CME/SAM. Study on Hyperuricemia in HBV-Associated Glomerulonephritis

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1 AJCP / Originl Article Study on Hyperuricemi in HBV-Associted Glomerulonephritis Yongze Zhung, MD, PhD, 1 Yingho Yu, MD, PhD, 2 Yingfng Hung, MD, 3 nd Xiorong Zhong, MD 1 From the 1 Deprtment of Nephrology, Fuzhou Generl Hospitl of Nnjing Militry Commnd, Fuzhou, Chin; 2 Deprtment of Pthology, Fuzhou Generl Hospitl of Nnjing Militry Commnd, Fuzhou, Chin; nd 3 Fujin Hypertension Reserch Institute, The First Affilited Hospitl of Fujin Medicl University, Fuzhou, Chin. CME/SAM Key Words: HBV-ssocited glomerulonephritis; Hyperuricemi; Glomerulr filtrtion rte; Tubulr interstitil injury DOI: /AJCP2H0FOVIRWMSU ABSTRACT Objectives: To determine the prevlence nd risk fctors for hyperuricemi in heptitis B virus ssocited glomerulonephritis (HBV-GN). Methods: Univrite nd multivrite logistic regression nlysis ws pplied to decide the risk fctors of hyperuricemi in HBV-GN, nd clinicl nd pthologic dt were compred between HBV-GN ptients with hyperuricemi nd those with norml serum uric cid. Results: Among our 227 HBV-GN cses, 31.3% of the ptients hd hyperuricemi t the time of renl biopsy. Univrite nlysis showed tht the level of serum cretinine nd the severity of glomerulr nd tubulr interstitil injury were significntly relted to hyperuricemi. Multivrite logistic regression nlysis identified the levels of serum cretinine nd tubulr interstitil injury s independent fctors for hyperuricemi. The incidence of hypertension nd lower estimted glomerulr filtrtion rte ws significntly higher in hyperuricemic ptients with HBV-GN thn in normouricemic ptients. There were lso fewer membrnous nephropthy, more prolifertive sclerosing glomerulonephritis, nd more tubulr interstitil injury in hyperuricemic ptients with HBV-GN. Conclusions: Our study results suggest tht hyperuricemi is common in HBV-GN, which my fcilitte the progression of HBV-GN nd renl tubulr interstitil injury s well s the development of hypertension. Upon completion of this ctivity you will be ble to: list the types of liver injury tht my be seen in ptients with heptitis B virus ssocited glomerulonephritis (HBV-GN). describe the role of hyperuricemi in the progression of HBV-GN. define symptoms ssocited with HBV-GN. The ASCP is ccredited by the Accredittion Council for Continuing Medicl Eduction to provide continuing medicl eduction for physicins. The ASCP designtes this journl-bsed CME ctivity for mximum of 1 AMA PRA Ctegory 1 Credit per rticle. Physicins should clim only the credit commensurte with the extent of their prticiption in the ctivity. This ctivity qulifies s n Americn Bord of Pthology Mintennce of Certifiction Prt II Self-Assessment Module. The uthors of this rticle nd the plnning committee members nd stff hve no relevnt finncil reltionships with commercil interests to disclose. Questions pper on p 141. Exm is locted t Heptitis B virus ssocited glomerulonephritis (HBV- GN) is one of the most prevlent secondry glomerulr diseses in Chin nd ccounts for 0.25% of renl biopsies. 1 The nturl history of HBV-GN is not completely understood. Although spontneous regression of nephrotic syndrome ws reported in 30% to 60% cses with membrnous nephropthy (MN) cused by HBV, these ptients still remin symptomtic with ctive HBV serology for 12 months or longer. Ptients who do not cler the virus my hve renl insufficiency. 2 Isoltion of immune complexes from the kidney nd expression of HBV virl ntigens in kidney tissue suggest tht the pthogenesis of HBV-GN hs n immunologic bsis. However, biosocil studies hve detected no correltion between HBV crrige nd proteinuri. Genetic studies on humn leukocyte ntigen clss I nd II genes hve showed only predisposition to MN nd no correltion in those with milder degrees of proteinuri. 3 These findings suggest tht development of 72 Am J Clin Pthol 2014;141: DOI: /AJCP2H0FOVIRWMSU Americn Society for Clinicl Pthology Zhung_ indd 72

2 AJCP / Originl Article HBV-GN is not relted to HBV crrige or genetic fctors but with interctions between the virus nd host fctors. Uric cid, metbolite involved in the development of gouty rthritis nd kidney stones, constitutes the finl oxidtion product of purines. 4 Humns cnnot oxidize uric cid to the more soluble compound llntoin due to lck of uricse enzyme. A diet tht genertes uric cid, long with kidney dysfunction tht reduces uric cid excretion, cn induce hyperuricemi. Incresed uric cid levels hve been shown to be predictive of insidious, chronic, nd progressive renl disese, 5 while reduction of serum uric cid by llopurinol tretment hs been ssocited with slower progression of renl disese. 6 These studies suggest tht hyperuricemi not only is consequence of renl insufficiency but lso contributes to the progression of chronic kidney diseses (CKDs). A recent study hs shown n independent ssocition of hyperuricemi with the severity of liver dmge in ptients with nonlcoholic ftty liver disese, 7 including heptitis C virus. 8 However, n ssocition between hyperuricemi nd HBV-GN hs not been reported to our knowledge. This study investigted the prevlence, underlying fctors, nd significnce of hyperuricemi in 227 ptients with HBV-GN dignosed by renl biopsy. Our study demonstrted tht hyperuricemi is common nd prllels the level of serum cretinine nd the degree of renl tubulr interstitil injury. Hyperuricemi my fcilitte the development of hypertension, cn ggrvte renl tubulr interstitil injury, nd is one of the risk fctors for the progression of HBV-GN. Mterils nd Methods Ptients Of the 5,157 ptients who were hospitlized in Fuzhou Generl Hospitl of Nnjing Militry Commnd nd underwent renl biopsy from Jnury 1999 through July 2007, 227 were dignosed with HBV-GN, ccounting for 4.4% of ll renl biopsy ptients in the sme period. Percutneous renl biopsy ws performed by using n utomtic biopsy gun tht ws guided by ultrsound. The dignostic criteri for HBV- GN used in Chin re s follows: () heptitis B surfce ntigen (HBsAg) positive serum; (b) the presence of glomerulr nephritis, excluding lupus nephritis nd other secondry glomerulr diseses; nd (c) positive HBV ntigens, including HBsAg or heptitis B core ntigen, or HBV DNA determined by polymerse chin rection in kidney tissue. Approvl of the study ws obtined from the ethics committee of Fuzhou Generl Hospitl of Nnjing Militry Commnd, Chin. Hyperuricemi ws defined s condition when the blood uric cid level ws more thn 7.0 mg/dl for mle ptients nd more thn 6.0 mg/dl for femle ptients. Of the 227 HBV-GN cses, 71 were hyperuricemic (group A), nd the blood uric cid level ws norml in the other 156 cses (group B). Clinicl Definitions Clinicl dt were collected from medicl records by the time of renl biopsy, including ge, sex, weight, course of disese, blood pressure, serum uric cid, cretinine, triglycerides, cholesterol, serum lbumin, hemturi, nd 24-hour urinry protein. The Schwrtz formul ws used for ptients younger thn 18 yers tht is, estimted glomerulr filtrtion rte (egfr) = 0.55 Height (cm) [Serum Cretinine (mg/dl)/88.4] 1. The simplified Modifiction of Diet in Renl Disese formul ws used for ptients older thn 18 yers tht is, egfr = 186 (Serum Cretinine/88.4) Age (Femle 0.742). Ptients were grouped into different stges by CKD stndrds ccording to their egfr (ml/min) level: stge 1 ( 90 ml/min), stge 2 ( 60 to <90 ml/min), stge 3 ( 30 to <60 ml/min), stge 4 ( 15 to <30 ml/min), nd stge 5 (<15 ml/min). The 227 HBV-GN cses were clssified into four clinicl ctegories: hemturi only, proteinuri only, proteinuri ccompnied with hemturi, nd nephrotic syndrome. Pthologic Clssifiction Pthologic ctegories were sorted ccording to the Pthologicl Ctegories of Renl Glomerulr Diseses mended by the World Helth Orgniztion in Among the 227 HBV-GN cses, eight different pthologic types were found: MN, membrnoprolifertive glomerulonephritis (MPGN), immunoglobulin A nephropthy, mesngil prolifertive glomerulonephritis (MsPGN), miniml chnge disese, focl segmentl prolifertive GN, focl segmentl glomerulosclerosis, nd prolifertive sclerosing glomerulonephritis (SGN; 50%-75% of glomerulus showed sclerosis, nd remnnt showed prolifertion nd segmentl sclerosis). The presence of Bowmn cpsule dhesion, crescent formtion, glomerulosclerosis, nd immune complex deposit ws lso exmined. Mesngil prolifertion nd tubulr interstitil injury were clssified into four levels: 0 (no injury), 1 (mild injury, injury re <25%), 2 (moderte injury, injury re 25%-50%), nd 3 (severe injury, injury re >50%). Sttisticl Anlysis Sttisticl nlyses were performed using SPSS 11.5 (SPSS, Chicgo, IL). Continuous vribles were expressed s men ± SD, while ctegoricl vribles were shown s frequency nd percentge. Ctegoricl dt were tested using the Person c 2 test. Differences in the continuous vribles between the groups were compred using the t test or onewy nlysis of vrince. Univrite nd multivrite logistic regression nlyses were used to exmine the potentil Americn Society for Clinicl Pthology Am J Clin Pthol 2014;141: DOI: /AJCP2H0FOVIRWMSU 73 Zhung_ indd 73

3 Zhung et l / HBV-Associted Glomerulonephritis nd Hyperuricemi predisposing fctors for hyperuricemi. In univrite nd multivrite nlyses, vribles were expressed s binry scle or multiple scles, such s bsence/presence (coded s 0/1) or no/mild/moderte/severe (coded s 0/1/2/3). The results of the univrite nd multivrite nlyses were expressed s odds rtio (ORs) nd their 95% confidence intervls. The Person c 2 test ws one-tiled while ll other tests were two-tiled, nd fctors with P vlue less thn.05 were considered sttisticlly significnt. Results Prevlence of Hyperuricemi in Ptients With HBV-GN Seventy-one of the 227 ptients who hd HBV-GN hd hyperuricemi. The incidence of hyperuricemi ws not significntly different (P >.05) between mles (33.7%) nd femles (24.6%). However, the occurrence of hyperuricemi mong children (ge <15 yers) ws significntly lower thn mong dults (6/50 vs 65/177; P <.01). Clinicl nd Histopthologic Risk Fctors for Hyperuricemi in Ptients With HBV-GN Univrite nlysis showed tht the prevlence of hyperuricemi ws significntly higher in ptients with HBV-GN with serum cretinine of 1.50 mg/dl or higher, moderte to severe degree of mesngil prolifertion, glomerulr sclerosis of 50% or more, crescent formtion, nd moderte to severe degree of tubulr interstitil dmge of the kidney. Among the clinicl nd pthologic fctors, OR nlysis showed tht n increse of serum cretinine nd the degree of renl tubulr interstitil dmge were ssocited with hyperuricemi in HBV-GN Tble 1, which were proven s independent risk fctors by multivrite logistic regression nlysis Tble 2. We observed tht the decrese of egfr ws ssocited with serum uric cid Figure 1. To further exmine the effect of renl function on hyperuricemi, we divided ptients into three groups ccording to the level of the glomerulr filtrtion rte (GFR). When the egfr ws below 60 ml/min, the prevlence of hyperuricemi incresed to 60.5%, which ws significntly higher thn tht in ptients with stge 1 nd stge 2 CKD (P <.05) Tble 3. To further detect the effect of tubulr interstitil injury on hyperuricemi, we compred the serum uric cid level of ptients with different levels of tubulr interstitil injury. Compred with ptients with no renl tubulr interstitil injury, the level of serum uric cid ws significntly higher in ptients who hd HBV-GN with moderte or severe renl tubulr interstitil injury Figure 2. 1, Tble 1 Univrite Anlysis of Risk Fctors for Hyperuricemi in Ptients With HBV-GN Fctors c 2 OR (95% CI) P Vlue SUA (mmol/l) Serum cretinine 1.50 mg/dl ( ) <.001 Glomerulosclerosis ( ).003 Crescent formtion ( ).035 Mesngil prolifertion ( 2) ( ).017 Tubulr interstitil injury ( 2) ( ).001 CI, confidence intervl; HBV-GN, heptitis B virus ssocited glomerulonephritis; OR, odds rtio. 2 Indictes moderte or severe level of mesngil prolifertion or tubulr interstitil injury egfr (ml/min) Figure 1 Effect of the decrese in estimted glomerulr filtrtion rte (egfr) on serum uric cid (SUA) level in heptitis B virus ssocited glomerulonephritis (R = 0.382; P <.001). Tble 2 Multivrite Regression Anlysis of Risk Fctors for Hyperuricemi in HBV-GN Risk Fctors Exp(β) (SE) c 2 OR (95% CI) P Vlue Scr 1.50 mg/dl (0.435) ( ).001 Tubulr interstitil injury ( 2) (0.271) ( ).049 CI, confidence intervl; HBV-GN, heptitis B virus ssocited glomerulonephritis; OR, odds rtio; Scr, serum cretinine. 2 Indictes moderte or severe level of mesngil prolifertion or tubulr interstitil injury. 74 Am J Clin Pthol 2014;141: DOI: /AJCP2H0FOVIRWMSU Americn Society for Clinicl Pthology Zhung_ indd 74

4 AJCP / Originl Article Clinicl nd Histopthologic Prmeters in Hyperuricemic Ptients With HBV-GN We divided 227 cses of HBV-GN into hyperuricemic group (n = 71) nd normouricemic group (n = 156). No significnt difference ws observed when vribles, including sex, body weight, course of disese, serum triglycerides, serum cholesterol, nd serum lbumin, were compred between the two groups (P >.05). There ws lso no significnt difference in the type of clinicl mnifesttions. However, the men ± SD ge of the ptients in the hyperuricemic group ws 28.2 ± 11.6 yers, which ws older thn tht of the normouricemic group. The prevlence of hypertension in the hyperuricemic group ws 29.6% (21/71), which ws significntly higher thn tht of the normouricemic group (18.0%) Tble 4. Anlysis on the HBV-GN pthologic ctegories between the hyperuricemic nd normouricemic groups reveled tht most normouricemic ptients with HBV-GN hd MN (n = 69; 44.2%), while there ws ner even distribution of MN (n = 21; 29.6%), MsPGN (n = 16; 22.5%), nd MPGN (n = 15; 21.1%) in hyperuricemic ptients with HBV-GN. The percentge of MN ws significntly lower (P <.05), while SGN ws higher (P <.01), in the hyperuricemic HBV-GN cses compred with the normouricemic HBV-GN cses Tble 5. Comprisons of pthologic indices between hyperuricemic nd normouricemic groups showed tht the prevlence of glomerulosclerosis (>50%), crescent formtion, scculus dhesion, moderte to severe mesngil prolifertion, nd renl interstitil tubulr injury in hyperuricemic ptients with HBV-GN ws significntly higher thn tht in the normouricemic ptients with HBV-GN (P <.05) Tble 6. Tble 3 Reltionship Between Prevlence of Hyperuricemi nd Stge of CKD in HBV-GN CKD Stges Prevlence of Hyperuricemi, No. (%) Stge 1, egfr 90 ml/min 132 (21.2) Stge 2, egfr ml/min 57 (35.1) Stges 3-5, egfr <60 ml/min 38 (60.5 ) Totl 227 (31.3) CKD, chronic kidney disese; egfr, estimted glomerulr filtrtion rte; HBV-GN, heptitis B virus ssocited glomerulonephritis. P <.05 compred with stges 1 nd 2. SUA (mmol/l) 1, * * Figure 2 Effect of the degree of renl tubulr interstitil injury (TIL) on serum uric cid (SUA) level in heptitis B virus ssocited glomerulonephritis. Circles represent outliers tht extend between 1.5 nd 3.0 times the interqurtile rnge. Asterisks indicte extreme outliers beyond 3.0 times the interqurtile rnge. 2.0 Degree of TIL 3.0 Tble 4 Comprisons of Clinicl Fetures Between Hyperuricemic vs Normouricemic Ptients With HBV-GN Vribles Hyperuricemic (n = 71) Normouricemic (n = 156) P Vlue Age, men ± SD, y 28.2 ± ± Sex, M/F, No. 56/15 110/ Disese course 3 y, No Clinicl ctegory, No..259 Hemturi only 0 8 Proteinuri only 3 6 Proteinuri with hemturi Nephrotic syndrome Hypertension, No. (%) 21 (29.6) 28 (18.0).048 Lbortory vlues, men ± SD b 24-h Urinry protein, g/d 4.12 ± ± Serum cholesterol, mg/dl ± ± Serum triglyceride, mg/dl ± ± Serum lbumin, g/dl 2.73 ± ± Scr 1.50 mg/dl, No <.001 Scr, mg/dl 1.87 ± ± 1.14 <.001 egfr, ml/min ± ± <.001 egfr, estimted glomerulr filtrtion rte; HBV-GN, heptitis B virus ssocited glomerulonephritis; Scr, serum cretinine. P <.05 between hyperuricemic nd normouricemic HBV-GN. b Lbortory vlues re given in conventionl units; conversions to Système Interntionl units re s follows: serum cholesterol (mmol/l), multiply by ; serum triglyceride (mmol/l), multiply by ; serum lbumin (g/l), multiply by 10; Scr (mmol/l), multiply by Americn Society for Clinicl Pthology Am J Clin Pthol 2014;141: DOI: /AJCP2H0FOVIRWMSU 75 Zhung_ indd 75

5 Zhung et l / HBV-Associted Glomerulonephritis nd Hyperuricemi Discussion Our study showed tht the prevlence of hyperuricemi in ptients with HBV-GN is 31.3%, which is similr to other GN. We did not find tht liver function nd HBV titer ffected blood uric cid level. However, when the serum cretinine level ws 1.50 mg/dl or higher n indictor of impired renl function nd when the GFR decresed by more thn 50%, the prevlence of hyperuricemi in HBV-GN ws four times higher thn in ptients with HBV-GN with norml serum cretinine level (OR, 5.04), which is consistent with other studies. This suggests tht reduced glomerulr filtrtion nd decresed uric cid excretion from tubules contribute to the development of hyperuricemi in HBV-GN. It ws believed tht long-term hypertension leds to benign rteriosclerosis in the kidney glomerulus nd tht lck of oxygen nd blood supply to the kidney tubules cuses lctic cidosis, which chllenges the excretion of uric cid nd cuses retention of uric cid nd subsequent hyperuricemi. 10 Hyperuricemi my lso promote the progression of HBV-GN. An erlier study by Syrjnen et l 11 indicted tht hyperuricemi incresed the risk of progression of immunoglobulin A (IgA) nephropthy by 2.4-fold compred with the IgA nephropthy ssocited with norml level of blood uric cid. In the Jpnese popultion, the reltive risk of developing high serum cretinine in people with serum uric cid level of 8 mg/dl or higher ws 2.91 in men nd in women, which is much higher thn those with serum uric cid level less thn 5.0 mg/dl. 12 It hs been reported tht, in cispltin-induced cute kidney injury, hyperuricemi results in more severe kidney injury without significnt formtion of uric cid crystls. 13 Tomit et l 14 reported tht once blood uric cid levels rose, the risk of renl filure incresed significntly. Dt from our study showed tht hyperuricemic ptients with HBV-GN hd more severe hypertension nd more severe glomerulr nd renl interstitil tubulr injury thn those with norml levels of blood uric cid. The incidence of n egfr less thn 60 ml/min in hyperuricemic ptients with HBV-GN ws 32.4%, which ws significntly higher thn tht in ptients with HBV-GN who hd norml uric cid level (9.6%; P <.01). The mechnism of how hyperuricemi influences the progression of renl diseses is not cler. It hs been postulted tht uric cid cn promote the expression of chemotctic fctors nd cytokines, ctivte the renin-ngiotensin system, increse C-rective protein expression in blood vessels, fcilitte prolifertion of vsculr smooth muscle cells, nd promote hypertension nd therosclerosis. Hence, uric cid hs been one of the most importnt fctors to cuse inflmmtion, endothelil dysfunction, nd vsculr diseses. 15 In ddition, uric cid cn lso directly ctivte ntigen presenttion nd increse CD70 expression of T lymphocytes nd thus is involved in the development of immunologic diseses. 16 Even mild hyperuricemi cn increse trnsforming growth fctor β excretion into the urine nd ggregte hypertension nd renl dysfunction. 17 It hs been found tht n increse of Tble 5 Comprisons of HBV-GN Pthologic Ctegories Between HBV-GN With Hyperuricemi nd Normouricemi No. (%) Ctegories Totl No. MN MPGN IgAN MsPGN MCD FsPGN FSGS SGN Hyperuricemic (29.6) 15 (21.1) 6 (8.5) 16 (22.5) 3 (4.2) 1 (1.4) 4 (5.6) 5 (7.0) Normouricemic (44.2) 21 (13.5) 15 (9.6) 31 (19.9) 12 (7.7) 5 (3.2) 2 (1.3) 1 (0.6) FSGS, focl segmentl glomerulosclerosis; FsPGN, focl segmentl prolifertive glomerulonephritis; HBV-GN, heptitis B virus ssocited glomerulonephritis; IgAN, immunoglobulin A nephropthy; MCD, miniml chnge disese; MN, membrnous nephropthy; MPGN, membrnoprolifertive glomerulonephritis; MsPGN, mesngil prolifertive glomerulonephritis; SGN, prolifertive sclerosing glomerulonephritis. P <.05 between hyperuricemic nd normouricemic HBV-GN. Tble 6 Effect of Hyperuricemi on Pthologic Fetures of HBV-GN No. (%) Crescent Bowmn Cpsule Mesngil Tubulr Interstitil Ctegories Totl No. Glomerulosclerosis Formtion Adhesion Prolifertion ( 2) Injury ( 2) Hyperuricemic (25.4) b 17 (23.9) c 30 (42.3) 51 (71.8) c 15 (21.1) b Normouricemic (10.3) 20 (12.8) 46 (29.5) 86 (55.1) 10 (6.4) HBV-GN, heptitis B virus ssocited glomerulonephritis. 2 Indictes moderte or severe level of mesngil prolifertion or tubulr interstitil injury. b P <.01 between hyperuricemic nd normouricemic HBV-GN. c P <.05 between hyperuricemic nd normouricemic HBV-GN. 76 Am J Clin Pthol 2014;141: DOI: /AJCP2H0FOVIRWMSU Americn Society for Clinicl Pthology Zhung_ indd 76

6 AJCP / Originl Article blood uric cid level by 1.0 mg/dl heightens the reltive risk of developing hypertension by 23%. A high blood uric cid level lso increses renin secretion nd hence promotes hypertension. 18 In our study, the prevlence of hypertension ws 29.6% in hyperuricemic ptients with HBV-GN, which ws significntly higher thn tht found in normouricemic ptients with HBV-GN (18.0%; P <.05). Control of serum uric cid level cn theoreticlly benefit HBV-GN therpy. A control study hd shown tht in ptients with dibetic nephropthy (serum cretinine <3 mg/dl), lowering the serum uric cid level with llopurinol tretment for four months cused significnt ttenution of proteinuri. 19 Due to the concerns of liver impirment cused by HBV nd the side effects of llopurinol, the effectiveness of llopurinol to tret proteinuri needs to be further investigted. It will lso be of interest to investigte gene polymorphisms potentilly involved in the development of hyperuricemi s well s the therpeutic responses to uric cid lowering regents in ptients with HBV-GN. In conclusion, our study results showed tht round 30% of ptients with HBV-GN hve hyperuricemi. Hypertension, elevted serum cretinine ( 1.50 mg/dl), severity of glomerulr dmge (mesngil expnsion, glomerulosclerosis, nd crescent formtion), nd renl tubulr interstitil injury re ssocited with hyperuricemi in HBV-GN. Our results from this retrospective cse control study my shed light on the necessity of future therpeutic regimens to control hyperuricemi in ptients with HBV-GN. Address reprint requests to Dr Zhung: Dept of Nephrology, Fuzhou Generl Hospitl of Nnjing Militry Commnd, 156 Xier Hun N Rd, Fuzhou, Fujin , Chin; zhungyongze@126.com. This study ws supported by grnt 2007Y0030 from the Science nd Technology Progrmme of Fujin Province. Acknowledgments: We thnk ll collegues who collected ll medicl informtion nd clinicl dt, performed renl biopsies, nd mde histopthologic dignoses. References 1. Li LS, Liu ZH. Epidemiologic dt of renl diseses from single unit in Chin: nlysis bsed on 13,519 renl biopsies. Kidney Int. 2004;66: Li KN, Li FM, Chn KW, et l. The clinico-pthologic fetures of heptitis B virus ssocited glomerulonephritis. Q J Med. 1987;63: Bhimm R, Coovdi HM. Heptitis B virus ssocited nephropthy. Am J Nephrol. 2004;24: Feig DI, Kng DH, Johnson RJ. Uric cid nd crdiovsculr risk. N Engl J Med. 2008;359: Li YL, Wng L, Li J, et l. The correltion between uric cid nd the incidence nd prognosis of kidney diseses: systemtic review nd met-nlysis of cohort studies [in Chinese]. Zhonghu Nei Ke Z Zhi. 2011;50: Siu YP, Leung KT, Tong MK, et l. Use of llopurinol in slowing the progression of renl disese through its bility to lower serum uric cid level. Am J Kidney Dis. 2006;47: Pett S, Cmm C, Cbibi D, et l. Hyperuricemi is ssocited with histologicl liver dmge in ptients with non-lcoholic ftty liver disese. Aliment Phrmcol Ther. 2011;34: Pett S, Mcluso FS, Cmm C, et l. Hyperuricemi: nother metbolic feture ffecting the severity of chronic heptitis becuse of HCV infection. Liver Int. 2012;32: Churg J, Bemstein J, Glssock RJ. Renl Disese: Clssifiction nd Atls of Glomerulr Disese. 2nd ed. New York, NY: Ikgu-Shoin; Johnson RJ, Kng DH, Feig D, et l. Is there pthogenetic role for uric cid in hypertension nd crdiovsculr nd renl disese? Hypertension. 2003;41: Syrjnen J, Mustonen J, Psternck A. Hypertriglyceridemi nd hyperuricemi re risk fctors for progression of IgA nephropthy. Nephrol Dil Trnsplnt. 2000;15: Iseki K, Oshiro S, Tozw M, et l. Significnce of hyperuricemi on the erly detection of renl filure in cohort of screened subjects. Hypertens Res. 2001;24: Roncl CA, Mu W, Croker B, et l. Effect of elevted serum uric cid on cispltin-induced cute renl filure. Am J Physiol Renl Physiol. 2007;292:F116-F Tomit M, Mizuno S, Ymnk H, et l. Does hyperuricemi ffect mortlity? prospective cohort study of Jpnese mle workers. J Epidemiol. 2000;10: Knellis J, Kng DH. Uric cid s meditor of endothelil dysfunction, inflmmtion, nd vsculr disese. Semin Nephrol. 2005;25: Webb R, Jeffries M, Swlh AH. Uric cid directly promotes humn T-cell ctivtion. Am J Med Sci. 2009;337: Tlt KM, el-sheikh AR. The effect of mild hyperuricemi on urinry trnsforming growth fctor bet nd the progression of chronic kidney disese. Am J Nephrol. 2007;27: Jin M, Yng F, Yng I, et l. Uric cid, hyperuricemi nd vsculr diseses. Front Biosci. 2012;17: Momeni A, Shhidi S, Seirfin S, et l. Effect of llopurinol in decresing proteinuri in type 2 dibetic ptients. Irn J Kidney Dis. 2010;4: Americn Society for Clinicl Pthology Am J Clin Pthol 2014;141: DOI: /AJCP2H0FOVIRWMSU 77 Zhung_ indd 77