| | Crystal-Induced Kidney Disease in 2 Kidney Transplant RecipientsReceived 19 December 2008; accepted 14 August 2009. published online 02 November 2009. Crystal-induced kidney disease refers to kidney injury caused by intratubular crystal deposition of calcium salts, medications, or other chemicals. The major risk factors for crystal deposition include hypercalcemia and/or hypercalciuria, hyperoxalosis and/or hyperoxaluria, and increased serum and/or urinary phosphate levels. The risk of crystal-induced kidney disease is increased further in the presence of hypovolemia and urinary concentration, changes in urinary pH, and decrease in level of urinary inhibitors of crystallization, such as citrate, magnesium, and pyrophosphate.1, 2 In the case of calcium phosphate crystal deposition, use of angiotensin-converting enzyme inhibitors is considered an additional risk factor.3 In addition to calcium salts and uric acid, drugs such as sulfonamides, foscarnet, methotrexate, triamterene, phosphate-containing bowel preparations, orlistat, ciprofloxacin, and indinavir can cause crystal-induced kidney disease.4, 5, 6, 7 Clinical manifestations of crystal-induced kidney disease are wide ranging, from no symptoms to flank pain, hematuria, sterile pyuria, crystalluria, and reduced kidney function. Although crystal-induced kidney disease is well documented in native kidneys, its occurrence in kidney allografts is not. We report 2 cases of crystal-induced kidney disease in transplant recipients that resulted in kidney failure. Case Reports  Case 1 Clinical History and Initial Laboratory Data A 67-year-old African American woman with end-stage renal disease from diabetic nephropathy underwent deceased donor kidney transplant in 2001. Her medical history included chronic hepatitis C infection, bronchial asthma, recurrent urinary tract infections, and ulcerative colitis treated using total proctocolectomy and permanent ileostomy in 1960. Posttransplant medication included tacrolimus, mycophenolate mofetil, losartan, furosemide, metalozone, multivitamin, and insulin. Allograft function was stable, with a serum creatinine level of 1.7 mg/dL (150.28 μmol/L) and estimated glomerular filtration rate (eGFR) of 36 mL/min/1.73 m2 (0.60 mL/s/1.73 m2) calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. In July 2008, the patient was admitted to the hospital because of a change in mental status, poor oral intake, and oliguria. Clinical examination was significant for confusion, a distal tremor, and volume depletion. Laboratory studies showed serum urea nitrogen level of 188 mg/dL (67.1 mmol/L), creatinine level of 7.1 mg/dL (627.64 μmol/L), and eGFR of 7 mL/min/1.73 m2 (0.12 mL/s/1.73 m2). Serum electrolyte results included the following values: sodium, 134 mEq/L (134 mmol/L); potassium, 4.8 mEq/L (4.8 mmol/L); chloride, 110 mEq/L (110 mmol/L); bicarbonate, 13 mEq/L (13 mmol/L); glucose, 295 mg/dL (16.37 mmol/L); calcium, 8.7 mg/dL (2.18 mmol/L); magnesium, 2.6 mg/dL (1.07 mmol/L); and phosphorus, 9.3 mg/dL (3.0 mmol/L). Tacrolimus trough level was 2.4 ng/mL. Urinalysis was notable for sterile pyuria, and an ultrasound was negative for hydronephrosis. The patient was initiated on daily intermittent hemodialysis therapy, and a kidney biopsy was performed. Kidney Biopsy The kidney allograft biopsy specimen showed extensive intratubular crystal deposition and moderate tubulointerstitial mononuclear cell infiltration with features of tubular injury (Fig 1). Examination of histologic slides showed colorless refractile crystals of polygonal appearance (Fig 2A). Multicolored birefringence under polarized light identified these crystals as calcium oxalate (Fig 2B). Additional studies were negative for rejection or infection. Reevaluation of the patient for possible causes showed high vitamin C intake (8 g/d) for 18 months to prevent asthmatic flares. Diagnosis Acute calcium oxalate crystal deposition secondary to excessive vitamin C intake. Clinical Follow-up Serum oxalate and vitamin C levels in our patient were not obtained at the time of diagnosis. While the patient was maintained on dialysis therapy, tacrolimus and diuretic therapies were discontinued, and a repeated biopsy was performed 8 weeks later. The second biopsy specimen showed persistence of extensive oxalate crystal deposition. Partial allograft recovery was achieved after 9 weeks of dialysis therapy, with a nadir serum creatinine level of 2.6 mg/dL (229.84 μmol/L) and eGFR of 24 mL/min/1.73 m2 (0.40 mL/s/1.73 m2). Case 2 Clinical History and Initial Laboratory Data A 66-year-old white man with end-stage renal disease secondary to presumed hyperfiltration in a single kidney underwent deceased donor kidney transplant in February 2008, with a nadir serum creatinine level of 1.0 mg/dL (88.4 μmol/L) and eGFR of 79 mL/min/1.73 m2 (1.32 mL/s/1.73 m2). Medical history included total colectomy and permanent ileostomy for carcinoma of the colon, deep venous thrombosis (a heterozygous mutation in the F5 gene was identified, indicative of factor V Leiden thrombophilia), coronary artery disease, and gouty arthritis. Posttransplant medication included tacrolimus, mycophenolic acid, potassium and sodium phosphate, magnesium oxide, lisinopril, amlodipine, metoprolol, and warfarin. Seven months posttransplant, he presented with abdominal pain and decreased urine output of 5 days' duration. He was hypotensive with an increased serum creatinine level of 10.0 mg/dL (880.4 μmol/L) and eGFR of 6 mL/min/1.73 m2 (0.10 mL/s/1.73 m2). Additional testing showed international normalized ratio of 6, parathyroid hormone level of 715.7 pg/mL, serum calcium level of 9.5 mg/dL (2.36 mmol/L), and phosphorus level of 9.9 mg/dL (3.20 mmol/L). The patient was initiated on daily hemodialysis therapy, and an allograft biopsy was performed. Kidney Biopsy The kidney allograft biopsy specimen showed extensive calcium phosphate crystal deposition in kidney tubules with features of tubular injury (Fig 3A). The presence of phosphate in the crystals was confirmed using von Kossa stain (Fig 3B). This was an unexpected finding in the absence of a large intake of sodium phosphate. Extensive evaluation of the patient for the cause of calcium phosphate deposition showed that in the week preceding his presentation, the patient consumed 3 L/d of carbonated beverages that contained sodium phosphate. Diagnosis Acute calcium phosphate crystal disease associated with excessive oral consumption of beverages containing sodium phosphate. Clinical Follow-up The patient was maintained on hemodialysis therapy, and a follow-up biopsy was performed after 2 months. The biopsy specimen showed persistence of calcium phosphate crystals and tubular injury. Tacrolimus therapy was stopped, but the remainder of his immunosuppression was continued. Six months after presentation, the patient remained dialysis dependent. Discussion Calcium crystal–induced kidney disease has not been reported previously in kidney transplant recipients, to the best of our knowledge. The noteworthy common factor in both our patients is total colectomy with ileostomy. Excess fluid loss from ileostomy with resultant volume depletion may have contributed to the development of crystal-induced kidney disease. Dietary factors in both these cases emphasize the importance of ongoing education and regular monitoring for over-the-counter medication and supplement use. In the first patient, the diagnosis of oxalate deposition disease was based on biopsy findings of extensive deposition of characteristic crystals with tubular cell necrosis (Fig 1). The crystals were colorless, refractile, and polygonal in appearance and showed multicolored birefringence under polarized light (Fig 2), identifying them as calcium oxalate.8 A study of unselected kidney allograft biopsies found that 4% showed calcium oxalate deposition, which could be divided broadly into 3 categories based on clinical situations.9 The first category is calcium oxalate deposition in association with acute tubular necrosis or rejection. Deposition usually is sparse, limited to proximal tubules, and resolves with recovery of kidney function. The second category is calcium oxalate deposition in the atrophic areas seen in patients with chronic allograft nephropathy. The third category is crystal deposition in patients with primary or secondary hyperoxaluria.9 Given the amount of vitamin C our patient was ingesting and that oxalic acid is a metabolite of ascorbic acid (Fig 4), vitamin C–induced hyperoxalosis is the most likely cause. Other causes of oxaluria include primary hyperoxaluria, enteric hyperoxaluria, other dietary intake of oxalate-containing foods, ethylene glycol intoxication, methoxyfluorane toxicity, or vitamin (thiamine or pyridoxine) deficiency–induced hyperoxalosis (Box 1).9, 10 Box 1 Causes of Secondary Hyperoxalosis There are several reports of vitamin C–induced acute oxalate native kidney disease. Wong et al11 reported a 61-year-old man who received 60 g of vitamin C intravenously and developed acute kidney injury (AKI) from calcium oxalate deposition. Similarly, Alkhunaizi et al12 reported a patient who developed AKI from extensive calcium oxalate deposition while on total parenteral nutrition containing 1 g of vitamin C daily. In a third case, a 31-year-old man presented to the emergency department with AKI and a subsequent biopsy showed massive calcium oxalate deposition. History in this patient showed consumption of 5 g of vitamin C daily for many days before presentation, similar to our patient.13 Although vitamin C often is viewed as a benign water-soluble supplement, these reports suggest that high doses can cause crystal-induced kidney disease in some patients. Unfortunately, consumption of vitamins and nutritional supplements by patients and healthy individuals is very common. A report published in 2002 showed that 36% of Americans routinely use complementary and alternative medicines, such as herbal, nonherbal, and vitamin products.14 In 2003, nearly 25,000 adverse events related to the use of complementary and alternative medicines were reported to the American Association of Poison Control, and 7% of all medication-related toxicities involved the kidney.14 Normal urine oxalate excretion is <40 mg/d, and it depends on many factors, such as dietary oxalate consumption, saturation of vitamin C absorption, and kidney function. Because kidney function commonly is decreased in patients with acute oxalate kidney injury, measuring the urine oxalate-creatinine ratio (reference value, <0.035) may better indicate urine oxalate load.10 The endogenous synthesis of oxalate from vitamin C is ∼1.5% of supplemental load, and based on this, urinary oxalate load is expected to be ∼30 mg (341 mmol) after consumption of 2,000 mg of vitamin C.15 Accordingly, the expected urine oxalate load in our patient, who consumed 8 g/d of vitamin C, is ∼120 mg/d. However, this can vary significantly, as seen in a report of a patient who had a urine oxalate concentration of 126 mg/d while using 1 g of vitamin C daily; the oxalate level decreased to 56 mg/d 18 days after discontinuation of vitamin C.16 The second case highlights acute phosphate-induced kidney disease. The factors that most likely contributed to crystal formation in this patient include consumption of >3 L/d of sodium phosphate–containing beverages (their corresponding phosphorus concentrations are listed in Table 1), excess fluid loss from the ileostomy resulting in volume depletion, secondary hyperparathyroidism resulting in increased fractional excretion of phosphate,17, 18 and supplementation with sodium and potassium phosphate (containing 1,500 mg [48 mmol] of elemental phosphorus) for posttransplant hypophosphatemia. | | |  | Beverage Type | Sodium (mg) | Phosphorus (mg) | |
|---|
| Root beer | 70 | 20 | | | Mountain Dew | 105 | 53 | | | Cool Mountain Gourmet Soda | 102 | 134 | | | Fruit punch | 80 | 123 | | | Coca-Cola | 52 | 68 | | | | |
Acute phosphate-induced kidney disease secondary to hyperphosphaturia is well documented in situations such as tumor lysis syndrome and X-linked hypophosphatemic rickets.19, 20 More recently, an epidemic of calcium phosphate crystal–induced kidney disease was reported with the use of oral sodium phosphate solution for bowel preparation before colonoscopy. The usual dose of oral sodium phosphate used for bowel cleansing that results in acute phosphate kidney injury is 11.5 g of phosphorus, which is 7 times the average daily dietary phosphorus intake. Normal urinary phosphorus excretion is <1,000 mg/d, and ∼57% of the dose is excreted in feces, 15% is excreted in urine, and 28% is retained in the body for 24 hours.21 Urine phosphorus level increases after the first and second doses of oral sodium phosphate (two 45-mL doses given during 10-12 hours) to 4 and 8 times the baseline level, respectively. Severe hyperphosphaturia occurs after the second dose of oral sodium phosphate as a result of the high parathyroid hormone levels induced by the first dose.22 In many kidney biopsy specimens of patients with acute phosphate kidney injury, varying degrees of distal tubular calcium phosphate deposition with tubular injury are seen.23, 24 Markowitz et al25 reviewed 7,349 native kidney biopsies in which 31 patients showed significant calcium phosphate crystal deposition, of which 21 satisfied the definition of acute phosphate-induced kidney disease. The pathogenesis in these patients appeared multifactorial, and possible risk factors are listed in Box 2.26 Because of this, the US Food and Drug Administration reviewed the safety of oral sodium phosphate preparations and urged physicians to be aware of its association with acute phosphate-induced kidney disease.27, 28, 29, 30 Box 2 Putative Risk Factors for Phosphate Kidney Disease ⧫Acute or chronic kidney disease ⧫Prior kidney transplant ⧫Advanced age ⧫Female sex ⧫Volume depletion ⧫ACE inhibitor, ARB, diuretic, or NSAID use ⧫Abnormal bowel motility ⧫Excess or repeated oral sodium phosphate solution use Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; NSAID, nonsteroidal anti-inflammatory drug. In our patient, total estimated phosphate load was ∼3,600 mg/d, including 700 mg/d from 3 L of beverages with a mean phosphate concentration of 80 mg/120 mL, 1,500 mg of phosphate supplementation daily, and 1,400 mg/d in his regular diet. However, the precise phosphate load on the kidney is difficult to estimate in our patient because of persistent secondary hyperparathyroidism, which would be expected to increase the fractional excretion of phosphate. Measurement of 24-hour urinary phosphate or fractional excretion of phosphorus would be helpful in such situations. Recently, consumption of carbonated beverages has been linked to diabetes, hypertension, and kidney stones. Beverages containing phosphoric acid have been shown to cause urinary changes that promote kidney stones.31, 32 A study by Saldana et al32 showed that drinking ≥ 2 cans of cola beverages daily increased the risk of chronic kidney disease (odds ratio, 2.27). Similarly, patients with kidney stones who consume phosphoric acid–acidified beverages had a 15% higher stone recurrence rate compared with those who consume citric acid beverages.33 Furthermore, food additives contribute an estimated 470 mg of phosphorus daily to the American diet, which can increase to 1,000 mg/d, depending on food choices.34 In summary, these 2 cases of calcium crystal–induced kidney disease represent previously unreported and preventable causes of AKI in transplant recipients. Crystal-induced kidney disease should be considered in the differential diagnosis of an acute decrease in allograft function because aggressive management in a timely manner may alter the course of the disease. Calcium oxalate crystal–induced kidney disease should be suspected when a decrease in allograft function is associated with clinical conditions that cause hyperoxaluria (Box 1). These cases also should be a reminder to review over-the-counter medications and appreciate the importance of sterile pyuria in the evaluation of AKI from crystal-induced kidney disease. Suspicion for acute phosphate-induced kidney disease may be especially pertinent in transplant recipients with reduced allograft function who have undergone colonoscopy with oral sodium phosphate preparations and/or receive phosphate supplementation for posttransplant hypophosphatemia. When the diagnosis of crystal-induced kidney disease is established, extended dialysis therapy is essential to prevent enduring injury from hyperoxalosis and hyperphosphatemia. Ongoing education regarding the adverse effects of dietary indiscretion is important to prevent crystal-induced kidney disease in both transplant recipients and patients with chronic kidney disease. Acknowledgements Support: None. Financial Disclosure: None. References 1. 1Coe F, Parks JH. Defenses of an unstable compromise: crystallization inhibitors and the kidney's role in mineral regulation. Kidney Int. 1990;38(4):625–631. MEDLINE |
CrossRef
2. 2Asplin JR, Mandel NS, Coe FL. Evidence of calcium phosphate supersaturation in the loop of Henle. Am J Physiol. 1996;270(4 pt 2):F604–F613. MEDLINE 3. 3Heher EC, Thier SO, Rennke H, Humphreys BD. Adverse renal and metabolic effects associated with oral sodium phosphate bowel preparation. Clin J Am Soc Nephrol. 2008;3(5):1494–1503. 4. 4Rose BD. Pathophysiology of Renal Disease. 2nd ed.. New York, NY: McGraw-Hill; 1987;http://www.loc.gov/catdir/description/mh031/86033710.html. 5. 5Kjellstrand CM, Cambell DC, von Hartitzsch B, Buselmeier TJ. Hyperuricemic acute renal failure. Arch Intern Med. 1974;133(3):349–359. MEDLINE 6. 6Perazella MA. Crystal-induced acute renal failure. Am J Med. 1999;106(4):459–465. Abstract | Full Text |
Full-Text PDF (425 KB)
|
CrossRef
7. 7Yarlagadda SG, Perazella MA. Drug-induced crystal nephropathy an update. Expert Opin Drug Saf. 2008;7(2):147–158.
CrossRef
8. 8Seshan SV. Renal Disease: Classification and Atlas of Tubulo-Intestitial and Vascular Diseases. Baltimore, MD: Williams & Wilkins; 1999;. 9. 9Truong LD, Yakupoglu U, Feig D, et al. Calcium oxalate deposition in renal allografts: morphologic spectrum and clinical implications. Am J Transplant. 2004;4(8):1338–1344. MEDLINE |
CrossRef
10. 10Rathi S, Kern W, Lau K. Vitamin C-induced hyperoxaluria causing reversible tubulointerstitial nephritis and chronic renal failure: a case report. J Med Case Rep. 2007;1:155. 11. 11Wong K, Thomson C, Bailey RR, McDiarmid S, Gardner J. Acute oxalate nephropathy after a massive intravenous dose of vitamin C. Aust N Z J Med. 1994;24(4):410–411. MEDLINE 12. 12Alkhunaizi AM, Chan L. Secondary oxalosis: a cause of delayed recovery of renal function in the setting of acute renal failure. J Am Soc Nephrol. 1996;7(11):2320–2326. MEDLINE 13. 13Mashour S, Turner JF, Merrell R. Acute renal failure: oxalosis, and vitamin C supplementation: a case report and review of the literature. Chest. 2000;118(2):561–563. MEDLINE |
CrossRef
14. 14Gabardi S, Munz K, Ulbricht C. A review of dietary supplement-induced renal dysfunction. Clin J Am Soc Nephrol. 2007;2(4):757–765. 15. 15Massey LK, Liebman M, Kynast-Gales SA. Ascorbate increases human oxaluria and kidney stone risk. J Nutr. 2005;135(7):1673–1677. MEDLINE 16. 16Gossel TA, Bricker DJ. Principles of Clinical Toxicology. In: New York: Raven Press Ltd; 1994;p. 415. 17. 17Laroche M, Boyer JF. Phosphate diabetes, tubular phosphate reabsorption and phosphatonins. Joint Bone Spine. 2005;72(5):376–381.
CrossRef
18. 18Bhan I, Shah A, Holmes J, et al. Post-transplant hypophosphatemia: tertiary ‘hyper-phosphatoninism’?. Kidney Int. 2006;70(8):1486–1494. MEDLINE |
CrossRef
19. 19Ettinger DS, Harker WG, Gerry HW, Sanders RC, Saral R. Hyperphosphatemia, hypocalcemia, and transient renal failure (Results of cytotoxic treatment of acute lymphoblastic leukemia). JAMA. 1978;239(23):2472–2474. MEDLINE 20. 20Verge CF, Lam A, Simpson JM, Cowell CT, Howard NJ, Silink M. Effects of therapy in X-linked hypophosphatemic rickets. N Engl J Med. 1991;325(26):1843–1848. MEDLINE 21. 21Science background paper: acute phosphate nephropathy and renal failure associated with the use of oral sodium phosphate bowel cleansing product. www.fda.gov/Drugs/DrugSafety/…/ucm161581.htm. 22. 22Lien YH. Is bowel preparation before colonoscopy a risky business for the kidney?. www.nature.com/clinicalpractice/neph. 23. 23Desmeules S, Bergeron MJ, Isenring P. Acute phosphate nephropathy and renal failure. N Engl J Med. 2003;349(10):1006–1007.
CrossRef
24. 24Orias M, Mahnensmith RL, Perazella MA. Extreme hyperphosphatemia and acute renal failure after a phosphorus-containing bowel regimen. Am J Nephrol. 1999;19(1):60–63. MEDLINE |
CrossRef
25. 25Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol. 2005;16(11):3389–3396. MEDLINE |
CrossRef
26. 26Markowitz GS, Nasr SH, Klein P, et al. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol. 2004;35(6):675–684. Abstract | Full Text |
Full-Text PDF (990 KB)
|
CrossRef
27. 27Heher EC, Rennke HG, Humphreys BD. Nephrocalcinosis, oral sodium phosphate solution, and phosphate nephropathy. Nephrol Rounds. 2007;5(2):1–6http://www.nephrologyrounds.org/crus/nephUS_0207.pdf. 28. 28Keeffe EB. Colonoscopy preps: what's best?. Gastrointest Endosc. 1996;43(5):524–528. Full Text |
Full-Text PDF (1493 KB)
|
CrossRef
29. 29DiPalma JA, Brady CE. Colon cleansing for diagnostic and surgical procedures: polyethylene glycol-electrolyte lavage solution. Am J Gastroenterol. 1989;84(9):1008–1016. MEDLINE 30. 30Schwetz BA. From the Food and Drug Administration. JAMA. 2001;286(21):2660. MEDLINE |
CrossRef
31. 31Murphy-Gutekunst L. Hidden phosphorus in popular beverages: part 1. J Ren Nutr. 2005;15(2):e1–e6. Full Text |
Full-Text PDF (58 KB)
|
CrossRef
32. 32Saldana TM, Basso O, Darden R, Sandler DP. Carbonated beverages and chronic kidney disease. Epidemiology. 2007;18(4):501–506.
CrossRef
33. 33Shuster J, Jenkins A, Logan C, et al. Soft drink consumption and urinary stone recurrence: a randomized prevention trial. J Clin Epidemiol. 1992;45(8):911–916. MEDLINE |
CrossRef
34. 34Calvo MS. Dietary considerations to prevent loss of bone and renal function. Nutrition. 2000;16(7-8):564–566. Full Text |
Full-Text PDF (39 KB)
|
CrossRef
1 Division of Nephrology and Transplantation, William Beaumont Hospital, Royal Oak, MI 2 Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, MI  Address correspondence to Ravi Parasuraman, MD, Kidney Transplant Outreach Program, Division of Nephrology and Transplantation, William Beaumont Hospital, Royal Oak, MI 48703
PII: S0272-6386(09)01144-5 doi:10.1053/j.ajkd.2009.08.012 © 2009 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved. | |
|
FULL TEXT01144-5/journalimage?img=PIIS0272638609011445.gr1.lrg.gif&fig=fig1&kwhquery=&issn=0272-6386&ishighres=false&allhighres=false&free=yes','journalimage');)
01144-5/journalimage?img=PIIS0272638609011445.gr2.lrg.gif&fig=fig2&kwhquery=&issn=0272-6386&ishighres=false&allhighres=false&free=yes','journalimage');)
01144-5/journalimage?img=PIIS0272638609011445.gr3.lrg.gif&fig=fig3&kwhquery=&issn=0272-6386&ishighres=false&allhighres=false&free=yes','journalimage');)
01144-5/journalimage?img=PIIS0272638609011445.gr4.lrg.gif&fig=fig4&kwhquery=&issn=0272-6386&ishighres=false&allhighres=false&free=yes','journalimage');)