CONTENTS

• Diagnosis
• Causes
• Investigation
  • History
  • Laboratory workup for RTA (renal tubular acidosis)
• Type IV RTA
• Treatment
• Podcast
• Questions & discussion
• Other topics
  • Urine anion gap (UAG)
• Pitfalls

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diagnosis

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The diagnosis of NAGMA may be made in one of two ways: (red arrows above)

1. Patient has normal anion gap with metabolic acidosis (bicarbonate < 22 mM).
2. Patient has an anion gap metabolic acidosis, but the decrease in bicarbonate is much greater than the elevation in anion gap (indicating the combination of an anion-gap metabolic acidosis plus a non-anion-gap metabolic acidosis).

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causes of NAGMA

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Etiologies can be divided into renal tubular acidosis (RTA) versus non-RTA causes. There are a small number of non-RTA etiologies, which can often be discerned based on history. In contrast, there are a broad variety of causes of RTA that may be difficult to discern.

non-RTA etiologies 

• Administration of osmotically active substances with a low strong ion gap:
  • Large amounts of NaCl administration (e.g., normal saline, hypertonic saline).
  • Large amounts of potassium chloride (either IV or PO).
  • Plasma exchange with 4% albumin replacement. (38837536)
  • Total parenteral nutrition with inadequate acetate.
  • Calcium chloride administration.
• Gastrointestinal bicarbonate loss:
  • Diarrhea (especially secretory).
  • High-output fistulas, pancreatic/biliary drainage.
  • Cholestyramine or sevelamer hydrochloride. (38837536)
• Moderate insufficiency (“RTA of kidney insufficiency”).
  • Often emerges as GFR falls to ~20-40 ml/min.
  • Inadequate ammoniagenesis leads to a NAGMA (if GFR falls further, AGMA develops).
  • Sevelamer use in renal failure may also promote NAGMA.
• Other:
  • Resolving diabetic ketoacidosis. 📖
  • Ureteroileostomy or ureterosigmoidostomy.
  • Chronic hyperventilation (extremely rare).

RTAs (renal tubular acidoses)

• Numerous causes area shown on the table below 👇

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investigation

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[1] Is there a clear cause based on clinical history? 

• The cause of NAGMA is often fairly clear, based on a review of clinical history, medications, and laboratory values (especially the non-RTA etiologies).
• If a likely cause is present, this may simply be treated. Additional diagnostic evaluation may not be needed (unless the patient fails to respond to therapy).

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[2] laboratory workup of renal tubular acidosis

labs to obtain

• Complete electrolytes (including Ca/Mg/Phos).
• Urinalysis.
• Urine sodium, potassium, glucose, urea (aka “urea nitrogen”), osmolarity, urine pH.

urine pH

• ⚠️ Urine pH should be measured accurately using a pH meter.
• Type I (distal) RTA: Urine pH is always pathologically elevated (>5.3-6.5).
• Type II (proximal) RTA:
  • Urine pH is usually <5.5 at steady state (bicarbonate falls low enough that the kidney is able to reabsorb it).
  • Alkali loading will cause bicarbonate to be spilled in the urine, causing an elevation in pH.
• Type IV RTA:
  • Aldosterone deficiency: pH usually <5.5 (with the acidosis largely being driven by impaired ammoniagenesis).
  • Structural damage to the cortical collecting duct: pH usually >5.5 (33367987)

urine glucose

• Normally should be negative (e.g., <30 mg/dL).
• Causes of positive urine glucose include: hyperglycemia with glucose above ~200 mg/dL, SGLT2 inhibitor use, or generalized type-2 RTA (Fanconi syndrome).

urine osmolar gap

• How to calculate:
  • Osmolar Gap = Urine osmolarity – 2(sodium + potassium) – Glucose(in mg/dL)/18 – Urea(in mg/dL)/28.
  • You can do this using this calculator from QXmD (it's designed for serum osmolal gap, but it works for urine too).
• The osmolar gap is an indirect measurement of the ammonium (i.e., acid) excreted by the distal nephron. Normally, the osmolar gap should be ~10-100 mOsm. (38837536) In the context of metabolic acidosis:
  • Osmolar gap <150 mOsm indicates inadequate renal ammonium excretion (suggests RTA type I or IV).
  • Osmolar gap >150 mOsm indicates appropriate ammonium excretion. This may occur with a non-renal source of acid loss, or with Type II (proximal) RTA. (29344509)

which type of RTA?

• Based on the urine osmolal gap, serum chemistries, and urinalysis it may be possible to classify the patient into one type of RTA shown below.
• RTA-2 (proximal) in adults may solely involve carbonic anhydrase inhibition due to medications that inhibit carbonic anhydrase (e.g., acetazolamide, topiramate). However, most cases of acquired proximal RTA in adults involve generalized proximal tubular dysfunction aka Fanconi syndrome (e.g., causing loss of glucose, phosphate, and uric acid). (33367987)

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type IV RTA

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Note: Type IV RTA is being used here to refer to both patients with aldosterone deficiency and also aldosterone resistance.

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differential diagnosis of NAGMA with hyperkalemia 

• Normal saline infusion.
• Exogenous acid administration (e.g., total parenteral nutrition).
• Type IV RTA.
• Chronic renal insufficiency:
  • Renal failure with GFR of ~20-40 ml/min may cause NAGMA.
  • GFR >40-50 ml/min with hyperkalemic NAGMA suggests type IV RTA.

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causes of type IV RTA

[#1/2] Type IV RTA with aldosterone deficiency (urine pH <5.5)

• Hyporeninemic hypoaldosteronism (impaired renin synthesis in renal juxtaglomerular cells; renal function is often mild-moderately impaired):
  • Chronic renal insufficiency due to diabetes and/or HTN (most common).
  • Tubulointerstitial diseases.
  • HIV.
  • Nephrosclerosis.
• Adrenal insufficiency, e.g.:
  • Addison disease.
  • Bilateral adrenal gland injury (e.g., Waterhouse-Friderichsen syndrome).
  • Isolated hypoaldosteronism of critical illness.
• Medications:
  • [1] Causing low renin synthesis:
    • NSAIDs.
    • Nonspecific beta-blockers.
    • Cyclosporine, tacrolimus.
  • [2] Causing low aldosterone synthesis
    • Heparin-induced suppression of aldosterone synthesis (either unfractionated or low molecular-weight heparin).
    • ACEi/ARBs.
    • Renin inhibitor (aliskiren).
    • Ketoconazole.

[#2/2] Type IV RTA with voltage gradient defect, aka aldosterone resistance (urine pH >5.5)

• Diseases involving the tubulointerstitium:
  • Obstructive uropathy.
  • Sickle cell disease.
  • Lupus nephritis.
  • Kidney transplant rejection.
  • Amyloidosis.
  • Multiple myeloma or monoclonal gammopathy.
• Medications impairing principal cell function:
  • ENaC inhibitors:
    • Amiloride, triamterene.
    • Trimethoprim.
    • Pentamidine.
  • Aldosterone inhibitors:
    • Spironolactone.
    • Eplerenone.
  • Cyclosporine, tacrolimus (Na/K-ATPase inhibitors).

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diagnostic investigations for type IV RTA

• The table below shows the electrolyte patterns usually seen in type IV RTA.
• Measurement of urine electrolytes, urine pH, and the urine osmolal gap is described above: ⚡️
• Type IV RTA involves renal potassium retention:
  • Urinary K+ is <40 mM. (33367987)
  • Fractional urinary potassium excretion is <20%. (33367987)
• Measurement of renin, aldosterone, and cortisol levels may be helpful (however these will take some time to return).
• A therapeutic trial of fludrocortisone may be considered (discussed below).

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management of type IV RTA

⚠️ If there is concern for adrenal insufficiency, this may require emergent therapy: 📖

fludrocortisone

• Oral fludrocortisone may be diagnostic and therapeutic.
• Fludrocortisone trial may help confirm the diagnosis of type IV RTA with aldosterone deficiency:
  • 0.2 mg fludrocortisone is administered PO.
  • If the patient has a mineralocorticoid deficiency, the following should be seen:
    • Fludrocortisone induces an increase in the urinary trans-tubular potassium gradient (TTKG) after four hours. (24259739, 18216310)
    • The potassium level will be decreased the following day.
• From a pragmatic standpoint, administration of fludrocortisone is often faster than obtaining aldosterone levels.
• Fludrocortisone may be continued among patients with a favorable response. However, chronic use of fludrocortisone is contraindicated among patients with heart failure or hypertension. (33367987) In some patients, a combination of fludrocortisone plus furosemide may be useful. (Reddi 2020)

hyperkalemia management

• Treatment options may include:
  • Sodium zirconium cyclosilicate may reduce potassium and also improve bicarbonate levels (perhaps partially due to binding of NH4+ in the gut). (33367987)
  • Loop diuretics may be useful.
• Lowering the potassium level often causes correction of the metabolic acidosis (reduction in potassium causes increased ammoniagenesis in the proximal tubule). (33367987)
• (Further discussion on the management of hyperkalemia here: 📖)

metabolic acidosis management

• Metabolic acidosis is often mild. It may improve solely with management of hyperkalemia.
• Oral bicarbonate may be useful for persistent acidosis.

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treatment

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resolution of underlying cause

• Whenever possible, the underlying cause should be identified and corrected. For example:
  • Causative drugs should be discontinued if possible.
  • Fludrocortisone may be effective in some patients with type IV RTA due to aldosterone deficiency (discussed above).
• Unfortunately, treatment of the cause is often insufficient to cause rapid resolution (e.g., in patients with moderate kidney injury). In most cases, further treatment is required as described below.
• Type I or type IV RTA patients require chronic therapy with oral alkali supplementation and occasionally various diuretics. This is beyond the scope of this chapter (consult nephrology for help with longitudinal management and follow-up).

should NAGMA be treated?

• It is controversial whether NAGMA requires treatment. Although NAGMA frequently correlates with poor outcomes, it's unclear to what extent it may cause harm.
• The rationale for treatment include the following includes:
  • (1) Hyperchloremic metabolic acidosis may increase the risk of renal injury. (24335444, 22580944, 29485926)
  • (2) Hyperchloremic metabolic acidosis appears to cause systemic inflammation. (17035425, 24335444, 21645639, 29435315)
  • (3) Metabolic acidosis will increase the work of breathing (by triggering a compensatory respiratory alkalosis). This may be particularly detrimental in patients with limited respiratory reserve (e.g., patients at risk for intubation, or patients who are struggling to be liberated from the ventilator).
  • (4) Acidosis increases insulin resistance, which may increase risk of recurrent DKA (among patients with resolving DKA in the process of coming off the insulin infusion).
• Reasonable indications to treat NAGMA with alkali might include:
  • The bicarbonate is below ~ 16-18 mEq/L.
  • The threshold for treatment may be lower for patients at increased risk of harm from metabolic acidosis (e.g. acute kidney injury or resolving diabetic ketoacidosis).

overview of NAGMA treatment

• NAGMA fundamentally represents an imbalance between sodium chloride and sodium bicarbonate. Treatment therefore may involve addition of sodium bicarbonate and/or removal of sodium chloride. The optimal approach depends on volume status, for example:
  • Hypovolemia –> Add sodium bicarbonate.
  • Euvolemia –> Add sodium bicarbonate and remove sodium chloride simultaneously. The goal here is to replace bicarbonate with chloride, without shifting the volume status.
  • Hypervolemia –> Remove sodium chloride via diuresis.
• This gets a bit more complicated, because different treatments will affect the sodium concentration (which is fundamentally a reflection of the free water balance). For example:
  • Hypertonic bicarbonate will increase the sodium concentration.
  • Diuresis using only a loop diuretic (e.g. furosemide) will increase the sodium concentration.
  • Diuresis using both a loop diuretic plus a thiazide may facilitate removal of sodium chloride without causing hypernatremia (more on this here).
• The optimal treatment will simultaneously address the NAGMA, the volume status, and the sodium concentration. For example, in a patient with hyponatremia and NAGMA, the use of hypertonic bicarbonate may simultaneously treat both problems.

bicarbonate therapy

• When repleting bicarbonate it is useful to calculate the patient's bicarbonate deficit, for example with this calculator from MDCalc. This isn't 100% accurate, but it provides a general concept of the amount of bicarbonate required.
• The use of IV bicarbonate is explored in greater detail here. Some brief comments on the various forms of bicarbonate:
• (1) Hypertonic bicarbonate:
  • May be preferred for patients with hyponatremia (will treat both NAGMA and hyponatremia).
  • May be used in limited quantities in patients with normonatremia (excessive doses will cause hypernatremia).
  • Contraindicated in patients with hypernatremia (will aggravate this).
• (2) Isotonic bicarbonate:
  • May be preferred for patients with hypovolemia (because it involves a substantial volume load, which will fix both NAGMA and hypovolemia).
• (3) Oral alkali:
  • This takes longer to work, is overall less effective, and may tend to cause hypernatremia.
  • Oral alkali may be useful in cases of mild NAGMA or in patients with ongoing bicarbonate loss (as a maintenance therapy).
  • Sodium bicarbonate may be given orally in tablet form (1300 mg = 15 mEq bicarbonate).
  • Sodium citrate liquid is an alternative to sodium bicarbonate (citrate is rapidly metabolized to bicarbonate).
    • Most formulations (e.g. BICITRA) contains the biologic equivalent of 1 mEq/ml sodium bicarbonate.
    • This may be logistically easier to give than sodium bicarbonate tablets (e.g., 30 ml q6hr provides 120 mEq of alkali daily. This is equivalent to sixteen 650-mg tablets of sodium bicarbonate).
  • Potassium citrate solution (e.g., POLYCITRA-K) might be useful in NAGMA with hypokalemia. POLYCITRA-K is twice as concentrated as sodium citrate solution (with 2 mEq/ml potassium and generation of 2 mEq alkali per ml).

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urine anion gap

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• Previously the urinary anion gap has been used to evaluate for the presence of renal tubular acidosis. However, the urinary anion gap has numerous limitations. (24403272) Specifically, the urinary anion gap may be unreliable due to:
  • Polyuria.
  • Urine pH > 6.5.
  • Presence of unusual anions such as ketoacids or penicillins. (29344509)
• Consequently, the urinary anion gap has been replaced by the urine osmolar gap as described above. (38837536)

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Failure to treat: NAGMA can generally be treated in a supportive fashion (e.g. with IV bicarbonate), even if the precise etiology is unknown. Patients with substantial acidosis should be treated while investigation is ongoing.
• Use of urine anion gap may be misleading. This should generally be avoided, with urine osmolar gap used instead (both of these tests are designed to evaluate for ammonium).

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