Only Hyperuricemia with Crystalluria, but not Asymptomatic Hyperuricemia, Drives Progression of Chronic Kidney Disease

BackgroundThe roles of asymptomatic hyperuricemia or uric acid (UA) crystals in CKD progression are unknown. Hypotheses to explain links between UA deposition and progression of CKD include that (1) asymptomatic hyperuricemia does not promote CKD progression unless UA crystallizes in the kidney; (2) UA crystal granulomas may form due to pre-existing CKD; and (3) proinflammatory granuloma-related M1-like macrophages may drive UA crystal-induced CKD progression.MethodsMALDI-FTICR mass spectrometry, immunohistochemistry, 3D confocal microscopy, and flow cytometry were used to characterize a novel mouse model of hyperuricemia and chronic UA crystal nephropathy with granulomatous nephritis. Interventional studies probed the role of crystal-induced inflammation and macrophages in the pathology of progressive CKD.ResultsAsymptomatic hyperuricemia alone did not cause CKD or drive the progression of aristolochic acid I-induced CKD. Only hyperuricemia with UA crystalluria due to urinary acidification caused tubular obstruction, inflammation, and interstitial fibrosis. UA crystal granulomas surrounded by proinflammatory M1-like macrophages developed late in this process of chronic UA crystal nephropathy and contributed to the progression of pre-existing CKD. Suppressing M1-like macrophages with adenosine attenuated granulomatous nephritis and the progressive decline in GFR. In contrast, inhibiting the JAK/STAT inflammatory pathway with tofacitinib was not renoprotective.ConclusionsAsymptomatic hyperuricemia does not affect CKD progression unless UA crystallizes in the kidney. UA crystal granulomas develop late in chronic UA crystal nephropathy and contribute to CKD progression because UA crystals trigger M1-like macrophage-related interstitial inflammation and fibrosis. Targeting proinflammatory macrophages, but not JAK/STAT signaling, can attenuate granulomatous interstitial nephritis.

High Incidence of Amoxicillin-Induced Crystal Nephropathy in Patients Receiving High Dose of Intravenous Amoxicillin

Background: Amoxicillin (AMX)-induced crystal nephropathy (AICN) is considered as a rare complication of high dose intravenous (IV) AMX administration. However, recently, its incidence seems to be increasing based on French pharmacovigilance centers. Occurrence of AICN has been observed mainly with IV administration of AMX and mostly under doses over 8 g/day. Given that pharmacovigilance data are based on declaration, the real incidence of AICN may be underestimated. Thus, the primary objective of the present study was to determine the incidence of AICN in the current practice. Materials and Methods: We conducted a retrospective study between 1 January 2015 and 31 December 2017 in Angers University Hospital. Inclusion criteria were age over 18 years-old and IV AMX administration of at least 8 g/day for more than 24 h. Patients admitted directly into the intensive care units were excluded. Medical records of patients that developed Kidney Disease:Improving Global Outcome (KDIGO) stage 2–3 acute kidney injury (AKI) were reviewed by a nephrologist and a specialist in pharmacovigilance. AICN was retained if temporality analysis was conclusive, after exclusion of other causes of AKI, in absence of other nephrotoxic drug administration. Results: A total of 1303 patients received IV AMX for at least 24 h. Among them, 358 (27.5%) were exposed to AMX doses of at least 8 g/day and were included. Patients were predominantly males (68.2%) with a mean age of 69.1 years-old. AMX was administered for a medical reason in 78.5% of cases. Patients received a median dose of AMX of 12 g/day (152.0 mg/kg/day). Seventy-three patients (20.4%) developed AKI, 42 (56.8%) of which were KDIGO stage 2 or 3. Among the latter, AICN diagnosis was retained in 16 (38.1%) patients, representing an incidence of 4.47% of total patients exposed to high IV AMX doses. Only female gender was associated with an increased risk of AICN. AMX dose was not significantly associated with AICN development. Conclusion: This study suggests a high incidence of AICN in patients receiving high IV AMX doses, representing one third of AKI causes in our study. Female gender appeared as the sole risk factor for AICN in this study.

Antiviral Drugs and Acute Kidney Injury (AKI)

The introduction of more efficient antiviral drugs are common cause drug-induced acute kidney injury (AKI). The true prevalence of antiviral drugs induced nephrotoxicity is hardly determined. It causes AKI by many mechanisms including acute tubular necrosis (ATN), allergic interstitial nephritis (AIN), and crystal nephropathy. ATN has been described with a few kinds of antiviral drugs such as cidofovir, adefovir and tenofovir with unique effects on transporter defects, apoptosis, and mitochondrial injury. AIN from atazanavir is a rapid onset of AKI and usually nonoliguric but dialytic therapy are needed because of severity. Additionally, crystal nephropathy from acyclovir, indinavir, and foscarnet can cause AKI due to intratubular obstruction. In this article, the mechanisms of antiviral drug-induced AKI were reviewed and strategies for preventing AKI were mentioned.

Erythrodermic Psoriasis Causing Uric Acid Crystal Nephropathy

Background. Erythrodermic psoriasis is a rare and severe variant of psoriasis. It is characterized by widespread skin erythema, scaling, pustules, or exfoliation of more than 75% of the body’s surface area. This condition has life-threatening complications to include hemodynamic, metabolic, immunologic, and thermoregulatory disturbances. One metabolic complication, hyperuricemia, occurs from rapid keratinocyte differentiation and infiltration of inflammatory cells into psoriatic lesions. Although renal injury caused by shunting of blood to the skin has been reported, there are no reports of erythrodermic psoriasis causing crystal-induced nephropathy. We present a case of erythrodermic psoriasis and hyperuricemia complicated by uric acid crystal nephropathy. Case Presentation. A 57-year-old male with long-standing psoriatic arthritis presented with diffuse scaling of his skin. He was being treated with adalimumab, leflunomide, and topical clobetasol, but had recently stopped taking his medications. Physical exam revealed yellow scaling covering his entire body with underlying erythema and tenderness without mucosal involvement. Labs were notable for a creatinine of 3.3 mg/dL, with no prior history of renal disease, and uric acid of 12.7 mg/dL. He was admitted to the intensive care unit given >80% of body surface area involvement and acute renal failure. Despite aggressive fluid resuscitation, renal function did not improve, and creatinine peaked at 4.61 mg/dL. Urine microscopy showed diffuse polymorphic uric acid crystals, consistent with uric acid crystal-induced nephropathy. He was started on rasburicase, urinary alkalinization, and fluids. His renal function improved dramatically; urine output, uric acid, and electrolytes normalized. He was discharged on topical clobetasol and leflunomide and started on secukinumab with little to no skin involvement. Conclusion. This case presents the rare complication of crystal-induced nephropathy in a patient with erythrodermic psoriasis. Uric acid crystal nephropathy is well described in diseases with rapid cell turnover such as tumor lysis syndrome. It is thought that rapid keratinocyte differentiation and inflammatory infiltration of psoriatic lesions produced life-threatening electrolyte abnormalities similar to tumor lysis syndrome. Early recognition of this rare complication is critical, and aggressive fluid resuscitation, urine alkalinization, and uric acid lowering agents should be administered immediately.

Dramatic Increase of Amoxicillin-Induced Crystal Nephropathy Found in a Cohort Study of French Pharmacovigilance Centers

ABSTRACTAn increase in amoxicillin-induced crystal nephropathy (AICN) incidence has been recently suggested. The aims of this study were to investigate the trend of AICN incidence through Paris' regional centers of pharmacovigilance (Paris RCPVs) and better describe this rare adverse drug reaction. Forty-five AICN cases were identified between 1985 and 2016. All cases, except one, were reported since 2010. Amoxicillin (AMX) was administered intravenously (65 [interquartile range {IQR}, 43 to 110] mg/kg of body weight/day) in all patients, either for treating infection (n= 15) or as surgical prophylaxis (n= 30). Delay between AMX administration and AICN onset was 1 (IQR, 1 to 3) day; 30, 4, and 11 patients developed KDIGO stage 1, 2, and 3 acute kidney injury, respectively. Delay between AICN onset and kidney function recovery was 4 (IQR, 2 to 6) days. Precipitating factors were identified in only one-third of cases. Twelve patients required intensive care unit admission, and 8 needed renal replacement therapy. Neither chronic kidney disease nor death was observed. We confirmed the recent and dramatic increase of AICN in the Paris RCPVs since 2010. The absence of precipitating factors in the majority of cases and the onset of AICN in apparent routine indications, such as surgical prophylaxis, are alarming and justify a high vigilance from all AMX prescribers.