The Friday evening case of acute kidney injury: a crystal dilemma

The Friday evening case of acute kidney injury: a crystal dilemma We report a case of acute kidney injury (AKI) induced by amoxycillin crystalluria suggested by massive amounts of urinary crystals of unusual morphology. This hypothesis was further reinforced by a particular solubility pattern when the urine sample was exposed to various temperatures, alkali, acids and alcohol. We therefore suspended amoxycillin, which produced a rapid and complete recovery of kidney function. Infrared spectroscopy later confirmed the amoxycillin composition of the crystals. Since infrared spectroscopy is not easily available, we propose that these solubility tests of urinary crystals be used as a first-step investigation when amoxycillin crystalluria is suspected. Key words: acute kidney injury, amoxycillin, crystalluria, solubility tests, urinary sediment Background Case report Acute kidney injury (AKI) is a serious complication occurring On 7 November 2016, an 80-year-old obese and hypertensive in 21% of critically ill hospitalized patients that is associated woman was admitted for severe back pain with fever. Her past with increased morbidity, mortality and costs [1]. Among causes clinical history was unremarkable. At admission, serum creati- of hospital-acquired AKI, amoxycillin may be rarely implicated nine was 79 mmol/L (0.9 mg/dL) with a normal urine dipstick. On 9 November, intravenous amoxycillin 2.2 g four times daily was through massive intrarenal or post-renal precipitation of crys- tals made up of the drug itself [2]. started following the diagnosis of pyogenic spondylodiscitis We report the case of a patient with AKI induced by amoxy- caused by Parvimonas micra. Other medications included ibupro- cillin crystalluria in which the diagnosis was suggested by a fen 600 mg twice daily for back pain and olmesartan 20 mg daily specific pattern of crystal solubility and was then confirmed by for hypertension. The next day, serum creatinine rose to infrared spectroscopy. 122 mmol/L (1.38 mg/dL). Ibuprofen and olmesartan were Received: July 26, 2017. Editorial decision: August 28, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/450/4557546 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Crystal dilemma in AKI | 451 Table 1. Behaviour of amoxycillin crystals compared with other crystals found in urine when exposed to different physical and chemical condi- tions: heat (27, 30 and 60 C), alkali (NaOH 0.1 M), acids (HCl 25% and CH COOH 1.0 mmol/L) and alcohol (70%) HCl 25% CH COOH 1.0 mmol/l NaOH 0.1 M Crystals Heat (pH 3) (pH 5.5) (pH 8) Alcohol 70% Uric acid S I I S I Calcium oxalate unk S I S unk Calcium phosphate I S S I unk Cholesterol unk unk unk unk S Cystine unk S I S I Leucine unk I I/S S S Tyrosine S S I S I Ammonium S S S S unk Amoxycillin I S I S I Similar to calcium oxalate, cystine, tyrosine and ammonium crystals, urinary crystals from our patient were found to be soluble in highly acidic (pH 3.0) and alkaline (pH 8.0) solutions. In contrast, they were insoluble when exposed to different temperatures, pH 5.5 and alcohol 70%. Please note that calcium oxalate and amoxycillin crystals show the same solubility behaviour when exposed to alkali (NaOH 0.1 M) and different acids (HCl 25% and CH COOH 1.0 mmol/L), but they are easily distinguishable in morphology. I, insoluble; S, soluble; unk, unknown. withdrawn and the patient was hydrated with intravenous of the drug and in adults treated with high doses of amoxycillin. sodium chloride. However, renal function continued to deterio- Crystalluria may be isolated or associated with microscopic rate rapidly, with serum creatinine peaking at 450 mmol/L and/or gross haematuria and leucocyturia, with or without oli- (5.09 mg/dL) in association with oliguria. This led to the so-called guric AKI. This may be due to urinary tract obstruction caused Friday evening call to the nephrologist. We found a normotensive by massive crystal precipitation in the renal pelvis or in the and mildly dehydrated patient with normal kidneys at bedside renal tubules, with subsequent tubulopathy and medullary con- abdominal echography. The fractional excretion of sodium of gestion. However, this hypothesis has not been confirmed by 0.6% indicated pre-renal AKI. Urinary dipstick showed a pH 5.0, renal biopsy [2]. relative density 1.030, albumin 100 mg/dL, haemoglobin Approximately 80% of amoxycillin is excreted unchanged in 250 erythrocytes/mL and leucocyte esterase 500 leucocytes/mL. The the urine and, similar to other antimicrobial agents, may cause urine sediment, examined by both bright field and phase contrast crystalluria, especially when the drug is overdosed, in hypoal- microscopy at low (100) and high (400) magnifications, buminaemic states or in mid-range urinary pH (between 4.0 and showed severe crystalluria [> 30 crytals/high-power field (HPF)] 7.0) [2]. associated with mild leucocyturia (8white blood cells/HPF) and Amoxycillin crystals differ in morphology from other urinary moderate isomorphic haematuria (20 red blood cells/HPF). crystals. In this context, the exposure of urine samples to a vari- Crystals appeared as thin and colourless needles and rods, either ety of standardized physical and chemical conditions is pro- in individual structures or in clusters, and strongly birefringent posed as a simple and inexpensive test to reinforce the under polarized light (Supplementary data, Figure S1). Since the suspicion of amoxycillin crystalluria. In our case, this test led to morphology of the crystals was unusual, the urine sample was immediate discontinuation of the drug, a difficult decision to exposed to the following physical and chemical conditions [3]: make in this critical situation, which in turn induced a rapid various temperatures (27, 30 and 60 C), alkali (NaOH 0.1 M), acids recovery from AKI. However, the definitive confirmation of this (HCl 25% and CH COOH 1.0 mmol/L) and alcohol 70%. Crystals diagnosis may only be provided by infrared spectroscopy [2], a showed a peculiar solubility pattern different from other known technique that is not easily and promptly available. urinary crystals (Table 1). In conclusion, we propose that the suspicion of amoxycillin Therefore, considering the short time interval between the crystalluria should prompt the use of these urinary solubility first administration of amoxycillin and the onset of AKI, we tests, which may prove to be instrumental for bedside clinical hypothesized that crystals could be due to intrarenal amoxycil- decisions, at least until infrared spectroscopy is performed. lin precipitation [4]. This drug was immediately suspended and replaced by clindamycin, 600 mg three times daily. In addition, Supplementary data 1.4% intravenous sodium bicarbonate was given to increase the crystals’ solubility through urine alkalinization and reverse Supplementary data are available online at http://ckj.oxford hypovolaemia. This led to a rapid induction of diuresis and the journals.org. disappearance of crystalluria within 24 h. Three days later, a full recovery of renal function was observed. Spondylodiscitis Acknowledgements was successfully treated with clindamycin. Infrared spectro- We would like to thank Valia Humbert-Delaloye, PhD from scopy of crystals, performed on 15 November, showed a wave the Department of Pharmacy, Central Institute of Hospitals, spectrum exactly matching the amoxycillin spectrum reported Hospital of Wallis, for providing us the infrared spectro- by others [5]. scopy urinary crystals analysis. Discussion Conflict of interest statement Amoxycillin crystalluria is rare. Single cases have been reported in paediatric patients after accidental ingestion and/or overdose None declared. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/450/4557546 by Ed 'DeepDyve' Gillespie user on 07 August 2018 452 | G. Guzzo et al. 3. Fogazzi GB. The Urinary Sediment – An Integrated View, 3rd edn. References Milano: Elsevier, 2010 1. Mehta RL, Cerda J, Burdmann EA et al. International Society of 4. Sjovall J, Westerlund D, Alvan G. Renal excretion of intrave- Nephrology’s 0by25 initiative for acute kidney injury (zero nously infused amoxycillin and ampicillin. Br J Clin Pharmacol preventable deaths by 2025): a human rights case for nephrol- 1985; 19: 191–201 ogy. Lancet 2015; 385: 2616–2643 5. Moffat AC, Osselton MC, Widdop B. Clarke’s Analysis of Drugs 2. Fogazzi G, Cantu M, Saglimbeni L et al. Amoxycillin, a rare but and Poisons, Vol. 2, 3rd edn. London: Pharmaceutical Press, possible cause of crystalluria. Nephrol Dial Transplant 2003; 18: 2004, 633 212–214 Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/450/4557546 by Ed 'DeepDyve' Gillespie user on 07 August 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

The Friday evening case of acute kidney injury: a crystal dilemma

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© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.
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Abstract

We report a case of acute kidney injury (AKI) induced by amoxycillin crystalluria suggested by massive amounts of urinary crystals of unusual morphology. This hypothesis was further reinforced by a particular solubility pattern when the urine sample was exposed to various temperatures, alkali, acids and alcohol. We therefore suspended amoxycillin, which produced a rapid and complete recovery of kidney function. Infrared spectroscopy later confirmed the amoxycillin composition of the crystals. Since infrared spectroscopy is not easily available, we propose that these solubility tests of urinary crystals be used as a first-step investigation when amoxycillin crystalluria is suspected. Key words: acute kidney injury, amoxycillin, crystalluria, solubility tests, urinary sediment Background Case report Acute kidney injury (AKI) is a serious complication occurring On 7 November 2016, an 80-year-old obese and hypertensive in 21% of critically ill hospitalized patients that is associated woman was admitted for severe back pain with fever. Her past with increased morbidity, mortality and costs [1]. Among causes clinical history was unremarkable. At admission, serum creati- of hospital-acquired AKI, amoxycillin may be rarely implicated nine was 79 mmol/L (0.9 mg/dL) with a normal urine dipstick. On 9 November, intravenous amoxycillin 2.2 g four times daily was through massive intrarenal or post-renal precipitation of crys- tals made up of the drug itself [2]. started following the diagnosis of pyogenic spondylodiscitis We report the case of a patient with AKI induced by amoxy- caused by Parvimonas micra. Other medications included ibupro- cillin crystalluria in which the diagnosis was suggested by a fen 600 mg twice daily for back pain and olmesartan 20 mg daily specific pattern of crystal solubility and was then confirmed by for hypertension. The next day, serum creatinine rose to infrared spectroscopy. 122 mmol/L (1.38 mg/dL). Ibuprofen and olmesartan were Received: July 26, 2017. Editorial decision: August 28, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/450/4557546 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Crystal dilemma in AKI | 451 Table 1. Behaviour of amoxycillin crystals compared with other crystals found in urine when exposed to different physical and chemical condi- tions: heat (27, 30 and 60 C), alkali (NaOH 0.1 M), acids (HCl 25% and CH COOH 1.0 mmol/L) and alcohol (70%) HCl 25% CH COOH 1.0 mmol/l NaOH 0.1 M Crystals Heat (pH 3) (pH 5.5) (pH 8) Alcohol 70% Uric acid S I I S I Calcium oxalate unk S I S unk Calcium phosphate I S S I unk Cholesterol unk unk unk unk S Cystine unk S I S I Leucine unk I I/S S S Tyrosine S S I S I Ammonium S S S S unk Amoxycillin I S I S I Similar to calcium oxalate, cystine, tyrosine and ammonium crystals, urinary crystals from our patient were found to be soluble in highly acidic (pH 3.0) and alkaline (pH 8.0) solutions. In contrast, they were insoluble when exposed to different temperatures, pH 5.5 and alcohol 70%. Please note that calcium oxalate and amoxycillin crystals show the same solubility behaviour when exposed to alkali (NaOH 0.1 M) and different acids (HCl 25% and CH COOH 1.0 mmol/L), but they are easily distinguishable in morphology. I, insoluble; S, soluble; unk, unknown. withdrawn and the patient was hydrated with intravenous of the drug and in adults treated with high doses of amoxycillin. sodium chloride. However, renal function continued to deterio- Crystalluria may be isolated or associated with microscopic rate rapidly, with serum creatinine peaking at 450 mmol/L and/or gross haematuria and leucocyturia, with or without oli- (5.09 mg/dL) in association with oliguria. This led to the so-called guric AKI. This may be due to urinary tract obstruction caused Friday evening call to the nephrologist. We found a normotensive by massive crystal precipitation in the renal pelvis or in the and mildly dehydrated patient with normal kidneys at bedside renal tubules, with subsequent tubulopathy and medullary con- abdominal echography. The fractional excretion of sodium of gestion. However, this hypothesis has not been confirmed by 0.6% indicated pre-renal AKI. Urinary dipstick showed a pH 5.0, renal biopsy [2]. relative density 1.030, albumin 100 mg/dL, haemoglobin Approximately 80% of amoxycillin is excreted unchanged in 250 erythrocytes/mL and leucocyte esterase 500 leucocytes/mL. The the urine and, similar to other antimicrobial agents, may cause urine sediment, examined by both bright field and phase contrast crystalluria, especially when the drug is overdosed, in hypoal- microscopy at low (100) and high (400) magnifications, buminaemic states or in mid-range urinary pH (between 4.0 and showed severe crystalluria [> 30 crytals/high-power field (HPF)] 7.0) [2]. associated with mild leucocyturia (8white blood cells/HPF) and Amoxycillin crystals differ in morphology from other urinary moderate isomorphic haematuria (20 red blood cells/HPF). crystals. In this context, the exposure of urine samples to a vari- Crystals appeared as thin and colourless needles and rods, either ety of standardized physical and chemical conditions is pro- in individual structures or in clusters, and strongly birefringent posed as a simple and inexpensive test to reinforce the under polarized light (Supplementary data, Figure S1). Since the suspicion of amoxycillin crystalluria. In our case, this test led to morphology of the crystals was unusual, the urine sample was immediate discontinuation of the drug, a difficult decision to exposed to the following physical and chemical conditions [3]: make in this critical situation, which in turn induced a rapid various temperatures (27, 30 and 60 C), alkali (NaOH 0.1 M), acids recovery from AKI. However, the definitive confirmation of this (HCl 25% and CH COOH 1.0 mmol/L) and alcohol 70%. Crystals diagnosis may only be provided by infrared spectroscopy [2], a showed a peculiar solubility pattern different from other known technique that is not easily and promptly available. urinary crystals (Table 1). In conclusion, we propose that the suspicion of amoxycillin Therefore, considering the short time interval between the crystalluria should prompt the use of these urinary solubility first administration of amoxycillin and the onset of AKI, we tests, which may prove to be instrumental for bedside clinical hypothesized that crystals could be due to intrarenal amoxycil- decisions, at least until infrared spectroscopy is performed. lin precipitation [4]. This drug was immediately suspended and replaced by clindamycin, 600 mg three times daily. In addition, Supplementary data 1.4% intravenous sodium bicarbonate was given to increase the crystals’ solubility through urine alkalinization and reverse Supplementary data are available online at http://ckj.oxford hypovolaemia. This led to a rapid induction of diuresis and the journals.org. disappearance of crystalluria within 24 h. Three days later, a full recovery of renal function was observed. Spondylodiscitis Acknowledgements was successfully treated with clindamycin. Infrared spectro- We would like to thank Valia Humbert-Delaloye, PhD from scopy of crystals, performed on 15 November, showed a wave the Department of Pharmacy, Central Institute of Hospitals, spectrum exactly matching the amoxycillin spectrum reported Hospital of Wallis, for providing us the infrared spectro- by others [5]. scopy urinary crystals analysis. Discussion Conflict of interest statement Amoxycillin crystalluria is rare. Single cases have been reported in paediatric patients after accidental ingestion and/or overdose None declared. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/450/4557546 by Ed 'DeepDyve' Gillespie user on 07 August 2018 452 | G. Guzzo et al. 3. Fogazzi GB. The Urinary Sediment – An Integrated View, 3rd edn. References Milano: Elsevier, 2010 1. Mehta RL, Cerda J, Burdmann EA et al. International Society of 4. Sjovall J, Westerlund D, Alvan G. Renal excretion of intrave- Nephrology’s 0by25 initiative for acute kidney injury (zero nously infused amoxycillin and ampicillin. Br J Clin Pharmacol preventable deaths by 2025): a human rights case for nephrol- 1985; 19: 191–201 ogy. Lancet 2015; 385: 2616–2643 5. Moffat AC, Osselton MC, Widdop B. Clarke’s Analysis of Drugs 2. Fogazzi G, Cantu M, Saglimbeni L et al. Amoxycillin, a rare but and Poisons, Vol. 2, 3rd edn. London: Pharmaceutical Press, possible cause of crystalluria. Nephrol Dial Transplant 2003; 18: 2004, 633 212–214 Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/450/4557546 by Ed 'DeepDyve' Gillespie user on 07 August 2018

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Clinical Kidney JournalOxford University Press

Published: Aug 1, 2018

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