A case of crystalline nephropathy
Authors: George S. Pazhayattil, Ursula C. Brewster, Mark A. Perazella
Journal: Kidney International (2015)

A 27-year-old woman with osteosarcoma involving the left distal femur was treated with high-dose methotrexate (5.5 g/m2 × 1 dose). One liter of isotonic sodium bicarbonate solution was infused and maintained to achieve a urine pH greater than 7.1. Within 48 h, serum creatinine rapidly rose from 0.9 to 1.6 mg/dl, consistent with acute kidney injury (AKI), despite urine output >100 ml/h. Methotrexate level was 49 μm/l. Urinalysis: SG 1.010, pH 8.5, and glucose, protein, and leukocyte esterase were negative. Urine microscopy revealed numerous brownish/gold crystals, which were in clumps (Figure 1a) and casts (Figure 1b)—consistent with methotrexate crystalline nephropathy. Five days later, kidney function returned to baseline. High-dose methotrexate causes AKI through multiple possible mechanisms including direct tubular toxicity associated with decreased adenosine deaminase activity and intratubular crystal precipitation.1Perazella M.A. Moeckel G.W. Nephrotoxicity from chemotherapeutic agents: clinical manifestations, pathobiology, and prevention/therapy.Sem Nephrol. 2010; 30: 570-581Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar Methotrexate and its metabolites, which are poorly soluble in an acid pH, precipitate within the renal tubular lumens in the setting of an acidic urine, decreased urinary flow rates, and when high urinary concentrations are present.1Perazella M.A. Moeckel G.W. Nephrotoxicity from chemotherapeutic agents: clinical manifestations, pathobiology, and prevention/therapy.Sem Nephrol. 2010; 30: 570-581Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar Crystal precipitation results in both distal renal tubular obstruction and associated tubulointerstitial inflammation.1Perazella M.A. Moeckel G.W. Nephrotoxicity from chemotherapeutic agents: clinical manifestations, pathobiology, and prevention/therapy.Sem Nephrol. 2010; 30: 570-581Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 2Mulay S.R. Evan A. Anders H.J. Molecular mechanisms of crystal-related kidney inflammation and injury. Implications for cholesterol embolism, crystalline nephropathies and kidney stone disease.Nephrol Dial Transplant. 2014; 29: 507-514Crossref PubMed Scopus (108) Google Scholar Methotrexate-associated AKI develops in approximately 2% of patients, is typically non-oliguric, and is generally reversible.1Perazella M.A. Moeckel G.W. Nephrotoxicity from chemotherapeutic agents: clinical manifestations, pathobiology, and prevention/therapy.Sem Nephrol. 2010; 30: 570-581Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar AKI prevention hinges on induction of high urinary flow rates and an alkaline urine pH (>7.1) by reducing precipitation of crystals within tubular lumens. When AKI develops, high-flux hemodialysis and carboxypeptidase-G2 are utilized to lower plasma levels. However, hemodialysis is inefficient and associated with post-dialysis rebound. Carboxypeptidase-G2 effectively lowers methotrexate levels via metabolism to nontoxic metabolites but is extremely costly.1Perazella M.A. Moeckel G.W. Nephrotoxicity from chemotherapeutic agents: clinical manifestations, pathobiology, and prevention/therapy.Sem Nephrol. 2010; 30: 570-581Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar Our case is unusual in that AKI and significant methotrexate crystalluria developed despite adequate urinary alkalinization and urine flow rates. In addition, methotrexate crystals and crystal-containing casts are rarely observed in the urine sediment and are the ‘liquid biopsy’ equivalent of intratubular crystals seen in kidney tissue.