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

Abstract

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.

Genetic Background but Not Intestinal Microbiota After Co-Housing Determines Hyperoxaluria-Related Nephrocalcinosis in Common Inbred Mouse Strains

“…This is consistent with reports indicating that CaOx supersaturation occurs independent of urine pH (3), while in other types of kidney stone disease, an acidic urine pH seems to be necessary for the formation of e.g. uric acid crystals, which in turn causes chronic uric acid crystal nephropathy (9).…”

“…Epidemiological studies reveal that genetic factors play a pivotal role in kidney stone formation ( 7 , 8 ). To study the pathogenesis of different types of kidney stones or crystal-induced chronic kidney disease ( 9 , 10 ), mice are most commonly used as experimental models. Although studies using genetically modified mouse strains indicate an association of certain genes with CaOx crystal formation ( 11 – 13 ), the role of the genetic predisposition remains poorly defined.…”

Management of gout in chronic kidney disease: a G-CAN Consensus Statement on the research priorities

“…The same is the case for the inflammation modulating effects in CKD and gout of obesity, type 2 diabetes mellitus and reninangiotensin system activation in the pathophysiology of hypertension, and for the use of statins (which modu late trained immunity in monocytes and macrophages) Management of gout in chronic kidney disease: a G-CAN Consensus Statement on the research priorities and metformin and ω3 fatty acids (which inhibit MSU crystal induced inflammation) [11][12][13] . Additionally, ultra sonography studies have demonstrated renal medullary echogenicity in patients with severe gout 14 , potentially attributable to MSU crystalluria and the development of tophi within the renal medulla 15 . MSU crystal driven inflammation might thus directly affect renal structure and function in patients with gout.…”

Factors Influencing the Serum Uric Acid in Gout with Cerebral Infarction

“…Therefore, impaired renal function may lead to an increase in sUA, which may be a decrease in glomerular filtration or a decrease in renal tubular resecretion [17], accompanied by an increase in CRE. Adversely, It has been proved that the level of sUA is closely related to the progression of nephropathy [18,19], which may be related to sUA causing kidney damage by stimulating the adrenaline-angiotensin system and promoting the proliferation of vascular smooth muscle cells [20,21], as well as high uric acid. Symptoms of hyperemia can affect renal hemodynamics and cause glomerular perfusion disorders [22].…”