Mesoamerican nephropathy: pathology in search of etiology
2018; Elsevier BV; Volume: 93; Issue: 3 Linguagem: Inglês
10.1016/j.kint.2017.09.025
ISSN1523-1755
Autores Tópico(s)Kidney Stones and Urolithiasis Treatments
ResumoMesoamerican nephropathy is a progressive, often fatal form of tubulointerstitial nephritis affecting young agricultural laborers in Central America. Initially described as a chronic disease, a study by Fischer and coworkers in this issue of Kidney International suggests that Mesoamerican nephropathy goes through an active, inflammatory phase. Although the pathologic findings are nonspecific and the etiology of Mesoamerican nephropathy remains unclear, inflammatory infiltrates in areas of evolving and established interstitial fibrosis appear to cause progressive kidney injury. Mesoamerican nephropathy is a progressive, often fatal form of tubulointerstitial nephritis affecting young agricultural laborers in Central America. Initially described as a chronic disease, a study by Fischer and coworkers in this issue of Kidney International suggests that Mesoamerican nephropathy goes through an active, inflammatory phase. Although the pathologic findings are nonspecific and the etiology of Mesoamerican nephropathy remains unclear, inflammatory infiltrates in areas of evolving and established interstitial fibrosis appear to cause progressive kidney injury. Mesoamerican nephropathy (MeN) is a progressive form of tubulointerstitial nephritis that primarily affects young agricultural laborers in Central America, often leading to end-stage renal disease and death.1Wesseling C. van Wendel de Joode B. Crowe J. et al.Mesoamerican nephropathy: geographical distribution and time trends of chronic kidney disease mortality between 1970 and 2012 in Costa Rica.Occup Environ Med. 2015; 72: 714-721Crossref PubMed Scopus (69) Google Scholar The first case series of MeN with renal biopsy data was published in 2013, although individual cases date back to the 1970s.2Wijkstrom J. Leiva R. Elinder C.G. et al.Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America.Am J Kidney Dis. 2013; 62: 908-918Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar To date, at least 20,000 people have died as a result of MeN.1Wesseling C. van Wendel de Joode B. Crowe J. et al.Mesoamerican nephropathy: geographical distribution and time trends of chronic kidney disease mortality between 1970 and 2012 in Costa Rica.Occup Environ Med. 2015; 72: 714-721Crossref PubMed Scopus (69) Google Scholar Furthermore, similar lesions have been noted in agricultural workers in poor, tropical countries in other parts of the world, including Sri Lanka, leading to the alternative term chronic interstitial nephritis in agricultural communities (CINAC).3Jayasumana C. Orantes C. Herrera R. et al.Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational, and environmental determinants.Nephrol Dial Transplant. 2017; 32: 234-241PubMed Google Scholar The etiology or etiologies of MeN/CINAC are not known. Early pathologic descriptions of the lesion noted interstitial fibrosis and tubular atrophy (IFTA), with prominent accompanying glomerulosclerosis and variable but not severe interstitial inflammation,2Wijkstrom J. Leiva R. Elinder C.G. et al.Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America.Am J Kidney Dis. 2013; 62: 908-918Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar raising repeated episodes of dehydration with associated ischemic injury and/or direct tubular toxicity due to agricultural product(s) such as pesticides as potential etiologies. In this issue of Kidney International, Fischer and coworkers4Fischer R.S.B. Vangala C. Truong L. et al.Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy.Kidney Int. 2018; 93: 681-690Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar (2018) report a pathologic study of patients biopsied during an earlier (although still relatively advanced, with creatinine clearances between 32 and 62 ml/min) phase of MeN, characterized by renal insufficiency that was persistent after administration of i.v. fluids, with leukocytosis, neutrophilia, and leukocyturia in the absence of a positive blood culture, and no history of hypertension, diabetes, or heart disease. The renal biopsies in the series from Fischer et al.4Fischer R.S.B. Vangala C. Truong L. et al.Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy.Kidney Int. 2018; 93: 681-690Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar differed from those in previous series in that there was generally patchy but quite prominent interstitial inflammation in addition to and often associated with areas of IFTA, involving the cortex and frequently the region of the cortico-medullary junction. This inflammation consisted mainly of T lymphocytes, although multiple cases showed focal intratubular neutrophils and cellular debris. Notably, there was relative sparing of glomeruli and arteries, absence of intratubular crystals, and no evidence of an immune complex-mediated etiology.4Fischer R.S.B. Vangala C. Truong L. et al.Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy.Kidney Int. 2018; 93: 681-690Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar The focal intratubular neutrophils, together with the leukocytosis and neutrophilia seen in many of the patients, suggest the possibility of an infectious etiology for MeN, and Fischer et al.4Fischer R.S.B. Vangala C. Truong L. et al.Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy.Kidney Int. 2018; 93: 681-690Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar appear to favor such an etiology while not ruling out a toxic or drug-induced etiology. However, if this were the case, the infection would likely have to be of a kind other than a typical ascending bacterial pyelonephritis; it is worth noting that only one of the authors' 11 patients had frequent urinary tract infections, all but two had no or scarce bacteria on urinalysis, and the biopsies showed sparing of the deeper medulla. In addition, the absence of eosinophilia in all patients tends to argue against a parasitic infection. Although an infectious etiology of MeN cannot be excluded, the histology and immunohistology of the cases reported by Fischer et al.4Fischer R.S.B. Vangala C. Truong L. et al.Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy.Kidney Int. 2018; 93: 681-690Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar actually draw a number of important parallels to chronic, active cell-mediated tubulointerstitial nephritis of the types reported in T cell–mediated renal allograft rejection (TCMR) and some examples of chronic, drug-induced interstitial nephritis. The progressive renal injury in these cases results from, or appears to be the result of cell-mediated immunity. In tubulointerstitial lesions of TCMR, the initial pathologic finding is interstitial inflammation in the cortex composed mainly of T lymphocytes with accompanying interstitial edema and lymphocytic tubulitis. If not effectively treated, this is followed by the development of IFTA with inflammation persistent within scarred areas of the cortex, the latter now often referred to in the transplant community as i-IFTA.5Nankivell B, Shingde M, Keung K, et al. The causes, significance, and consequences of inflammatory fibrosis in kidney transplantation: the Banff i-IFTA lesion. Am J Transplant., in press. https://doi.org/10.1111/ajt.14609.Google Scholar Although once thought to represent nonspecific inflammation and thus omitted as a form of rejection-associated injury in the original Banff classification for renal allograft pathology, i-IFTA (Figure 1, left panel) has clearly been shown to be associated with graft failure and loss, to a much greater extent than bland, uninflamed IFTA (Figure 1, right panel).6Mannon R.B. Matas A.J. Grande J. et al.Inflammation in areas of tubular atrophy in kidney allograft biopsies: a potent predictor of allograft failure.Am J Transplant. 2010; 10: 2066-2073Crossref PubMed Scopus (176) Google Scholar Furthermore, recent studies have demonstrated that i-IFTA in the renal allograft represents a sequela of active TCMR, often associated with inadequate or suboptimal immunosuppression.5Nankivell B, Shingde M, Keung K, et al. The causes, significance, and consequences of inflammatory fibrosis in kidney transplantation: the Banff i-IFTA lesion. Am J Transplant., in press. https://doi.org/10.1111/ajt.14609.Google Scholar This hypothesis that the pathogenesis of MeN (or CINAC) involves persistent T cell–mediated immune injury progressing from an active state resembling acute TCMR or drug-induced interstitial nephritis, to a chronic, active state characterized by i-IFTA and resembling the cases reported by Fischer et al.,4Fischer R.S.B. Vangala C. Truong L. et al.Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy.Kidney Int. 2018; 93: 681-690Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar to a scarred and relatively inactive state resembling that in earlier descriptions of MeN,2Wijkstrom J. Leiva R. Elinder C.G. et al.Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America.Am J Kidney Dis. 2013; 62: 908-918Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar while intriguing, raises a number of key questions. First, what are the inciting agents/events? Second, why are agricultural workers in Central America and other regions of the world particularly susceptible to this lesion? Third, although the histology of MeN is nonspecific, is there a way using molecular diagnostics to establish that MeN involves similar mechanisms to TCMR? Finally, can the information from these three questions be used to prevent and/or treat MeN? As Fischer et al.4Fischer R.S.B. Vangala C. Truong L. et al.Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy.Kidney Int. 2018; 93: 681-690Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar note, identification of inciting agents and/or events will require working closely with the physicians and other health professionals treating patients with MeN/CINAC in regions where this lesion is prevalent. Are there specific compounds within or applied to the crops (typically sugarcane) harvested by the patients? Do the workers ingest or otherwise expose themselves to drugs or other substances that can, in susceptible individuals, trigger an immune response within the renal parenchyma? Next, are there genetic features of agricultural workers in regions where MeN/CINAC is endemic that differ from those of populations doing similar work in other parts of the world, and predispose the former to the disease? A notable parallel here might be the APOL1 gene; risk alleles of this gene, mainly in individuals of African descent, are associated with the development of focal segmental glomerulosclerosis, including collapsing glomerulopathy in patients infected with human immunodeficiency virus.7Rosenberg A.Z. Kopp J.B. Focal segmental glomerulosclerosis.Clin J Am Soc Nephrol. 2017; 12: 502-517Crossref PubMed Scopus (252) Google Scholar Although APOL1 risk alleles confer susceptibility to focal segmental glomerulosclerosis, most individuals with two such alleles do not develop the disease,7Rosenberg A.Z. Kopp J.B. Focal segmental glomerulosclerosis.Clin J Am Soc Nephrol. 2017; 12: 502-517Crossref PubMed Scopus (252) Google Scholar suggesting other factors are required as well. With regard to determining a potential role of T cell–mediated immunity in the pathogenesis of MeN, advances in molecular pathology developed for analysis of renal transplant biopsies may be helpful. Over the past decade, Halloran and colleagues have studied the expression of multiple pathogenesis-based transcripts sets in tissue from a large number of renal allograft biopsies with TCMR, antibody-mediated rejection, and a number of different nonrejection lesions. From these studies, they have developed a "molecular TCMR score" based on expression of 30 nonredundant transcripts; with high specificity (95%) and accuracy (89%), this molecular score distinguishes renal allograft biopsies showing TCMR from those showing non-TCMR lesions, including antibody-mediated rejection and BK virus nephropathy.8Reeve J. Sellares J. Mengel M. et al.Molecular diagnosis of T cell-mediated rejection in human kidneys.Am J Transplant. 2013; 13: 645-655Crossref PubMed Scopus (155) Google Scholar Using biopsies with MeN in an active phase, it appears feasible that a similar approach could be taken to identify pathogenesis-based transcripts associated with active MeN and compare these with pathogenesis-based transcripts seen with TCMR and other inflammatory lesions in transplant and native kidneys to get a better understanding of the pathogenic mechanisms underlying MeN. With this information, potential therapeutic approaches might be developed to reverse or slow the progression of MeN if diagnosed when there is still sufficiently preserved renal parenchyma. In addition, should there be pathogenic similarities between MeN and TCMR, new therapeutic approaches developed for the latter could also be helpful in treating the former. Encouraging evidence for the likelihood of such similarities comes from a preliminary study reporting considerable overlap between genes upregulated in renal transplant biopsies with i-IFTA and native renal biopsies with interstitial nephritis.9Lyu Z. Pang L. Zeng G. et al.Expression of T-cell mediated rejection (TCMR) associated genes in native and renal allograft renal biopsies with inflamed scars (i-IFTA).Am J Transplant. 2017; 17: 300-301PubMed Google Scholar In summary, the study of Fischer et al.4Fischer R.S.B. Vangala C. Truong L. et al.Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy.Kidney Int. 2018; 93: 681-690Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar is potentially important because it identifies MeN/CINAC in an inflammatory stage, possibly amenable to treatment, as opposed to a lesion characterized only by advanced scarring. With this knowledge, it is hoped that work toward understanding the pathogenesis of this condition, including identification of possible etiologic agents and/or initiating events, potential genetic factors that render agricultural workers in Central America and other endemic areas particularly susceptible to it, and molecular characterization of gene expression patterns in tissue from renal biopsies with active MeN, can now proceed in the hope of preventing and/or slowing the progression of the devastating renal injury seen in affected patients. The author declared no competing interests. Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathyKidney InternationalVol. 93Issue 3PreviewMesoamerican nephropathy is a devastating disease of unknown etiology that affects mostly young agricultural workers in Central America. An understanding of the mechanism of injury and the early disease process is urgently needed and will aid in identification of the underlying cause and direct treatment and prevention efforts. We sought to describe the renal pathology in Mesoamerican nephropathy at its earliest clinical appearance in prospectively identified acute case patients in Nicaragua. We considered those with elevated (or increased at least 0.3 mg/dL or 1.5-fold from baseline) serum creatinine, leukocyturia, and either leukocytosis or neutrophilia for inclusion in this biopsy study. Full-Text PDF Open Archive
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