Detective Nephron: A new case

 Here is the next case on Detective Nephron - a tough case of acidosis
http://www.kidneynews.org/kidney-news/fellows-corner/detective-nephron/detective-nephron

Topic Discussion: Euglycemic Diabetic Ketoacidosis

The first time the term Euglycemic DKA(eDKA) was mentioned was in 1973- in British Medical Journal in patients who were diabetic but didn't have the full blown hyperglyecmic part.  Compared to classic DKA, eDKA presents with mild to moderate hyperglycemia typically <300mg/dl blood glucose levels.  

Why is this more important now?

In 2013, many SGLT2 inhibitors got approved for DM management( the glucoretics).  The FDA performed a FAERS search of adverse effects with these agents and 73 cases were identified of ketoacidosis linked to SGLT-2 inhibitors.  All patients required hospitalization, and 60% had DMII. Blood glucose levels ranged from 90mg/dl - 1300mg/dl( median 211).  Timing of onset was around 43 days or starting or dose change of the agent.  Majority of the cases also had dehydration, infection or change in insulin doses.   No mortality has been reported with this effect.  All patients respond quickly with intravenous hydration and insulin once recognized. The FDA did acknowledge that some of the cases occurred in DMI, where it's an off label use. More detail here. 



Is it a class effect? 
Yes. The initial FDA reporting was done with canagliflozin(invokana). A more recent study found an incidence rate of 0.07% with this agent.  In a large study with dapagliflozin( Farxiga), 0.1% of patients got eDKA.  Empagliflozin(Jardiance) also has been found to cause eDKA. 

What are the risk factors for development of eDKA with SGLT2 inhibitors?

Dehydration
Alcohol use
decrease in insulin use
Infection
Low carbohydrate diet
Reduction in caloric intake
Advance age

Mechanism of action

Ketosis results from restriction of carbohydrate usage with increased reliance on fat oxidation for energy production. The pathogenesis of hyperglyemic DKA is well established. Since SGLT2 are glucoretics as described before, they can lead to volume depletion- like a diuretic and perhaps leading to a "starvation" like ketoacidosis with normal glucose levels. SGLT2 induced glycosuria can happen over 24 hours and this artificial low plasma glucose do not stimulate insulin. In eDKA, insulin deficiency and insulin resistance are milder; therefore, glucose overproduction and under-utilization are quantitatively lesser than in DKA. More importantly, renal glucose clearance (i.e., the ratio of glycosuria to prevailing glycemia) is twice as large with eDKA than with DKA. Ketoacidosis follows with the same sequence of events in eDKA as in DKA. Insufficient insulin levels will then decrease glucose utilization and promote lipolysis and ketogenesis. In addition, these drugs can increase glucagon levels leading to increase ketone production.

In summary, eDKA is pathophysiologically similar to DKA except for the circumstance—SGLT2-induced glycosuria—that “artificially” lowers plasma glucose levels and predisposes to increased ketogenesis.

Prevention and treatment
Blood and urine monitoring of ketones is essential especially when patients get ill or are experiencing one of the risk factors.  Adequate hydration and carbohydrate intake will help and holding the offending agent is indicated.  No data exists on a safe time to restart the agent. 

Here is a nice review on this topic
http://onlinelibrary.wiley.com/doi/10.1111/jdi.12401/pdf

CONCEPT MAP: Gap acidosis- GOLDMARK

Based on Lancet Article that gives a better ddx for Gap acidosis
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61398-7/fulltext

Delta –Delta or corrected HCO3- where is this other disorder hiding?

Often when we have a severe gap acidosis, we are forced to calculate the “delta/delta” and look for either a non gap acidosis or met alkalosis. How does this work?

Let’s work an example:

Ph 7.1, AG is 22 and serum Hco3 is 10 with a premise of AG metabolic acidosis.

Method one:

            Corrected bicarbonate = measured bicarbonate +( change in AG)

            Corrected bicarbonate = 10 + (22-12) = 20

If corrected bicarbonate is <22, a non gap acidosis is present as well
If corrected bicarbonate is >26, a met alk is also present.
If 22-26, a pure gap acidosis remains.

Method two: 
Think out loud,   “If the AG dropped increased from 12 to 22, there was a change of 10, hence bicarbonate should be roughly down by 10meq.  Normal bicarbonate is 24 and hence bicarbonate should be 14, but it’s 10, hence a non gap acidosis is present as well.”

Most online calculators use this method:

http://www.pharmacologyweekly.com/app/medical-calculators/anion-gap-calculator
http://errolozdalga.com/medicine/pages/AnionGap.DeltaDelta.cr.6.7.10.html

Problem with this method: Assumptions about all buffering occurring in the ECF and being totally by bicarbonate are not correct. Fifty to sixty percent of the buffering for a metabolic acidosis occurs intracellularly.

Method three: using the delta-delta ratio

delta ratio = (Increase in Anion Gap / Decrease in bicarbonate)

delta ratio = ( 10/14)=  <1 giving us the same diagnosis of combined gap and non gap acidosis.

See the below table

Delta Ratio	Assessment Guideline
0.4 - 0.8	Consider combined high AG & normal AG acidosis
1 to 2	Usual for uncomplicated high-AG acidosis Lactic acidosis: average value 1.6 DKA more likely to have a ratio closer to 1
> 2	Suggests a pre-existing elevated HCO3 level so consider: concurrent metabolic alkalosis

 As a general rule, in uncomplicated lactic acidosis, the rise in the AG should always exceed the fall in bicarbonate level.

The situation with a pure DKA  is a special case as the urinary loss of ketones decreases the anion gap and this returns the delta ratio downwards towards one. A further complication is that these patients are often fluid resuscitated with 'normal saline' solution which results in a increase in plasma chloride and a decrease in anion gap and development of a 'hyperchloraemic normal anion gap acidosis' superimposed on the ketoacidosis. The result is a further drop in the delta ratio.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/2240729?dopt=Abstract

ANION GAP ACIDOSIS: GOLD-MARK makes a MARK:

GOLDMARK  is the new MUD PILES

A new mnemonic has been created in the last few years for anion gap acidosis. 

Glycols( ethylene glycol, propylene glycol)
Oxoproline
L- lactate
D-lactate
Methanol
Aspirin
Renal failure
Ketoacidosis

Two popular mnemonics were often used to remember the major causes of the high-gap metabolic acidoses. The first is KUSMALE which represents Ketoacidosis, Uremia, Salicylate poisoning, Methanol, Aldehyde (paraldehyde), Lactate, and Ethylene glycol. 

The second is MUD PILES( most popular), spells out Methanol, Uremia, Diabetic ketoacidosis, Paraldehyde, Iron (and Isoniazid), Lactate, Ethylene glycol, and Salicylate.

Why GOLDMARK then? The causes have changed in the 21^st century. We barely see any more paraldehyde any more, neither we see that much Iron and INH related causes.

Newer causes: D-lactate: seen with short gut syndrome( especially after sugary drinks), diabetes can lead to d-lactate as well. Other new causes is pyroglutamic acid ( oxoproline) seen with chronic Tylenol use. Finally, propylene glycol infusion that is usually found in lorazepam, phenobarb and banana bags.

Initially this was proposed in LANCET

Consult Rounds: Why does infusion of normal saline cause metabolic acidosis?

Why does infusion of normal saline cause metabolic acidosis?

       

This should be an easy answer but when you review the literature, the literature is all over the place( literally!!).Collection of responses I received when I asked few experts in the field:

1. “ The bicarbonate ions are diluted by the isotonic fluid, and acidosis occurs as a result.”

            
            2. “The fall in serum bicarbonate is due to the expansion of the extracellular fluid volume                                   with large IV fluids”

3.  The "strong ion difference" (SID) helps explain this that in order to maintain electroneutrality. Since there is diluting fluid, water must dissociate, providing excess protons which leads to metabolic acidosis. “- via the stewart method of acid base

4.  “Usually 60% of the filtered bicarbonate load is reabsorbed in euvolemia. When extracellular volume is low the proximal tubular absorption is increased, maybe to 80%,due to changes in oncotic pressure and hydrostatic pressure of peri tubular capillaries and glomerulus.  This results in increased reabsorption in setting of volume depletion.  When extracellular volume is increased then proximal tubular absorption of bicarbonate is decreased, thus an acidosis.”

5. “ The ph of normal saline is 5.5, won't that also lead to dissociation and use of Hco3 and cause an acidic environment”

            
6. “Nacl is a weak acid so despite the low ph it will not change systemic ph.”

            
7. “The PCT reabsorbs 80 to 90 % of filtered HCO3. When micropuncture needle is not inserted in the terminal PCT, just the last accessible PCT that can be seen on the cortical surface. When Walker et  al micro-disceted the entire PCT, the reabsorption was close to 90% of filtrate, which prevents bicarbonaturia and percipitation of CaHPO4 in the deepest bend of the LOH, as this would cause  obstructive nephron damage and kidney stone disease among our ancestors and we would not be alive.

            
8.  “With a pH of isotonic saline of 5.5, there are far too few H+ added to cause metabolic                           acidosis if infusion volumes are less than 50 L/day.”

Take your pick! 

References:

http://www.ncbi.nlm.nih.gov/pubmed/19533091

http://m.anesthesia-analgesia.org/content/103/1/144.full

Concept map: Osmolar gap and Anion gap made simple

ABG vs. VBG

Arterial blood gas is gold standard to get the oxygenation and acid base information. Venous blood gas has been tried for patient comfort. How does VBG compare to ABG?
Check out the a post by a NYU resident on this topic. Very informative.

http://www.clinicalcorrelations.org/?p=5608

Topic Discussion: Old and New view of "Contraction Alkalosis"

Older View ( traditional taught to us)
Name: Contration Alkalosis
Prevalence: Most common cause of metabolic alkalosis
Primary Insult: Change in Extracellular volume
View Then: increase in sodium absorption in the proximal tubule led to obligatory bicarbonate absorption rather than chloride.
View Then: Correct the volume with expansion of ECF.
Culprit: Volume

Venue to play a major role: Proximal tubule

Dogma: Volume expansion is the key and correct with any volume expander to correct the alkalosis.

Newer View( the new data)
Name: Chloride Depletion Alkalosis
Prevalence: Most common cause of metabolic alkalosis
Primary insult: Chloride depletion
View Now: chloride depletion is the problem and not volume and Na depletion. repeating with Chloride will correct the insult.
View Now: Correct the volume and expand ECF but also make sure it has a Chloride containing fluid as just albumin or Na Bicarbonate will not correct this problem.
Culprit: Chloride depletion

Venue to play a major role: Cortical Collecting Duct

Dogma: Chloride administration without volume expansion is necessary and sufficient to correct this alkalosis.

What happens: There is chloride depletion which leads to reduced Cl delivery to cortical collecting duct(CCD)__>  pendrin activity increases secretion of Hc03 is limited as there isn't much Cl that can be absorbed in exchange.  You deliver more Cl to the CCD, pendrin activity shuts down and Hco3 is released and alkalosis starts resolving. In the principal cell, the K is exchanged for Na and there is kaliuresis.
The urinary Cl is low, Hco3 is low, Ph is low and K is high
The serum Cl is low, Hco3 is high and ph is alkaline

Pendrin is a newly discovered Cl/ HCo3 exchanger on the luminal side of the CCD's intercalated cells.  It is very dependent on the Cl delivery to CCD. So low chloride diet, Chloride depletion alkalosis increase its activity and high chloride diet, met acidosis, resp acidosis and K depletion alkalosis decreases pendrin activity.

Take a look at the recent editorial from JASN and original article:
http://www.ncbi.nlm.nih.gov/pubmed/21849227
http://jasn.asnjournals.org/content/23/2/204.abstract

CLINICAL CASE 52: ANSWERS and SUMMARY

TRUE OR FALSE: SEVERE METABOLIC OR RESPIRATORY ALKALOSIS CAN LEAD TO AN ANION GAP METABOLIC ACIDOSIS.

True 60%

False 40%

Severe alkalemia can cause an increase in anion gap.  Alkalemia leads to glycolysis in the liver and a mild lactic acidosis. In severe volume contracted state, the anion gap can be seen with change in valence of circulating proteins to preserve extracellular volume.  

A prior post had discussed this as well. 

See the references below:

Emmett M, Narins R. Clinical use of the anion gap. Medicine 1977; 56:38–45.

Kraut J, Madias N. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2007; 2: 162–174.

CLINICAL CASE 50: Answers and Summary

WHICH OF THE FOLLOWING ARE POTENTIAL CAUSES OF DEATH IN DIABETIC KETOACIDOSIS(DKA?)

Hyperkalemia	11 (15%)
Aspiration	1 (1%)
Hypokalemia	17 (23%)
Relative hypoglycemia	2 (2%)
Underlying lesion and complications	1 (1%)
All of the above	40 (55%)

Diabetic Ketoacidosis is a common entity that we encounter often leading to ICU level of care.  Standard treatment is usually volume expansion, insulin to stop ketoacid production.  As you give therapy with fluids and insulin, plasma glucose will fall, HCO3 will rise but slowly, ketoacids will decline, anion gap will close, plasma K will decrease, Na will increase and Phos will decrease. 

The five big reasons of complications in treatment of DKA are hyperkalemia that is present during admission and if not treated right away with insulin.  Due to the coma state sometimes, aspiration is likely.  As one starts treating, the K will drop and replacement with IV KCL is important.  6-8 hours later, relative hypoglycemia is also a major contributor and finally making sure the underlying cause of going into DKA is found and treated:- infection perhaps or whatever it might be. So all of the above is the correct answer.

For a good review on this topic: please read the short book:

The ACID Truth and BASIC facts with a SWEET touch, and enLYTEnment by Mitch Halperin, MD
by Rossmark Medical Publishers, 2004, Ontario, Canada.

Consult Rounds: Alkalemia causing Metabolic Acidosis

Can severe metabolic or resp alkalemia lead to Metabolic Acidosis?
Yes it can!!

Metabolic alkalosis, if from vomiting or diuretic use can be associated with a small increment of anion gap ( around 4-6meq/L) and this is ofcouse if no other disorder has been identified.  Why? Largely due to increase in albumin and some due to other increase in anionic proteins.  

Serum anion gap does not change notably in acute respiratory alkalosis, but small increases up to 3meq/L have been observed in chronic respiratory alkalosis.  

Alkalemia also causes glycolysis in the liver and a mild lactic acidosis (seen in our patient). In addition, in a volume contracted patient, the change in anion gap can be due to the change in valence of circulating proteins to preserve extracellular volume.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/401925

http://www.ncbi.nlm.nih.gov/pubmed/17699401

http://www.ncbi.nlm.nih.gov/pubmed/18974769

TOPIC DISCUSSION: Hibernating Bear's urine?

                                                                                                     

1.Mostly TG in adipose tissues are used to generate all ATP needed
2. Some urea is still generated and bear has to get rid of this urea- but not via urine and the bear cannot metabolize urea directly.
3. Urea enters the GI tract and bacteria secrete urease which splits to Nh4+ and HCO3-.  Bacteria then convert that ammonium to non essential and essential amino acids. And then they are re synthesized to bear's needs.
4. Small rate at which the bear catabolizes proteins is matched by the synthesis of new proteins via the bacteria in the GI tract.
For more details read:
Clinical Detective Stories- By Mitch Halperin, MD and below
http://www.ncbi.nlm.nih.gov/pubmed/6998737

CONSULT ROUNDS: Ethylene Glycol Toxicity

Role of Dialysis in Ethylene Glycol Toxicity

Key Points:

1.     Immediate dialysis should be done if the Anion Gap is significantly increased and there is evidence of acute renal injury

2.      Experts suggested HD in any patient with even suspected toxic alcohol ingestion with unexplained AG and osmolal gap.  Some say ph of 7.3, others ph of 7.1 to initiate dialysis

3.     If non acidemic or not in renal failure, perhaps HD can be put on hold and fomepizole can be tried. But HD can be used to clear the parent alcohol and shorten the course of the other therapies

4.     Long and good HD is needed.  Not real need to start slow. Sometimes two sessions in one day or daily HD might be needed. PD might not be that good for clearance.

5.     Continue HD till Osmolal gap closes or and ph normalizes or other renal parameters permit

TOPIC DISCUSSION: Contraction Alkalosis or CDMA?

Contraction alkalosis has been associated with volume contraction and we throw that term out all the time.
This issue of Nephsap has an interesting editorial about the nomenclature of this entity and the pathophysiology behind it.  Most of the time, severe volume contraction, leads to lactic acidosis, and not metabolic alkalosis unless you have a selective chloride depletion.  Hence, the authors feel that this entity should be really called Chloride Depletion Metabolic Alkalsois (CDMA).
Studies summarized showed that such alkalosis corrected more when Na or any other cation was supplemental Cl rather than any other anion. CDMA was produced by gastric aspiration, chloruretic diuretics , NaNo3 infusions, and post hypercapnia and all got better with Cl- repletion and not Na or K replacements.
So CDMA is corrected by selective Cl repletion despite maintained or increasingly negative Na or K balance, continued Hc03 loading and high levels of Ang II.
It was not corrected by Na or K repletion without Cl-. It was hard to correct with Cl- alone in abnormal renal function. What happens is the distal nephron in the collecting duct ensures a bicarbonate diuresis in response to Cl repletion.

Take a look in more detail at Nephsap March 2011
Also other good ref:
http://www.ncbi.nlm.nih.gov/pubmed/4875677

TOPIC DISCUSSION: Lactate levels and B2 agonists? any connection

Lactic acidosis has been reported in many cases in severe asthma due to production by over worked respiratory muscles. However, there is some thought that the b2 agonist agents might induce lactic acidosis or just elevated lactate levels. Even patients who are not asthmatics who get these agents have had similar reports. So far, lactic acidosis occurring in association with β-2 agonist treatments such as salbutamol, ritodrine,  meta-proterenol,  and albuterol have been reported, and its mechanism remains poorly understood. In one study, healthy volunteers without respiratory distress who were given intravenous infusions of either salbutamol or rimiterol had dose-related increases in lactic acid levels. In the absence of any clinical signs of circulatory shock or severe hypoxia , this would be considered a type B acidosis.  β-2 Receptor activation produces excess glycogenolysis and lipolysis. Increased glycogenolysis eventually leads to increased concentrations of pyruvate. Pyruvate is converted to acetyl CoA, which enters the citric acid cycle. If pyruvate does not enter this aerobic pathway, it is converted to lactate instead, thereby potentially causing lactic acidosis. 
An emergency medicine evaluation of this event was done prospectively. In total, 18 subjects who presented to an emergency department were enrolled in the study.  All patients were treated with albuterol; four puffs (100 microg/puff) at 10 minute intervals, delivered by a pressurised metered dose inhaler into a spacer device over a 2 hour period. At the end of treatment, mean plasma lactate level 2.94 mmol/l was significantly higher (p = 0.001) than baseline. Of the 18 patients, nine (50%) showed lactate levels > or = 2.5 mmol/l (four patients presented values > 4 mmol/l); however, there were no significant differences in the airway response between groups. Their conclusions: "This study confirmed previous observations that high lactate concentrations can develop during the first hours of inhaled beta agonist treatment. The presence of a previous hyperadrenergic state may predispose to the development of this condition. A significant improvement in lung function was associated with elevated lactate levels."


Interesting:
take a look:
Ref:
http://www.ncbi.nlm.nih.gov/pubmed/15911945
http://www.ncbi.nlm.nih.gov/pubmed/18410827
http://www.ncbi.nlm.nih.gov/pubmed/12883427
http://www.ncbi.nlm.nih.gov/pubmed/1299986

CONSULT ROUNDS: Propofol Infusion Syndrome

Why does a nephrologist care about Propofol infusion syndrome (PRIS)?
Its an important entity for us to know. It is a known cause of Rhabdomyolysis and hence AKI and also causes lactic acidosis. PRIS is a rare but fatal syndrome described in adults and children who get high dose propofol infusion(usually for CNS injury sedation or alcoholics). Usually >48 hours of infusion of 5mg/kg or higher.
Classic features: Rhabdomyolysis, hyperkalemia, hypocalcemia, elevated troponin, severe metabolic lactic acidosis, renal injury, high Triglycerides and features of SIRS without other real findings of Sepsis.  Usually these patients are neurological injuries and getting catecholamines as well or steroids. Tmax could be very high in such cases sometimes in 106-107F range. Cardiac features can include Bradycardia, hypotension, PEA, VT, Atrial Fibrillation and SVTs. Some of the cases described have been with concurrent severe infection as well. What happens at cellular level- this drug impairs free fatty acid utilization and mitochondrial activity leading to these findings?
In summary: Steroids, catecholamines and propofol alter energy production alter the SIRS and MODS syndrome and that leads to worsening rhabdomyolysis and cardiac failure that then leads to metabolic acidosis and acute renal injury. Cerebral Microdialysis can monitor brain energy related metabolites including lactate and pyruvate during head injury.  The cerebral lactate to pyruvate ratio is increased in PRIS. One way to monitor this syndrome.
Some people think that the term PRIS might be misleading and really it is a pathophysiologic state.  Critical illness of any kind is the priming factor and the propofol along with steroids or pressors can be triggering factors.  So really the name critical illness cardiac, renal failure and rhabdomyolysis associated with high dose propofol, steroids or pressors seems more appropriate.

In such cases where this risk is high, best is to use a different agent for sedation and remove propofol from the culprit.

Ref: 

http://www.ncbi.nlm.nih.gov/pubmed/21063807

http://www.ncbi.nlm.nih.gov/pubmed/20844346

http://www.ncbi.nlm.nih.gov/pubmed/20017894

http://www.ncbi.nlm.nih.gov/pubmed/12904852