Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France

Caroline Prot-Bertoye^{1

2}, Saïd Lebbah³, Michel Daudon⁴, Isabelle Tostivint⁵, Jean-Philippe Jais^{6

7}, Agnés Lillo-Le Louët⁸, Clément Pontoizeau⁹, Pierre Cochat¹⁰, Pierre Bataille¹¹, Franck Bridoux¹², Pierre Brignon¹³, Christian Choquenet¹⁴, Christian Combe¹⁵, Pierre Conort¹⁶, Stéphane Decramer^{17

18}, Bertrand Doré¹⁹, Bertrand Dussol²⁰, Marie Essig^{21

22}, Marie Frimat²³, Nicolas Gaunez²⁴, Dominique Joly²⁵, Sophie Le Toquin-Bernard²⁶, Arnaud Méjean²⁷, Paul Meria²⁸, Denis Morin^{29

30}, Hung V N'Guyen²⁸, Michel Normand³¹, Michel Pietak³², Pierre Ronco^{33

34}, Christian Saussine³⁵, Michel Tsimaratos³⁶, Gérard Friedlander^{1

37}, Olivier Traxer³⁸, Bertrand Knebelmann²⁵, Marie Courbebaisse^{1

37}; French Cystinuria Group

Affiliations

¹ Department of Physiology, Functional Renal Explorations Department, AP-HP (Public Assistance Hospitals of Paris), Georges Pompidou European Hospital, Paris Descartes University, Paris, France.
² INSERM UMRS 1138, Paris, France.
³ Department of Biostatistics, AP-HP, Necker Hospital for Sick Children, Paris Descartes University, Medicine, Paris, France.
⁴ Department of Physiology, Functional Renal Explorations Department, AP-HP, Tenon Hospital Pierre and Marie Curie University, INSERM UMR S 1155, Paris, France.
⁵ Department of Nephrology, AP-HP, Pitié-Salpétrière Hospital, Paris, France.
⁶ Department of Biostatistics, AP-HP, Necker Hospital for Sick Children, Paris Descartes University, Paris, France.
⁷ Inserm UMRS 1138 team 22, Paris, France.
⁸ Department of Pharmacovigilance, AP-HP, Georges Pompidou European Hospital, Paris, France.
⁹ Functional Unit of Metabolomics, Functional Explorations Department, APHP, Necker Hospital for Sick Children, Paris Descartes University, Paris, France.
¹⁰ Department of Pediatrics, Hospices Civils de Lyon, Centre de Référence des Maladies Rénales Rares Néphrogones, Lyon, France.
¹¹ Department of Nephrology, Boulogne-sur-Mer Hospital, Boulogne sur Mer, France.
¹² Department of Neprhology, Poitiers University Hospital, Poitiers University, Poitiers, France.
¹³ Department of Nephrology, Pasteur Hospital, Colmar, France.
¹⁴ Department of Urology, Princesse Grace Hospital, Monaco, France.
¹⁵ Department of Nephrology, Bordeaux University Hospital, Bordeaux University, Bordeaux, France.
¹⁶ Department of Urology, AP-HP, Pitié-Salpétrière Hospital, Paris, France.
¹⁷ Department of Nephrology and Internal Medicine, Toulouse University Children Hospital, Toulouse, France.
¹⁸ INSERM U1048, Toulouse, France.
¹⁹ Department of Urology, Poitiers University Hospital, Poitiers University, Poitiers, France.
²⁰ Department of Nephrology, AP-HM (Public Assistance Hospitals of Marseille), Conception Hospital, Aix-Marseille University, Marseille, France.
²¹ Department of Nephrology, Dialysis and Transplantation, Limoges University Hospital, Limoges University, Limoges, France.
²² INSERM UMR-S850, Limoges, France.
²³ Department of Nephrology, Claude Huriez University Hospital, Lille, France.
²⁴ Department of Urology, Niort Hospital, Niort, France.
²⁵ Department of Nephrology, AP-HP, Necker Hospital for Sick Children, Paris Descartes University, Medicine, Paris, France.
²⁶ Department of Urology, Private Saint-Martin Hospital, Caen, France.
²⁷ Department of Urology, AP-HP, Georges Pompidou European Hospital, Paris Descartes University, Medicine, Paris, France.
²⁸ Department of Urology, AP-HP, Saint-Louis Hospital, Paris, France.
²⁹ Department of Pediatrics (Pediatric Nephrology and Diabetology), Montpellier University Hospital, Montpellier, France.
³⁰ CNRS, UMR 5203-INSERM U661, Montpellier, France.
³¹ Department of Nephrology, Private Saint-Martin Hospital, Pessac, France.
³² Department of Urology, AP-HP, Georges Pompidou European Hospital, Paris, France.
³³ Department of Nephrology and Dialysis, AP-HP, Tenon Hospital, Pierre and Marie Curie University, Paris, France.
³⁴ INSERM Unit 702, Paris, France.
³⁵ Department of Urology, Strasbourg University Hospital, Strasbourg University, Strasbourg, France.
³⁶ Department of Pediatrics, AP-HM, La Timone Hospital, Aix-Marseille University, Marseille, France.
³⁷ INSERM U1151, Paris, France.
³⁸ Department of Urology, AP-HP, Tenon Hospital, Pierre and Marie Curie University, Paris, France.

PMID: 30801923
DOI: 10.1111/bju.14721

Free article

Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France

Caroline Prot-Bertoye et al. BJU Int. 2019 Nov.

Free article

. 2019 Nov;124(5):849-861.

doi: 10.1111/bju.14721. Epub 2019 Mar 25.

Authors

Affiliations

¹ Department of Physiology, Functional Renal Explorations Department, AP-HP (Public Assistance Hospitals of Paris), Georges Pompidou European Hospital, Paris Descartes University, Paris, France.
² INSERM UMRS 1138, Paris, France.
³ Department of Biostatistics, AP-HP, Necker Hospital for Sick Children, Paris Descartes University, Medicine, Paris, France.
⁴ Department of Physiology, Functional Renal Explorations Department, AP-HP, Tenon Hospital Pierre and Marie Curie University, INSERM UMR S 1155, Paris, France.
⁵ Department of Nephrology, AP-HP, Pitié-Salpétrière Hospital, Paris, France.
⁶ Department of Biostatistics, AP-HP, Necker Hospital for Sick Children, Paris Descartes University, Paris, France.
⁷ Inserm UMRS 1138 team 22, Paris, France.
⁸ Department of Pharmacovigilance, AP-HP, Georges Pompidou European Hospital, Paris, France.
⁹ Functional Unit of Metabolomics, Functional Explorations Department, APHP, Necker Hospital for Sick Children, Paris Descartes University, Paris, France.
¹⁰ Department of Pediatrics, Hospices Civils de Lyon, Centre de Référence des Maladies Rénales Rares Néphrogones, Lyon, France.
¹¹ Department of Nephrology, Boulogne-sur-Mer Hospital, Boulogne sur Mer, France.
¹² Department of Neprhology, Poitiers University Hospital, Poitiers University, Poitiers, France.
¹³ Department of Nephrology, Pasteur Hospital, Colmar, France.
¹⁴ Department of Urology, Princesse Grace Hospital, Monaco, France.
¹⁵ Department of Nephrology, Bordeaux University Hospital, Bordeaux University, Bordeaux, France.
¹⁶ Department of Urology, AP-HP, Pitié-Salpétrière Hospital, Paris, France.
¹⁷ Department of Nephrology and Internal Medicine, Toulouse University Children Hospital, Toulouse, France.
¹⁸ INSERM U1048, Toulouse, France.
¹⁹ Department of Urology, Poitiers University Hospital, Poitiers University, Poitiers, France.
²⁰ Department of Nephrology, AP-HM (Public Assistance Hospitals of Marseille), Conception Hospital, Aix-Marseille University, Marseille, France.
²¹ Department of Nephrology, Dialysis and Transplantation, Limoges University Hospital, Limoges University, Limoges, France.
²² INSERM UMR-S850, Limoges, France.
²³ Department of Nephrology, Claude Huriez University Hospital, Lille, France.
²⁴ Department of Urology, Niort Hospital, Niort, France.
²⁵ Department of Nephrology, AP-HP, Necker Hospital for Sick Children, Paris Descartes University, Medicine, Paris, France.
²⁶ Department of Urology, Private Saint-Martin Hospital, Caen, France.
²⁷ Department of Urology, AP-HP, Georges Pompidou European Hospital, Paris Descartes University, Medicine, Paris, France.
²⁸ Department of Urology, AP-HP, Saint-Louis Hospital, Paris, France.
²⁹ Department of Pediatrics (Pediatric Nephrology and Diabetology), Montpellier University Hospital, Montpellier, France.
³⁰ CNRS, UMR 5203-INSERM U661, Montpellier, France.
³¹ Department of Nephrology, Private Saint-Martin Hospital, Pessac, France.
³² Department of Urology, AP-HP, Georges Pompidou European Hospital, Paris, France.
³³ Department of Nephrology and Dialysis, AP-HP, Tenon Hospital, Pierre and Marie Curie University, Paris, France.
³⁴ INSERM Unit 702, Paris, France.
³⁵ Department of Urology, Strasbourg University Hospital, Strasbourg University, Strasbourg, France.
³⁶ Department of Pediatrics, AP-HM, La Timone Hospital, Aix-Marseille University, Marseille, France.
³⁷ INSERM U1151, Paris, France.
³⁸ Department of Urology, AP-HP, Tenon Hospital, Pierre and Marie Curie University, Paris, France.

PMID: 30801923
DOI: 10.1111/bju.14721

Abstract

Objective: To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria.

Patients and methods: Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects logistic regression model was used to estimate how urine pH, specific gravity and cysteine-binding thiols (CBT) correlate with risk of cystine crystalluria.

Results: Alkalizing agents and CBT agents were given to 88.8% (n = 381) and 55.3% (n = 238) of patients, respectively. Gastrointestinal AEs were reported in 12.3%, 10.4% and 2.6% of patients treated with potassium bicarbonate, potassium citrate and sodium bicarbonate, respectively (P = 0.008). The percentages of patients who experienced at least one AE with tiopronin (24.6%) and with D-penicillamine (29.5%) were similar (P = 0.45). Increasing urine pH and decreasing urine specific gravity significantly reduced the risk of cystine crystalluria, whereas D-penicillamine and tiopronin treatments did not reduce this risk (odds ratio [OR] 1 for pH ≤6.5; OR 0.52 [95% confidence interval {95% CI} 0.28-0.95] for 7.0 <pH ≤7.5, P = 0.03; OR 0.26 [95% CI 0.13-0.53] for 7.5 < pH ≤8.0, P <0.001; OR 1 for specific gravity ≤1.005 OR 5.76 [95% CI 1.45-22.85] for 1.006 ≤ specific gravity ≤1.010, P = 0.01; and OR 11.06 [95% CI 2.76-44.26] for 1.011 ≤ specific gravity ≤ 1.014, P < 0.001). Increased urine pH significantly increased the risk of calcium phosphate crystalluria (OR 1 for pH≤ 6.5; OR 6.09 [95% CI 2.15-17.25] for pH >8.0, P <0.001).

Conclusion: Adverse events were frequent with D-penicillamine and tiopronin. Alkaline hyperdiuresis was well tolerated and reduced cystine crystalluria. Urine specific gravity ≤1.005 and urine pH >7.5, while warning about calcium-phosphate crystallization, should be the goals of medical therapy.

Keywords: D-penicillamine; cystinuria; potassium citrate; sodium bicarbonate; tiopronin.

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References

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Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France

Affiliations

Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France

Authors

Affiliations

Abstract

References

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LinkOut - more resources

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