Detective Nephron, world-renowned for his expert analytic skills, trains budding physician-detectives in the diagnosis and treatment of kidney diseases. Mackenzie Ula Densa, a budding nephrologist, plans to present a new case to the master consultant.
Nephron: It's been a while, Mac. What do you have for me?
Mac: I have a 68-year-old male with an allogeneic stem cell transplant and now with unexplained lactic acidosis.
Nephron: (excited) Whoa! Stop right there. Why is that a nephrology consult?
Mac: Trust me, you are going to love this one! You are like a king when it comes to figuring out non-nephrology stuff. Aren't nephrologists the wizards of internal medicine?
Nephron: Well, in that case, we may have to put on our onconephrology hat or call a friend over for some New York-style coffee. I think I shall invite my friend Dr. Car T. He is just a phone call away.
Mac: Hmm…oh well. I can totally relate to that one.
Pause as Dr. Car T enters
Car T: Dear Nephron and Mac, please continue to discuss the case. What do we have in store for “The Car”?
Mac: This is a 68-year-old male with a history of an allogeneic stem cell transplant for leukemia earlier this year. He is doing well for being post-transplant for the last 5 months on a non-CNI [calcineurin inhibitor]-based GvHD [graft-versus-host disease] regimen. He was admitted and sent for a full laboratory workup, as his care team noticed a low bicarbonate level on recent laboratory results, and he has been experiencing some fatigue. Just to lay it out: His arterial pH was 7.31, and base excess was −12.8 mEq/L. His serum electrolytes and kidney function are normal with an anion gap of 18. His serum lactate level came back at 18 mmol/L.
Nephron: Stop! This is ridiculous. This is likely sepsis and/or hypotension. Just hydrate him, and he can go home.
Mac: (laughing out loud) Can we move on? I would not be here if it was that simple.
Car T: (angry at Nephron) Oh, come on! Please continue, Mac.
Mac: His vitals are normal, and he has not been hypotensive. In the last 4 days, his blood cultures have been negative. After small doses of sodium bicarbonate treatment, fluid replacement, and 2 good days of hydration, his lactate levels increased to 30 mmol/L and are now 45 mmol/L.
Nephron: (bored, rolling his eyes) Oh yes, you just nailed point number 1: This is still a boring case. If this isn't type A lactic acidosis, this is type B. Come on!
Car T: Interesting. I was thinking you might say that his anion gap is normal. Lactic acidosis is the most common cause of metabolic acidosis in patients who are hospitalized. Although the acidosis is usually associated with an elevated anion gap, moderately increased lactate levels can be observed with a normal anion gap. When lactic acidosis exists as an isolated acid-base disturbance, the arterial pH is reduced. Mac, can you tell us a bit about what you understand about lactate production in our body?
Nephron: (winking) Dr. Car T, are we done with your medicine lecture yet?
Mac: Lactate generation and metabolism play a key role in understanding lactic acidosis, which results from both overproduction and impaired metabolism of lactate. Cellular lactate production is influenced by a redox state, reflected in the nicotinamide adenine dinucleotide (NAD+/NADH [NAD plus hydrogen]) ratio. A low NAD+/NADH ratio shifts the balance toward lactate production, often due to factors such as inadequate oxygen delivery or rapid oxidation of substances like ethanol. Lactate dehydrogenase catalyzes the conversion between pyruvate and lactate, primarily producing L-lactate, the dominant isomer in humans. Normal metabolism generates 15–20 mmol/kg of lactate daily, primarily through glycolysis. The liver, kidneys, and heart metabolize lactate by oxidizing it to CO2 and water (70%–80%) or converting it back to glucose (15%–20%) via the Cori cycle.
Lactic acid accumulation is buffered by extracellular bicarbonate, and its metabolism helps restore bicarbonate levels.
Nephron: (yawning) This is really boring me. It reminds me of those complex lectures in medical school that make students not want to go into kidney medicine.
Car T: Why is this not lactic acidosis type A? Lactic acidosis is classified as L-lactic acidosis and D-lactic acidosis; L comes in two types: A and B. Type A is caused by impaired tissue oxygenation, and type B occurs without obvious oxygenation issues. However, overlaps exist, such as in sepsis, in which both increased lactate production and reduced clearance contribute.
Type A lactic acidosis results from severe tissue hypoperfusion due to hypovolemia, cardiac failure, sepsis, or cardiopulmonary arrest. Clearly you are telling me this is not type A.
Nephron: Hmm, I like the way you split L into A and B. So much alphabet play here. So, what about D?
Mac: (trying to remember) D-Lactic acidosis is a rare condition seen in short bowel syndrome and gastrointestinal malabsorption. Excess glucose and starch fermentation by gut bacteria produce D-lactate, which accumulates due to slow human metabolism, leading to metabolic acidosis and neurological symptoms like weakness, cerebellar dysfunction, and confusion.
Sometimes we see this in high-dose intravenous propylene glycol and diabetic ketoacidosis, in which D-lactate forms from lactaldehyde and methylglyoxal, respectively.
Car T: (jumping in) Standard lactate tests do not detect D-lactate, requiring specialized analysis. From an onconephrology perspective, I doubt this is D-lactate. I assume a CT [computed tomography] scan was done looking for infections, and it was negative.
Silence
Mac: Hmm. Yes, of course.
Nephron: (shocked) Let me guess; it's cancer or some strange new cancer drug causing this?
Mac: (smirking) Clearly this is type B lactic acidosis. Now what do we think is causing this? The patient is not diabetic, and the medication list does not include metformin, if that is what you are thinking.
Let's get rid of the obvious: There were no seizures or carbon monoxide poisoning that could lead to increased oxygen requirements and decreased delivery issues. Urine toxicology was done but a day late. It was negative for cocaine or toxic alcohols, and the patient is not getting any major form of propylene glycol. He is not on salicylates, albuterol, or any nucleoside reverse-transcriptase inhibitors. Phew! I think I covered most causes of type B lactic acidosis…. Oh, and his cancer is in remission per the recent bone marrow and scans.
Car T: Linezolid?
Silence
Mac: (confidently) No!
Car T: Hmmm…. Fascinating. Just to remind you, inherited mitochondrial disorders, such as MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], which result from defects in mitochondrial DNA, lead to lactic acidosis and stroke-like episodes. Thiamine deficiency can also cause lactic acidosis by impairing key enzymes in the tricarboxylic acid cycle. This condition worsens with high glucose loads but resolves with intravenous thiamine. Certain drugs, particularly HIV nucleoside reverse-transcriptase inhibitors, disrupt mitochondrial function, leading to lactic acidosis and lipid accumulation in the liver and muscles.
Nephron: (showing off) He did mention something regarding the HIV-related medications, but thiamine is a very good point.
Mac: Thiamine infusion was given but led to no change in lactate levels.
Car T: I think the patient may have a malignancy. Are you sure the scan was good quality?
Mac: (nodding up and down) So, what do we do here?
Nephron: (boastfully) There is also an entity called stress hyperlactatemia.
Mac: I know that entity. Stress hyperlactatemia, seen in exercise and disease, predicts mortality but remains controversial in literature. Traditionally linked to anaerobic glycolysis from hypoxia, newer evidence suggests increased aerobic lactate production, often due to adrenergic stimulation. Lactate aids energy efficiency, supports gluconeogenesis, and acts hormonally to enhance the metabolism. But he doesn't seem to have a stressful disease right now.
Nephron: Mac, what are you going to do? The ball is in your court.
Mac: I am going to ask for more imaging, as his lactate dehydrogenase is high as well, and make sure a lymphoma is not brewing here. The time course for post-transplant lymphoma fits, given he received a stem cell transplant.
A few days later
Mac: I guess there is a reason Car T is here. Repeat scans with intravenous contrast confirmed new retroperitoneal and inguinal lymph nodes. A lymph node biopsy confirmed lymphoma.
Car T: (jumping in) Lactic acidosis is rare in leukemia, lymphoma, and solid tumors, with an unclear cause. Proposed mechanisms include anaerobic metabolism in tumor clusters, liver metastases, and increased lactate production via the Warburg effect. Even patients with small tumor burdens can develop lactic acidosis. Thiamine or riboflavin deficiency may contribute, along with impaired lactate clearance. I would check for Epstein-Barr virus by PCR [polymerase chain reaction].
Mac: (confident) We did, and it was very high. He has Epstein-Barr virus plus post-transplant lymphoproliferative disorder. That is likely what is driving the type B lactic acidosis.
Car T: Superbly done, my friend. Quick diagnosis!
Nephron: (jumping in) Yes, of course. Tell your team your plan to give some “vitamin R.”
Car T: Although you use rituximab for all diseases in nephrology, it's not the only treatment hematologists have in store.
Nephron: (laughing) There you go again, Car T! Fascinating diagnosis and treatment, Mac. Special thanks to our onconephrologist in helping us figure out this tough case. I must say, this was a true learning experience.
Car T takes a bow and winks.
