Sulfadiazine‐induced crystal nephropathy: a new ‘old’ problem

Abstract

With a greater awareness of toxoplasmosis infections, and increased prescribing of sulfadaizine, it is timely to remind colleagues of a largely forgotten clinical presentation. We present the case of crystal nephropathy secondary to sulfadiazine prescribed for retinal toxoplasmosis.A 60 year-old with left chorioretinal toxoplasmosis presented with 18 h of severe bilateral constant flank pain, nausea and acute kidney injury. He had no known renal disease. He had normal renal function prior to commencement of pyrimethamine 75 mg and sulfadiazine 1.5 g four times daily 6 days earlier.He was afebrile, blood pressure was 163/99 mmHg, and his abdominal examination revealed marked bilateral renal angle tenderness. His urine output was reduced. Initial plasma creatinine was 309 umol/L, and peaked at 530 umol/L, before rapidly improving following intervention. Urine microscopy showed many crystals, including dumbbell-shaped crystals ( Fig. 1) with a positive Lignin test. Urinalysis showed no haematuria or proteinuria, pH 6 and <10 × 10 6 white cells/L. These urinary findings confirmed a diagnosis of sulfadiazine-induced crystal nephropathy.The patient was treated with intravenous sodium bicarbonate, 0.9% saline and frusemide to achieve a urine output over 100 mL/h and urine pH above 7.15. Following 3 days of treatment, the urine was devoid of crystals, and the lignin test was now negative, indicating resolving sulfadiazineinduced crystal nephropathy. One week later, his renal function had returned to normal. DISCUSSIONSulfadiazine was well known to induce a crystal nephropathy in the two decades after it was introduced in 1936 before the availability of more water-soluble sulphonamides.1 With the relatively recent increased use of sulfadiazine to treat toxoplasmosis, sulfadiazine-induced crystal nephropathy has re-emerged as a clinical entity.Known predisposing factors to favour crystal deposition include volume depletion, hypoalbuminaemia, chronic kidney disease and inadequate dose adjustment, thereby increasing the urinary sulfadiazine concentration. A persistent acidic urinary pH (pH < 5.5) increases the likelihood of crystal deposition in the renal tubules.1 Urinary sediment examination reveals crystals typically shaped of needles, rosettes or 'shocks of wheat'. 2Treatment involves cessation of sulfadiazine, aggressive volume repletion and urine alkalization to target a urinary pH of >7.15.1 Prognosis in sulfadiazine-induced crystal nephropathy is favourable, with renal recovery over a mean of 8.3 days.3 Recommencement of sulfadiazine therapy is not contraindicated provided there is a high urine flow rate and urine alkalinization (pH >7.15) with monitoring of renal function and urinalysis for crystals.

Drug-Induced Acute Kidney Injury

“…Low urinary solubility of these drugs and their metabolites, especially in acid urine, promotes crystal precipitation within distal tubular lumens. Sulfadiazine and sulfamethoxazole crystals can be visualized in urine sediment as free crystals or crystals within casts (97–100,106). Crystals have hourglass shapes with prominent radial striations, are described as “sheaves of wheat,” and are birefringent.…”

“…Sulfadiazine and sulfamethoxazole are sulfa-based antimicrobial agents associated with crystalline nephropathy (97–100,106). Low urinary solubility of these drugs and their metabolites, especially in acid urine, promotes crystal precipitation within distal tubular lumens.…”

The Crystalline Nephropathies

“…Examination of the urine sediment may reveal sulfadiazine and sulfamethoxazole crystals, which appear as free crystals or crystals within casts (1)(2)(3)(4)15). Crystals have hourglass shapes with prominent radial striations, also described as "sheaves or shocks of wheat"(Figure 2A), and are birefringent on polarization.…”

“…Nevertheless, because it has utility for treating certain infections, clinicians should be aware of it as a cause of crystalline nephropathy. 1 , 2 , 3 , 4 , 15 , 16 Sulfamethoxazole, another sulfa-based antibiotic, can also cause crystalluria and crystalline nephropathy, but less frequently. 1 , 2 , 3 , 4 Low urinary solubility of these sulfa-drugs and their metabolites, especially in acid urine, promotes crystal precipitation within the distal tubular lumens.…”

“…Examination of the urine sediment may reveal sulfadiazine and sulfamethoxazole crystals, which appear as free crystals or crystals within casts. 1 , 2 , 3 , 4 , 15 Crystals have hourglass shapes with prominent radial striations, also described as “sheaves or shocks of wheat” ( Figure 2 a), and are birefringent on polarization. Although sulfa crystals have not been observed in kidney tissue, interstitial fibrosis with mild mononuclear inflammation likely represents the effects of unseen, intrarenal crystals.…”