The kidney,chronic kidney disease and WAGR kidney

disease

Jeffrey Kopp, MDCAPT, US Public Health Service

Kidney Disease Section

jbkopp@nih.gov

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