The kidney,chronic kidney disease and WAGR kidney
disease
Jeffrey Kopp, MDCAPT, US Public Health Service
Kidney Disease Section
Kidneys on computerized tomography (CT) scan
Kidneys and what they do (1)
Product
Waste
Cars
Smoke
Homeostasis
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
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
Why does the kidney filter everything, and then reclaim what is needed and discard the rest?
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
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%
Gold standard test
•Infuse iothalamate, measure serum and urine levels, calculate kidney clearance of iothalamate
•Requires IV and takes ~3 hr
Chronic kidney disease stages
Stage 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 BP -
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
Example of urines taken from the same patient at two different
times of the dayConcentrated urine: albumin 10 mg/dL, creatinine 100 mg/dL =
ACR 100 mg/gDilute urine: albumin 2 mg/dL, creatinine 20 mg/dl = ACR 100
mg/g
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
Assessing kidney function: urine testsBlood 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)
NA 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: normal0.2-2 g/g: proteinuria>2 g/g: nephrotic
24 hour urine collection(adult values)
NA Albumin 30-300 mg/d: microalbuminuria >300 mg/d: macroalbuminuria – kidney disease
Protein>150 mg/d: proteinuria> 3.5 g/d: nephrotic
WAGR kidney disease
Wilms tumor: CKD is common when there is a genetic basis
Breslow Cancer Res 2000
National registry of Wilms tumor, 1969-1995 N = 5965 enrolled at <16 yrRenal failure: cr>2.5 or dialysis
WAGRDenys-Drash
Genotype/phenotype: relate phenotype to genes deleted Random urine A/C in 24 subjects
NIH WAGR study
ACR mg/g <10 10-17 18+
<30 5 2 3
30-300 0 4 3
>300 0 2 3
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 1
Angiotensin receptor
Angiotensinogen
Angiotensin 2Angiotensinconvertingenzyme
Blood vessel constriction Aldosterone
Renin-angiotensin-aldosterone system
(RAAS)
SpironolactoneEplerenone
ACE inhibitors
Angiotensin receptor blockers (ARB)
Aliskiren
Aldosteronereceptor
Sodium retentionFibrosis
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
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 useFigure 7.28 (Volume 2)
Patients age 18 & older receiving a first-time, kidney-only transplant.
USRDS 2011
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
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