Chronic kidney disease of unknown etiology in Central America and Sri Lanka : renal morphology and clinical characteristics

Background: Chronic kidney disease (CKD) is a global health problem. The most common etiologies of CKD are diabetes mellitus, hypertension, and glomerulonephritis, but over the last several decades a high prevalence of CKD of unknown etiology (CKDu) has been reported from rural communities in some tropical countries, including Central America, and Sri Lanka. The CKDu endemics share some mutual characteristics, they usually affect rural communities and men are more often affected than women. In Central America, the disease often affects male sugarcane workers. In Sri Lanka, male rice farmers in certain areas are at risk of developing CKDu. The cause or causes behind the CKDu endemics have not been elucidated. Furthermore, it has not been determined whether the two endemics are similar diagnostic entities. Kidney biopsy is an important tool to evaluate CKD, but in Central America, biopsy studies from patients with CKDu were lacking at the beginning of our studies. Aim: The aims were to describe the renal morphology and biochemical characteristics in patients with CKDu in Central America and Sri Lanka in order to find pathogenetic mechanisms, to study the natural history of the disease, and to compare the endemics to determine if they are related diagnostic entities. Material and Methods: Patients with CKDu were evaluated with kidney biopsy, biochemical tests and a questionnaire. Light- and electron microscopy as well as immunofluorescence evaluation were performed on the biopsies. Follow-up blood and urine samples were collected from subjects in Studies I and II after 1-2.5 years. Study I: Eight male agricultural workers in El Salvador with an estimated glomerular filtration rate (eGFR) between 27-79 ml/min/1.73m² were included. The kidney biopsies showed a unique renal morphology with extensive glomerulosclerosis, signs of glomerular ischemia, mild to moderate tubular atrophy, and interstitial fibrosis. Vascular structures were generally only mildly changed. In serum, low potassium levels were a common finding. Study II: Nineteen males from Nicaragua with a history of sugarcane work were included. eGFR was between 33-96 ml/min/1.73m² and low serum sodium, potassium, and magnesium were frequent findings. Sixteen biopsies were representative and the morphology displayed chronic glomerular changes with glomerulosclerosis, glomerular hypertrophy, and signs of glomerular ischemia. Mild to moderate tubulointerstitial changes and mostly mild vascular changes were found. Follow-up samples from 7 participants from Study I and 18 participants from Study II showed a mean eGFR change of -4.4 ± 8.4 ml/min/1.73m² per year. Study III: Eleven male rice farmers from Sri Lanka with an eGFR between 21-70 ml/min/1.73m² were included. Again, low sodium, potassium, and magnesium were common. The main biopsy findings were chronic glomerular changes (glomerulosclerosis, glomerular hypertrophy) and mild to moderate tubulointerstitial changes. Vascular changes were in most cases mild but in a few cases moderate. The biopsies showed a more mixed morphology compared to Studies I and II. Interstitial inflammation and vascular pathology were more frequent. Conclusions: Studies I and II show that CKDu in Central America is a unique diagnostic entity with a renal morphology characterized by chronic damage in both glomerular and tubulointerstitial compartments. Although Study III in Sri Lanka revealed a more mixed kidney biopsy morphology, the majority of the subjects had a morphology quite similar to the findings in Central America. Low levels of serum electrolytes were a typical finding in all studies. In summary, CKDu in Sri Lanka and Central America have more similarities than differences in both the morphological and the biochemical characteristics, which supports the theory that the endemics have a common etiology

Renal Morphology, Clinical Findings, and Progression Rate in Mesoamerican Nephropathy.

BACKGROUND: Mesoamerican nephropathy (MeN) is a chronic kidney disease affecting rural inhabitants in Central America. We have previously described the renal morphology in 8 patients from El Salvador. To confirm the renal pathology, we have studied kidney biopsies from patients with MeN in Nicaragua. Follow-up urine and blood samples from both biopsy studies were collected to investigate the natural history. STUDY DESIGN: Case series. SETTINGS & PARTICIPANTS: In the kidney biopsy study, 19 male sugarcane workers in Nicaragua with suspected MeN were investigated with questionnaires, kidney biopsies, and blood and urine analysis. Inclusion criteria were age 20 to 65 years and plasma creatinine level of 1.13 to 2.49mg/dL or estimated glomerular filtration rate (eGFR) of 30 to 80mL/min/1.73m2. Exclusion criteria were proteinuria with protein excretion > 3g/24 h, uncontrolled hypertension, diabetes mellitus, or other known kidney disease. In the follow up-study, blood and urine from the kidney biopsy study in Nicaragua (n=18) and our previous biopsy study of MeN cases in El Salvador (n=7) were collected 1 to 1.5 and 2 to 2.5 years after biopsy, respectively. OUTCOMES: Renal morphology, clinical, and biochemical characteristics, change in eGFR per year. MEASUREMENTS: eGFR was calculated using the CKD-EPI creatinine (eGFRcr), cystatin C (eGFRcys), and creatinine-cystatin C (eGFRcr-cys) equations. RESULTS: In the kidney biopsy study, participants had a mean eGFRcr of 57 (range, 33-96) mL/min/1.73m2. 47% had low plasma sodium and 21% had low plasma potassium levels. 16 kidney biopsies were representative and showed glomerulosclerosis (mean, 38%), glomerular hypertrophy, and signs of chronic glomerular ischemia. Mild to moderate tubulointerstitial damage and mostly mild vascular changes were seen. In the follow up-study, median duration of follow-up was 13 (range, 13-27) months. Mean change in eGFRcr was -4.4±8.4 (range, -27.7 to 10.2) mL/min/1.73m2 per year. Most patients had stopped working with sugarcane cultivation. LIMITATIONS: 3 biopsy specimens had 4 or fewer glomeruli. CONCLUSIONS: This study confirms the renal morphology of MeN: chronic glomerular and tubulointerstitial damage with glomerulosclerosis and chronic glomerular ischemia. Follow-up data show that eGFRs, on average, deteriorated

An explorative study of inflammation-related proteins associated with kidney injury in male heat-stressed workers

Chronic kidney disease of non-traditional origin (CKDnt) and acute kidney injury (AKI) often affect heat-stressed Mesoamerican manual workers. Inflammation occurs concurrently with AKI in this population, but its role remains unknown. To explore links between inflammation and kidney injury in heat stress, we compared levels of inflammation-related proteins in cutters with and without increasing serum creatinine levels during sugarcane harvest. These sugarcane cutters have previously been identified to be repeatedly exposed to severe heat stress during the five month harvest season. A nested case-control study was conducted among male Nicaraguan sugarcane cutters in a CKDnt hotspot. Cases (n = 30) were defined as having an increase in creatinine of ≥0.3 mg/dL across the five-month harvest. Controls (n = 57) had stable creatinine levels. Ninety-two inflammation-related proteins in serum were measured before and after harvest using Proximity Extension Assays. Mixed linear regression was used to identify differences in protein concentrations between cases and controls before harvest, differential trends during harvest, and association between protein concentrations and the urine kidney injury markers Kidney Injury Molecule (KIM)-1, Monocyte Chemoattractant Protein (MCP)-1 and albumin. One protein, chemokine (C–C motif) ligand 23 (CCL23), was elevated among cases at pre-harvest. Changes in seven inflammation-related proteins (CCL19, CCL23, colony-stimulating factor 1 [CSF1], hepatocyte and fibroblast growth factors [HGF and FGF23], and tumor necrosis factor beta [TNFB] and TNF-related activation-induced cytokine [TRANCE]) were associated with case status and at least two out of three urine kidney injury markers (KIM-1, MCP-1 and albumin). Several of these have been implicated in myofibroblast activation, which likely is an important step in kidney interstitial fibrotic disease such as CKDnt. This study provides an initial exploration of immune system determinants of, and activation during, kidney injury experienced during prolonged heat stress

Pathophysiological mechanisms by which heat stress potentially induces kidney inflammation and chronic kidney disease in sugarcane workers

Background: Chronic kidney disease of non-traditional origin (CKDnt) is common among Mesoamerican sugarcane workers. Recurrent heat stress and dehydration is a leading hypothesis. Evidence indicate a key role of inflammation. Methods: Starting in sports and heat pathophysiology literature, we develop a theoretical framework of how strenuous work in heat could induce kidney inflammation. We describe the release of pro-inflammatory substances from a leaky gut and/or injured muscle, alone or in combination with tubular fructose and uric acid, aggravation by reduced renal blood flow and increased tubular metabolic demands. Then, we analyze longitudinal data from >800 sugarcane cutters followed across harvest and review the CKDnt literature to assess empirical support of the theoretical framework. Results: Inflammation (CRP elevation and fever) and hyperuricemia was tightly linked to kidney injury. Rehydrating with sugary liquids and NSAID intake increased the risk of kidney injury, whereas electrolyte solution consumption was protective. Hypokalemia and hypomagnesemia were associated with kidney injury. Discussion: Heat stress, muscle injury, reduced renal blood flow and fructose metabolism may induce kidney inflammation, the successful resolution of which may be impaired by daily repeating pro-inflammatory triggers. We outline further descriptive, experimental and intervention studies addressing the factors identified in this study

Morphological and clinical findings in Sri Lankan patients with chronic kidney disease of unknown cause (CKDu): Similarities and differences with Mesoamerican Nephropathy

<div><p>In Sri Lanka, an endemic of chronic kidney disease of unknown origin (CKDu) is affecting rural communities. The endemic has similarities with Mesoamerican Nephropathy (MeN) in Central America, however it has not yet been clarified if the endemics are related diagnostic entities. We designed this study of kidney biopsies from patients with CKDu in Sri Lanka to compare with MeN morphology. Eleven patients with CKDu were recruited at the General Hospital, Polonnaruwa, using similar inclusion and exclusion criteria as our previous MeN studies. Inclusion criteria were 20–65 years of age and plasma creatinine 100–220 μmol/L. Exclusion criteria were diabetes mellitus, uncontrolled hypertension and albuminuria >1g/24h. Kidney biopsies, blood and urine samples were collected, and participants answered a questionnaire. Included participants were between 27–61 years of age and had a mean eGFR of 38±14 ml/min/1.73m². Main findings in the biopsies were chronic glomerular and tubulointerstitial damage with glomerulosclerosis (8–75%), glomerular hypertrophy and mild to moderate tubulointerstitial changes. The morphology was more heterogeneous and interstitial inflammation and vascular changes were more common compared to our previous studies of MeN. In two patients the biopsies showed morphological signs of acute pyelonephritis but urine cultures were negative. Electrolyte disturbances with low levels of serum sodium, potassium, and/or magnesium were common. In the urine, only four patients displayed albuminuria, but many patients exhibited elevated α-1-microglobulin and magnesium levels. This is the first study reporting detailed biochemical and clinical data together with renal morphology, including electron microscopy, from Sri Lankan patients with CKDu. Our data show that there are many similarities in the biochemical and morphological profile of the CKDu endemics in Central America and Sri Lanka, supporting a common etiology. However, there are differences, such as a more mixed morphology, more interstitial inflammation and vascular changes in Sri Lankan patients.</p></div

Urine test results including urine heavy metals, n = 11.

<p>Urine test results including urine heavy metals, n = 11.</p

Serum test results, n = 11.

<p>Serum test results, n = 11.</p

Light microscopy images of vascular pathology in Sri Lankan patients with CKDu.

<p>Most of the biopsies showed no or mild intimal fibrosis in arteries (arrow head in A). Three patients showed moderate intimal fibrosis (B). [Fig A: hematoxylin-eosin from Patient 6, bar = 100μm. Fig B: hematoxylin-eosin from Patient 3, bar = 100μm.].</p