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The kidney,chronic kidney disease and WAGR kidney disease

The kidney,chronic kidney disease and WAGR kidney disease . Jeffrey Kopp, MD CAPT, US Public Health Service Kidney Disease Section. jbkopp@nih.gov. Kidneys on computerized tomography (CT) scan. Kidneys and what they do (1). Product. Homeostasis. Cars. Smoke. Urine. Waste.

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The kidney,chronic kidney disease and WAGR kidney disease

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  1. The kidney,chronic kidney disease and WAGR kidney disease Jeffrey Kopp, MD CAPT, US Public Health Service Kidney Disease Section jbkopp@nih.gov

  2. Kidneys on computerized tomography (CT) scan

  3. Kidneys and what they do (1)

  4. Product Homeostasis Cars Smoke Urine Waste

  5. Kidneys came early in animal evolution

  6. 1 million nephrons in each kidney: each is glomerulus + tubule

  7. Glomerular filtration: filtering small molecules from the circulation • Renal blood flow ~1000 mL/min • Renal plasma flow ~600 mL/min • Glomerular filtration rate (GFR) ~100 mL/min = ~150 L/day

  8. One kidney, one million nephrons

  9. Tubular reabsorption: reclaiming what we need before it heads down the tubule to the ureter, bladder, and out Why does the kidney filter everything, and then reclaim what is needed and discard the rest? THE GOOD (unless excess) Sodium Potassium Chloride Bicarbonate Calcium Magnesium Glucose Amino acids Vitamins B, C etc THE BAD Urea Uric acid Creatinine Toxins etc Keeping the baby, throwing out the bathwater

  10. Creatinine physiology • Small molecule, released from muscle turnover • Production depends on muscle mass • Freely filtered through the the glomerulus • Serum levels depend upon muscle mass (higher when muscle mass is higher) and kidney function (higher when kidney function is poor)

  11. When kidney function is impaired GFR declines linearlyserum creatinine rises geometrically

  12. Estimating kidney function from serum tests Gold standard test • Infuse iothalamate, measure serum and urine levels, calculate kidney clearance of iothalamate • Requires IV and takes ~3 hr

  13. Chronic kidney disease stages

  14. Assessing urine protein levels • Problem: in a particular patient at a particular phase of disease, protein concentration in urine fluctuates with urine concentration from sample to sample • Since the amount of urine creatinine/day is relatively constant, the concentration in urine provides an index of urine concentration or dilution • Solution: the protein/creatinine ratio or albumin/creatinine ratio will adjust for changes in urine concentration • Example of urines taken from the same patient at two different times of the day • Concentrated urine: albumin 10 mg/dL, creatinine 100 mg/dL = ACR 100 mg/g • Dilute urine: albumin 2 mg/dL, creatinine 20 mg/dl = ACR 100 mg/g

  15. Assessing kidney function: urine tests

  16. WAGR kidney disease

  17. Wilms tumor: CKD is common when there is a genetic basis • National registry of Wilms tumor, 1969-1995 • N = 5965 enrolled at <16 yr • Renal failure: cr>2.5 or dialysis WAGR Denys-Drash Breslow Cancer Res 2000

  18. NIH WAGR study • Genotype/phenotype: relate phenotype to genes deleted • Random urine A/C in 24 subjects

  19. Patterns of WAGR kidney diseases Immature podocytes Diffuse mesangial sclerosis Focal segmental glomerulosclerosis

  20. Screening for WAGR kidney disease • Screening: yearly BP check, serum creatinine and cystatin C, urine ACR (and possibly PCR) • Strive to maintain normal body weight: “bigness” stresses 2 kidneys, more so 1 kidney, and most 1 kidney with glomerulosclerosis • Maintain normal BP: if borderline, restrict dietary salt (2 g/d target) and check BP at home. BP target is 50th percentile BP for age and height. • If albuminuria appears, consider kidney biopsy to confirm that glomerulosclerosis is present (but probably no biopsy if single kidney) • No role for kidney ultrasound in diagnosing glomerular disease – will be normal until extensive fibrosis develops and substantial loss of function has occurred.

  21. Treatment for WAGR kidney disease • Probably start therapy with renin-angiotensin pathway blockers – one drug and possibly two drugs • This approach slows glomerulosclerosis in other diseases but has not been tested in WAGR • These drugs lower BP and rise potassium, so these must be monitored. • Low sodium diet potentiates the anti-proteinuric effect of RAS blockers

  22. Renin-angiotensin-aldosterone system (RAAS) Angiotensinogen Aliskiren Trauma: maintains blood pressure, promotes wound healing Chronic kidney disease: elevates blood pressure, promotes fibrosis – blocking RAAS is a key to slowing or halting kidney disease progression ACE inhibitors Angiotensin 1 Renin Angiotensin 2 Angiotensin receptor blockers (ARB) Angiotensin converting enzyme Angiotensin receptor Spironolactone Eplerenone Blood vessel constriction Aldosterone Aldosteronereceptor Sodium retention Fibrosis

  23. Renal replacement therapy

  24. Hemodialysis • Dialysis center or home • 3x week or 6x week • Advantages: effective in large people, less for patient/family to do • Disadvantages: needles, vascular access problems, time spent in center, arranging treatments when traveling, disequilibrium after dialysis sessions

  25. Peritoneal dialysis • Continuous ambulatory: 4 1-2 liter exchanges/d • Intermittent: 10-15 liters overnight, 1 exchange at night • PD Advantages: mobility, control, no needles • Disadvantages: more patient/family effort, less effective in large person, peritonitis

  26. Kidney transplant: the preferred approach to renal replacement therapy

  27. Kidney transplant: requirements to be donor • Age 18 – 55 • Normal kidney function • No diabetes • No cancer, HIV, hepatitis B or C • Normal BP or possibly on 1 BP medication • Blood group match (can do plasmapheresis if not) USRDS 2011

  28. Induction antibody useFigure 7.28 (Volume 2) Patients age 18 & older receiving a first-time, kidney-only transplant. USRDS 2011

  29. Immunosuppression useFigure 7.27 (Volume 2) Patients age 18 & older receiving a first-time, kidney-only tx. CsA: cyclosporine A; CsM: cyclosporine microemulsion. USRDS 2011

  30. Acute rejection within the first year post-transplantFigure 7.19 (Volume 2) Patients age 18 & older. USRDS 2011

  31. Outcomes: living donor transplantsFigure 7.18 (Volume 2) Patients age 18 & older receiving a first-time, kidney-only transplant. Adj (survival): age/gender/race/primary diagnosis. USRDS 2011

  32. Renal transplant vs chronic dialysis • Longer survival • Better quality of life • There are concerns: immunosuppressive medications, infections (virus), cancer

  33. The future • Therapies for chronic kidney disease improve every year • Perhaps we can develop specific therapies for WAGR kidney disease

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