Volume 54, Issue 6 , Pages 1158-1161, December 2009
Gentamicin-Induced Bartter-like Syndrome
Article Outline
Index Words: Bartter-like syndrome, gentamicin
Introduction
Gentamicin, a widely used antibiotic, is a well-known nephrotoxin responsible for acute nonoligouric kidney injury and tubular dysfunction. Among the rarest of these is Bartter-like syndrome, which reportedly occurs in adults and children as a toxic manifestation of gentamicin therapy with unclear pathophysiology. Subclinical hypermagnesiuria and hypercalciuria are detected immediately after administering gentamicin. However, the responsible target of gentamicin-associated tubular damage is unclear. This report presents a case of Bartter-like syndrome induced by gentamicin with delayed recovery of as long as 6 weeks and reviews the literature for possible mechanisms of this complication.
Case Report
Clinical History and Initial Laboratory Data
A 45-year-old woman presented with hand tremor, weakness, numbness, and frequent cramping in all 4 limbs during the prior 10 days. She was discharged from the hospital several days earlier after undergoing intraperitoneal chemotherapy with 100 mg of cisplatin for ovarian carcinoma. One year earlier, she had received 6 courses of chemotherapy with paclitaxel and carboplatin during a 5-month period without complications. In her latest hospitalization, she received a 10-day course of gentamicin, 60 mg, every 8 hours for a urinary tract infection. Other medical history includes thyroidectomy for hyperthyroidism 20 years earlier and subsequent propylthiouracil therapy with euthyroid status. No medical history of kidney disease, electrolyte disorder, alcohol consumption, or diuretic use was noted.
Physical examination showed normal blood pressure and positive Trousseau's and Chvostek's signs. Vital signs included blood pressure of 103/63 mm Hg, heart rate of 63 beats/min, respiratory rate of 18 breaths/min, and body temperature of 36.0°C. Serum sodium level was 129 mEq/L (129 mmol/L); potassium, 2.2 mEq/L (2.2 mmol/L); bicarbonate, 34.3 mEq/L (34.3 mmol/L); calcium, 6.4 mg/dL (1.6 mmol/L); magnesium, 0.24 mEq/L (0.12 mmol/L); and phosphate, 5.3 mg/dL (1.71 mmol/L). Serum urea nitrogen level was 13 mg/dL (4.64 mmol/L); serum creatinine, 0.6 mg/dL (53.0 μmol/L); and 24-hour creatinine clearance, 104.2 mL/min (1.74 mL/s). Urine glucose was negative. In addition to dietary intake, oral magnesium oxide and calcium carbonate, daily administration of potassium chloride (104 mEq of potassium), magnesium sulfate (48 mEq of magnesium), and calcium gluconate (0.376 g of calcium) could not correct hypokalemia, hypomagnesemia, and hypocalcemia.
Additional Investigations
Additional tests showed a high transtubular potassium gradient (11.6) and high fractional excretion of urinary potassium (42%), calcium (11%), and magnesium (51%). Plasma intact parathyroid hormone level was 47.4 pg/mL (47.4 ng/L), renin level was 17.8 ng/mL, and aldosterone level was 131 pg/mL (0.39 nmol/L).
Diagnosis
Gentamicin-induced Bartter-like syndrome.
Clinical Follow-up
Potassium, calcium, and magnesium supplements initially were given with intravenous potassium chloride, calcium gluconate, and magnesium sulfate. Later, oral tablets were used when the patient's condition stabilized. However, prolonged and fluctuating electrolyte imbalance continued for >6 weeks. Interestingly, analysis of urinary electrolyte wasting showed persistent potassium and calcium wasting despite resolution of magnesium wasting (Fig 1). During a later hospitalization for chemotherapy, the patient again developed urinary potassium, calcium, and magnesium wasting after a 1-week course of gentamicin, 80 mg/d, before starting treatment with doxorubicin and carboplatin.
Figure 1.
Urine electrolyte changes in the patient with gentamicin-induced Bartter-like syndrome. Arrows indicate the late recovery phase of urinary electrolyte wasting. Abbreviations: FeK, fractional excretion of potassium; FeCa, fractional excretion of calcium; FeMg, fractional excretion of magnesium.
Discussion
Our patient developed hypokalemic metabolic alkalosis, hypocalcemia, and hypomagnesemia after a 10-day treatment with gentamicin, 60 mg, every 8 hours (total, 1.8 g; cumulative dose, 35 mg/kg). Bartter-like syndrome, Fanconi syndrome, and Gitelman syndrome are among the differential diagnoses. Fanconi syndrome was not likely because of the absence of metabolic acidosis, hypouricemia, hypophosphatemia, and glycosuria. Gitelman syndrome would be unusual in the presence of hypercalciuria.
Acquired Bartter-like syndrome can be induced by diuretic abuse or therapeutic agents, such as capreomycin, viomycin, amphotericin B, cyclosporine, cisplatin, and aminoglycosides.1, 2 In addition to gentamicin, cisplatin was used for chemotherapy in our patient and might account for the renal tubular damage. However, the minimum cumulative dose of cisplatin required to induce hypomagnesemia and hypokalemia is 300 mg/m2 according to several previous reports.3, 4, 5, 6 The intraperitoneal cisplatin dose of 100 mg administered to this patient is too low to account for tubular dysfunction. Moreover, the same electrolyte abnormalities recurred when she was rechallenged with another 1-week treatment with gentamicin, 80 mg/d.
Bartter-like syndrome characterized by hypokalemic metabolic alkalosis, hypomagnesemia, hypocalcemia, and normal kidney function has been described in patients treated with aminoglycosides. Although the mechanisms of gentamicin-induced Bartter-like syndrome are still unclear, some authors have proposed mechanisms based on inherited Bartter syndrome, including dysfunction of the Na+-K+-2Cl− cotransporter NKCC2 (encoded by the SLC12A1 gene), the apical adenosine triphosphate (ATP)-dependent potassium channel ROMK (encoded by KCNJ1), the chloride channel ClC-Kb (encoded by CLCNKB), and inappropriate activation of the basolateral calcium-sensing receptor (CaSR). 7
In the thick ascending limb of the loop of Henle, the entry of sodium chloride primarily occurs through NKCC2 in the luminal membrane, which is driven by the adenosine triphosphatase (ATPase) sodium-potassium pump (Na+-K+-ATPase) in the basolateral membrane. The reabsorbed sodium and chloride ions return to systemic circulation through Na+-K+-ATPase and the C1C-Kb chloride channel, respectively. Recycling of potassium ion to the lumen through ROMK leads to a positive potential there, which results in the paracellular reabsorption of divalent cations, such as calcium and magnesium. Reabsorption of sodium and calcium ions is linked closely in this nephron segment, and the activities of both NKCC2 and ROMK are influenced by CaSR. When divalent or polyvalent cationic materials or antibiotics inappropriately activate CaSR, intracellular cAMP (cyclic adenosine monophosphate) production decreases and arachidonic acid (20-hydroxyeicosatetraenoic acid) formation through phospholipase A2 increases, which inhibits ROMK and NKCC2. In turn, this inhibition decreases potassium recycling and the positive potential in the lumen that is required for the paracellular transport of divalent cations.8, 9, 10 Therefore, inappropriate activation of CaSR leads to reduction of the luminal positive driving force and results in increased urinary calcium and magnesium excretion.
Our patient had gentamicin-induced Bartter-like syndrome with delayed recovery of as long as 6 weeks. Furthermore, resolution of urinary magnesium wasting preceded that of calcium and potassium. Inappropriate activation of CaSR produces urinary loss of both calcium and magnesium, whereas NKCC2 and ROMK dysfunction usually result in hypercalciuria, but relatively normal urinary magnesium excretion (and normal serum calcium and magnesium levels). Chloride channel dysfunction usually presents with normal serum calcium level and variable urinary loss of calcium and magnesium (Table 1).11
Table 1. Subtypes of Bartter Syndrome
| Type I | Type II | Type III | Type IV | Type V | |
|---|---|---|---|---|---|
| Channel Dysfunction | Na+-K+-2Cl− Cotransporter (NKCC2) | Apical ATP-regulated Potassium Channel (ROMK) | Distal Tubule Cl− Channel (ClC-Kb) | Barttin, β Subunit of Cl− Channel | Ca2+/Mg2+ Sensing Receptor (CaSR) |
| Serum Mg2+ | ↔ | ↔ | ↔ or↓ | ↔ | ↓ |
| Serum Ca2+ | ↔ | ↔ | ↔ | ↔ | ↓ |
| Urine Mg2+ | ↔ | ↔ | ↔or↑ | ↔ | ↑ |
| Urine Ca2+ | ↑ | ↑ | ↔or↑ | ↔or↑ | ↑ |
The initial laboratory data in this case (ie, predominant urinary calcium and magnesium wasting [with hypocalcemia and hypomagnesemia]) are identical to those in patients with gain-of-function mutations of CaSR. However, follow-up urinary chemistry data in this patient showed persistent urinary potassium and calcium wasting despite resolution of magnesium wasting. One possible explanation for this set of observations is earlier recovery of CaSR to normal activity with persistence of dysfunction of NKCC2 or ROMK; the normal serum calcium and magnesium levels fit with the latter observation.
These clinical findings need to be looked at in light of a recent animal study. This investigation showed that low-dose gentamicin administration was associated with decreased NKCC2 function in the ascending limb of the loop of Henle, but with unchanged abundance of CaSR and ROMK.8 However, high-dose gentamicin administration was associated with decreased NKCC2 and ROMK, as well as increased CaSR expression. It is unclear whether downregulation of NKCC2 resulted mainly from gentamicin toxicity or was mediated by the influence of an activated CaSR. Nevertheless, our patient shows the ability of gentamicin to cause multiple renal tubular abnormalities,12, 13, 14 likely including inappropriate activation of CaSR and NKCC2 or ROMK dysfunction. Last, recovery of CaSR activity to normal levels may precede repair of tubular transport systems.
In summary, this report of a woman presenting with Bartter-like syndrome after gentamicin therapy suggests that this syndrome is caused by a polyvalent toxin of gentamicin that induces multiple renal tubular abnormalities. Patients receiving gentamicin therapy should be monitored for complication with acquired Bartter-like syndrome. Prompt diagnosis and correction of these electrolyte and acid-base imbalances can reduce the risk of potentially life-threatening complications.
Acknowledgements
Support: This work was supported by grants from Kaohsiung Veterans General Hospital to Dr C.-L. Chen (VGHKS98-027) and Dr Fang (VGHKS98-25).
Financial Disclosure: None.
References
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- . Renal magnesium wasting associated with therapeutic agents. Miner Electrolyte Metab. 1991;17:58–64
- . Acute and chronic effects of cisplatin therapy on renal magnesium homeostasis. Med Pediatr Oncol. 1997;28:35–40
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- . Hypomagnesemia and renal magnesium wasting in patients treated with cisplatin. Am J Kidney Dis. 1986;8:164–169
- . Cisplatinum induced hypomagnesemia and peripheral neuropathy. Gynecol Oncol. 1983;16:309–318
- . Acquired Bartter-like syndrome associated with gentamicin administration. Am J Med Sci. 2005;329:144–149
- Dysregulation of renal sodium transporters in gentamicin-treated rats. Kidney Int. 2006;70:1026–1037
- . Fluid, electrolyte and acid-base disorders associated with antibiotic therapy. Nat Rev Nephrol. 2009;5:193–202
- . Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev. 2001;81:239–297
- . Hypokalemic tubular disorders. In: Davison AM, Cameron JS, Grunfeld JP, et al. editor. Oxford Textbook of Clinical Nephrology. 3rd ed.. New York: Oxford University Press; 2005;p. 995–1004
- . Aminoglycoside antibiotics induce pH-sensitive activation of the calcium-sensing receptor. Biochem Biophys Res Commun. 2002;297:71–77
- . Calcium-regulated renal calcium handling in healthy men: relationship to sodium handling. J Clin Endocrinol Metab. 1998;83:2366–2372
- Reduced expression of renal Na+ transporters in rats with PTH-induced hypercalcemia. Am J Physiol Renal Physiol. 2004;286:534–545
Originally published online as doi: 10.1053/j.ajkd.2009.07.016 on September 22, 2009.
PII: S0272-6386(09)01045-2
doi:10.1053/j.ajkd.2009.07.016
© 2009 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved.
Volume 54, Issue 6 , Pages 1158-1161, December 2009
