How to approach a lone low serum bicarbonate: some illustrative cases

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Metabolic acidosis is a common condition encountered routinely by Nephrologists. Etiology of this condition is quite varied often requiring detailed history and a battery of tests to tease out the diagnosis. In most of the scenarios, co-existing biochemical abnormalities aid in the diagnosis eg. an elevated blood glucose with elevated serum ketones. But what if the only abnormality we encounter in the labs is an isolated low serum bicarbonate?  Here we present two cases in which a lone low serum bicarbonate unearthed some serious underlying diagnoses that are important to be mindful of when presented with this scenario.

Case 1

A 53 year-old woman with end stage kidney disease due to diabetic nephropathy, on intermittent hemodialysis at baseline, required Continuous Kidney Replacement Therapy (CKRT) (CVVHDF modality) after a cardiac arrest. Her background history also included insulin dependent type 2 diabetes, significant coronary artery disease and heart failure. Her dose of CKRT was 24 ml/kg/hour with Prismasol-4 bags (glucose free), without any interruption during the first 4 days of therapy. She had poor oral intake with intermittent episodes of vomiting and was placed on a subcutaneous insulin sliding scale. 

After 96 hours, she had a mostly normal metabolic panel apart from a low serum HCO3 of 17 mmol/l. The venous blood gas pH was 7.35, pCO2 33 mm Hg and corrected anion gap (AG) 25 mmol/l.

How to approach a patient with low serum bicarbonate ? 

  1. Along with a thorough history, the first step in the evaluation includes an arterial blood gas analysis to assess for respiratory compensation. A simple formula can help calculate the degree of respiratory compensation expected for metabolic acidosis known as Winter’s formula – pCO2 = 1.5 x HCO3 + 8 ± 2 mm Hg. 
  1. If measured pCO2 = calculated pCO2, then it’s an appropriate respiratory compensation.
  2. If measured pCO2 < calculated pCO2, it suggests associated respiratory alkalosis.
  3. If measured pCO2 > calculated pCO2, there is likely an underlying, co-existing respiratory acidosis with poor compensation.
  4. Next step is calculating the serum anion gap (AG) [serum sodium – (serum chloride + serum bicarbonate)] and correcting the AG for serum albumin (uncorrected AG increases by 2.5 mmol/l for every 10 g/L decrease in serum albumin from a normal value of 40 g/L). This helps in differentiating the two important categories of metabolic acidosis- normal AG ( 4-12 mmol/l) and high AG (> 12 mmol/l). 

In patients with normal AG metabolic acidosis (NAGMA), estimating the urine AG [(Urine sodium + urine potassium) – Urine chloride] is critical to differentiate renal from extra renal etiology. Normal urine AG ranges from 0 to < 10 mmol/l. Common causes of NAGMA are outlined in Table 1.

Table 1: Common causes of NAGMA

Negative urine AG (-20 to -50 mmol/l)Positive (+20 to +90 mmol/l) or Zero urine AG 
Gastrointestinal losses (diarrhea, fistula)
Ureteric diversion (eg. ileal loop)
Type 2 RTA
Acetazolamide
Type 1 or 4 renal tubular acidosis (RTA)
  1. With high AG metabolic acidosis (AGMA), the etiology is more diverse and requires evaluation with serum lactate, ketones (beta hydroxybutyrate), renal function, salicylate and alcohol levels (Table 2). Numerous mnemonics exist to help recall the etiologies of this condition – MUDPILES, DR.MAPLES, SLUMPED, and most recently GOLD MARK described in The Lancet in 2008. The latter stands for Glycols (ethylene and propylene) , Oxoproline, L-lactate, D-lactate, Methanol, Aspirin, Renal failure and Ketoacidosis. 
  2. With AGMA, the delta gap should  be calculated. This is the ratio of delta AG/ delta bicarbonate ratio and helps in determining co-existing NAGMA or metabolic alkalosis. 
  1. Ratio = 1 is due to uncomplicated high AGMA. 
  2. Ratio <1 is seen in combined NAGMA and high AGMA and early chronic kidney disease due to type 4 RTA + accumulation of unmeasured anions. 
  3. Ratio > 1 is due to coexisting metabolic alkalosis or high baseline bicarbonate as compensation to chronic respiratory acidosis.

6. Calculating the serum osmolal gap (measured serum osmolality – calculated serum osmolality) is important to diagnose alcohol-related toxicity. Calculated osmolality is the sum of serum sodium, serum glucose and serum urea (all in mmol/l) as follows: serum sodium (mmol/l) + serum glucose (mg/dl) /18 + blood urea (mg/dl)/ 2.8. Elevated osmolal gap (> 10 mOsm/L) is associated with ethylene glycol, methanol or propylene glycol toxicity. 

Table 2: Common causes of AGMA

Lactic acidosis → L- or D-lactate elevation
Ketoacidosis → Diabetic, starvation, Euglycemic
Toxic ingestions → Ethylene glycol, methanol, propylene glycol, Aspirin, etc
Pyroglutamic acidosis -Acetaminophen overdose
Advanced kidney disease

In this patient, the serum lactate was normal. There was no acetaminophen overdose based on the history or toxic alcohol ingestion. The patient was well dialysed as seen with the serum creatinine value (< 150 umol/l or < 1.7 mg/dl). The serum beta hydroxybutyrate level was found to be elevated at 7.14 mmol/l (normal: ≤ 0.27 mmol/l). However, the serum glucose only ranged between 7-9 mmol/l which made a diagnosis of classic diabetic ketoacidosis less likely. Therefore, we suspected that this may instead be a case of euglycemic ketoacidosis (EuDKA) which was then managed with intravenous insulin infusion and glucose, resulting in resolution of metabolic derangements.

What can potentially cause EuDKA in a patient on CKRT?  The increase in serum glucagon to insulin ratio is critical in accumulation of ketones, and yet maintaining blood glucose in the normal range, in patients with EuDKA, as depicted in the flowchart below.

Figure 1: Proposed pathophysiology of euglycemic ketoacidosis (EDKA) in patients on continuous venovenous hemodiafiltration (CVVHDF) with glucose-free solutions. Reproduced from Sriperumbuduri et al. Kidney Int Rep. 2020.

EuDKA is an uncommon cause of high anion gap metabolic acidosis characterised by elevated urine and serum ketones and serum glucose < 13.9 mmo/l (250 mg/l). The condition should be suspected when high anion gap metabolic acidosis is noted in a diabetic patient with blood glucose levels within normal limits. Known causes of EuDKA include starvation, pancreatitis, pregnancy and most recently the use of SGLT2 inhibitors. This was described for the first time in patients on CKRT in a case series of 18 patients including non-diabetics (50%) and diabetics. The median onset of EuDKA in this series was 43 hours (interquartile range 26-75 hours).

The most important risk factors for the development of EuDKA in CKRT include the use of glucose free dialysate +/- replacement solutions and poor caloric intake. This condition should be suspected if there is an unexplained anion gap metabolic acidosis in patients on an adequate dose of CKRT, after excluding other common etiologies. Potential preventive strategies include the use of CKRT solutions with glucose, especially if there is concern of poor enteral feeding due to ileus, nausea or vomiting and possibly early initiation of parenteral nutrition to prevent negative caloric balance in such cases.

In summary, EuDKA is a potentially missed etiology of unexplained high AG metabolic acidosis in patients on CKRT which is rapidly correctable with insulin and glucose infusion.

Case 2

A 47 year-old woman with normal baseline renal function was recently diagnosed with acute myeloid leukemia and received chemotherapy with Cytarabine and Daunorubicin.  She then developed acute kidney injury secondary to tumor lysis syndrome (TLS) within 2 days of starting chemotherapy. Her course was also complicated by diffuse alveolar hemorrhage due to severe thrombocytopenia and she required transfer to ICU as well as aggressive fluid resuscitation. She developed significant volume overload even with high dose combination diuretics. Despite stable hemodynamics, to facilitate diuresis with ongoing AKI and high daily fluid gains, she received kidney replacement therapy by sustained low efficiency dialysis (SLED), followed by kidney recovery to a nadir creatinine level of 120 umol/l (1.4 mg/dl). Unfortunately, her leukemia relapsed and she was started on Gilteritinib (a tyrosine kinase inhibitor) on Day 50 of her admission.  Over the ensuing days her kidney function slowly worsened despite adequate fluid resuscitation. Her laboratory results are shown in Table 3.

Table 3: Laboratory results on consecutive days 

Serum parameters (reference range) Day 50 of admission- day of initiation of GilteritinibDay 51 Day 52 (morning)  
Sodium (136-144 mmol/l) 134 134 132 
Potassium (3.5-5.1 mmol/l) 3.9 4.1 4.5 
Bicarbonate (19-30 mmol/l) 18 17 14 
Anion gap (8-16 mmol/l) 12 15 19 
Calcium (2.24- 2.58 mmol/l) (9-10.3 mg/dl)2.31 (9.3 mg/dl)
Albumin (36-47 g/l) 36 
Phosphate (0.83-1.40 mmol/l) 0.82 
Creatinine (49-84umol/l) (0.6-1.0 mg/dl)194 (2.2 mg/dl)210 (2.4 mg/dl)193 (2.2 mg/dl)
White cell count (*109/L)14.916.1

Of note, she had developed worsening metabolic acidosis with an increasing anion gap despite stable kidney function over a three-day period. She did not have any diarrhea and did not appear to be taking any potentially culprit medications. Her serum lactate was 0.8 mmol/l (normal), and her glucose was 8 mmol/l. At this point, given her history of recent chemotherapy and the unexplained anion-gap metabolic acidosis, we suspected a recurrence of TLS. Additional labs as highlighted in Table 4 confirmed this diagnosis. 

Table 4: Lab confirmation of TLS

Serum parameters (reference range)Day 52 (evening) 
Calcium (2.24-2.58 mmol/l) 2.10 
Albumin (36-47 g/l) 37 
Phosphate (0.83-1.40 mmol/l) 2.79 
Uric acid (155-400 mmol/l) 864 
Potassium (3.5-5.1 mmol/l) 

The final diagnosis was TLS recurrence and the only obvious initial abnormality from the labs was a progressive anion-gap metabolic acidosis. The patient was started on I.V. Rasburicase along with I.V. fluids and her condition improved without the need for further dialysis.  

The Cairo-Bishop classification of TLS, proposed in 2004, provides specific laboratory criteria for the diagnosis of TLS both at presentation and within seven days of treatment:

  1. Laboratory TLS – when two or more abnormal serum values exist within 3 days before or 7 days after initiating chemotherapy in the setting of adequate hydration and use of a hypouricemic agent including-
  1.  uric acid ≥ 476 umol/l (≥8 mg/dl) 
  2. Potassium ≥ 6 mmol/l
  3. Phosphate ≥1.45 mmol/l (≥4.5 mg/dl)
  4. Calcium ≤ 1.75 mmol/l (≤ 7 mg/dl) 

Or 25 % decrease from baseline in any of the above parameters

     2.  Clinical TLS – Laboratory TLS plus one or more of the following:

  1. increased serum creatinine concentration (≥1.5 times the upper limit of normal)
  2. cardiac arrhythmia/sudden death
  3. Seizure

Certain factors increase the risk of TLS, some of them are tumor-related factors – high tumor proliferation rate, extent to which the tumor is chemosensitive and increased burden of the tumor (eg. bone marrow involvement, high pretreatment LDH, organ involvement, etc.) and other clinical features including pretreatment hyperuricemia (> 446 umol/l or >7.5 mg/dl), pre existing renal disease, concomitant use of other nephrotoxins, acidic urine and volume depletion. In particular, hematologic malignancies like aggressive non-Hodgkin lymphoma and acute lymphoblastic leukemia (eg. Burkitt’s lymphoma) are associated with very high risk of TLS. Other malignancies like AML, chronic lymphocytic leukemia and plasma cell disorder are less prone to this complication. 

However, in a case series of 130 patients with AML, 17 % were diagnosed with TLS (combined clinical and laboratory TLS). Independent risk factors associated with TLS included pretreatment serum creatinine >1.4 mg/dl (> 124 umol/l), serum LDH levels above normal value, uric acid >7.5 mg/dl (> 446 umol/l) and WBC >25 *109/L.  The scoring system based on the latter three values had AUC of 0.81 (suggestive of excellent discriminant function) and was accurate for predicting clinical and laboratory TLS. This patient had several of these risk factors including elevated pretreatment serum creatinine (180-190 umol/l) and serum LDH (450 U/l, normal: 99-186 U/l). High AGMA in TLS is the result of kidney injury and in some cases, the high serum phosphate contributes to the elevation in AG due to increase in unmeasured anions. 

Of course, the diagnosis would have been obvious had we had all the workup in the first place. But quite often, we encounter situations where we only have a limited set of labs, usually the very routine ones and a clinical scenario. In summary, conditions that should be suspected in unexplained high anion-gap metabolic acidosis include – ketoacidosis (diabetic, euglycemic or starvation- related), toxic alcohol intake (ethylene glycol, methanol), aspirin toxicity, D- or L-lactic acidosis, pyroglutamic acidosis (due to the use of acetaminophen), and TLS in the appropriate clinical context. Sometimes, the only clinical clue is a low serum bicarbonate that needs to be evaluated in a systematic way while remaining mindful of some less common but important causes.

Post by:

Sriram Sriperumbuduri DM

Clinical Fellow in Nephrology, The Ottawa Hospital, Canada.

Twitter: @sriperumbuduris

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