Mesoamerican Nephropathy in Central Panama

chronic kidney disease; Panama; nontraditional; traditional; mesoamerican nephropathy; 65 clinical presentation 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted February 22, 2022. ; https://doi.org/10.1101/2022.02.19.22271236doi: medRxiv preprint 87 88

89 Chronic kidney disease (CKD) belongs to the group of noncommunicable diseases and, according to 90 estimates from the Global Burden of Disease group, produced a 19.6% increase in the disability-adjusted 91 life years (DALYs) and has been associated with 4% of deaths worldwide from 2005 to 2015, 92 representing 2.2 million deaths per year [ 1,2]. 93 In 60% of patients, the cause of CKD is identified. Among the traditional causes of CKD are diabetes 94 mellitus, essential hypertension, and obesity, followed by a minority secondary to immunological 95 diseases, nephrolithiasis, and genetic conditions [ 3]. Approximately 25% of adult patients with CKD may 96 have a family history of this pathology. In 10% of patients, the cause of CKD cannot be identified, which 97 is classified as unknown or nontraditional cause (CKDnt) [ 4]. For several years, an increase in the 98 frequency of diagnoses of CKDnt from agricultural areas of Central America (El Salvador, Nicaragua, 99 Guatemala, and Costa Rica) has been identified, which is why it has been denominated Mesoamerican 100 nephropathy. This pathology has been presented mainly in young male patients with irreversible 101 impairment of kidney function. It has been proposed that among the probable causes of CKDnt would be 102 chronic exposure to pesticides, working conditions with exposure to high temperatures and dehydration, 103 chronic use of anti-inflammatory drugs, high consumption of alcohol and tobacco. These risk factors also 104 contribute with the high morbidity and mortality of CKD, since exposure increases with the diagnoses 105 advanced-stage CKD [ 5,6]. 106 The Pan-American Health Organization defined CKDnt as impaired kidney function with a glomerular 107 filtration rate (GFR) below 60 mL/min/m 2 [ 7]. in absence of predisposing factors for traditional CKD 108 (namely, type 2 diabetes mellitus, essential hypertension, heart disease, urinary tract malformations, 109 immunological and congenital diseases. In addition, the diagnosis of CKDnt includes kidney damage 110 defined by structural abnormalities (i.e., renal atrophy without obstructive pattern) or abnormality in the 111 urinary sediment as a marker of kidney damage. There may be exposure to occupational risk factors or 112 living in a risk area [ 8]. 113 In Panama, since 2014, an increase in patients who meet the criteria for CKDnt have been reported in the 114 provinces of Coclé, Herrera, and Los Santos [ 9]. In 2017, Panamanian health authorities started the 115 Information System for the Epidemiological Surveillance of CKD to establish mandatory notification of 116 all patients diagnosed with CKD in all its stages and to identify associated risk factors [ 10]. The system 117 aims to diagnose and establish the real prevalence of CKD in Panama to inform public policies for 118 promotion, prevention, and treatment of CKD. The 2017 Preventive Health Census of the Ministry of 119 Health estimated the national prevalence of CKD at 3.24% [ 11]. 120 The objective of this study is to characterize the risk factors and clinical phenotype of patients diagnosed 121 with CKDnt from the provinces of Herrera and Los Santos in the central region of Panama and to 122 compare them with patients with CKDt from the same geographic area. 123

124 We conducted a retrospective, descriptive study with the patients records at the Nephrology Department 125 of the Dr. Gustavo N. Collado Hospital. This hospital is the nephrology reference center for Central 126 Panama (provinces of Herrera and Los Santos, serving a population estimated in 2012 at 214,539 127 inhabitants) [ 12]. 128 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted February 22, 2022. ; https://doi.org/10.1101/2022.02.19.22271236doi: medRxiv preprint Records between January 1 and December 31, 2018 and a minimum of two evaluations by Nephrology at 129 least 3 months apart during the study period were included. Records also reported at least two urinalyses 130 and blood samples. The patient record was also the data source for sociodemographic variables, personal 131 history, laboratory results, and renal ultrasound evaluation. 132 Data was extracted into MS Excel (The Microsoft Corporation; Redmond, WA) and the clean dataset was 133 exported to Stata v. 11.0 (StataCorp, LLC; College Station, TX) for data analyses. Analyses included 134 descriptive statistics. Fisher's exact test was used to compare proportions and the Mann-Whitney U test to 135 compare medians, setting alpha at 0.05 for statistical significance when comparing the frequencies of the 136 CKDt and CKDnt groups. 137

138 The chart review identified 224 records of patients diagnosed with stage 3 and 4 CKD during 2018. After 139 two reviews of the inclusion criteria, 106 patient files were included (Figure 1). 140 Of the 106 patient charts included, 66% (70) were male and 34% (36) were female, with a median age of 141 68.8 years. Forty-five percent of patients were 70 years or older. The median weight was 73 kg, the 142 median height was 1.61 m and the median body mass index (BMI) was 27.7 kg/m2. 143 In the occupation evaluation, 22% of the patients were retired, followed by 20% agricultural workers, 144 19% household administrators, 14% unemployed, and 13% practiced other professions. Eighty percent of 145 the patients had a history of essential hypertension, 30% type 2 diabetes mellitus, 19% cardiovascular 146 disease, 15% hyperuricemia, and 10% cerebrovascular disease. 147 Of the total of 106 patients included with a diagnosis of CKD, 14% (n=15) met the definition of CKDnt, 148 while 86% (n=91) were diagnosed with CKDt. Table 1 summarizes the relevant clinical, history, 149 ultrasound, and laboratory data for both groups. 150 A statistically significant predominance of young men was observed in the group of patients with CKDnt 151 compared to the group with CKDt. Additionally, workers in agriculture or transportation presented with 152 significantly(P<0.001) higher frequencies of CKDnt than with CKDt. Although not statistically 153 significant ( P=0.09), patients with CKDnt tend to exhibit a lower BMI than patients with CKDt. The 154 personal history of type 2 diabetes mellitus, essential hypertension, and cardiovascular disease were 155 significantly less frequent among patients with CKDnt than among those with CKDt. Of note, ultrasound-156 confirmed that renal atrophy was significantly more frequent ( P<0.001) among patients with CKDnt than 157 among patients with CKDt. Patients with CKDnt show significantly lower levels of glucose and higher 158 levels of uric acid in the blood. 159

160 In Central American countries, the cases of CKDnt have been increasing during the last decades. 161 However, it has not yet been possible to establish a single causal factor, but rather different agents that 162 can produce chronic kidney damage leading to CKDnt. Various causes have been proposed, including 163 chronic occupational exposure to high temperatures and repeated dehydration due to frequent episodes of 164 heat stress, exposure to pesticides with nephrotoxic effect, contamination of water with heavy metals, 165 lifestyle risk factors (e.g., alcoholism, smoking, and diet), all of which could have a significant impact on 166 the pathophysiology of CKD [ 13-15]. 167 168 In 2015 in El Salvador, a country where the epidemiology of CKDnt has been extensively studied, the 169 regional prevalence ranged from 7.1% in the Paracentral region; 5.2% in the Eastern region; and 2% in 170 the Central region [ 16] , and that depending on the community and the work activity carried out by the 171 inhabitants, prevalence peaked at 18% in regions near the coast [ 17]. In Nicaragua, regional prevalence 172 ranged between 8% and 10% [ 18]. In Panama, a 2014 study estimated the prevalence of CDK requiring 173 dialysis in the province of Coclé at 40 per 100,000 population towards the north of the province, but up to 174 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted February 22, 2022. ; https://doi.org/10.1101/2022.02.19.22271236doi: medRxiv preprint 200 per 100,000 population towards the south of the province. The southern part of Coclé’s economy is 175 characterized by sugar cane and rice agriculture. In this study, the prevalence of CKDnt could not be 176 determined, but it was the first study that reported an increase in CKD prevalence in a specific region of 177 the country [ 9]. 178 179 For greater robustness of the data and to confirm chronicity of the renal function, patient charts should 180 have included at least two measurements of serum creatinine instead of only one [ 19]. Most previously 181 published studies have measured creatinine only once. The diagnosis of CKD required the calculation of 182 the GFR estimate after achieving a stable creatinine value, at least 3 months apart, to establish the degree 183 of chronicity and be able to rule out acute renal failure [ 20]. 184 185 In the group of patients with CKDnt, a male predominance was observed compared to the group with 186 CKDt. This has also been observed in other countries, such as El Salvador (78%) [ 21] , Nicaragua (77%) 187 [ 22] and Costa Rica (70%) [ 5]. The median age was lower in the CKDnt group (55 years), compared with 188 a median age of 68 years in the CKDt group. The latter is similar to what was observed in the study group 189 of agricultural communities in El Salvador, where the age of the patients was an average of 45 years [ 21]. 190 The increased frequencies of patients with diagnoses of CKDnt have been observed mainly in some 191 defined areas in Central America. Particularly, areas heavy on agricultural employment are involved, 192 where young labor is hired to perform difficult tasks under the tropical sun. These factors may explain, at 193 least in part, the younger age, lower BMI, and higher prevalence in males presenting with CKDnt. In turn, 194 these patients did not present with chronic diseases typically associated with CKDt, such as type 2 195 diabetes mellitus and essential hypertension [ 23]. 196 197 This study showed that a significantly higher proportion of patients with CKDnt presented with a history 198 of agricultural work, compared to patients in the CKDt group (60% vs. 15%, respectively; P<0.001). The 199 central region of Panama has the largest area with crops of corn in the country, with over 26,000 hectares 200 of land per year. The province of Herrera is the fourth in sugarcane production nationwide [ 24]. The 201 patients in this study belong to the central provinces of Herrera and Los Santos, mostly land at sea level 202 dedicated to agriculture, in a peninsular area that frequently exhibits the highest temperatures in the 203 country of up to 35°C, especially in the dry season between December and April [ 25]. It has also been 204 described that in the region of Central America and Panama there has been an increase in temperature of 205 up to 1ºC between 2010 and 2015 and that this has been important in the central provinces of Herrera and 206 de Los Santos [ 25]. Predictive models of temperature increase have been proposed, up to 15% in the next 207 decades in the central region of Panama [ 25]. This could contribute to the increase in cases of CKDnt 208 compared to the CKDt causes in recent years, as a consequence of continuous dehydration due to 209 exposure to high temperatures during strenuous working hours, as has been studied in other groups of 210 sugarcane farmers in Central America [ 26,27]. 211 212 Twenty percent of patients with CKDnt worked as drivers of road transport vehicles or heavy equipment. 213 Studies have associated poor diet, continuous hours of work, lack of adequate hydration, and exposure to 214 high temperatures during the sunniest and hottest hours of the day while driving in freight transport 215 drivers [ 28]. This phenomenon has also been described for workers in a block factory [ 29]. Thus, this 216 pathology would not be exclusive to agriculture and transportation, but in occupations where there are 217 sustained exposure to high temperatures with risk of dehydration. 218 219 Glycosuria without hyperglycemia and HbA1c levels greater than 6.5% can be found in less than 3% of 220 patients with CKDnt [ 23] , probably secondary to the pathophysiological damage caused by CKDnt and 221 not to the presence of type 2 diabetes mellitus [ 18]. In the present study, no patient in the CKD group 222 presented with type 2 diabetes mellitus, compared to 34% in the CKDt group. A trend towards increased 223 glucose associated with the higher frequency of type 2 diabetes mellitus was observed in the CKDt group, 224 in which poor control could help the progression to worsening of CKDt. 225 226 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted February 22, 2022. ; https://doi.org/10.1101/2022.02.19.22271236doi: medRxiv preprint A higher frequency of essential hypertension was evidenced in the group of patients with CKDt compared 227 to the group of patients with CKDnt. Previous studies have found that arterial hypertension is rare in 228 patients with CKDnt and it is highly prevalent in CKDt [ 30]. Hypertensive nephrosclerosis is a chronic 229 disease that gradually and progressively produces chronic kidney involvement [ 30,31]. The finding of 230 mild hypertension in some patients with CKDnt (33%) in our study could be due to the fact that it is a 231 consequence of CKD and not the cause, as it has been previously suggested [ 19]. The presence of mild 232 hypertension of less than 5 years of evolution, associated with advanced chronic kidney disease, in the 233 absence of other risk factors, should lead us to suspect CKDnt. 234 235 In this study, uric acid values showed a significant elevation above the normal value in the group of 236 patients with CKDnt compared to CKDt. In dehydration states, fructose is produced endogenously from 237 glucose, leading to uric acid generation, inflammation, and fibrosis in the kidney [ 32]. Furthermore, 238 asymptomatic hyperuricemia has been associated with the development of mild hypertension, which, 239 when treated and normalized, improves blood pressure control [ 33 The present study supports the concept 240 that hyperuricemia is a biomarker of CKDnt. More studies are necessary to determine its role in the 241 diagnosis, evolution and prognosis of CKDnt. 242 243 In the evaluation of the imaging studies, by renal ultrasound, 87% of the patients diagnosed with CKDnt 244 presented with a decrease in the cortico-medullary relationship with increased echogenicity and renal 245 atrophy. This translates into renal morphological damage observed in early stages of asymptomatic 246 patients. Renal ultrasound studies in El Salvador have found an increase in echogenicity of up to 95% and 247 a decrease in the cortex-medulla ratio in up to 82% of patients with CKDnt [ 21]. The present study 248 supports the concept that renal atrophy is a clinical marker of CKDnt. More studies are necessary to 249 determine its role in the diagnosis, evolution and prognosis of CKDnt. 250 251 Patients with CKD frequently present proteinuria mostly due to glomerular involvement, hypertension, or 252 diabetic nephropathy. In the present study, there were no significant differences proteinuria levels 253 between patients with CKDnt and CKDt. This may be due to the fact that patients included in this study 254 had moderate stages (3 and 4), and not advanced stages of CKD. In patients with CKDnt, low proteinuria 255 (<1 g/dL) was observed. Renal biopsy studies in patients with CKDnt have shown that the 256 histopathological damage is not due to damage to the glomeruli but rather to tubulointerstitial 257 nephropathy [ 34,35]. This could explain the difference in the presentation of proteinuria that they have 258 these patients in advanced stages of CKD. 259 260 There are various studies with patients affected by CKDnt, but there are few prevalence studies with 261 progression to end-stage CKD [ 23,36]. In the present study, in the group of patients with CKDt, five 262 patients progressed to stage 5 CKD, requiring initiation renal replacement therapy. At follow-up, no 263 patient in the CKDnt group progressed to terminal illness. In early stages of kidney involvement by an 264 external agent, recovery depends on exposure time, as has been observed in drug-caused interstitial 265 nephropathies. When the causative agent is withdrawn early, the patient can recover due to the fact that 266 the damage does not involve the glomeruli. When evaluating histopathological studies, it is important to 267 point out that damage in CKDnt mainly affects the tubules and interstices and not the glomeruli [ 37,38] , 268 so that early identification could delay the progression to terminal disease. Due to the lack of knowledge 269 on prevalence, the information on the frequency of patients diagnosed with CKDnt who progress to renal 270 replacement therapy is still uncertain in Central America [ 39]. This entity has different names depending 271 on the region, either as CKDnt, CKD of unknown cause, or Mesoamerican nephropathy, which further 272 complicates its epidemiological traceability [ 15]. Thus, it is essential not only to diagnose it, but also 273 consistently code it as the same diagnosis. 274 275 There are environmental exposures that interact with gene function. Several occupational-environmental 276 risk factors predisposing to CKDnt were already discussed, with a possible summative effect and 277 sustained for a certain time that would lead to kidney involvement. However, not all people who live in 278 the same geographic region with the same gender and occupational risk factors will develop kidney 279 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted February 22, 2022. ; https://doi.org/10.1101/2022.02.19.22271236doi: medRxiv preprint involvement leading to CKDnt. Thus, so it is also believed that genetic and epigenetic factors could play 280 an important role in the etiology of CKDnt [ 40]. It is possible that individual genetic susceptibilities in a 281 triggering environment could induce development and/or worsening of renal involvement [ 41]. 282 Longitudinal follow-up studies of patients in early stages that could include the genetic and epigenetic 283 component that can also contribute to the identification of biomarkers in patients at risk and help prevent 284 kidney involvement [ 42]. 285 286 A limitation of this study is the small sample size in the case of patients with CKDnt. Thus, the 287 interpretation of its implications, including considerations on risk factors, should be prudent. Another 288

is that not all patients had renal ultrasound available to compare the results. Despite its 289 limitations, this study makes important contributions to the understanding of CKDnt since to our 290 knowledge it is the first published study in Panama and one of the few in Central America to address the 291 clinical presentation of patients with early stage CKDnt compared to patients with CKDt. 292 293

294 CKDnt is more common in younger-aged male patients than in patients with CKDt. CKDnt is diagnosed 295 in areas where agricultural activity predominates; however, it is not the only work activity to which this 296 condition has been associated, but more generally it is related to long-term strenuous work and high 297 temperatures that could lead to dehydration. 298 299 Because CKDnt remains asymptomatic for a long time, early detection is important in patients with 300 elevated creatinine values, without comorbidities such as diabetes and hypertension, in which it is 301 important to identify whether there are other risk factors for occupational and environmental exposure and 302 efforts should be directed at halting the progression of the disease at an early stage. The early detection of 303 patients with CKDnt could have an important effect in preventing progression to terminal CKD. 304 305 It is important to provide information and education to the population that works in chronic exposure to 306 high temperatures. Likewise, work should be done on the generation of public policies so that employers 307 are aware of the risk factors and allow the necessary rest and hydration times during the working hours of 308 their employees at risk. 309 310 New prospective follow-up studies are important to allow the study of genetics, epigenetics, the 311 identification of biomarkers and a better understanding of the pathophysiology, as well as the better 312 therapeutic management of patients at risk or diagnosed with CKDnt. 313 314 315 Abbreviations 316 CKD: chronic kidney disease; CKDnt: nontraditional chronic kidney disease; CKDt: traditional chronic 317 kidney disease; DALYs: Disability-adjusted life years; GFR: glomerular filtration rate; BMI: body mass 318 index. 319 320 Acknowledgments: The authors would l ike t o ac knowledg e Humbert o López Castillo , MD, PhD for his 321 review of the manuscript. Iván Landires is a member of the Sistema Nacional de Investigación (SNI), 322 which is supported by Panama’s Secretaría Nacional de Ciencia, Tecnología e Innovación (SENACYT). 323 324 Authors’ contributions: Conceptualization, K.C., N.B., V. N-S., and I.L.; methodology, K.C., N.B., 325 B.H., M.P., C. R., V. N-S., and I.L.; software, K.C., and I.L.; validation, K.C., N.B., V. N-S., and I.L.; 326 formal analysis, K.C., N.B., V. N-S., and I.L.; investigation, K.C., N.B., B.H., M.P., C. R., V. N-S., and 327 I.L.; resources, K.C., V. N-S., and I.L.; data curation, K.C., N.B., B.H., M.P., C. R., V. N-S., and I.L.; 328 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted February 22, 2022. ; https://doi.org/10.1101/2022.02.19.22271236doi: medRxiv preprint writing—original draft preparation, K.C., N.B., V. N-S., and I.L.; writing—review and editing, I.L.; 329 visualization, K.C., N.B., V. N-S., and I.L.; supervision, K.C., and I.L.; project administration, K.C., and 330 I.L.; funding acquisition, K.C., V. N-S., and I.L.; All authors have read and agreed to the published 331 version of the manuscript. 332 Funding: No funding was received for this study. 333 Availability of data and materials : All data generated or analysed during this study are included in this 334 published article. 335 Ethics approval and consent to participate: The study was conducted according to the guidelines of the 336 Declaration of Helsinki, and approved by the Interinstitutional Ethics Committee of the Social Security 337 Fund and the National Directorate for Teaching and Research (DENADOI-SIBI-008-2020). The need for 338 informed consent was waived by the Interinstitutional Ethics Committee of the Social Security Fund and 339 the National Directorate for Teaching and Re search (DENADOI-SIBI-008-2020). No further 340 administrative permissions were needed to access the raw data used in this study. The data used in this 341 study were anonymized before use. 342 Consent for publication: Not applicable. 343 Competing interests: The authors declare that they have no competing interests. 344 345

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R el evant C l in ica l and Pa rac lin ica l Dat a of pat i ents w ith CK Dnt and CK Dt. 495 Characteristics CKDt (n=91) CKDnt (n=15) P value Medi an a ge, yea rs 68.8 55.4 <0.001 Medi an we i ght, k g 73.7 70.7 0.50 Medi an he igh t, m 1.6 1.64 0.14 Medi an BMI, kg /m 2 28.03 25.85 0.09 Gender 0.016 Men 56 (61) 14 (93) W omen 35 (38) 1 (7) Ag r icu l t ura l w o r ke rs 14 (15) 9 (60) <0.001 Transp o r tat i on w or ke rs 0 (0) 3 (20) <0.001 Pers ona l h ist o r y of: Ty pe 2 di ab etes me l l it us 31 (34) 0 (0) 0.02 Hyp er tens i on 80 (88) 5 (33) <0.001 Card i o vascu la r d ise ase 20 (22) 0 (0) 0.04 Cer eb r ovasc u lar d isease 11 (12) 0 (0) 0.32 Obes it y 1 (1) 0 (0) 0.84 CKD 17 (19) 2 (13) 0.80 Obstr uct iv e ur o pa thy 9 (10) 0 (0) 0.40 Hyp er u r icemia 12 (13) 4 (27) 0.37 Rena l u lt ras o und 1 No rmal f ind ings 28 (31) 2 (13) 0.16 Rena l a tr o ph y 36 (50) 13 (87) 3 RBCs/f ie ld 8 (9) 1 (7) 0.78 Pr ote in u r ia >3+ 15 (16) 1 (7) 0.32 Medi an b l o o d chemist r y va l ues Gl uc ose 1, mg/ dL 105 97.5 0.07 Gl uc ose 2, mg/ dL 111 96.5 0.04 Gl ycated hemo g l o b in A1c, % 6.71 5.005 0.11 Cre at in in 1, mg/ dL 1.85 2.14 0.10 Cre at in in 2, mg/ dL 1.89 2.17 0.13 Bl o o d ure a n it r o gen, mg/dL 26.8 23.5 0.31 Ur ic ac id 1, mg /dL 6.8 7.8 0.04 Ur ic ac id 2, mg /dL 7 8.1 0.09 Sod ium, mEq/L 139 138 0.60 Po tassi um, mEq/L 4.5 4.4 0.55 Ca lci um, mg/dL 9.75 9.7 0.72 Tr ig l yce r ides, mg/d L 171 167 0.90 To ta l ch o les ter o l , mg/dL 182 188 0.68 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted February 22, 2022. ; https://doi.org/10.1101/2022.02.19.22271236doi: medRxiv preprint HDL cho l este r o l, mg/ dL 51.4 45.7 0.70 LDL ch o leste r o l, md/dL 108.8 101.7 0.59 1 Only 72 of the CKD t f il es had rena l u lt ras o und on fi le. 496 BMI: b ody mass ind ex, CKD t: tr ad it i ona l chr on i c k idne y d ise ase, CK Dnt: n on - tra d it i ona l 497 chron ic k idn ey d isease , RB C, red b l o od ce l ls; HDL, hi gh-d ensi ty l i p o pr o te in; LD L, l o w-d ensi t y 498 lipop rot ei n . 499 500 501 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted February 22, 2022. ; https://doi.org/10.1101/2022.02.19.22271236doi: medRxiv preprint 224 Eligible entries 129 Charts assessed 106 Charts included •   2    ARI: acute renal insufficiency; CKD: chronic kidney di s KT : kidney transplant; PKD: polycystic kidney disease. Figure 1. Patient chart selection flow 95 Excluded:  Only 1 assessment by nephrology in 2018  GFR > 61 mL/min/m2 or <15 mL/min/m2  ARI, PKD, KT 23 Excluded:  Regresson to CKD 1 or 2  Progression to CKD 5  Incomplete information in the chart s ease; GFR: glomerular filtration rate; w diagram. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprintthis version posted February 22, 2022. ; https://doi.org/10.1101/2022.02.19.22271236doi: medRxiv preprint