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 Cars Homeostasis Waste Smoke Urine

Kidneys came early in animal evolution

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

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

One kidney, one million nephrons

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

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)

When kidney function is impaired GFR declines linearly serum creatinine rises geometrically

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 Population Name Variables P30% 40: 28, 52 Children Schwartz 1976 Creatnine, height Schwartz 2012 + BUN, Cystatin C Adults MDRD Age, sex, race, creatinine 75% CKD-EPI (2012) Same 87% CKD-EPI-Cr/CystC (2012) + Cystatin C 92%

Chronic kidney disease stages GFR ml/min/1.73m2 Possible complications Dose adjustment for meds excreted by kidney 1 Normal GFR; proteinuria or hematuria >90 BP - 2 Mild CKD 60-90 3 Moderate CKD 30-60 BP, bone, CVD + 4 Severe CKD 15-30 BP, bone, CVD, anemia ++ 5 Kidney failure = ESKD <15 BP, bone, CVD, anemia, infection +++

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

Assessing kidney function: urine tests Blood Protein Urinalysis dipstick Negative, Trace, 1, 2, 3 Negative, Trace, 1 ,2, 3 Urinalysis microscopic Did the red blood cells come from the kidney? NA Random urine (children, adults) Albumin/creatinine ratio (ACR) 30-300 mg/g: microalbuminuria (metabolic syndrome, early glomerulosclerosis) >300 mg/g: macroalbuminuria - kidney disease >1 g/g: nephrotic Protein/creatinine ratio (PCR) <0.2 g/g: normal 0.2-2 g/g: proteinuria >2 g/g: nephrotic 24 hour urine collection (adult values) Albumin 30-300 mg/d: microalbuminuria >300 mg/d: macroalbuminuria – kidney disease >150 mg/d: proteinuria > 3.5 g/d: nephrotic

WAGR kidney disease

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

NIH WAGR study Genotype/phenotype: relate phenotype to genes deleted Random urine A/C in 24 subjects ACR mg/g <10 10-17 18+ <30 5 2 3 30-300 4 >300

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

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.

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

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 converting enzyme Angiotensin receptor blockers (ARB) Angiotensin receptor Spironolactone Eplerenone Blood vessel constriction Aldosterone Aldosterone receptor Sodium retention Fibrosis

Renal replacement therapy

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

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

Kidney transplant: the preferred approach to renal replacement therapy

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

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

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

Acute rejection within the first year post-transplant Figure 7 Acute rejection within the first year post-transplant Figure 7.19 (Volume 2) Patients age 18 & older. USRDS 2011

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

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

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