospital stay and a higher mortality rate. The study also found that the risk of VATCs increased with higher cumulative vancomycin doses and longer duration of vancomycin therapy, both previously recognized risk factors for VAN. Biopsy monitoring for VATCs could be a useful tool for identifying patients at risk for VAN, and adjusting their treatment dosing accordingly.



visual abstract vancomycin-associated tubular casts and vancomycin nephrotoxicity
vancomycin-associated tubular casts and vancomycin nephrotoxicity

Visual abstract by @CTeodosiu


Immune-mediated mechanisms have also been proposed as a potential mechanism of VAN. Vancomycin can cause immune-mediated nephrotoxicity through hypersensitivity reactions such as interstitial nephritis and glomerulonephritis. These reactions are thought to be mediated by drug-specific T cells and antibodies that activate inflammatory pathways in the kidney. Finally, hemodynamic effects have been proposed as a potential mechanism of vancomycin-associated nephrotoxicity. Vancomycin can cause changes in renal blood flow and glomerular filtration rate, which may contribute to nephrotoxicity. Vancomycin-induced vasoconstriction and altered renal autoregulation can reduce renal perfusion and lead to ischemic injury.


Proposed mechanisms of vancomycin-associated nephrotoxicity
Proposed mechanisms of vancomycin-associated nephrotoxicity

In short, the exact mechanisms underlying vancomycin-associated nephrotoxicity are not fully understood, but multiple unique processes have been proposed and may be additive. Direct tubular toxicity, intracellular accumulation of vancomycin, immune-mediated mechanisms, and hemodynamic effects may contribute to the development of nephrotoxicity in patients receiving vancomycin. Further research is needed to fully elucidate the mechanisms underlying vancomycin-associated nephrotoxicity and to develop better preventive strategies.


Management

One, seemingly obvious but critical aspect of managing VAN, is regular monitoring of kidney function. This involves measuring serum creatinine and urine output to identify early signs of kidney damage. It is important to recognize that nephrotoxicity typically occurs 5-7 days after vancomycin initiation. Dosage adjustment is also a key component of managing VAN. Inappropriate dosing can lead to accumulation of the drug in the kidneys. Adjusting the dose, based on changes in renal function during therapy and trough or AUC calculations, can decrease the risk of VAN. Adequate hydration is also essential to prevent nephrotoxicity by maintaining adequate renal perfusion and enhancing drug clearance. Finally, in severe cases of nephrotoxicity, or if the patient has other risk factors for kidney damage, vancomycin may need to be discontinued and an alternative antibiotic considered.


If VAN is severe, renal replacement therapy may be necessary. The primary route of vancomycin elimination is via kidney excretion of the unchanged drug. Rates of elimination are directly related to creatinine clearance. Vancomycin itself is dialyzable, and 20-55% of serum vancomycin is removed by a single session of hemodialysis with a modern high-flux hemodialysis. If continuation of vancomycin therapy is necessary after initiation of hemodialysis in patients with AKI, vancomycin is generally dosed after dialysis sessions, while trough levels are typically drawn prior to dialysis sessions. In addition, peritoneal dialysis may remove as much as 10-20% of serum vancomycin. Trough levels in peritoneal dialysis patients should be drawn 48-72 hours after an IV dose, with redosing to maintain trough levels 15-20 mcg/ml at varying intervals. Vancomycin may also be given intraperitoneally, which is preferable in bacterial peritonitis cases. Vancomycin has a long half-life of 100-200 hours in patients with ESKD or dialysis dependent AKI, and thus may be dosed thrice weekly following dialysis or less frequently if trough levels remain high.


Prevention

In addition to routine therapeutic drug monitoring, using alternative antibiotics to vancomycin has been suggested, especially in patients with pre-existing renal impairment. Linezolid and daptomycin are two alternative antibiotics that have been studied as potential replacements for vancomycin. A meta-analysis of vancomycin versus linezolid by Kato et al was completed in 2021. Seven randomized control trials were identified with more than 1200 patients. Although linezolid was more successful in resolving MRSA pneumonia, there was no significant difference in adverse events including nephrotoxicity (OR 1.72, CI 0.8-3.45). Despite some trials reporting increased AKI with vancomycin, newer antimicrobials have not consistently shown decreased acute kidney injury risk.


Avoiding the use of other medications in conjunction with vancomycin, such as aminoglycosides, vasopressors, loop diuretics, NSAIDs, or contrast agents can help reduce the risk of nephrotoxicity. It is interesting to note that around 2011 there was an increasing number of case reports of nephrotoxicity associated with the combination of vancomycin and piperacillin-tazobactam. Several studies of the last few years attempted to delineate the cause of this associated azotemia. First, it is important to note that anywhere from 10 to 40% of excreted creatinine is cleared by proximal tubule secretion, in addition to the amount filtered by the glomerulus. Velez et al in 2018 showed that vancomycin suppresses the expression of organic anion transporters (OAT1 and OAT3) inhibiting proximal tubular secretion of creatinine, causing serum creatinine levels to rise irrespective of changes in glomerular filtration. Additionally, piperacillin-tazobactam is a substrate for OAT1 and OAT3, competitively decreasing tubular secretion of creatinine, and causing “pseudo-toxicity” due to rising serum creatinine levels without tubular damage. Discontinuation of vancomycin and piperacillin-tazobactam often leads to a rapid decline in serum creatinine levels. Finally, it is known that cystatin C is a useful marker of glomerular filtration that is not secreted by proximal renal tubular cells, but is exclusively filtered by the glomerulus. In an elegant study in 2022 by Miano et al, they showed that while there was a rise in serum creatinine on day 2 of combined vancomycin and pipercillin-tazobactam therapy, there was no change in cystatin C levels, confirming the pseudo-toxicity theory of decreased renal creatinine secretion without underlying kidney injury or loss of glomerular filtration.


prevention strategies for vancomycin-associated nephrotoxicity
prevention strategies for vancomycin-associated nephrotoxicity

Conclusion

In conclusion, vancomycin-associated nephrotoxicity is a common and potentially serious complication of vancomycin therapy. VAN may present several days to weeks into therapy in critically ill patients with multiple risk factors for AKI. Risks for VAN include intravascular volume depletion, incorrect dosing, length of treatment, and genetic polymorphisms that may influence vancomycin metabolism. VAN mechanisms may include direct tubular toxicity, lysosome disruption, tubular cast formation, immune mediated cell death and hemodynamic changes. VAN is a well-known adverse effect of vancomycin therapy, of variable incidence and definition. Careful monitoring of renal function and vancomycin levels with appropriate dose adjustment can help to reduce the risk of nephrotoxicity in high-risk patients. A better understanding of the epidemiology, risk factors, mechanisms, clinical presentation, management, and prevention of this condition is critical to optimize the use of vancomycin and minimize the risk of nephrotoxicity in patients.


AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.


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