NephMadness 2015: Infectious Disease and Nephrology Region

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This virulent bracket has it all: insidious latent viruses, CNS toxic antibiotics, nephrotoxic antibiotics and nephrotoxic viruses. Infectious Disease specialists have now adopted nephrology as their favorite cousin! With what other medical specialty can ID consultants be constantly challenged by spur of the moment changes in drug pharmacokinetics and pharmacodynamics due to alterations in GFR leading to the potential for numerous adverse drug reactions!! Yes, this bracket is not for the frail or weak of heart (kidney)! The winner of this bracket is going to be an odds on favorite to infect their way to the Final Four and even the Championship – it’s only a virion or MIC away!

Selection Committee member for the Infectious Disease and Nephrology Region:

Gupta, SamirSamir K. Gupta, MD

Dr. Gupta is an Associate Professor of Medicine in the Division of Infectious Diseases and Vice-Chair for Research in the Department of Medicine at the Indiana University School of Medicine. Dr. Gupta conducts research on HIV-related renal epidemiology and was the lead author of the inaugural Guidelines for the Management of Chronic Kidney Disease in HIV-Infected Patients.

Meet the Competitors for the Infectious Disease and Nephrology Region

Vancomycin Renal Toxicity
Piperacillin/Tazobactam Toxicity

Cefepime & Mental Status
Acyclovir & Mental Status


Transplant CMV
Transplant Polyoma BK

Vancomycin Renal Toxicity vs Piperacillin/Tazobactam Toxicity

This matchup pits the crafty veteran team of Vancomycin Renal Toxicity against an up-and-coming qualifier in the tournament: Piperacillin/Tazobactam Toxicity. You can never overlook a hungry Piperacillin/Tazobactam rookie team that has only recently been gaining momentum and recognition in the nephrotoxic league. However, what more can be said about Vancomycin Renal Toxicity that hasn’t already been fleshed out over the years. Pinpoint accuracy and relentless offense against the proximal tubule makes Vancomycin Renal Toxicity the odds-on favorite but reputation only goes so far – the game is played on the field and anything can happen when the filtering begins.

Vancomycin Renal Toxicity

Who would have thought that vancomycin would earn a reputation as among the elite of nephrotoxic antibiotics when it was first introduced in 1958. This team has been the savior for the treatment of MRSA and has enjoyed a solid reputation for efficiency and effectiveness among housestaff and practicing physicians. However this stellar reputation was not always the case and many physicians still remember the early days of “Mississippi Mud”, the nickname given to vancomycin due to its cloudy appearance in the intravenous solution. Vancomycin had a sordid reputation for nephrotoxicity and ototoxicity that restricted its early acceptance and use. It rivaled the Detroit Piston “Bad Boys” team of the 80s – lethally effective, often victorious, but tended to play rough and commit many personal fouls.

Improved purity of vancomycin preparations significantly reduced the risk of nephrotoxicity and it appeared that vancomycin had undergone an extreme makeover, with widespread popularity even among nephrologists. However, in spite of the newer formulations, the emergence of reduced vancomycin sensitivities and the targeting of higher trough levels by ASHP/IDSA/SIDP recommendations (15-20 mg/L) has now revealed a resurgence of drug-induced nephrotoxicity.

Targeting the mitochondria of the proximal tubule, vancomycin puts on a relentless full court press 24 hours a day resulting in oxidative injury and ATN. Working in concert with other risk factors such as preexisting renal disease, hypotension, critical care unit patients, obesity, and African American race, vancomycin nephrotoxicity is a serious cause of AKI that leads to prolongation of the  hospital admission and increased patient morbidity and mortality.

The only defense that has worked so far to prevent nephrotoxicity has been intensive pharmacy intervention  for therapeutic drug dosing and monitoring.

Vancomycin nephrotoxicity is a strong contender as a veteran team that should not be underestimated.

Piperacillin/Tazobactam Toxicity

This backcourt combination combines speed with excellent defensive skills. Formulated to neutralize the production of beta lactamase, the piperacillin/tazobactam combination has enjoyed an excellent reputation as a “go to” antibiotic for a variety of Gram-negative infections. Piperacillin/tazobactam has played around in the minor leagues of nephrotoxicity for many years but recently appears to be making a move to join the major leagues of antibiotic-associated nephrotoxicity.

Piperacillin/tazobactam has been associated with 3 forms of renal injury:

  1. increased risk of nephrotoxicity when co-administered with vancomycin
  2. an independent cause of direct ATN
  3. through the development of acute interstitial nephritis

Particular concerns about the renal toxicity of Piperacillin/tazobactam have been raised when administered in the elderly and in ICU patients where drug dosing can be extremely complex due to unpredictable volume shifts and changes in GFR.

In order to separate and distinguish themselves from the rest of the nephrotoxic antibiotics, Piperacillin/tazobactam in the ICU setting was associated with a higher rate and severity of AKI with a marked delay in recovery compared to the nephrotoxicity of other beta lactam antibiotics. This recently described slam dunk over other drugs in its class boosted Piperacillin/tazobactam as a worthy entry into the tournament.

Piperacillin/Tazobactam Toxicity is an emerging team with a clinical impact that is just now being increasingly recognized and appreciated.

Cefepime & Mental Status Changes vs Acyclovir & Mental Status Changes

This matchup pits 2 extremely well-balanced teams that wreak havoc on the differential diagnosis of acute mental status changes in critically ill patients. Sherlock Holmes said it best– “Eliminate all other factors, and the one which remains must be the truth”: each of these teams possess the ability to cause life-threatening neurotoxicity in the presence of acute or chronic kidney disease and force physicians to carefully and sequentially consider all possible alternative causes other than the actual antibiotics themselves. How deliriously devious, how encephalopathically elegant! You have to admire the simplicity of their game plan–pretend to be helpful and then a game-winning bank shot off the cerebrum. Only one neurotoxic agent can move on to the next round. Which one dominates the brain more effectively?

Cefepime & Mental Status Changes

Cefepime is a 4th generation bactericidal beta lactam cephalosporin whose pharmacokinetics make it an ideal team to induce CNS neurotoxicity. Confusion, hallucinations, agitation, coma, myoclonus, and seizures represent the hallmark of cefepime neurotoxicity and result from competitive antagonism of g-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the brain. In addition, NCSE (non convulsive status epilepticus) is a characteristic finding in cefepime neurotoxicity and its presence should raise a suspicion of cefepime-induced CNS injury. This disorder may prove to be fatal unless immediate drug discontinuation is initiated. This syndrome has been consistently underappreciated and overlooked as a cause of mental status changes in septic patients and this makes cefepime neurotoxicity a dangerous opponent.

Cefepime neurotoxicity however has an Achilles heel in that it is almost completely dependent on the presence of an acute or chronic decline in GFR. Freedom from protein binding and the lack of modification or degradation by the hepatic P450 system forces the unchanged parent compound cefepime to rely exclusively on renal clearance for systemic elimination. In the presence of a reduction in GFR, cefepime blood levels rapidly increase and with a 10% CNS/blood concentration gradient, exposure of the brain to these high serum levels leads to marked CNS irritability. Rarely has neurotoxicity been reported in the presence of normal renal function, limiting this team’s efforts to produce a consistent winning record as the vast majority of patients tolerate it without incident.

Prevention of cefepime neurotoxicity is focused on proper pharmacokinetic dosing using estimated GFR calculations. The pediatric population may be at significant risk due to the variability of these mathematical GFR estimates to accurately determine the GFR in this unique population. Finally, for critically ill ICU patients or comatose patients on cefepime the development of neurotoxicity may be difficult to assess and detailed EEG monitoring may be necessary or complete avoidance of cefepime in these conditions should be considered. As a last resort, hemodialysis can be an effective rescue therapy to remove cefepime in critically ill patients experiencing acute neurotoxicity.

Small and undersized but agile, cefepime neurotoxicity can sneak in a victory here and there but remains beatable by careful defensive drug dosing strategies.

Acyclovir & Mental Status Changes

Deception is often the key to victory and this is what makes acyclovir neurotoxicity a formidable opponent. Imagine the following scenario: first there is a herpetic infection localized or disseminated – this is followed by initiation of high-dose acyclovir therapy – suddenly the patient develops acute mental status changes – is it herpetic encephalitis requiring the infusion of higher acyclovir doses or is it acyclovir neurotoxicity and acyclovir must be immediately stopped? What a conundrum! Guess wrong and…

Acyclovir is a nucleoside analog that is primarily excreted unchanged (85%) in the urine based on GFR. Most scouting reports of this team fail to recognize the importance of the other 15% of acyclovir that undergoes metabolism by alcohol dehydrogenase to a bioactive product 9-carboxymethoxymethylguanine (CMMG) that is excreted by the kidney strictly through glomerular filtration. Surreptitiously, in patients with altered renal function or who are on dialysis, a greater percentage of acyclovir gets retained and is gradually converted to CMMG which then crosses the blood brain barrier leading to neurotoxicity.

The typical “run and gun” presentation of Acyclovir Neurotoxicity includes:

  • tremor/myoclonus (58%)
  • confusion ( 50%)
  • agitation (38%)
  • hallucinations (25%)
  • extrapyramidal symptoms (21%)
  • sedation (17%)

In comparison to cefepime neurotoxicity, which does not appear for 7-10 days after initiation of therapy, acyclovir neurotoxicity can lead to acute delirium within 24-48 hours of therapy particularly in patients with advanced renal failure.

The best defensive strategy to counter acute acyclovir neurotoxicity appears to be immediate cessation of drug administration and hemodialysis, which can remove approximately 45% of the drug and its CMMG metabolite in each session. Prevention is focused on proper drug dosing in the setting of any patient with a reduced GFR. However acyclovir neurotoxicity has still occurred even with proper drug dosing in patients on dialysis due to ongoing CMMG accumulation.

Acyclovir neurotoxicity has been in the headlines for over 20 years and shows no sign of slowing down. Its novel mechanism of toxicity and rapid onset distinguish it as a strong team in the ID region.


The battle of the acronyms!!! HIVAN (HIV-associated nephropathy) and HIVICK (HIV immune complex disease of the kidney) used to be perennial powerhouses garnering worldwide attention. Now they may be past their primes as HAART therapy has been relegating both of these teams back to the minor leagues.  However, with 35% of the world HIV population still untreated by HAART, both of these HIV-induced renal diseases still occasionally try to recapture their glory days of relentless glomerular injury and progressive fibrosis. Can either of them make one final run through the tournament or should they both default and retire so people will still remember them in their youthful glory years?


With a longer championship winning streak than UCLA and the Boston Celtics, HIVAN dominated the kidney from 1984 through 2005. HIVAN was always considered synonymous with HIV renal involvement but now accounts for less than 40% of the cases of renal disease found in HIV infected patients.

The offensive strategy of HIV was simple and direct – attack the podocyte, attack the podocyte, and then attack the podocyte again.  With no trick plays or complicated secondary use of immune complexes, HIV directly infected the podocyte forcing the transcription of its own 9-gene viral DNA and altering the entire phenotype of the visceral epithelial cell. The subsequent gene products lead to a dysregulation of the cell cycle and the development of the classic collapsing FSGS glomerular lesion that has become synonymous with the term HIVAN. As if to leave a calling card proclaiming who was responsible for this lesion, HIVAN patients expressed characteristic reticulo-tubular inclusion bodies, which have also been called interferon footprints within the renal tubules.

HIVAN does not have only a one dimensional podocyte-centric game – additional viral infection of the tubular cells results in microcystic dilation and a concomitant acute interstitial nephritis which further intensifies the renal dysfunction. However one important weakness of HIVAN lies in the fact that it almost always requires a genetic predisposition of the host in the form of Apolipoprotein L1 variants, particularly with homozygous expression of these mutations. This significantly limits the HIV population that will be susceptible to developing HIVAN.

This simple direct viral infection strategy puzzled ID experts for years as to how HIV was able to enter the podocytes and tubular cells in the absence of the required CD4 receptor. The answer appears to be through the use of passenger T cells that transfer the HIV virus through cell-cell contact from both the blood and urine compartments. HIVAN requires active HIV infection and until HAART became an effective regimen for eliminating viremia there was no consistent therapy for preventing or treating HIVAN.

For decades throughout the world, the presentation of an HIV patient with nephrotic syndrome, minimal hypertension, larger size kidneys on ultrasound, black race, and active HIV was virtually assured to be HIVAN with typical collapsing FSGS. However, as Bob Dylan sang, “the times they are a-changin” and in recent years HIVAN has been upstaged by both HIVICK, its opponent in the first round, as well as by classical FSGS. Moreover, HAART-related renal disease has also been dominating the discussions recently as it has significantly eliminated both HIVAN and HIVICK through sustained viral control and has even caused regression of these lesions after they have developed.

It looks like the twilight is setting on this remarkable team as a consequence of HAART. You have to give credit to HIVAN for such a consistent career and no matter what happens in this tournament, HIVAN is likely a certainty to be voted into the viral-mediated renal disease Hall of Fame.


Clearly the underdog and flying under the radar of most physicians in the differential diagnosis of renal dysfunction in an HIV patient, HIVICK in its own right has become a more common renal lesion than HIVAN in HAART-naïve HIV patients. This team utilizes a completely different offensive strategy that eliminates the need to directly infect the kidney one cell at a time as is the case in HIVAN.

HIVICK is an immune complex attack on the kidney that leads to a variety of histopathologic glomerular lesions: membranous, diffuse/membrano proliferative, IgA nephropathy. The unique aspect of these immune complexes is their composition involving specific HIV antigens as the source target of the antibody response. Therefore the development of HIVICK is completely dependent on the presence of active HIV viremia.

HIVICK boasts that its immune complexes produce more permanent injury than HIVAN whose podocyte dysregulation can actually regress after HAART. Unless diagnosed early when reversal is still feasible, after initiating HAART and resolution of viremia, the resorption of the HIVICK lesions leaves glomerular “holes” that never completely heal over.

In addition, HIVICK has a much broader population base in which to produce nephrotoxic immune complexes. The Apolipoprotein L1 genetic variants do not appear to be as important as they are for increasing the risk of HIVICK as opposed to their major influence for HIVAN. Most HIVICK cases actually occur in heterozygotes or in patients with both wild-type genes.

Interestingly, HIVICK has recently bypassed HIVAN in frequency in HAART-naïve HIV patients for reasons that are not entirely clear. But similar to HIVAN, HIVICK is still decreasing overall in frequency with the widespread use of HAART.

Overall, scouting reports state that HIVICK is not as unique in its pathogenesis as HIVAN since the immune complex approach is also used by other viruses like HCV and HBV.  HIVAN also remains the only renal lesion definitively caused by viral genomic infection of the podocyte.

Regardless, HIVICK is still a serious team that must be at the top of the differential diagnosis of glomerular disease in a HAART-naïve HIV patient.

Transplant CMV vs Transplant Polyoma BK

For decades, CMV and the herpes group family ruled post-transplant infections the way the Godfather and the Corleone family ruled the lower east side of New York. It was a tradition and requirement that all transplant centers pay homage and respect to CMV otherwise there would be a terrible price to be paid by the allograft and the patient. But now there is a rival family in town – The Polyomas – specifically, BK infection, that is threatening to upstage and usurp the authority of CMV in transplant patients through its own unique pathologic behavior. This is going to be a “Clash of the Titans” in the first round and in this tournament when the dust settles there is room for only one main virus to move on.

Transplant CMV

CMV has been called the Michael Jordan of the Post Transplant Infection League because it has been awarded the MVV trophy (Most Valuable Virus) for more than 25 consecutive years. This team is versatile and challenging because it can play an up tempo game almost from start to finish or it can slow down the pace and then just when the opponent has been lulled into a sense of complacency, surge at the end and put on a systemic offensive display that is lethally effective to the both allograft and patient outcomes. With 75% of the US population already harboring CMV from adolescence, the most common clinical manifestation post transplant has been re-activation from dormant latency. The use of T cell-depleting induction therapy, purine inhibition, and corticosteroid therapy have all been implicated in resulting in excessive immunosuppression and a resurgence of hibernating CMV often weeks to months after the transplant.

Alternatively, CMV can be directly acquired from the donor tissue if the recipient is CMV naïve. This primary CMV infection can be clinically far more severe than the cases of CMV reactivation, with a greater propensity to cause multiorgan involvement (liver, pulmonary, GI). In both cases CMV can directly infect the allograft and can be recognized by classic intracytoplasmic inclusions within the renal tubular cells and even may result in glomerular disease such as collapsing FSGS.

As if this massive systemic attack wasn’t enough, transplant CMV makes sure there is no chance for allograft recovery by increasing the risk of rejection through upregulation of interferon production, leading to an induction of allograft HLA antigen expression. Game over!

CMV has had no true rivals for years and easily should be a guaranteed Final Four candidate except for the recent development of the ganciclovir defense. Indeed, CMV finally appears to have met its match. The prophylactic use of ganciclovir and its superior derivative valgancyclovir by all allograft recipients has virtually eliminated CMV infections in the early post transplant period from a peak incidence of 20-60% down to its current level of <5% . In addition, coming off the bench of every transplant center if needed is IVIG, which can pull out a last-minute victory against CMV if valgancyclovir is not enough. Other than the occasional case where CMV has erupted due to inappropriate valganciclovir dosing, CMV resistance has not been a major clinical issue and most transplant centers have called their CMV prevention strategies now employed  “Mission Accomplished!”

Transplant CMV appears ready for retirement and the time may be ripe for a new MVV in the post transplant infection league. But never count out a champion ready for one last run at the title.

Transplant Polyoma BK

There is a new family moving into the transplant neighborhood called the Polyomas, BK and JC. With JC concentrating more on the CNS league, specializing in PML (polymorphonuclear leukoencephalopathy), BK has concentrated exclusively on winning the nephrotoxicity title. Similar to CMV, the majority of transplant recipients and donors have already been exposed to BK in adolescence and it remains in hibernation within the uroepithelium until a critical state of immune-incompetence is established after transplantation. While CMV may be in the twilight of its career and now occurs in <5% of solid organ recipients, BK is a team on the rise and complicates 7-10% of renal transplant patients.

Although one dimensional in its game plan approach of direct uroepithelial cell infection, who can criticize a team that has mastered the perfect three point shot at the weakest link of the allograft: the tubules. Over and over again scattered throughout the proximal and distal tubules, BK reactivates in the allograft, but this time instead of merely causing rejection as CMV does, BK leads to interstitial nephritis, allograft dysfunction and then directly to increased apoptotic cell death!! Further infection of the uroepithelium continues the damage by leading to ureteral strictures and obstructive uropathy. Finally, BK has become the second most common cause of hemorrhagic cystitis after adenovirus in transplant patients. The triple BK threat: tubules, ureter, and bladder!

As if to taunt its opponents, BK sheds virally infected transitional cells into the urine as “decoy cells” and forms intranuclear inclusions that can be easily detected by biopsy using the SV40 stain. You have to be impressed by a virus whose stain is named after a primate (SV = simian virus). Detected by blood PCR, BK is not difficult to find yet even though the opponents know what is coming, stopping BK nephropathy has proven to be exceptionally difficult.

A variety of offensive and defensive strategies have been employed over the years with variable levels of success including a reduction of immunosuppression, addition of ciprofloxacin, IVIG infusions, discontinuation of mycophenolate and switching to pyrimidine inhibition with Leflunamide.

Transplant BK is the team no one wants to have on their schedule. It leads to an insidious progressive decline of allograft function the prevention of which has stymied most transplant centers. No one has yet been able to clearly dominate this team and with newer and more potent immunosuppressive agents being constantly employed, transplant BK unfortunately has a promising future ahead. Do not underestimate this new family.

– Post written and edited by Drs. Warren Kupin and Samir Gupta.


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