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.
Mac runs into the office of Dr. Nephron, moving everything in his path, asking excitedly for Detective Nephron.
Nephron: (enjoying his cup of steaming coffee) Calm down! Why are you in such a hurry?
Mac: A 28-year-old man on hemodialysis is in the emergency room.
Nephron: (abruptly interrupted, rolling his eyes) Hemodialysis? I know the answer already…volume overload or insufficient dialysis.
Mac: Not at all! This case is extraordinary, with all its letters!
Nephron: Really? Your enthusiasm deserves my attention. On previous occasions, when I see you like this, you always surprise me. What do you have for me this time, my apprentice (as he slowly resumes sipping his cup of coffee)?
Mac: The patient was sent from his hemodialysis unit because during his session, he developed bluish discoloration of his skin and oxygen desaturation of 46% with a headache, which did not improve despite supplemental oxygen of up to 6 liters of nasal cannula.
Nephron: (surprised look) Easy…pulmonary thromboembolism…an expected event given the great thrombogenicity generated by the hemodialysis circuit. It is not as extraordinary as you think, my dear apprentice. However, the cyanosis has me perplexed.
Mac: We thought the same when he arrived at the emergency department, but how do you explain that all seven dialysis session partners simultaneously experienced the same symptoms and signs? The medical director of the unit decided to suspend the session and sent everyone for evaluation at emergency services of different hospitals.
Nephron: (after 3 seconds of silence) This is getting interesting; give me more information please.
Mac: In the report, they write, and I quote: “The blood in the circuit turned chocolate-colored; the patients presented with cyanosis, dizziness, and slight dyspnea, and all of them had low oxygen saturation when measured with two different pulse oximeters.” Upon arrival at the emergency room, our patient presented with a blood pressure of 126/86 mm Hg, heart rate of 96 beats per minute, respiratory rate of 22 breaths per minute, temperature of 36.2°C, and pulse oxygenation of 882% on room air; the lungs were clear; and the lung POCUS evaluation did not reveal too many B-lines. His exam was not noted for any cardiac murmurs or edema. The hemoglobin level was 9.5 g/dL; the last value 1 month ago was 11.8 g/dL.
Nephron: Cyanosis with relatively decent peripheral oxygen saturation (SpO2)? How interesting. Cyanosis is caused by high levels of deoxygenated hemoglobin circulating within the superficial dermal capillaries and subpapillary venous plexus. Central cyanosis is generally of great concern, as it requires reduced arterial oxygen saturation or abnormal hemoglobin derivatives to be present. This problem can be approached in two ways. The first focus is on pulmonary and cardiac abnormalities, which do not seem to be the etiologies of this case. The second group focuses on abnormalities related to hemoglobin.
Mac: The chest X-ray and EKG were both unremarkable. An arterial blood sample was done on room air and showed chocolate-colored blood with a pH of 7.54, PaCO2 of 31 mm Hg, PaO2 of 108 mm Hg, and HCO3 of 29 mEq/L. When 4 liters of nasal cannula was added, there was a slight increase in oxygen saturation (97%).
We need to focus on something that all the patients would have been exposed to since they all had the same signs and symptoms.
Nephron: (shocked) I completely agree with you. The hemodialysis session was the point of convergence. But what did all of them share? The unit's air conditioning and the dialysis fluid! Call the hemodialysis unit and ask if this has happened before and if any events in the last few hours have been conspicuous.
A few minutes later, Mac returns.
Mac: They tell me that this has never happened before. The only new, relevant finding is that last night, the unit received the monthly maintenance cleaning process of the water system.
Nephron: That matters a lot! Remember that municipal water is impure and presents a risk for contamination. The water must be treated thoroughly before it can be used as a dialysate. There are standards that regulate this purification process. Please request a measurement of chlorine derivatives in the water, and verify the patency of the carbon filters and the reverse osmosis (RO) processes.
Mac: The dialysis unit told us that the carbon filters were changed just 4 months ago (the average durability is 6 months) and that its RO machine works perfectly. The dialysis unit already requested an independent evaluation of chemical derivatives in the water.
Nephron: Let's get back to the patient. Remember that pulse oximetry relies on the red and infrared light absorption characteristics of oxy- and deoxygenated blood (hemoglobin); therefore, its accuracy is affected in those patients with peripheral cyanosis (falsely low PaO2). This can be circumvented with an arterial blood gas sample, as co-oximetry uses at least four wavelengths of light to measure not only oxy- and deoxy-hemoglobin but also other forms of hemoglobin (e.g., carboxyhemoglobin and methemoglobin). Please, my apprentice, take an arterial blood gas with co-oximetry.
Minutes later, Mac returns with the arterial blood co-oximetry in his hand and a huge smile on his face. Nephron turns to stare at him and after 2 seconds of silence…
Mac: The methemoglobin value is high at 7.9%; normal is <1.0%. This could explain the clinical presentation!
Nephron: Indeed, methemoglobinemia has this clinical presentation. In these patients, it is important to distinguish between congenital and acquired causes. In this case, it is obviously acquired. Dear apprentice, chloramines derived from chlorine and ammonium are usually added to municipal water as disinfectants and may contaminate dialysis fluid and enter the blood of dialysis patients leading to hemolytic anemia or in some cases, methemoglobinemia. In most dialysis centers, activated carbon filters are used to remove chlorine and chloramine, which are not usually removed by RO. Correct functioning of the carbon filter in the dialysis unit watertreatment room is essential for this process. One important aspect of the proper functioning of carbon beds within the carbon filter is the contact time of the water with the carbon. At least 10 minutes are required for thorough removal of both chlorine and chloramine. This may require adjustment of the pH of the feed water and assurance that no other substances are preventing the chloramine to reach the carbon surface (such as corrosion inhibitors).
Mac: How does this lead to anemia?
Nephron: The chloramines are a group of compounds that contain chlorine and nitrogen. There are three different forms: monochloramine (NH2Cl), dichloramine (NHCl2), and trichloramine (NCl3). They are easily converted from one to another. Chloramines are yellow to colorless liquids with a strong ammonia odor. Chloramines, especially monochloramine, have been used as water disinfectants. Monochloramine is a weaker disinfectant than chlorine but is more stable. Because of this, monochloramine provides better protection against bacterial regrowth in systems with large storage tanks and deadend water mains. Chloraminated water that meets local standards is safe to use for drinking, bathing, cleaning laundry, and other household activities but at certain levels, can lead to toxicity.
In toxic amounts, the chloramines can liberate hypochloric acid, hypochlorite, and free oxygen radicals. In addition, chloride and chlorates are oxidants that reduce glutathione, further enhancing the oxidative effect of free radicals, and can produce organic halogenation by chlorinating the amino acids of structural proteins (spectrin, a large cytoskeletal protein, and hemoglobin), changing the shape of erythrocytes and causing the formation of micronuclei, followed by complete hemolysis, resulting in Heinz bodies. The oxidation of hemoglobin by chlorates and chlorides leads to formation of methemoglobin, which is an altered form of hemoglobin. The iron molecule in this remains in an oxidized state (ferric /Fe3+), which alters its ability to transport oxygen to tissues leading to oxygen desaturation, cyanosis, and ultimately hemolytic anemia.
Mac: Hemolytic anemia? That explains the drop in hemoglobin compared with the previous month. I will request that the hematology service review the case.
Nephron: Let's not waste more time while the hematologists search for hemolysis. Let's treat the methemoglobinemia, administer intravenous methylene blue, and check methemoglobin levels 1 hour after application. Methylene blue reacts with red blood cells to form leukomethylene blue, which is a reducing agent of oxidized hemoglobin converting the ferric ion back to its oxygen-carrying ferrous state.
Mac returns 2 hours later.
Mac: The new post-methylene blue methemoglobin values decreased and are now at normal levels, 0.7%, like magic! The hematologist found Heinz bodies in his peripheral blood smear. After a transient decrease during methylene blue administration, SpO2 gradually improved to 100% over the next 20 minutes.
The next day, Mac walks into Nephron's office with a sheet.
Nephron: Does that sheet have important information?
Mac: Yes. It is the quantitative report of the chloramine values in the water of the hemodialysis unit, which are elevated to 0.78 mg/L (when what is allowed is <0.5 mg/L). With this, we can conclude that it was a case of methemoglobinemia acquired by chloramine poisoning. I think the carbon filters were defective. Something did not go as planned.
Nephron: What an interesting and unexpected case. Hemodialysis is not a procedure that is free of risks and complications. The blood of patients is exposed to a large amount of municipal water, 100–200 liters per session, and the only barrier between the blood of the patient and the dialysate is a small, permeable filter. Given these complications, the quality of the water used for hemodialysis should be monitored, ensuring limited exposure to potentially harmful contaminants. The most effective way to remove chlorine and chloramine from municipal water is the activated carbon filter. Older methods of activated charcoal, sodium bisulfite, and/or ascorbic acid are rarely used now. We have a lot of processes of cleaning the water: RO, deionization, and the carbon filter. All are essential in their functioning to provide safe water to the patient.
Mac: (with excitement) Well put!
A few hours later…
Mac: The carbon filter was defective. It is being rectified at this moment.
Nephron: (laughing) There you go again! Fascinating diagnosis and quick thinking, my apprentice. Do no harm first, my friend, do no harm! Let's have some NY-style coffee today.