Chronic Kidney disease of unknown etiology

Transcription

1 Course: Global Health and Disasters Chronic Kidney disease of unknown etiology Wednesday 11 Oct-2017 Carlos A. Roncal Jiménez Assistant Research Professor University of Colorado

2 Carlos A. Roncal-Jiménez Learning objectives 1. Discuss the clinical manifestations of the epidemic of kidney disease in Central America. 2. Will discuss potential role of dehydration in the chronic kidney disease epidemic. 3. Discuss role of uric acid and fructose in this disease.

3 Mesoamerican Nephropathy A CKD of unknown etiology in Central America Carlos A. Roncal Jiménez Assistant Research Professor University of Colorado

4 Mesoamerican Nephropathy Occurs predominantly along the Pacific Coast. Primarily men working in sugar cane fields, but can occur with other occupations Also affects women, possibly children. 20,000 Deaths so far!

5 Clinical Manifestations Not due to Hypertension or Diabetes Asymptomatic Rise in Creatinine Low grade proteinuria Blood pressure normal Hypokalemia and Hyperuricemia common Biopsies show Chronic Tubulointerstitial Disease

6 Sugarcane Workers are Especially at Risk for CKD egfr Loss (ml.min/1.73 m2) Sugar Cane Workers Show a Fall in their Kidney Function During the Harvest Season Seed Cutter Cane Cutter Irrigator Factory Worker Laws et al Int J Oc Envir Health 2015

7 Pesticides are Likely not the Cause of Mesoamerican Nephropathy Disease occurs in occupations that do not use pesticides (miners, construction workers, fishing industry, port workers) During the season, those cutting sugarcane are at higher risk for kidney damage than those who are applying the pesticides

8 For example, this study shows Change in NGAL (kidney damage biomarker) during the sugarcane harvest 25 NGAL (ug/g cretinine) Start End Start End Pesticide Applicator Sugarcane Cutter Laws et al AJKD 2015

9 What are the other Candidates besides pesticides that might be causing Mesoamerican Nephropathy? Proposed, but Little evidence: Environmental toxins NSAIDS (nonsteroidal agents) Heavy metals: Cadmium, Lead, Arsenic Aristolochic Acid (Balkans) cause of Chinese Herb Nephropathy Leptospirosis and other infections Most Important Risk Factor: Volume Depletion and Dehydration: Repeated kidney injury from recurrent dehydration, such as from Heat Stroke or Rhabdomyolysis

10 Sugar Cane Workers are Exposed to Extreme Heat Wet bulb temperature (temp and humidity) am 8 am 9 am 10 am 11 am noon Work starts at 5:30 am By 9:30 am they are working under heat conditions that exceeds the recommendations of the OSHA (Occupational Safety Health Administration) Crowe et al Am Indus Med 56:1157; 2013

11 This Raises the Question Could Mesoamerican Nephrophaty be a Dehydration Disorder?

12 The Classic Teaching is that Dehydration Results in Reversible Kidney Disease Classic Teaching Sweat--- loss of sodium and water Results in Pre-renal dysfunction High BUN/Cr Ratio Concentrated urine Renal Function is REVERSIBLE

13 Can Heat Induced Dehydration cause CKD? Water Please! GROUPS Controls Heat: + water Heat: water at night (Heat = Dehydrated) Heating at 39.5 C 30 min every hour No heating 8:00 AM 9:00 AM 10:00 AM 11:00 AM 12:00 AM 01:00 AM 02:00 AM 03:00 AM 04:00 AM 05:00 PM TOTAL DURATION 5 weeks 8:00 AM Roncal-Jimenez et al Kidney Int. 2013

14 Recurrent Dehydration Causes Chronic Kidney Disease in Laboratory Mice Serum Creatinine - mg/dl Serum Creatinine CON Dehy+H2O Dehy Heat +Dehydrated Heat + Dehydrated Collagen III (% positive area) CON Dehy+H2O Dehy Heat + hydration Heat + hydration Roncal-Jimenez et al Kidney Int. 2013

15 How Does Dehydration Cause Kidney Disease?

16 Renal Consequences of Dehydration Dehydration Water loss > Salt Loss Serum Osmolarity Vasopressin Aldose Reductase glucose sorbitol Urinary Concentration

17 Vasopressin and Fructose May be Mediators for Dehydration Kidney Injury Vasopressin glucose Aldose Reductase sorbitol fructose Oxidative stress, inflammation Kidney Damage

18 Rats Given Fructose in diet Develop Kidney Damage Nakayama T. et al Am J Physiol Renal 2010; 298 : F712-20

19 Dehydration Results in Increased Fructose Generation in the Kidney Aldose Reductase Dehydration Increases Kidney Fructose glucose sorbitol fructose fructokinase Fructose-1-P ATP AMP Fructose (nmol / mg prot) CON Dehy + H2O Dehy Uric acid, oxidants Roncal-Jimenez et al Kidney Int. 2013

20 WT WT Mice that cannot metabolize fructose (fructokinase knockout) are Protected from Dehydration associated CKD Fructokinase KO Fructokinase KO Roncal-Jimenez et al Kidney Int. 2013

21 This suggests Mesoamerican Nephropathy might be a Fructose Dependent Disease Recurrent Dehydration Increases Serum Osmolarity Aldose Reductase Kidney Fructose Accumulation Vasopressin Fructokinase Oxidative Stress Kidney Injury Roncal-Jimenez et al Kidney Int 2013

22 Could Sugar-containing Rehydration Solutions Worsen Dehydration Induced Kidney Disease? Soft Drinks containing fructose Recurrent Dehydration Increases Serum Osmolarity Aldose Reductase Kidney Fructose Accumulation Vasopressin Fructokinase Oxidative Stress Kidney Injury

23 Rehydration with Soft Drinks Causes Kidney Damage in Dehydrated Rats Urine NGAL Sanchez-Lozada et al Submitted

24 While these studies suggest a role for dehydration in kidney damage, There is a Possibly More Important Mechanism for Mesoamerican Nephropathy!

25 Acute Kidney Injury may occur from a Sudden Increase in Uric acid during cancer chemotherapy (tumor lysis syndrome) Chemotherapy Tumor Cell Death and Release of DNA, RNA Increase in Uric acid High Urine Uric acid Crystal mediated AKI

26 Mesoamerican Nephropathy: A Uric acid Disorder? Heat and Exercise Subclinical Rhabdomyolysis Release of DNA, RNA Lactic acid Increase in Uric acid High Urine Uric acid Urine acidification Crystal mediated AKI

27 Sugarcane Workers Show a Rise in Serum Uric Acid and Creatinine while working (during shift) 1 Serum Creatinine Serum Uric acid Morning Afternoon Morning Afternoon Pilot Data in El Salvador Sugarcane Workers, Garcia-Trabanino, Env Res in press

28 Urine ph falls during shift which increases risk for uric acid crystal formation Urine ph ph data measured by dipstick in the field Morning Afternoon Pilot Data in El Salvador Sugarcane Workers, Ramón Garcia-Trabanino, submitted

29 Urate crystals are Common in the Urine of Sugarcane workers during the sugarcane harvest Pilot Data in El Salvador Sugarcane Workers, Roncal-Jimenez AJKD

30 Urine Uric Acid Appears to Rise but when corrected for ph the rise is dramatic Urine Uric Acid Actual ph ph 7 Actual ph ph 7 Morning Afternoon Pilot Data in El Salvador Sugarcane Workers, Roncal-Jimenez AJKD

31 Given that Mesoamerican Nephropathy may be due to heat stress, is there a role of Global Warming and Water Shortage in this Disease?

32 Chichigalpa Quezalguaque Central America: Site of High Solar Radiation Correlates with Site of CKD Epidemic Guanacaste

33 Temperature Change in El Salvador Global Warming is responsible for majority of heat waves Fischer and Knutti Nature Clim Change 2015;5:560 Berkely Earth.

34 Sugar cane Workers in Chinandega, Nicaragua Showed Marked Uricosuria in One of Four Urines > 100 mg/dl Urine Uric acid (mg/dl) Nov 26th Dec 5th May 13 th, 2013

35 Record Temperature in nearby San Miguel, El Salvador, May 14 th, 2013 May 104 F Urine Uric Acid Results of 7 Sugarcane Workers in Chinandega, May 13th 2013 May 13 Supernatant Sediment Total

36 Summary: Mechanism for Mesoamerican Nephropathy

37 Special Thanks Richard Johnson Gaby Sanchez-Lozada Miguel Lanaspa Ramon Garcia Jason Glaser Tamara Milagres And to all collaborators, especially Aurora Aragon Emmanuel Jarquin David Wegman Lars Barregard Diana Jalal Catharina Wesseling Theo Bodin Channa Jayasumana Ilana Weiss Ricardo Correa Rotter Jay Lemery Anika Wernerson Henry Diaz Magdalena Madero Ganghadar Taduri Marvin Gonzalez Lee Newman

38 Thanks for your Attention