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DISCLOSURE

6.

The author declared no competing interests. ACKNOWLEDGMENTS

7.

The author is grateful to Melody Wang for critical reading and editing of the manuscript. 8.

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Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 2006; 69: 213–217. Kato M, Natarajan R. MicroRNA circuits in transforming growth factor-beta actions and diabetic nephropathy. Semin Nephrol 2012; 32: 253–260. Chandrasekaran K, Karolina DS, Sepramaniam S et al. Role of microRNAs in kidney homeostasis and disease. Kidney Int 2012; 81: 617–627. Kasinath BS, Feliers D. The complex world of kidney microRNAs. Kidney Int 2011; 80: 334–337. Li R, Chung ACK, Dong Y et al. The microRNA miR-433 promotes renal fibrosis by amplifying the TGF-b/Smad3-Azin1 pathway. Kidney Int 2013; 84: 1129–1144.

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Chung AC, Huang XR, Meng X et al. miR-192 mediates TGF-beta/Smad3-driven renal fibrosis. J Am Soc Nephrol 2010; 21: 1317–1325. Liu L, Santora R, Rao JN et al. Activation of TGF-beta-Smad signaling pathway following polyamine depletion in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2003; 285: G1056–G1067. Deshpande SD, Putta S, Wang M et al. Transforming growth factor-b induced cross talk between p53 and a microRNA in the pathogenesis of diabetic nephropathy. Diabetes 2013; 62: 3151–3162. Kato M, Arce L, Wang M et al. A microRNA circuit mediates transforming growth factorbeta1 autoregulation in renal glomerular mesangial cells. Kidney Int 2011; 80: 358–368. Kato M, Dang V, Wang M et al. TGF-beta induces acetylation of chromatin and of Ets-1 to alleviate repression of miR-192 in diabetic nephropathy. Sci Signal [online] 2013; 6: ra43. Cai X, Xia Z, Zhang C et al. Serum microRNAs levels in primary focal segmental glomerulosclerosis. Pediatr Nephrol 2013; 28: 1797–1801. Sun L, Zhang D, Liu F et al. Low-dose paclitaxel ameliorates fibrosis in the remnant kidney model by down-regulating miR-192. J Pathol 2011; 225: 364–377.

see clinical investigation on page 1207

JC viruria and kidney disease in APOL1 risk genotype individuals: is this a clue to a geneenvironment interaction? Jeffrey B. Kopp1 APOL1 nephropathy occurs in a minority of genetically at-risk individuals, suggesting that other factors, such as other genes or environmental factors, contribute. Divers and colleagues report that among individuals with two APOL1 risk alleles, those with JC viruria are less likely to manifest kidney disease compared with those lacking JC viruria. These data might suggest that JC virus infection confers protection against glomerular injury, perhaps by altering cell function or generating immunity against a related polyomavirus. Kidney International (2013) 84, 1069–1072. doi:10.1038/ki.2013.299

1 Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA Correspondence: Jeffrey B. Kopp, Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, 10 Center Drive, Bethesda, Maryland 20892, USA. E-mail: [email protected]

Kidney International (2013) 84

The identification of two coding-region variants in APOL1, encoding apolipoprotein L1 was a major advance in understanding why African-Americans experience more glomerular disease.1,2 In all the kidney diseases examined to date, the effect is strongly recessive,

with two copies of the variant alleles (G1/G1, G2/G2, or G1/G2) increasing risk; there is a small effect of a single risk variant that has not reached statistical significance in any single study. Risk is increased for several kidney diseases, including HIVassociated nephropathy (odds ratio (OR) 29),3 focal segmental glomerulosclerosis (OR 17),3 and hypertensionattributed kidney disease, which is perhaps better termed arterionephrosclerosis (the OR ranges from 2.5 for AASK (African-American Study of Kidney Disease and Hypertension) study participants4 to 7.3 for endstage kidney disease1); allograft loss following deceased donor transplant (OR 3.8);5 sickle nephropathy (OR 3.4);6 and most recently, collapsing glomerulopathy in lupus nephritis (OR 5.4).7 Among population studies, risk allele frequency is highest among the Yoruba people of West Africa, reaching 60%. This high frequency is explained by the protection afforded by the risk alleles against Trypansoma brucei rhodesiense. We have only very approximate estimates of the risk of glomerular disease among individuals with two APOL1 risk variants; in individuals with HIV-1 infection, in the absence of anti-viral therapy, the lifetime risk is estimated as 50%; in focal segmental glomerulosclerosis, the lifetime risk is estimated at 4%;3 and the risk for clinically manifest arterionephrosclerosis is probably several fold higher. These powerful genetic associations raise many important research questions. What are the cellular mechanisms by which the APOL1 variants induce kidney disease? Within kidney, ApoL1 expression has been localized to the podocyte, arteriolar endothelium and with glomerular disease, to the arterial and arteriolar media;8 how does this localization relate to glomerular injury? We have no insight into the cell biology of APOL1-associated glomerular injury. As only a minority of individuals with two APOL1 risk alleles develop glomerular disease, what are the contributing factors that interact with the risk genotype? Diseases with a genetic 1069

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component and with low penetrance are considered complex genetic diseases, in which a second factor (genetic or environmental) interacts with the disease-associated gene variants. As pointed out by Freedman et al.9 many years ago, some African-American kindreds have multiple affected members with kidney disease and manifest inheritance pattern suggests a complex genetic disease—and we now understand that many and probably most of these families have APOL1 risk variants causing the kidney disease. Among genegene interactions, Freedman et al. carried out a genome-wide association study in African-Americans with non-diabetic nephropathy and reported several interacting single-nucleotide polymorphisms; the strongest associations were in or near NPHS2, encoding podocin (OR 0.72, P ¼ 0.004), SUCLA2 (OR 0.27, P ¼ 0.0002), PRKCE (OR 2.22, P ¼ 0.0005), and ENOX1 (OR 0.31, P ¼ 0.0005).10 The same group found an interaction between FRMD3 and MYH9 (the gene lying immediately centromeric to APOL1, encoding non-muscle myosin heavy chain 9 and initially identified as the source of the chromosome 22 association with African-American kidney disease susceptibility; there were weaker interactions between FRMD3 and APOL1. In the current issue of Kidney International, Divers et al.11 have addressed the hypothesis that among African-Americans with non-diabetic nephropathy, there might be a relationship between JC viruria and kidney disease among those with a genetic risk for kidney disease, two APOL1 nephropathy risk alleles. Specifically, they have hypothesized that the presence of the APOL1 risk genotype might predispose to JC viruria, and this might be an environmental cofactor that would interact with the genetic risk locus to further increase the risk for kidney disease. The authors were perhaps surprised to learn that while there was an association, it was the inverse of the hypothesis—APOL1 two-risk allele subjects who had detectable JC viruria were less likely to manifest kidney disease than those who lacked JC 1070

viruria. The authors propose two possible explanations. First, the presence of JC virus in the kidney might protect against other viruses that cause nephropathy, perhaps via shared antigenic epitopes. Second, JC virus might alter cellular function in such a way that reduces glomerular injury from other sources, either viral or toxic. If the other virus is a polyomavirus, what might that virus be? Polyomaviruses are small viruses containing a circular, double-stranded DNA genome ranging in size from 4.5 to 5.4 kb; the family name derived from the finding that they caused multiple tumors in rodents. The first human polyomaviruses were reported in the same issue of the journal Lancet in 1971, BK virus isolated from the urine of a renal transplant patient12 and JC virus from the brain of a patient with multifocal leukoencephalopathy13. Infections with the polyomaviruses BK virus and JC virus are generally acquired in childhood. BK virus establishes latency in the kidney at the time of primary infection, which occurs in childhood and may be asymptomatic or associated with mild upper respiratory tract infection. Under conditions of immunosuppression, replicating virus is most likely to be present within the distal tubular epithelium, causing interstitial nephritis. Two case reports suggest that BK virus can also (rarely) infect glomerular parietal epithelial cells; cytopathic changes were seen in parietal cells in 17% of kidney transplants with BK interstitial nephritis14 and a case report suggested an association with crescentic glomerulonephritis.15 Like BK, JC virus infection is common in childhood; the virus establishes latency in brain oligodendrocytes and renal tubular cells and, to a lesser extent, in B lymphocytes. JC virus is shed from the urine of healthy individuals, and interestingly, the rates are higher than for BK virus.16 Nevertheless, compared with BK virus, JCV is much less commonly associated with kidney disease, for reasons that are not well understood. With immunosuppression, JC virus has been rarely associated with interstitial nephritis, and in a single case report JC virus

was associated with infection of parietal epithelial cells and perhaps podocytes, although overt glomerular pathology was not described.17 After a lag of 25 years, the past 6 years have seen the discovery of nine new human polyomaviruses, as PCRbased techniques have been applied to samples obtained from diverse populations and clinical settings. These include KI virus (named after the Karolinska Institute),18 WU virus (named after the Washington University),19 Merkel cell virus (MC virus),20 HPy6 and HPy7,21 Trichodysplasia-associated Py (HPy8),22 HPy9,23,24 Malawi polyomavirus,25 and St Louis polyomavirus.26 As shown in Table 1, the source of the new polyomaviruses has been most commonly respiratory tract, skin, or stool. Their role in human disease remains speculative. The strongest case for a pathogenic role can be made for the MC virus, as the tumors show clonal integration of the virus (i.e. the cells from a particular tumor have virus integrated at single genomic location) and the MC tumors are associated with immunodeficiency (suggesting a predisposing factor). The seroprevalence rates for human polyomaviruses tend to be 450%, as summarized in Table 1 (data from the review by Decaprio and Garcea27). Thus, human polyomavirus infections are common infections and individuals with normal immune systems are able to suppress viral replication, to a large extent but not always completely. By contrast, individuals with compromised immune systems are at risk for polyomavirus-associated disease, typically due to reactivation of latent infection, particularly with BK virus, JC virus, and MC polyomavirus. Four polyomaviruses are known to be present in urine, including BK virus, JC virus, MC virus, and HPyV9 (and HPvY7 in urine from a child following organ transplantion28), although the absence of data from the more recently discovered viruses does not preclude that they could infect the kidney. As noted above, BK virus and JC virus are well-recognized causes of interstitial nephritis. Husseiny et al.29 reported that low levels of MC virus Kidney International (2013) 84

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Table 1 | Human polyomaviruses Full name

Major isolation sources

Presence in urinary tract or urine

Seroprevalence estimates

Interstitial nephritis, ureteritis, cystitis

Urine

82%, 92%

Urine

2007

Multifocal leukoencephalopathy; interstitial nephritis Acute respiratory illness

Tubules, glomerular parietal epithelium, urothelium Tubules

Respiratory secretions

Not reported

55%, 70%, 90%

WUPyV

2007

Acute respiratory illness

Respiratory secretions

Not reported

70%, 80%, 90%

HPyV5 HPyV6 HPyV7 TSPyV

2008 2010 2010 2010

Tumor, normal skin Respiratory tract Skin

Urine Not reported Not reported Not reported

60–80% 70% 35% 70–80%

HPyV9 MWPyV STLPyV

2011 2012 2012

Merkel cell carcinoma None None Trichodysplasia spinulosoa None None None

Blood, skin, urine Stool, wart Stool

Urine Not reported Not reported

25–50% Unknown Unknown

Abbreviation

Year reported

BK polyomavirus

BKPyV

1971

JC polyomavirus

JCPyV

1971

Karolinska Institute polyomavirus Washington University polyomavirus Merkel cell polyomavirus Human polyomavirus 6 Human polyomavirus 7 Trichodysplasia spinulosaassociated polyomavirus Human polyomavirus 9 Malawi polyomavirus St Louis polyomavirus

KIPvV

Disease association

40–55%

Primary infection and seroconversion for most human polyomaviruses is the greatest in childhood, except for HPyV7 and HPyV9, for which seropositivity rates rise throughout adulthood. The seroprevalence data for adults are as summarized in reference 27, with some modifications.

were detected in urine in 15% of healthy individuals, 30% of kidney transplant patients, and 0% of kidney transplant recipients with BK virus activation and/or nephropathy. By comparison, BK virus was seen in 5, 30, and 100% of subjects in the three groups. Without kidney biopsy and localization of viral proteins or genome, it remains unclear whether MC virus infects the kidney, the lower urinary tract, or conceivably enters urine collections as a contaminant from skin. HPyV9 is closely related to the simian lymphotrophic virus, whose natural host is the African green monkey, and was initially isolated from the serum of a kidney transplant patient (representing the only sample among 179 tested to harbor DNA from the virus).24 Neither MC virus nor HPyV9 have been localized to kidney, and their possible role in causing kidney disease remains speculative. Can we relate this evolving polyomavirus story to the observation by Divers et al.11 that JC viruria is less common in individuals with two APOL1 risk alleles? The authors’ first proposal involves infection with an unknown virus that confers crossreactive immunity to JC virus. There is some in vitro evidence that human serum contains anti-polyomavirus antibodies that cross-react with other Kidney International (2013) 84

polyomavirus antigens when expressed on virus-like particles;30 whether such cross-reactivity would be capable of neutralizing viral infection is unknown. The second proposed mechanism suggests that JC virus infection alters cellular function in way that reduces propensity to glomerular injury in subjects with two APOL1 risk alleles. As JC virus infection in the kidney is largely confined to the distal portion of the nephron, it is not yet clear how this interaction might occur, as APOL1 nephropathy presents as a spectrum of glomerulopathies. APOL1 expression is induced by interferon and ApoL1 is a component of the innate immune response to extracellular pathogens, particularly trypanosomes. Further, the strongest interaction recognized to date involves APOL1 risk genotypes and HIV infection, an example of geneenvironment interaction. Further work on the relationship between APOL1 nephropathy and viral infection, including polyomavirus infecton, may help solve the riddle of this complex disorder.

REFERENCES

DISCLOSURE

10.

The author declares no competing interests.

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8.

9.

ACKNOWLEDGMENTS

This work was supported by the NIDDK Intramural Research Program.

11.

Genovese G, Friedman DJ, Ross MD et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010; 329: 841–845. Tzur S, Rosset S, Shemer R et al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet 2010; 128: 345–350. Kopp JB, Nelson GW, Sampath K et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 2011; 22: 2129–2137. Lipkowitz MS, Freedman BI, Langefeld CD et al. Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans. Kidney Int 2013; 83: 114–120. Reeves-Daniel AM, DePalma JA, Bleyer AJ et al. The APOL1 gene and allograft survival after kidney transplantation. Am J Transplant 2011; 11: 1025–1030. Ashley-Koch AE, Okocha EC, Garrett ME et al. MYH9 and APOL1 are both associated with sickle cell disease nephropathy. Br J Haematol 2011; 155: 386–394. Larsen CP, Beggs ML, Saeed M et al. Apolipoprotein L1 risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy. J Am Soc Nephrol 2013; 24: 722–725. Madhavan SM, O’Toole JF, Konieczkowski M et al. APOL1 localization in normal kidney and nondiabetic kidney disease. J Am Soc Nephrol 2011; 22: 2119–2128. Freedman BI, Spray BJ, Tuttle AB et al. The familial risk of end-stage renal disease in African Americans. Am J Kidney Dis 1993; 21: 387–393. Bostrom MA, Kao WH, Li M et al. Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy. Am J Kidney Dis 2012; 59: 210–221. Divers J, Nunez M, High K. JC polyoma virus interactions with APOL1 in African Americans

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with non-diabetic nephropathy. Kidney Int 2013; 84: 1207–1213. Gardner SD, Field AM, Coleman DV et al. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet 1971; 1: 1253–1257. Padgett BL, Walker DL, ZuRhein GM et al. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1971; 1: 1257–1260. Celik B, Randhawa PS. Glomerular changes in BK virus nephropathy. Hum Pathol 2004; 35: 367–370. Mazzucco G, Costa C, Bergallo M et al. Severe crescentic BK virus nephropathy with favourable outcome in a transplanted patient treated with Leflunomide. Clin Nephrol 2008; 70: 163–167. Polo C, Perez JL, Mielnichuck A et al. Prevalence and patterns of polyomavirus urinary excretion in immunocompetent adults and children. Clin Microbiol Infect 2004; 10: 640–644. Wen MC, Wang CL, Wang M et al. Association of JC virus with tubulointerstitial nephritis in a renal allograft recipient. J Med Virol 2004; 72: 675–678. Allander T, Andreasson K, Gupta S et al. Identification of a third human polyomavirus. J Virol 2007; 81: 4130–4136. Gaynor AM, Nissen MD, Whiley DM et al. Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog 2007; 3: e64. Feng H, Shuda M, Chang Y et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008; 319: 1096–1100. Schowalter RM, Pastrana DV, Pumphrey KA et al. Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host Microbe 2010; 7: 509–515. van der Meijden E, Janssens RW, Lauber C et al. Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient. PLoS Pathog 2010; 6: e1001024. Sauvage V, Foulongne V, Cheval J et al. Human polyomavirus related to African green monkey lymphotropic polyomavirus. Emerg Infect Dis 2011; 17: 1364–1370. Scuda N, Hofmann J, Calvignac-Spencer S et al. A novel human polyomavirus closely related to the African green monkey-derived lymphotropic polyomavirus. J Virol 2011; 85: 4586–4590. Siebrasse EA, Reyes A, Lim ES et al. Identification of MW polyomavirus, a novel polyomavirus in human stool. J Virol 2012; 86: 10321–10326. Lim ES, Reyes A, Antonio M et al. Discovery of STL polyomavirus, a polyomavirus of ancestral recombinant origin that encodes a unique T antigen by alternative splicing. Virology 2013; 436: 295–303. DeCaprio JA, Garcea RL. A cornucopia of human polyomaviruses. Nat Rev Microbiol 2013; 11: 264–276. Siebrasse EA, Bauer I, Holtz LR et al. Human polyomaviruses in children undergoing transplantation, United States, 2008–2010. Emerg Infect Dis 2012; 18: 1676–1679. Husseiny MI, Anastasi B, Singer J et al. A comparative study of Merkel cell, BK and JC polyomavirus infections in renal transplant recipients and healthy subjects. J Clin Virol 2010; 49: 137–140. Viscidi RP, Clayman B. Serological cross reactivity between polyomavirus capsids. Adv Exp Med Biol 2006; 577: 73–84.

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Biomarkers of acute injury: predicting the long-term outcome after transplantation Simi Ali1 and Neil S. Sheerin1 Biomarkers of ischemia–reperfusion injury allow risk stratification and early identification of delayed graft function after kidney transplantation. Welberry Smith et al. describe a novel serum biomarker, aminoacylase-1, that not only is associated with delayed graft function but can predict the long-term outcome years after transplantation. Kidney International (2013) 84, 1072–1074. doi:10.1038/ki.2013.305

Kidney transplantation is the treatment of choice for patients with end-stage renal disease. However, the number of potential recipients exceeds the number of available organs. This has lead to greater use of kidneys procured by donation after cardiac death (DCD) and from extended-criteria donors (ECD). The type of donor, along with inevitable periods of warm and cold ischemia, drug toxicity, and immune activation, determine the severity of ischemia–reperfusion injury (IRI). The rate of delayed graft function (DGF) is twofold higher in ECD and DCD kidneys.1 The development of DGF after transplantation is associated with higher mortality,2 a twofold greater risk of graft loss,3 higher rates of acute rejection,3 and increased length of hospital stay. The association between DGF and worse outcomes has led to increasing efforts to better understand the mechanisms of IRI and to develop interventions to reduce its impact. This has included initiatives to use biomarkers to stratify the risk of DGF, to diagnose it early and to target any 1 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK Correspondence: Neil S. Sheerin, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. E-mail: [email protected]

treatment to those patients who will benefit most. The science of biomarker discovery has expanded rapidly over the past decade. This is in part due to new techniques in proteomics, transcriptomics, and metabolomics that can measure the concentration of thousands of analytes in clinical samples. Unlike traditional laboratory methods, which measure the concentration of candidate biomarkers, newer ‘omics’ based approaches identify novel biomarkers that can be developed into diagnostics and also provide information about disease processes. Modern bioinformatics and a systems biology approach promise qualitative information about interdependence of complex processes that is difficult to access using conventional diagnostic tools. Clinically useful novel biomarkers can be diagnostic, providing information about the nature of a disease that is not evident by clinical assessment and currently available tests. This type of biomarker may allow diagnosis of a disease before it is evident by current diagnostic criteria or allow the diagnosis to be made by less invasive testing. Alternatively, biomarkers can be prognostic, providing information about the severity of tissue injury, disease activity, or response to a treatment and therefore helping to predict Kidney International (2013) 84

JC viruria and kidney disease in APOL1 risk genotype individuals: is this a clue to a gene × environment interaction?

APOL1 nephropathy occurs in a minority of genetically at-risk individuals, suggesting that other factors, such as other genes or environmental factors...
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