Bmk9 and Uricase Nanoparticle Complex for the Treatment of Gouty Arthritis and Uric Acid Nephropathy

Uric acid is the final product of purine metabolism, and excessive serum uric acid can cause gouty arthritis and uric acid nephropathy. Therefore, lowering the uric acid level and alleviating inflammation in the body are the key points to treating these diseases. A stable nanosuspension of peptide BmK9 was prepared by the precipitation-ultrasonication method. By combining uricase on the surface of a positively charged carrier, a complex consisting of neutral rod-shaped BmK9 and uricase nanoparticles (Nplex) was formed to achieve the delivery of BmK9 and uricase, respectively. The formulation of Nplex has a diameter of 180 nm and drug loading up to 200%, which releases BmK9 and uricase slowly and steadily in drug release tests in vitro. There was significantly improved pharmacokinetic behavior of the two drugs because Nplex prolonged the half-life and increased tissue accumulation. Histological assessments showed that the dual drug Nplex can reduce the inflammation response in acute gouty arthritis and chronic uric acid nephropathy in vivo. In the macrophage system, there was lower toxicity and increased beneficial effect on inflammation with Nplex than free BmK9 or uricase. Collectively, this novel formulation provides a dual drug delivery system that can treat gouty arthritis and uric acid nephropathy.

MO427SAFE USE OF ALLOPURINOL TO TREAT ACUTE URIC ACID NEPHROPATHY IN PREGNANCY: A CASE REPORT

Introduction Acute uric acid nephropathy (UAN) is characterized by acute kidney injury (AKI) due to uric acid crystal precipitation within the distal tubules and collecting ducts. We present a young woman, with a history of hyperuricaemia, who was treated with allopurinol for acute UAN during her first pregnancy. She also continued allopurinol treatment during her second pregnancy for prevention of further acute UAN. To the author’s knowledge, this is the first case report of biopsy-confirmed acute UAN during pregnancy. Case report A 20 year old woman, who was 13 weeks pregnant, was admitted with AKI. Past medical history included chronic kidney disease (CKD) and gout since the age of 17. She had an extensive family history of CKD and gout (without diagnosis, despite genetic testing). She had been on daily allopurinol 300mg, but this was stopped 8 weeks prior by her rheumatology team due to concerns about teratogenicity. At that time serum creatinine was at her baseline of 100 μmol/L (normal range 50-120 μmol/L) and serum uric acid had been 740 μmol/L (normal range 140-360 μmol/L). On admission, she felt well and was euvolemic. Serum creatinine was now 352 μmol/L and her serum uric acid level was 1720 μmol/L, with an elevated urine uric acid to creatinine ratio of 1.1. She underwent renal biopsy, which showed significant deposition of uric acid crystals in the renal tubules, confirming a diagnosis of acute UAN. She was given intravenous fluids. The uncertainties of allopurinol use in pregnancy were discussed with her, and she was restarted on allopurinol 200 mg daily. Over the next 3 weeks, serum uric acid decreased to 470 μmol/L and serum creatinine to 116 μmol/L. She was maintained on allopurinol during her pregnancy and delivered a healthy baby girl. She was advised against further pregnancies due to increased risk of maternal and fetal complications. However, three years later she presented at 15 weeks’ gestation. After a discussion regarding the potential teratogenic effects of allopurinol versus the risk of recurrent severe AKI due to acute UAN if it was again discontinued, she chose to continue allopurinol. The pregnancy proceeded without complication. Her daughters are now 8 and 5 years old. They do not have any congenital malformations, though both have mild to moderate learning difficulties. Discussion Allopurinol is approved for the treatment of hyperuricaemia outside of pregnancy, but given it interrupts purine synthesis there is a biologically plausible concern regarding teratogenicity. However, in our patient with long-standing hyperuricaemia it was the discontinuation of allopurinol that precipitated AKI due to the resultant crystal formation when serum uric acid reached very high levels. Biopsy confirmation of acute UAN was vital in this case, given the possibility of missing an alternative diagnosis and the risks of giving empirical allopurinol therapy. Once the diagnosis for her severe AKI was confirmed, it was clear our patient would benefit from uric acid lowering therapy. Our patient had two healthy girls despite using allopurinol from week 16 in her first pregnancy and throughout her second pregnancy. Unfortunately, both girls have mild to moderate learning needs, though it is unprovable whether allopurinol was causative as no study has followed up long term outcomes after foetal exposure during pregnancy.

Hyperuricemia causes kidney damage by promoting autophagy and NLRP3-mediated inflammation in rats with urate oxidase deficiency

Epidemiological research has shown that elevated serum urate concentration is a risk factor for the development of kidney disease, but the mechanisms underlying this process have not been elucidated. To examine the role of urate in the kidney, we performed functional disruption of urate oxidase (UOX) using the CRISPR/Cas9 system in Wistar rats. In comparison to wild-type (WT) rats, serum urate levels spontaneously and persistently increased in UOX-KO rats without a significant decrease in survival rate. The architecture and function of the kidneys in UOX-KO rats were impaired. Injury to the kidney resulted in increased interstitial fibrosis, macrophage infiltration, expression of NLRP3 and IL-1β, and activation of multiple cell-signaling pathways associated with autophagy, including the AMPK, p38 MAPK, ERK, and JNK pathways. Inhibition of autophagy with 3-MA abrogated the development of kidney damage and attenuated renal fibrosis, macrophage infiltration, and expression of NLRP3 and IL-1β in injured kidneys. In conclusion, the UOX-KO rat is a great model to study hyperuricemia-related diseases. Hyperuricemia-induced autophagy and NLRP3 dependent inflammation are critically involved in the development of renal damage. The inhibition of autophagy and inflammation are potential therapeutic strategies for uric acid nephropathy.

Lipophilic Extract and Tanshinone IIA Derived from Salvia miltiorrhiza Attenuate Uric Acid Nephropathy through Suppressing Oxidative Stress-Activated MAPK Pathways

Uric acid nephropathy (UAN) is caused by excessive uric acid, which results in the damage of renal tissue via urate crystals deposition in the kidneys. The roots and rhizomes of Salvia miltiorrhiza Bunge (S. miltiorrhiza) have been clinically used in many prescriptions to treat uric acid-induced renal damage. This study investigates the uricosuric and nephroprotective effects of the ethyl acetate extract of S. miltiorrhiza (EASM) and tanshinone IIA (a major component of S. miltiorrhiza, Tan-IIA) on UAN and explores the underlying molecular mechanism. Both EASM and Tan-IIA significantly decreased serum uric acid (SUA), serum creatinine (SCR), urine uric acid (UUA), and increased urine creatinine (UCR), and blood urea nitrogen (BUN) levels in experimental UAN mice. In adenine and potassium oxonate-induced mice, EASM and Tan-IIA treatment alleviated renal dysfunction and downregulated the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Moreover, EASM treatment significantly prevented excessive reactive oxygen species (ROS) production in uric acid-induced HK-2 cells and suppressed the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). EASM also suppressed ROS-activated mitogen-activated protein kinases (MAPKs) in vivo and in vitro. These results suggest that both EASM and Tan-IIA demonstrated inhibitory effects on UAN through relieving NOX4-mediated oxidative stress and suppressing MAPK pathways activation.

Acute Uric Acid Nephropathy following Epileptic Seizures: Case Report and Review

Acute hyperuricemia most commonly occurs in patients who experience tumor lysis syndrome. Hyperuricemia along with other electrolyte abnormalities like hyperkalemia, hypocalcemia, and hyperphosphatemia leads to acute kidney injury (AKI) due to acute uric acid nephropathy which is associated with significant morbidity. High risk patients are thus closely monitored for signs of these laboratory abnormalities. Extreme exercise, rhabdomyolysis, and seizures are rare causes of acute hyperuricemia. Serum uric acid level is not routinely monitored as a part of postictal labs. We report an unusual case of AKI in a young male with recurrent seizures and no associated rhabdomyolysis who was found to have acute uric acid nephropathy. Timely administration of Rasburicase prevented the need for dialysis in this patient and led to complete renal recovery. This case illustrates the importance of doing a urine microscopy and checking uric acid level in patients with recurrent seizures who develop unexplainable AKI, as timely management helps improve outcome. We also briefly review the pathophysiology of seizure related hyperuricemia and acute uric acid nephropathy.