Mechanism for Dehydration Associated Kidney Disease Richard J Johnson, University of Colorado A sugarcane worker dying from kidney failure Dr Johnson has received funding from Danone Research
Chronic Kidney Disease Symptomatic (1 million) Diabetes Hypertension Glomerulonephritis Silent (20 million) Often unclear Aging Hypertension
Therapeutic approaches to Slow Progression of Renal Disease Lowering blood pressure Renin angiotensin system inhibitors Insulin; blood glucose control
The RENAAL Study-Type 2 Diabetes Renal function worsening slowed not stopped Brenner et al NEJM 345:861-869, 2001
Are we missing other Key Risk factors? Could Dehydration be playing a role in Kidney Disease?
An Epidemic of Kidney Disease in Central America
The Epidemic Subjects are usually men working in sugar cane fields Patients present with low grade proteinuria and elevated serum creatinine. Blood pressure is slightly elevated and diabetes is absent. Kidney biopsies show tubulointerstitial disease Dialysis is not always available. In the last 10 years (2002-2012), 46% of all male deaths in Chichigalpa were due to CKD of unknown etiology.
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 Model of Heat-Induced Dehydration Water Please! GROUPS WAT: water all time WAN: water at night CON: controls Heating at 39.5 C 30 min every hour x 10 No heating 8:00 AM TOTAL DURATION: 5 weeks
Recurrent Dehydration Causes Chronic Kidney Disease in Wild Type Mice Serum Creatinine (mg/dl) Collagen III Area (%) Serum Creatinine WAN WAN Dehyd Dehyd Control +H2O Fibrosis WAT WAT Dehyd Dehyd Control +H2O
Dehydration and Hypersomolarity Weight loss of 2.6 kg per day Increase in serum sodium to 145 mmol/l Serum Osmolarity 301 mosm/l Urine specific gravity of 1.026 Solis Zepeda, PhD thesis, 2007
Potential Mediators of Dehydration??? Dehydration Serum Osmolarity Vasopressin Aldose Reductase-Fructose Fructokinase Uric acid and Oxidants
Activation of Ald0se Reductase Results in Fructose Generation and Inflammation Dehydration The Polyol Pathway (Aldose Reductase)
Sugar Cane Nephropathy: A Fructokinase Summary Dependent Disease? Recurrent Dehydration Increases Serum Osmolarity Aldose Reductase Renal Fructose Accumulation Fructokinase Oxidative Injury Renal Injury
Developing a Model of Sugar Cane Nephropathy Wild Type mice (WT) Controls (WT-CON) n=6 Water all time (WT-WAT) n=6 Water at Night (WT-WAN) n=6 Fructokinase (KHK) knockout mice Controls (KHK-CON) n=6 Water all time (KHK-WAT) n=6 Water at Night (KHK-WAN) n=6 Roncal et al Kidney Int
Dehydration is Induced Weight Loss Serum Osmolarity Roncal et al, Kidney Int
Sorbitol (nmol/ug protein) Fructose (um/mg protein) Dehydration Results in an Increase in Renal Sorbitol and Fructose Levels in the Kidney Cortex WAT WAN CON WAT WAN CON
Fructokinase Knockout Mice are Protected from Chronic Kidney Disease Creatinine WAN-WT WAN-WT Fibrosis WAN-KHK WAN-KHK
Sugar Cane Nephropathy: A Fructokinase Summary Dependent Disease? Recurrent Dehydration Increases Serum Osmolarity Aldose Reductase Renal Fructose Accumulation Fructokinase Oxidative Injury Renal Injury Rehydration with Sugary Drinks
Could Soft Drinks Contribute to Dehydration Associated Renal Injury?
Fructose causes Tubular injury in the Rat Nakayama T. et al Am J Physiol Renal 2010; 298 : F712-20
m/kg /ml mosm/kg ml/24 h mosm/kg mosm/kg ng/ml ng/ml mosm/kg mosm/kg ml/24 h ml/24 h 300 10 200 200 0 0 Soft Drinks are Dehydrating 100 100-10 -10 p<0.0001 p<0.0001 Rats are given one-third of normal water intake for 22 hours of each day, 0 0-20 -20 then given water or sugar water ad Water libitum Water SBfor two Stevia hours. Stevia This is repeated daily for 4 weeks p<0.0001 p<0.0001 Water Water SB SB Stevia Stevia Plasma osmolality at 4 weeks 400 p<0.01 p<0.01 201200 Electrolyte-free Urine osmolality Urine water osmolality at clearance 4 weeks at 4 weeks 1200 p<0.0001 p<0.0001 p<0.0001 p<0.0001 175 175 Plasma Plasma copeptin concentration at 4 weeks p<0.0001 p<0.0001 p<0.0001 300 10 900 900 150 150 200 0 600 600 125 125 100 0 Water SB Stevia -10 300-20 0 300 * * p<0.0001 p<0.0001 Water 0 SB Stevia Water Water SB SB Stevia Stevia 100 100 1.0 1.0 0.5 0.5 0.0 0.0 * * * Water SB Stevia 1200 900 Urine osmolality at 4 weeks p<0.0001 p<0.0001 Plasma copeptin concentration at 4 weeks 175 150 p<0.0001 p<0.0001 Sanchez-Lozada et al Submitted 600 125
Rehydration with Soft Drinks Causes Oxidative Stress
Passive Dehydration with Rehydration with Soft Drinks Causes Kidney Damage Serum Creat 0.48±0.04 0.58±0.03* 0.49±0.1 Rats are given one-third of normal water intake for 22 hours of each day, then given water ad libitum for two hours. This is repeated daily for 5 weeks
Conclusions An Epidemic of Kidney Disease is occurring in Central America Epidemiological Studies Suggest Recurrent Dehydration may be critical Chronic Kidney Disease can be induced by recurrent dehydration in rodents and is mediated by the fructokinase system Rehydration with soft drinks may worsen kidney disease These studies raise the possibility that dehydration may be a novel risk factor for CKD
Special Thanks Carlos Roncal Gaby Sanchez-Lozada, PhD Miguel Lanaspa PhD And to all of my collaborators, past and present