#226 Kidney Boy on Acute Kidney Injury: Myths & Musings

July 20, 2020 | By Cyrus Askin

AKI Tips and Tricks from Joel Topf MD, Kashlak’s Chief of Nephrology

Get a grip on acute kidney injury (AKI) with Dr. Joel Topf (AKA @kidney_boy), Kashlak’s Chief of Nephrology! We’ve put together an AKI highlight reel – focusing on practical tips and tricks to help you identify, diagnose and manage AKI, plus how to recognize AIN and random myths and musings on vancomycin, NSAIDS, contrast nephropathy, and the risk of NSF from gadolinium.

Listeners can claim Free CE credit through VCU Health at http://curbsiders.vcuhealth.org/ (CME goes live at 0900 ET on the episode’s release date).

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Credits

Written (including CME questions) and Produced by: Cyrus Askin, MD

Infographic by: Cyrus Askin, MD

Cover Art: Kate Grant MBChb, MRCGP

Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP   

Editor: Matthew Watto MD, FACP (written materials); Clair Morgan of nodderly.com

Guest: Joel Topf, MD

Sponsor

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Time Stamps

• 00:00 Sponsors – VCU Health CE and Pediatrics On Call podcast by APP
• 00:30 Intro, disclaimer, guest bio
• 03:00 Guest one-liner, Picks of the Week*: Zoe Keating albums (Cellist); Mrs. America (TV series) on FX; The Last of Us (Videogame);
• 08:45 Sponsor – Pediatrics On Call podcast by APP
• 09:15 Definition of acute kidney injury (AKI) and fundamentals
• 11:00 Cardiorenal syndrome
• 12:24 Schema for AKI
• 17:30 Establish an etiology, determine urine output and address electrolyte abnormalities
• 21:22 AKI in the otherwise-healthy patient;
• 32:20 Rhabdomyolysis
38:21 Vancomycin
• 41:43 Acute interstitial nephritis (AIN)
• 44:52 Contrast induced nephropathy (CIN)
• 50:37 Gadolinium in AKI and/or CKD
• 52:53 Timing of dialysis 

• 56:37 AKI in the out-patient setting and how to handle home meds e.g. TMP-SMX, RAAS inhibitors;
• 62:01 Is Ultrasound necessary in AKI

• 64:58 Dr. Topf’s take home points and Plug for Seminars in Nephrology
• 68:45 Outro and Sponsor – VCU Health CE

Acute Kidney Injury (AKI) Pearls

1. The KDIGO definition of AKI is helpful for research… not so helpful from a clinical/practical standpoint
2. sCr is a somewhat flawed / lagging indicator of renal function, keep an eye out for electrolyte disturbances and oliguria / anuria
3. The majority of AKI can be fixed by “a bag of LR & a Foley Catheter”… tincture of time may be all that’s necessary in many other cases
4. History is king: ask about NSAIDs, cocaine for rhabdo, antibiotics for sepsis/AIN, PPI for AIN, diarrhea, vomiting, ACEi, hypotension, new diuretics.
5. Urine electrolytes and urine eosinophils are often unhelpful, may lead to more confusion than anything else
6. A good chart biopsy can be very helpful in AKI: identify nephrotoxins and avoid them 
7. Acute interstitial nephritis (AIN) is a diagnosis of exclusion with biopsy generally reserved for cases where steroids are being considered
8. Don’t fear contrast in AKI! There is no signal in the literature suggesting that contrast causes AKI
9. Save the renal ultrasound for part two of your AKI work up – consider an in-and-out catheterization and bladder scan if obstruction is on the differential

Acute Kidney Injury (AKI) In-Depth Show Notes 

AKI Fundamentals: 

According to Dr. Topf, the definition of AKI is a sudden drop in GFR. As of 2012, KDIGO (Kidney Disease: Improving Global Outcomes)  has published their definition of AKI with specific serum creatinine (sCr) cut offs. Dr. Topf feels these are useful for studies but not terribly helpful clinically:

• Stage 1: 

• • 1.5–1.9 x baseline OR 

• • ≥0.3mg/dl increase OR 

• • Urine output (UOP) <0.5 ml/kg/hr x 6-12 hrs

• Stage 2: 

• • 2.0-2.9 x baseline OR  

• • UOP <0.5 ml/kg/hr for ≥ 12 hrs

• Stage 3: 

• • 3x baseline OR 

• • increase in serum creatinine to ≥ 4.0mg/dl OR 

• • initiation of (renal replacement therapy) RRT OR

• • in patients < 18 years old, eGFR < 35ml/min /1.73 m2  OR

• • UOP <0.3 ml/kg/hr for ≥ 12 hrs OR

• • anuria for ≥ 12 hrs

•  
• Dr. Topf underlines the importance of UOP – often overlooked in favor of  sCr. He uses the example of a patient being aggressively resuscitated who does not have an appreciable elevation in sCr but does have anuria or oliguria. Resuscitation can “dilute” the sCr.
  • This is not seen in volume-overloaded heart failure patients suffering from cardiorenal syndrome – this condition is almost always associated with a rise in sCr.

Buckets of AKI

• Dr. Topf encourages folks to think of AKI in terms of pre-renal, intra-renal and post-renal etiologies:

Pre-renal

Pre-Renal: Inadequate renal perfusion due to volume deficiency (vomiting, diarrhea, decreased PO intake, bleeding, non-hemorrhagic shock) or heart-failure (volume overload with venous congestion resulting in poor renal perfusion)

Intra-renal

Intra-Renal: Acute Tubular Necrosis – the most common,  acute interstitial nephritis / drug toxicities (vancomycin, aminoglycosides, etc.), glomerulonephritis, vasculitis (Makras & Spanou, 2016)

• See the Clinical Problem Solver’s schema and discussion of intrinsic renal failure here

Post-renal

Post-Renal: Malignancy (ex: cervical cancer in women, prostate cancer in men), BPH, a kidney stone in a solitary kidney or retroperitoneal fibrosis

Key Insight for managing AKI

Somewhere between 70 & 90% of AKI is pre-renal or post-renal in etiology, meaning that fluid resuscitation and removal of the obstruction (i.e. a Foley) will resolve 70-90% of AKI! (Dr. Topf & Kaufman et al, 1991)

For intrinsic AKI, which is generally ATN, Dr. Topf says the treatment is also straight forward:

• Time
• Avoid nephrotoxins
• Avoid hypotension
• More time

AKI workup

Dr. Topf’s initial approach to a pathologic elevation in sCr – it doesn’t end with a high creatinine!

• Is the patient non-oliguric, oliguric or anuric? 
• Was this patient hypotensive?
• Does this patient have severe heart failure and possible cardiorenal syndrome?
• Was this patient on NSAIDs? Vancomycin? Other potential culprits?
• Does the patient have significant electrolyte derangements? 
• Do they have a significant acid-base derangement?

To FeNa or not to FeNa: Depends on what you are looking for, may lead to discordant information

• Ex: AKI associated with rhabdomyolysis is a cause of intrarenal AKI presenting with a low FeNa while most other intrinsic renal diseases should present with an elevated FeNa. (Corwin et al., 1984)

If you suspect the patient’s AKI is unlikely due to intrinsic renal disease – it is much faster to give fluid / assess for obstruction than to get urine electrolytes and other studies that take time and could lead to confounding results

Hyaline casts?

• Dr Topf: Can be seen in dry patients (urinalysis with high specific gravity, acidic urine) but generally, you’ll have assessed the patient and determined they are dry before looking at their urine for casts

AKI in the Previously Healthy Patient: 

Significant exercise history? Consider rhabdomyolysis. (Chavez et al. & Cabral et al.)

• Step 1: talk to the patient – See if their history is consistent with rhabdomyolysis
• The cornerstone of treating rhabdomyolysis is fluid resuscitation to increase renal perfusion – Dr. Topf recommends ~200cc/hr of LR
• Urine dipstick will be POSITIVE for blood, microscopy shows NO BLOOD – this is due to release of heme containing myoglobin from muscle tissue and the dipstick detecting free heme

How do you know if you are done treating?

• There isn’t much guidance on this. 
• Dr. Topf recommends looking for a downtrending sCr and CPK – if the patient is responsible, otherwise healthy, and able to continue oral hydration, this type of patient should be safe for discharge and outpatient follow up
• “If they don’t develop AKI early, they won’t develop it late.” – Dr. Topf’s expert opinion
  • A patient with evidence of rhabdomyolysis without AKI, who is otherwise healthy/stable and able to reliably hydrate at home, can likely be safely discharged without need for observation or admission

Volume Status

Heat? Exercise? Poor PO-intake? Consider volume depletion and pre-renal azotemia.

• • Dr. Topf recommends that, in an otherwise healthy patient who we suspect has pre-renal azotemia, it’s reasonable to give them 3-4 liters of fluid and recheck a sCr
  • The sCr should show a true improvement, assuming the patient has appropriate urine output (i.e. the volume should not dilute their sCr but instead truly improve renal perfusion)

• Volume status exam: One of the most challenging things in medicine, but important! (van der Mullen et al.)

• Dr. Topf recommends we favor “over-resuscitation” as young patients are at low-risk of suffering from clinically significant volume-overload, but the likelihood that they respond well to volume is high
  • Particularly important to remember in cases of rhabdomyolysis, as discussed above

NSAIDs? Consider NSAID-associated AKI.

• Talk to the patient!
• NSAIDs block prostaglandins. During volume depletion, prostaglandins help ensure adequate renal blood flow. NSAIDs, thus, can reduce the ability of the kidneys to maintain adequate perfusion during times of volume depletion, resulting in AKI. (Faubel & Topf, 1999; Imig, 2002; Zhang, 2017)
• Treatment: volume resuscitation, hold NSAIDs, hold other nephrotoxins

Younger patients? Obstruction is generally low on the differential.

• Dr. Topf tells us that these patients do, occasionally need RRT, however, they generally have an excellent prognosis if they don’t have prior kidney disease and/or have few-or-no medical comorbidities

AKI  In the Critically Ill: 

In Dr. Topf’s experience, 9/10 of these patients are suffering from acute tubular necrosis (ATN)

• These patients are almost always adequately resuscitated (unlikely to be pre-renal azotemia)
• Obstruction is unlikely – almost all these patients have foley catheters
• Bloody intubation? Think about ANCA vasculitis and pulmonary-renal syndrome
• Did patient recent vancomycin? And pip-tazo?
• Could this be AIN?

Vancomycin and Pip-tazo

• Don’t make the patient sicker – some evidence suggests the common combination of piperacillin-tazobactam and vancomycin may lead to an increased incidence of AKI in critically ill patients, however, it is admittedly difficult to determine whether this is association or true causation (luther et al., 2018) (Hammond et al., 2017) (Avedissian et al., 2020) –see below for more

• Dr. Topf  explains that there is not a significant signal in the literature for piperacillin-tazobactam, itself, leading to AKI
• Vancomycin, historically, was plagued by nephrotoxic impurities – this is no longer an issue, perhaps explaining why some studies show a 0% incidence of AKI in patients given vancomycin monotherapy (Filippone et al.)
• Vigilant monitoring of vancomycin levels can also help reduce AKI, however, this is confounded as well (Filippone et al.)
• Dr. Topf mentioned there are some cases where patients on vancomycin have had renal biopsies, showing evidence of vancomycin casts, acute interstitial nephritis and damage to proximal tubular cells
• Neither drug is as nephrotoxic as aminoglycosides or amphotericin (conventional more so than liposomal) (Wargo & Edwards) (Aguierre & Hamid)

Acute Interstitial Nephritis (AIN)

• A very difficult diagnosis – so many other usual suspects normally at play (vancomycin, pressors, contrast, etc.)
• AIN should be considered a diagnosis of exclusion, in many cases
• Urine eosinophils? In some cases, more common in ATN than AIN, certainly no utility in differentiating between different forms of intrinsic kidney injury (Lusica et al.) (Muriithi et al.)
• Takeaways: (Moledina & Perazella)(Fernandez-Juarez et al.)
  • White blood cells (pyuria) and red blood cells are reliably found in AIN, per Dr. Topf
  • PPIs, certain antibiotics and NSAIDs are common causes
  • AKI + Fever + Rash (classic triad) comes from beta-lactam literature
  • Treatment: remove offending agent, consider getting a biopsy, consider using steroids

What about Contrast induced nephropathy

• Dr. Topf: controlled (but not randomized) trials consistently show no signal for contrast causing AKI… there is a cost to not give contrast in these patients (i.e. suboptimal imaging)
  • “If you think you need contrast to save (a) patient’s life… give them contrast.”
  • See prior Curbsiders episode for review of literature: #69 CKD Prescribing Do’s and Don’ts

What about gadolinium?

• Doesn’t cause AKI, but historically, not given to patients with CKD due to risk of nephrogenic systemic fibrosis (NSF) 
• A 2019 JAMA review and meta-analysis of 4,931 patients found zero cases of NSF in patients with CKD 4 or 5, suggesting that the harms of withholding gadolinium-based contrast agents are likely greater than this minimal risk of NSF (Woolen et al.)

Who needs Renal Replacement Therapy?

• Does it make sense to start RRT earlier in a patient’s course? Well, the AKIKI trial would suggest that there is no benefit to this strategy, and you may save resources by going with a delayed approach to RRT. (Gaudry et al.)
• Based on this data, Dr. Topf does not recommend early dialysis – instead, he will look for dangerous electrolyte abnormalities or volume overload to prompt initiation of RRT
• Update! – the START-AKI trial just published in NEJM also found no mortality benefit with early dialysis.

AKI  In the Outpatient Setting:

Trimethoprim-Sulfamethoxazole & AKI

• • Dr. Topf recommends listening to The Curious Clinician’s episode on this!
  • Trimethoprim blocks secretion of creatinine in the proximal tubule, resulting in a rise in the sCr

• Can cause classic AKI via (Fraser et al & Dr. Topf)

• • AIN
  • Crystalization in the tubules leading to and obstructive pattern
  • Can act like a potassium-sparing diuretic leading to hyperkalemia 
  • If concerned for AIN, get a UA, look for pyuria / hematuria

ACE-Is and ARBs – when do you stop them?

• Dr. Topf recommends not stopping them routinely for mild AKI but certainly recommends cessation of these drugs in a patient with a steadily rising AKI when the etiology is unclear

Renal/Bladder Ultrasound

• Discussed on Episode #109 Things We Do For No Reason and #145 Hepatorenal Syndrome vs AKI
• A 2010 JAMA study suggests that the cost of renal ultrasound, and prevalence of obstruction make routine use inadvisable (Licurse et al)
• Dr. Topf: “A low yield test,” use the renal ultrasound as part of your “second line” work up and instead, take a good history, consider a bladder scan and/or an in-and-out catheterization as a more cost-conscious means to evaluate for obstruction

Dr. Topf’s Take-Home Points:

• We all learn about “neat” little AKI buckets – in reality, often times patients suffer from a combination of causes leading to their AKI
• Urine electrolytes are overused in AKI – they are unreliable in many cases
• Does the patient have volume-responsive AKI? Give the patient volume, look for a response!
• Respect AKI, but remember, most patients will get better with some LR and a Foley Catheter… those that don’t likely have ATN which will get better with time!

Links*

1. Dr. Topf: Nephrology & Social Media – May 2020, Vol 50, Issue 3, p 247-328 of Seminars in Nephrology
2. Dr. Topf: Zoe Keating – cellist & composer
3. Dr. Topf: Mrs. America a miniseries which dramatizes the women’s movement and fight for and against the Equal Rights Amendment in the 1970s
4. Dr. Williams: Last of Us 2

*The Curbsiders participates in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising commissions by linking to Amazon. Simply put, if you click on our Amazon.com links and buy something we earn a (very) small commission, yet you don’t pay any extra.

Goal

Listeners will develop a rational approach to the diagnosis and management of the patient with acute kidney injury (AKI).

Learning objectives

After listening to this episode listeners will…  

1. … be facile with the definition of AKI
2. … have a framework for approaching AKI including an understanding of what features in a patient’s history may shed light on the diagnosis
3. … appreciate prerenal azotemia and the relationship with ATN
4. … develop an approach to rhabdomyolysis and AKI
5. … be able to discuss the various types of AKI likely to be seen in the critically ill patient
6. … recognize the paradigm shift related to the safety when using iodinated contrast and gadolinium with regards to renal function
7. … know common medications implicated in AKI
8. … appreciate common AKI-related issues in the outpatient setting and have a head-start on how best to deal with them

Disclosures

Dr. Topf has received honoraria from AstraZeneca and Cara Therapeutics. He is joint venture partner in Davita Dialysis centers receiving dividends. The Curbsiders report no relevant financial disclosures. 

Citation

Topf J, Askin CA, Williams PN,  Watto MF. “#226 Kidney Boy on Acute Kidney Injury: Myths & Musings”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list. Original Air Date: July 20th, 2020.