Renal Grand Rounds - What Lurks in the Gap

I recently presented the case of a middle-aged man with a history of a remote Roux-en-Y gastric bypass, chronic diarrhea, and colon cancer on chemotherapy who initially presented with progressive fatigue and weakness in the setting of increased diarrhea. Shortly after admission he developed agitation that progressed to encephalopathy with dysarthria. His baseline labs from a month prior to presentation were notable for a chronically low serum bicarbonate of 15-17 with no anion gap. When he presented he was hypokalemic to 2.5 and his bicarbonate had dropped to 11 with a new elevated anion gap of 25 and normal L-lactate. Metabolic acidosis was confirmed on VBG. Interestingly, his urine electrolytes demonstrated a positive urine anion gap of 26.

He was ultimately diagnosed with D-lactic acidosis based on his clinical presentation which was confirmed with a serum D-lactate of 6.28. For the week prior to admission, he had been drinking 1.5 L of Gatorade (224 g of sugar!) daily to replace diarrhea losses.

This was a classic presentation of D-lactic acidosis in which overgrowth of gram positive anaerobes in the setting of short bowel syndrome is combined with a large carbohydrate load resulting in bacterial fermentation and D-lactate production.  He even had the classic neurologic findings!  His chronic non-gap acidosis likely represented chronic diarrhea and D-lactate production, and his rising anion gap when he presented was consistent with increased D-lactate production.

In D-lactic acidosis, the findings of hypokalemia and a positive urine anion gap can provide a helpful clue. With elevated serum D-lactate levels, the fractional excretion of D-lactate approaches 100%, i.e. everything that's filtered is excreted. This is because the stereospecificity of the sodium-L-lactate cotransporter in the proximal tubule results in poor reabsorption of D-lactate relative to L-lactate. The negatively charged D-lactate essentially drags positively charged sodium and potassium into the urine causing hypokalemia as well as a positive urine anion gap (Na + K - Cl) due to the increased urine sodium and potassium.


This patient did well after his Gatorade was cut off and he was treated with antibiotics to address gram positive anaerobic overgrowth.

Posted by Patrick Reeves

(Image taken from here - an educational blog for ED residents)

Type B Lactic Acidosis

Nice case report in AJKD recently raised the issue of Type B Lactic Acidosis. Lactic acidosis occurs when there is excessive anaerobic glycolysis or decreased removal of lactate from the circulation. Classically, Type A lactic acidosis is related to tissue hypoperfusion resulting in an increase in anaerobic glycolysis. Type B lactic acidosis occurs despite the presence of sufficient oxygen for aerobic glycolysis. There are a number of important causes:

Drugs/Toxins	Metformin Linezolid Propofol Nucleoside Reverse Transcriptase Inhibitors Salicylates Isoniazid Alcohol Cyanide
Enzyme Deficiencies	Glucose-6-phosphatase Pyruvate carboxylate Pyruvate Dehydrogenase Oxidative Phosphorylation Defects
Other Disorders	Kidney Failure Liver Failure Thiamine Deficiency Malignancy

The case report in AJKD was a patient with myeloma who developed a severe lactic acidosis. The preference of tumor cells for anaerobic glycolysis has been known since the 1920s and is called the Warburg Effect. It is thought to be due to a combination of increased IGF and TGF-alpha production by tumor cells and thiamine deficiency which is common in patients with malignancies. The discussion in the case report gives a nice summary of the literature.

Lactate gap in ethylene glycol toxicity

From Brindley P.G et al., CMAJ 4-10-07, 176(8) pg1097-1099

When making a decision about urgent dialysis it is important to have an much information as quickly as possible. In suspected ethylene glycol toxicity time is of the essence. Waiting 3-4 hours or more for the ethylene glycol level to come back can be deleterious to the patient. Often times we are left to make the decision to begin dialysis or therapy based upon a high degree of suspicion from the available laboratory data and patient circumstances. During conference recently I heard of another pearl that could help in determining if ethylene glycol was ingested.

This is termed the lactate gap. Essentially this is the difference in values obtained from 2 different analyzer methods. As seen in the graph, taken from this paper, the commonly used Radiometer method can result in a falsely elevated lactate level when compared to other assays (iSTAT, Bayer, Vtros and Beckman).

Why is this the case?

This likely occurs because metabolites of ethylene glycol cross react with L-lactate oxidase. The Radiometer assay uses the enzyme L-lactate oxidase to accelerate the reaction between L-lactate and oxygen, the products of the reaction being hydrogen peroxide and pyruvate (click here for discussion of this). The L-lactate concentration is then computed from the measured hydrogen peroxide concentration. It is thought that glycolate (a metabolite of ethylene glycol) is able to interact with L-lactate oxidase and produces a significant amount of hydrogen peroxide and thus the test reports as a high lactate level.

The enzymatic L-lactate assay are also subject to interference from certain drugs at toxic levels such as; Isoniazid, Acetaminophen and Thiocyanate.

The radiometer method of detecting lactate is commonly used in point-of-care testing such as those reported by ABG's. It is important to know what your lab is using when interpreting lactate values. Serum lactate levels are typically computed using a non-radiometry method.

Obtaining simultaneous radiometer lactate and another method of lactate measurement and computing the lactate gap (the difference between the two values) can help in distinguishing true lactic acidosis from ethylene glycol toxicity.

Surviving lactic acidosis; lessons from turtles

Lactic acidosis is frequently seen in the hospital setting. Diverse etiologies account for the accumulation of lactic acid as reviewed by Nathan last year. The main impetus for the production of lactate is having a hypoxic state either in the entire organism, the cellular level or an isolated vascular bed. Most cells in the body break down glucose to form water and carbon dioxide. This is a two-step process. First, glucose is broken down to pyruvate through glycolysis. Then, mitochondria oxidize the pyruvate into water and carbon dioxide by means of the Krebs cycle and oxidative phosphorylation. This second step requires oxygen. The net result is ATP, the energy carrier used by cells. If oxygen supply is inadequate (hypoxia), the mitochondria are unable to continue ATP synthesis at a rate sufficient to supply the cell with the required ATP. In this situation, glycolysis is increased to provide additional ATP, and the excess pyruvate produced is converted into lactate and released from the cell into the bloodstream, where it accumulates over time.

I met Nathan at the Origin's of Renal Physiology Course at Mount Desert Island, Maine a few years ago. This is an outstanding course where you get hands on experience exploring renal physiology using marine life just as Homer Smith did. I remember learning that the painted turtle, Chrysemys picta is able to survive extreme lactic acidosis. As a renal fellow we are frequently consulted for this devastating entity. Unfortunately, we are mostly unable to intervene as the answer in a majority of these cases is to correct the underlying problem. Interestingly, many aquatic vertebrates can remain submerged underwater for remarkably long periods of time. A prime example is the painted turtle, Chriysemys picta, a freshwater species found in Canada and the U.S. Its natural winter habit is to continuously submerge itself in ice-covered ponds for months. The turtle is able to sustain vital organ function for long periods of time despite severely hypoxic or even anoxic conditions. Lab studies have shown that these turtles an fully recover for submergences lasting 3 months at 3 C. The plasma concentration of lactate have been measured as high at 200mM. How is this possible?

The turtle has adapted to this environment by using several unique mechanisms. First, the major extracellular buffer, bicarbonate, is particularly high at baseline (40 mM) in the plasma as well as the peritoneal fluid (80 mM) and pericardial fluid (120 mM). This however, does not account for all of the buffering capacity needed to sustained such profound acidosis. The second and most interesting mechanism is its use of is bone-like shell. The shell accounts for 32% of the turtles total body mass. The portion of its skeleton not incorporated into the shell represents an additional 5.5%. Besides the obvious role it plays as a protective armor, the turtle's shell is also the major mineral reservoir for the body. Over 99% of the total body calcium, magnesium and phosphate and 60% of the body's sodium reside in the shell and bone.

Two mechanisms account for the shells buffering of lactate. First, supplemental buffers are released from the shell directly when needed. During periods of extreme anoxia. Plasma levels of calcium and magnesium increase dramatically. Likely, this is a passive process by which the shell is demineralized by acids. Mainly, calcium carbonate is released. So much calcium is sequestered in the shell that little loss is evident even with prolonged periods of acidosis. A similar process occurs during untreated acidosis in CKD. However, the calcium stores are not quite as profound in the human body. The second mechanism involves the uptake on lactate and a proton directly by the shell. The enormous buffering capacity of the shell allows for this.

Chriysemys picta's unique habit of hibernating during the winter months have allowed for this interesting ability to survive profound lactic acidosis by using its shell as a buffer. Unfortunately, lactic acidosis in the hospital setting is typically extremely difficult to control as the buffering capacity of the body cannot tolerate lactate accumulation for an extended period of time. Research performed on marine life, like at Mount Desert Island, allow for the discovery of novel and interesting ways to survive extremes in physiology.

Differential Diagnosis: Lactic Acidosis

As discussed in a recent post describing the success of early goal-directed therapy for sepsis, the test for serum lactate has enjoyed a rise in prominence in recent years.

However, all that is lactic acid is not necessarily sepsis! Here's a differential diagnosis for lactic acidosis:

1. Shock--especially cardiogenic and septic shock, which is indicative of an inability of the circulatory system to match the metabolic demands of tissue.

2. Bowel Ischemia--mesenteric ischemia, necrotic bowel, etc.--the necrosis of cells in the intestine will release free lactate into the bloodstream.

3. Cirrhosis/Liver Failure--since lactate is metabolized to bicarbonate by the liver, patients with end-stage liver disease often have elevated lactate levels, which is NOT necessarily indicative of shock/hypoperfusion (although this group of patients often represents a conundrum in that they are precisely the type of patient who can get septic & die rapidly.)

4. Grand-mal Seizures: can lead to a transient increase in serum lactate which typically reverses on its own pretty quickly.

5. Thiamine Deficiency: thiamine is a cofactor for enzymes in the glycolytic pathway; its absence prevents adequate cellular metabolism and lactate can build up.

6. Citrate Toxicity in patients on CVVH given citrate-based replacement solution--this is heralded by an increased total calcium concentration along with a decreased ionized calcium concentration.

7. D-lactic acidosis: this atypical form of lactic acidosis occurs when bacterial overgrowth (as might occur in patients with GI bypass surgery) results in the metabolic synthesis of the D-isoform of lactic acidosis, which is not metabolizable to bicarbonate endogenously as is the naturally-occurring L-isoform of lactate.

8. Severe alkalosis: an increase in lactic acid level is a compensatory response to either severe metabolic or respiratory acidosis.

9. Drugs: a variety of drugs can cause lactic acidosis, usually by virtue of mitochondrial toxicity--for example, nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV patients, Metformin, and nitroprusside as a consequence of production of cyanide, a known mitochondrial toxin.