Clinical markers to predict progression from acute to chronic kidney disease in Mesoamerican nephropathy
Authors: Rebecca S.B. Fischer, Chandan Vangala, Sreedhar Mandayam, Denis Chavarria, Ramón García-Trabanino, Felix Garcia, Linda L. Garcia, Kristy O. Murray
Journal: Kidney International (2018)

An epidemic of chronic kidney disease (CKD) of unknown etiology, known as Mesoamerican Nephropathy (MeN), has been ongoing in Latin America for at least two decades. MeN primarily affects young adults without traditional CKD risk factors, and agricultural workers are disproportionately afflicted. We previously identified an acute phase of MeN that involves acute kidney injury (AKI) with tubulointerstitial nephritis and systemic inflammation. Because clinical disease progression in MeN is not yet understood, we sought to determine clinical predictors for progression from acute MeN to CKD. Through ongoing surveillance in Nicaragua, local physicians reported cases of acute MeN and CKD among agricultural workers. We analyzed clinical data collected during the acute MeN encounter to identify factors associated with progression to CKD. From February 2015 to May 2017, 586 agricultural workers (median age 27.8 years, 90% male) presented with acute MeN. The majority had a normal baseline creatinine, and leukocyturia (98.8%) and peripheral leukocytosis (80.7%) were common. Ultimately, 49 (8.4%) progressed to CKD, the majority of those within 6 months. CKD was attributed to MeN in all cases, and none had diabetes or hypertension. The strongest predictors of CKD progression were anemia and paresthesias at presentation, while leukocytosis was associated with renal recovery. Clinical markers of acute MeN may help clinicians identify patients at high risk for rapid progression to CKD, which in turn can inform early clinical management. Future studies should seek to determine the underlying etiology of disease and identify optimal interventions to interrupt the pathophysiologic process of MeN. An epidemic of chronic kidney disease (CKD) of unknown etiology, known as Mesoamerican Nephropathy (MeN), has been ongoing in Latin America for at least two decades. MeN primarily affects young adults without traditional CKD risk factors, and agricultural workers are disproportionately afflicted. We previously identified an acute phase of MeN that involves acute kidney injury (AKI) with tubulointerstitial nephritis and systemic inflammation. Because clinical disease progression in MeN is not yet understood, we sought to determine clinical predictors for progression from acute MeN to CKD. Through ongoing surveillance in Nicaragua, local physicians reported cases of acute MeN and CKD among agricultural workers. We analyzed clinical data collected during the acute MeN encounter to identify factors associated with progression to CKD. From February 2015 to May 2017, 586 agricultural workers (median age 27.8 years, 90% male) presented with acute MeN. The majority had a normal baseline creatinine, and leukocyturia (98.8%) and peripheral leukocytosis (80.7%) were common. Ultimately, 49 (8.4%) progressed to CKD, the majority of those within 6 months. CKD was attributed to MeN in all cases, and none had diabetes or hypertension. The strongest predictors of CKD progression were anemia and paresthesias at presentation, while leukocytosis was associated with renal recovery. Clinical markers of acute MeN may help clinicians identify patients at high risk for rapid progression to CKD, which in turn can inform early clinical management. Future studies should seek to determine the underlying etiology of disease and identify optimal interventions to interrupt the pathophysiologic process of MeN. CKD of unknown etiology (CKDu) is a phenomenon that afflicts individuals of working age, largely without chronic comorbidities, in various tropical regions of the world. CKDu in Central America, termed MeN, was first documented in El Salvador in 1999.1Trabanino R.G. Aguilar R. Silva C.R. et al.Nefropatía terminal en pacientes de un hospital de referencia en El Salvador [End-stage renal disease among patients in a referral hospital in El Salvador].Rev Panam Salud Pública. 2002; 12 ([in Spanish]): 202-206Crossref PubMed Scopus (111) Google Scholar It has since swept across the region, resulting in an estimated 50,000 premature deaths.1Trabanino R.G. Aguilar R. Silva C.R. et al.Nefropatía terminal en pacientes de un hospital de referencia en El Salvador [End-stage renal disease among patients in a referral hospital in El Salvador].Rev Panam Salud Pública. 2002; 12 ([in Spanish]): 202-206Crossref PubMed Scopus (111) Google Scholar, 2Ramirez-Rubio O. McClean M.D. Amador J.J. Brooks D.R. An epidemic of chronic kidney disease in Central America: an overview.J Epidemiol Community Health. 2012; 67: 1-3Crossref Scopus (66) Google Scholar, 3Ordunez P. Nieto F.J. Martinez R. et al.Chronic kidney disease mortality trends in selected Central America countries, 1997–2013: clues to an epidemic of chronic interstitial nephritis of agricultural communities.J Epidemiol Community Health. 2018; 72: 280-286Crossref PubMed Scopus (37) Google Scholar The epidemic of MeN currently affects communities in nearly all of Mesoamerica, from southern Mexico to Panama, and new evidence points to its emergence as early as the mid-1970s.1Trabanino R.G. Aguilar R. Silva C.R. et al.Nefropatía terminal en pacientes de un hospital de referencia en El Salvador [End-stage renal disease among patients in a referral hospital in El Salvador].Rev Panam Salud Pública. 2002; 12 ([in Spanish]): 202-206Crossref PubMed Scopus (111) Google Scholar, 2Ramirez-Rubio O. McClean M.D. Amador J.J. Brooks D.R. An epidemic of chronic kidney disease in Central America: an overview.J Epidemiol Community Health. 2012; 67: 1-3Crossref Scopus (66) Google Scholar, 3Ordunez P. Nieto F.J. Martinez R. et al.Chronic kidney disease mortality trends in selected Central America countries, 1997–2013: clues to an epidemic of chronic interstitial nephritis of agricultural communities.J Epidemiol Community Health. 2018; 72: 280-286Crossref PubMed Scopus (37) Google Scholar, 4Cuadra S. Hogstedt C. Jakobsson K. et al.Chronic Kidney Disease: Assessment of Current Knowledge and Feasibility for Regional Research Collaboration in Central America. SALTRA, IRET-UNA, Heredia, Costa Rica2006Google Scholar, 5García-Trabanino R. Trujillo Z. Colorado A.V. et al.Prevalencia de pacientes con tratamiento sustitutivo renal en El Salvador en 2014 [Prevalence of patients receiving renal replacement therapy in El Salvador in 2014].Nefrología. 2016; 36 ([in English and Spanish]): 631-636Crossref PubMed Scopus (9) Google Scholar, 6Orantes C.M. Herrera R. 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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, 10Laux T.S. Barnoya J. Guerrero D.R. Rothstein M. Dialysis enrollment patterns in Guatemala: evidence of the chronic kidney disease of non-traditional causes epidemic in Mesoamerica.BMC Nephrol. 2015; 16: 54Crossref PubMed Scopus (31) Google Scholar, 11Cerdas M. Chronic kidney disease in Costa Rica.Kidney Int. 2005; 68: 31-33Abstract Full Text Full Text PDF Scopus (62) Google Scholar, 12Torres C. Aragón A. González M. et al.Decreased kidney function of unknown cause in Nicaragua: a community-based survey.Am J Kidney Dis. 2010; 55: 485-496Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 13O'Donnell J.K. Tobey M. Weiner D.E. et al.Prevalence of and risk factors for chronic kidney disease in rural Nicaragua.Nephrol Dial Transplant. 2011; 26: 2798-2805Crossref PubMed Scopus (111) Google Scholar, 14Correa-Rotter R. Wesseling C. Johnson R.J. CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.Am J Kidney Dis. 2014; 63: 506-520Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 15PanAmerican Health Organization. Chronic kidney diseases (N18): renal failure (N17-N19) mortality, countries of the Americas. Available at: http://ais.paho.org/phip/viz/nmh_renalfailure_ckd_visualization.asp. Accessed November 17, 2017.Google Scholar A major barrier to ending the MeN epidemic is the lack of understanding about its underlying cause and pathophysiology. The epidemiology, risk factors, and clinical features of MeN differ from those of renal diseases most commonly occurring in most of the world. Classic risk factors, such as hypertension and diabetes, do not underlie disease; MeN first appears as a community-onset, rather than hospital-acquired, renal disease, and young, working-age individuals bear the highest disease burden.2Ramirez-Rubio O. McClean M.D. Amador J.J. Brooks D.R. An epidemic of chronic kidney disease in Central America: an overview.J Epidemiol Community Health. 2012; 67: 1-3Crossref Scopus (66) Google Scholar, 16Orantes C.M. Herrera R. Almaguer M. et al.Epidemiology of chronic kidney disease in adults of Salvadoran agricultural communities.MEDICC Rev. 2014; 16: 23-30Crossref PubMed Google Scholar, 17Weiner D.E. McClean M.D. Kaufman J.S. Books D.R. The Central American epidemic of CKD.Clin J Am Soc Nephrol. 2013; 8: 504-511Crossref PubMed Scopus (88) Google Scholar, 18Fischer R.S.B. Mandayam S. Chavarria D. et al.Clinical evidence of acute Mesoamerican nephropathy.Am J Trop Med Hyg. 2017; 97: 124-1256Crossref Scopus (37) Google Scholar, 19Ponce D. Balbi A. Acute kidney injury: risk factors and management challenges in developing countries.Int J Nephrol Renovasc Dis. 2016; 9: 193-200Crossref PubMed Scopus (39) Google Scholar MeN clusters geographically in hot, tropical Pacific lowlands of Central America and disproportionately affects communities of low socioeconomic status who depend primarily on agriculture work and other manual labor. Hotspots of high MeN prevalence exist where resources for diagnosis and management, such as renal biopsy, dialysis and transplant are scarce.5García-Trabanino R. Trujillo Z. Colorado A.V. et al.Prevalencia de pacientes con tratamiento sustitutivo renal en El Salvador en 2014 [Prevalence of patients receiving renal replacement therapy in El Salvador in 2014].Nefrología. 2016; 36 ([in English and Spanish]): 631-636Crossref PubMed Scopus (9) Google Scholar, 19Ponce D. Balbi A. Acute kidney injury: risk factors and management challenges in developing countries.Int J Nephrol Renovasc Dis. 2016; 9: 193-200Crossref PubMed Scopus (39) Google Scholar, 20Pecoits-Filho R. Rosa-Diez G. Gonzalez-Bedat M. et al.Renal replacement therapy in CKD: an update from the Latin American Registry of Dialysis and Transplantation.J Bras Nefrol. 2015; 37: 9-13Crossref PubMed Scopus (10) Google Scholar, 21Remuzzi G. Perico N. International Society of Nephrology's perspective on the emergence of chronic kidney diseases of unknown/undetermined etiology.MEDICC Rev. 2014; 16: 75-76Google Scholar Clinical recognition and management at the earliest possible stage are imperative for reducing MeN-associated mortality. The incidence of CKD at a major MeN hotspot in Nicaragua, where our studies are based, was 239 per 100,000 agricultural workers in 2015. In the same year, the incidence of acute kidney injury (AKI) was 1593 per 100,000 workers.18Fischer R.S.B. Mandayam S. Chavarria D. et al.Clinical evidence of acute Mesoamerican nephropathy.Am J Trop Med Hyg. 2017; 97: 124-1256Crossref Scopus (37) Google Scholar In this locale, CKD is overwhelmingly attributed to MeN, and we previously documented AKI as a precursor to MeN in this same population. Patients with acute MeN usually present with AKI and marked systemic inflammation, and renal biopsies demonstrate tubulointerstitial nephritis as the hallmark pathology.18Fischer R.S.B. Mandayam S. Chavarria D. et al.Clinical evidence of acute Mesoamerican nephropathy.Am J Trop Med Hyg. 2017; 97: 124-1256Crossref Scopus (37) Google Scholar, 22Fischer 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 A subset of individuals with acute MeN, though not all, develop CKDu. A greater understanding of the roles of acute clinical markers in the disease process can provide clues to the curious pathophysiology of MeN and guide research into its underlying cause. Until we know its etiology, evidence-based guidelines for clinical recognition and management of AKI to prevent CKD and end-stage renal disease (ESRD) are the most urgent needs. In order to facilitate the early, noninvasive identification of individuals at high risk for CKDu in Mesoamerica, we analyzed clinical data on patients with acute MeN to identify clinical predictors of disease progression. From February 27, 2015, to May 04, 2017, 586 agriculture workers presented with acute signs of renal impairment and were presumptively diagnosed with acute MeN; 35 patients (6.0%) presented with multiple episodes. Patients were typically young (median: 27.8 years [range 18.4–58.5]), primarily male (90.3%), and had been working at the agriculture estate for a median of 6 years (range 0–40) (Table 1 and Supplementary Table S1). The most common occupations were crop cutting (29.9%) and irrigation and drainage systems work (17.6%). Medical histories were largely unremarkable, except that 11.3% reported having frequent urinary tract infections at some point in the past, 14.3% self-reported a history of anemia, and 11.9% were classified as obese (body mass index ≥30). Diabetes (2.0%) and hypertension (4.1%) were uncommon. No patient had a prior CKD diagnosis, though 16.5% reported a prior episode of elevated creatinine.Table 1Characteristics of study population (N = 586)nNo CKDn (%)CKDn (%)Alln (%)P value537 (91.6)49 (8.4)Demographics SexMale586484 (90.1)45 (91.8)529 (90.3)1.000Female53 (9.9)4 (8.2)57 (9.7) Age (yr)<25586187 (34.8)9 (18.4)196 (33.5)0.03325-29142 (26.4)12 (24.5)154 (26.3)30-3494 (17.5)10 (20.4)104 (17.8)≥35114 (21.2)18 (36.7)132 (22.5)Social history Number of years working in sugarcane fields≤2518153 (32.3)5 (11.4)158 (30.5)0.0113–6151 (31.9)16 (36.4)167 (32.2)7–1091 (19.2)9 (20.5)100 (19.3)>1079 (16.7)14 (31.8)93 (18) OccupationCrop cutter585157 (29.3)18 (36.7)175 (29.9)0.276Irrigation, drainage worker58592 (17.2)11 (22.5)103 (17.6)0.353Seeder, planter58581 (15.1)3 (6.1)84 (14.4)0.092Pest, weed control worker58554 (10.1)7 (14.3)61 (10.4)0.356Past medical history Prior elevated creatinine56883 (15.96)11 (22.92)94 (16.55)0.215 Frequent UTIs56058 (11.3)5 (10.4)63 (11.3)1.000 Diabetes55911 (2.2)0 (0)11 (2)0.611 Hypertension55819 (3.7)4 (8.3)23 (4.1)0.126 Gout5593 (0.6)1 (2.1)4 (0.7)0.302 Anemia55869 (13.5)11 (23.4)80 (14.3)0.064 Kidney stones56011 (2.1)1 (2.1)12 (2.1)0.931 Renal injury5582 (0.4)0 (0)2 (0.4)1.000 Pancreatitis5575 (0.98)0 (0)5 (0.9)1.000 Sexually transmitted infection5583 (0.6)0 (0)3 (0.5)1.000 Hepatitis5603 (0.6)0 (0)3 (0.5)1.000 Leptospirosis5593 (0.6)1 (2.2)4 (0.7)0.291 Malaria2367 (3.1)0 (0)7 (3.0)1.000 Dengue23510 (4.5)2 (18.2)12 (5.1)0.102 Chikungunya24440 (17.3)2 (15.4)42 (17.2)1.000 Any of above infections24448 (20.88)3 (23.1)51 (20.9)0.738nMedian (range)P valueAge (yr)58627.5 (18.4–58.5)31.2 (19.6–53)27.8 (18.4–58.5)0.013Number of years working cane fields5185 (0–40)7.5 (1–36)5 (0–40)0.004CKD, chronic kidney disease; UITs, urinary tract infections. Open table in a new tab CKD, chronic kidney disease; UITs, urinary tract infections. At the time of acute presentation, patients were largely normotensive (90.6% <130/90 mm Hg) and reported diverse symptoms (Table 2 and Supplementary Table S1). The most common complaints were nausea or vomiting (72.7%), fever (70.8%, self-reported or measured at ≥38.0 °C), back pain (60.5%), and headache (54.9%). Paresthesia was notably common (41.7%) and was associated with anemia (P < 0.001) but not with electrolyte imbalance. Most patients were treated with intravenous fluids and electrolytes (91.6%), while only a few were administered acetaminophen (5.4%), ranitidine (5.6%), allopurinol (3.6%), or antibiotics (1.4%).Table 2Clinical Assessment and ManagementnNo CKDn (%)CKDn (%)Alln (%)P value537 (91.6)49 (8.4)Acute presentation Normotensive (<120/80 mm Hg)577458 (86.7)43 (87.8)501 (86.8)0.841 BMI ≥25 kg/m2564240 (46.2)15 (33.3)255 (45.2)0.095 Fever, chills504328 (70.8)29 (70.7)357 (70.8)0.988 Nausea, vomiting579390 (73.6)31 (63.3)421 (72.7)0.121 Back pain557311 (61.1)26 (54.2)337 (60.5)0.348 Headache548278 (55.6)23 (47.9)301 (54.9)0.307 Debility533190 (39.2)20 (41.7)210 (39.4)0.736 Paresthesia459162 (38.7)30 (75.0)192 (41.8)<0.001 Cramps468202 (47.3)23 (56.1)225 (48.1)0.282 Abdominal pain534159 (32.7)11 (22.9)170 (31.8)0.164 Myalgia533163 (33.5)13 (28.3)176 (33.0)0.473 Arthralgia538154 (31.2)13 (28.9)167 (31.0)0.744 Dizziness29084 (31.8)10 (38.5)94 (32.4)0.490 Urinary symptoms52988 (18.2)7 (15.2)95 (18.0)0.612 Fatigue52496 (20.1)13 (28.3)109 (20.8)0.192 Decreased or loss of appetite48130 (6.8)6 (14.6)36 (7.48)0.069 Tremors52041 (8.6)6 (13.3)47 (9.0)0.293 Neck pain51143 (9.3)4 (8.7)47 (9.2)1.000 Diarrhea42623 (5.9)3 (8.8)26 (6.1)0.452 Cough52323 (4.8)7 (15.2)30 (5.7)0.004 Chest pain51225 (5.4)2 (4.4)27 (5.3)1.000 Blurred vision51913 (2.8)0 (0)13 (2.5)0.618 Edema5156 (1.3)1 (2.1)7 (1.4)0.490 Respiratory difficulty, dyspnea52113 (2.7)0 (0)13 (2.5)0.617 Rash5166 (1.3)0 (0)6 (1.7)1.000 Jaundice5174 (0.9)0 (0)4 (0.8)1.000 Confusion2404 (1.8)2 (10.0)6 (2.5)0.081 Asymptomatic5864 (0.7)0 (0)4 (0.7)1.000nMedian (range)P valueTemperature (°C)58536.7 (36.0–40.0)36.5 (36.0–38.9)36.7 (36.0–40.0)0.206BMI (kg/m2)56424.5 (14.8–61.1)22.8 (20.2–35.9)24.4 (14.8–61.1)0.075BMI, body mass index; CKD, chronic kidney disease. Open table in a new tab BMI, body mass index; CKD, chronic kidney disease. The median serum creatinine level during these acute episodes was 2.0 mg/dl (range 0.9–5.1) (Table 3 and Supplementary Table S2). Hematology and blood chemistry revealed leukocytosis (80.5%), neutrophilia (85.4%), and elevated C-reactive protein (75.9%); 19.1% had extreme leukocytosis (>20,000 cells/mm3). A high proportion of patients had lymphopenia (46.5%), anemia (63.6%), low red blood cell (RBC) counts (57.3%), hyperuricemia (29.7%), elevated blood urea nitrogen ([BUN]; 30.6%), elevated creatinine phosphokinase (18.2%) or decreased electrolytes (hypomagnesemia [38.6%], hypokalemia [35.8%], and hyponatremia [9.9%]). BUN-creatinine ratios were low (<10.0) in more than half of patients (53.2%).Table 3Clinical laboratory findings–hematology and blood chemistrynNo CKDn (%)CKDn (%)Alln (%)P value537 (91.6)49 (8.4)Creatinine >2.0 mg/dl586240 (44.7)28 (57.1)268 (45.7)0.094Leukocytosis >10,000 cells/mm3581440 (82.4)29 (61.7)469 (80.7)0.001Neutrophilia >67%581456 (85.4)40 (85.1)496 (85.4)0.957Lymphopenia <20%581256 (47.9)14 (29.8)270 (46.5)0.017Eosinophilia >4%56433 (6.4)3 (6.5)36 (6.4)1.000Hemoglobin anemia<13.5 g/dl male, <12.0 g/dl female308168 (60.9)28 (87.5)196 (63.6)0.003Hematocrit anemia<38.8% male, <34.9% female581305 (57.1)38 (80.9)343 (59)0.002Low red blood cell count<4.3 × 106 cells/ml male, <3.9 × 106 cells/ml female7524 (45.3)19 (86.4)43 (57.3)0.002Hyperuricemia>7.0 mg/dl male, >6.0 mg/dl female552143 (28.2)21 (47.7)164 (29.7)0.006Hypocalcemia (ionized) <1.1 mmol/l56476 (14.7)10 (21.7)86 (15.3)0.201Hypomagnesemia <1.9 mg/dl536186 (37.7)21 (50.0)207 (38.6)0.115Hypokalemia <3.5 mmol/l573191 (36.4)14 (29.2)205 (35.8)0.318Hyponatremia <135 mmol/l56446 (8.9)10 (20.8)56 (9.9)0.008CPK>336 μ/l male; >176 μ/l female47482 (18.9)4 (10.0)86 (18.1)0.201BUN >23.3 mg/dl408112 (30.2)13 (35.1)125 (30.6)0.534BCR <10.0408196 (52.8)21 (56.8)217 (53.2)0.817C-reactive protein ≥6 mg/dl212153 (76.9)8 (61.5)161 (75.9)0.311nMedian (range)P valueCreatinine (mg/dl)5862.0 (0.9–5.1)2.1 (1.2–3.4)2.0 (0.9–5.1)0.178Leukocytes (cells/mm3)58114,800 (4,600–36,000)11,150 (6,016– 23,400)14,500 (4,600–36,000)0.001Neutrophils (%)58179.5 (40–96)75 (51–94)79 (40–96)0.071Lymphocytes (%)58120 (4–54)24 (6–49)20 (4–54)0.042Hemoglobin (g/dl)30812.8 (8.1–19.5)11.1 (8.0–16.0)12.5 (8.0–19.5)<0.001Hematocrit (%)58137.4 (23.0–54.0)34.0 (20.0–51.0)37.0 (20.0–54.0)0.001Red blood cell count (× 106 cells/ml)754.4 (3.0–5.7)3.8 (2.7–5.5)4.0 (2.7–5.7)0.015Uric acid (mg/dl)5526.0 (1.7–35.0)6.9 (3.4–12.5)6.0 (1.7–35.0)0.003BUN (mg/dl)40820.0 (1.9–81.0)22.0 (10.2–39.0)20.0 (1.9–81.0)0.116BCR, BUN-creatinine ratio; BUN, blood urea nitrogen; CKD, chronic kidney disease; CPK, creatine phosphokinase. Open table in a new tab BCR, BUN-creatinine ratio; BUN, blood urea nitrogen; CKD, chronic kidney disease; CPK, creatine phosphokinase. Urine microscopy demonstrated leukocyturia in 98.8% of patients, and some had clumping of leukocytes (24.1%) and leukocyte casts (30.7%) (Table 4 and Supplementary Table S3). Bacteriuria (24.2%; >few) was noted but was associated with epithelial cells in the specimen (P < 0.001), and urine cultures performed on 12 patients were negative. Crystalluria (49.0%) was often composed of amorphous urate crystals (49.1%). Urine dipstick findings included proteinuria (42.0%; >trace levels), hemoglobinuria (35.6%), and occasional glucosuria (13.7%). Specific gravity (median: 1.020 [range 1.000–1.030]) and pH (median: 6.0 [range 5.0–9.0]) were mostly normal.Table 4Clinical laboratory findings—urine analysisnNo CKDn (%)CKDn (%)Alln (%)P value537 (91.6)49 (8.4)Turbid aspect583405 (75.7)21 (43.8)426 (73.1)<0.001Protein (mg/dl) None583261 (48.8)33 (68.8)294 (50.4)0.060 Trace40 (7.5)4 (8.3)44 (7.6) 3098 (18.3)6 (12.5)104 (17.8) 100106 (19.8)5 (10.4)111 (19.0) >10030 (5.6)0 (0)30 (5.2)GlucoseaPresent at any level.58379 (14.8)1 (2.1)80 (13.7)0.008HemoglobinaPresent at any level.581191 (35.8)16 (33.3)207 (35.6)0.729Leukocytes 0–2 per field58326 (4.9)6 (12.5)32 (5.5)0.095 3–14 per field95 (17.8)10 (20.8)105 (18.0) 15–29 per field91 (17.0)10 (20.8)101 (17.3) ≥30 per field150 (28.0)13 (27.1)163 (28.0) Too numerous to count173 (32.3)9 (18.8)182 (31.2)CastsaPresent at any level.579238 (44.7)11 (23.4)249 (43.0)0.005Leukocytic castsaPresent at any level.579169 (31.8)9 (19.2)178 (30.7)0.072CrystalsaPresent at any level.580268 (50.3)16 (34.0)284 (49.0)0.033Amorphous uratesaPresent at any level.580229 (43.0)14 (29.8)243 (41.9)0.079Microalbuminuria ≥30 mg/dl331193 (62.9)7 (29.2)200 (60.4)0.001Bacteriuria >Few per field583138 (25.8)3 (6.3)141 (24.2)0.001nMedian (range)P valueSpecific gravity5821020 (1000–1030)1020 (1005–1030)1020 (1000–1030)1.000pH5826.0 (5.0–9.0)6.0 (5.0–8.0)6.0 (5.0–9.0)1.000CKD, chronic kidney disease.a Present at any level. Open table in a new tab CKD, chronic kidney disease. Healthy baseline serum creatinine levels were available for 514 patients. Using these baseline levels (median: 1.0 mg/dl [range 0.6–1.3]), we assessed change in creatinine from baseline to acute presentation and found that 90.5% of patients presented acutely with AKI, most with Acute Kidney Injury Network (AKIN) stage 2 (40.3) or stage 3 (38.5%) AKI (Table 5); the remaining 9.5% of patients did not meet specific AKIN criteria, despite having abnormal creatinine levels or creatinine clearance. Acute creatinine levels reflected a 2-fold (range 0.9–6.1) increase over baseline after a median of only 113 (range 5–356) days.Table 5Change in renal function from healthy baseline to acute presentationnNo CKDn (%)CKDn (%)Alln (%)P valueAKI at acute presentation None51442 (9.0)7 (15.6)49 (9.5)0.315 Stage 1193 (41.2)14 (31.1)207 (40.3) Stage 2181 (38.6)17 (37.8)198 (38.5) Stage 353 (11.3)7 (15.6)60 (11.7)CrCl at baseline (ml/min) ≥90498320 (70.6)22 (48.9)342 (68.7)0.003 <90133 (29.4)23 (51.1)156 (31.3)eGFR (CKD-EPI) at baseline (ml/min per 1.73 m2) ≥90514307 (65.5)23 (51.1)330 (64.2)0.055 <90162 (34.5)22 (48.9)184 (35.8)eGFR (MDRD) at baseline (ml/min per 1.73 m2) ≥90514178 (38.0)13 (28.9)191 (37.2)0.229 <90291 (62.1)32 (71.1)323 (62.8)nMedian (range)P valueSerum creatinine at baseline (mg/dl)5141.0 (0.6–1.3)1.1 (0.7–1.3)1.0 (0.6–1.3)0.015CrCl at baseline (ml/min)498102.8 (54.2–219.1)89.4 (60.0–160.5)102.1 (54.2–219.1)0.003Time from baseline to acute presentation (days)514110 (5–356)139 (9–278)113 (5–356)0.040Change from healthy baseline Serum creatinine increase from baseline (mg/dl)5141.0 (−0.1 to 4)1.2 (0.1–2.3)1.0 (−0.1 to 4.0)0.090 Serum creatinine fold-increase from baseline5142.0 (0.9–6.1)2.1 (1.1–3.2)2.0 (0.9–6.1)0.489 Serum creatinine % increase from baseline514100.0 (−6.4 to 514.3)108.3 (8.3–218.2)100.0 (−6.4 to 514.3)0.489AKI, acute kidney injury; CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease–Epidemiology Collaboration; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease study. Open table in a new tab AKI, acute kidney injury; CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease–Epidemiology Collaboration; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease study. Of these 586 patients with acute MeN, 49 (8.4%) have been diagnosed with CKD (as of November 30, 2017), most (65.4%) with stage 3 or worse (Table 6). Patients were notably young (median: 31.7 years [range 20.0–53.0]) at the time of CKD diagnosis, and most (91.8%) were male. When we consider the subset of cases from the first year of surveillance only (i.e., those with the longest follow-up time [range 642–1007 days]), 10.8% have developed CKD. All CKD diagnoses reported herein are attributed to MeN, and no patient had any other known cause of CKD. Progression from acute disease to CKD was rapid, with diagnoses following a median of 3 months (101 days [range 1–883]) from acute presentation. Most (78.5%; n = 38) were diagnosed within the first 6 months, while only 20.4% (n = 10) of patients developed CKD a year or more after their acute episodes.Table 6Characteristics at CKD diagnosis (n = 49)nn (%)Diagnosed CKD stage 1492 (4.1) 213 (26.5) 330 (61.2) 42 (4.1) Unknown2 (4.1)Age at CKD diagnosis (yr) <25497 (14.3) 25–<3012 (24.5) 30–<3512 (24.5) ≥3518 (36.7)nMedian (range)Age at CKD diagnosis (yr)4931.7 (20.0–53.3)Serum creatinine at CKD diagnosis (mg/dl)481.5 (1.1–3.2)Change from acute presentation Change in serum creatinine from acute presentation to CKD (mg/dl)48−0.6 (−2.1 to 0.4) Time from acute presentation to CKD (d)49101 (1–883)Change from healthy baseline Change in serum creatinine from baseline to CKD (mg/dl)460.5 (0–2.3) Percent Increase in serum creatinine from baseline to CKD (%)4647.7 (−3.2 to 263.6) Fold increase in serum creatinine from baseline to CKD461.5 (1.0–3.6) Time from baseline to CKD (d)46234 (42–925)nCKD-EPI (ml/min per 1.73 m2)MDRD (ml/min per 1.73 m2)n (%)Cockcroft-Gault (ml/min)Renal filtration rate at CKD diagnosis 90–<120481 (2.1)0 (0)5 (10.4) 60–<9018 (37.5)11 (22.9)20 (41.7) 45–<6022 (45.8)21 (43.8)18 (37.5) 30–<455 (10.4)14 (29.2)3 (6.3) <302 (4.2)2 (4.2)2 (4.2)nMedian (range)Renal filtration rate at CKD diagnosis4856.7 (24.6–90.9)50.4 (22.9–79.8)61.6 (29.3–110.4)Change in renal filtration rate from baseline46−33.3 (−90.4 to 3.0)−28.0 (−78.6 to 2.6)−29.0 (−92.9 to 2.5)CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease–Epidemiology Collaboration; MDRD, Modification of Diet in Renal Disease study. Open table in a new tab CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease–Epidemiology Collaboration; MDRD, Modification of Diet in Renal Disease study. We could characterize change in renal function from healthy baseline for 46 of the CKD case-patients, who were diagnosed with CKD a median of only 8 months (234 days [range 42–925]) from the time of their healthy baseline serum creatinine measurements. Median final serum creatinine levels were 47.7% (range −3.2 to 263.6) above baseline levels and correspond to an overall decrease in estimated glomerular filtration rate (eGFR) of 33.3 ml/min per 1.73 m2 (range −3.0 to 90.4) and a final, residual eGFR of 56.7 ml/min per 1.73 m2 (range 24.6–90.9). At least 1 patient in our study died due to MeN. He was 20 years old at the time of his death, only 14 months after his AKI and 10 months after being diagnosed with stage 2 CKD. He had worked <2 harvest seasons as a sugarcane cutter. He initially presented with stage 1 AKI, anemia (hematocrit 33.0%, hemoglobin 11.0 g/dl, and 3.7 × 106 RBC/ml), leukocyturia (too numerous to count), and borderline hyperuricemia (7.1 mg/dl); he lacked proteinuria and had normal white cell count (8780 cells/mm3), electrolytes, creatinine phosphokinase (170 μ/l), and BUN (20.0 mg/dl). Although individuals with acute MeN are largely young, patients who went on to be diagnosed with CKD were older and more likely than non-CKD cases to have presented with acute MeN at age ≥30 years (prevalence ratio [PR]: 1.99 [95% confidence interval [95% CI]: 1.16–3.41]; P = 0.012) (Table 7). They were also more likely to have worked >2 years in sugarcane fields (PR: 2.99 [95% CI: 1.14–7.82]; P = 0.026), though longe