Laboratory Evaluation of Renal Function S .POPLI. M.D.,F.A.C.P. 7/13/2005

Proteinuria Case 1 A 20 year old patient is referred to you for ,he has been diabetic for 6 years ,he was told to have some kidney problem by his MD.He wants to know the cause of renal dysfunction. GPE:BP 145/90 ,otherwise exam is normal How would you proceed ? BUN 15mg/dl, creatinine 1.0mg/dl ,U/A shows SG 1.024 ,trace protein ,a few hyaline casts What test would you order next ? 24h protein collection , U protein/U creatinine ratio or both?

Case 1 continued Urine protein /Urine creatinine returns 15mg/150mg ratio(<0.1) Does this patient have abnormal proteinuria ? Patient wants to know if he has microalbuminuria ,you order urine micro albumin result is :60mg micro albumin /gm creatinine . Is this abnormal, does this patient have diabetic nephropathy?

Urine Protein:Categories of persistent proteinuria Overflow: Capacity to reabsorb normally filtered protein in proximal tubules over whelmed due to overproduction:e.g.light chains,hemoglobinuria and myoglobinuria Tubular proteinuria: Decreased reabsorption of filtered proteins by tubules due to tubulointerstitial damage ; usually <2 gm Glomerular proteinuria: Microalbuminuria to overt proteinuria usually>3.5 gm

Screening for Urine protein Dipstick: Gives green color, does not check for light chains Negative – 10 mg/dl Trace – 15-25 mg/dl 1-2+ – 30-100 mg/dl 3+ – 300 mg/dl Sulfosalicylic acid: white precipitate 27

Urine protein :Quantitative measurement 24 hour collection of urine for protein normal excretion is <150 mg/24 hour Spot urine protein/urine creatinine ratio : (as 24 h urine creatinine excretion is a function of muscle mass i.e. 15 mg/kg for females and 20mg/kg for males ) a normal ratio is 150/1500 or <0.1 . A ratio >3 indicates nephrotic range proteinuria Case 1 has normal urine protein excretion, trace protein on u/a is due to highly concentrated urine ,pt may still have microalbuminuria

Microalbuminuria Urine albumin excretion below detection by regular dipstick First clinical sign of diabetic nephropathy Incidence increases with the duration of diabetes and may be present at the diagnosis of NIDDM Transient albuminuria may occur with fever,infection,exercise,decompensated CHF Associated with poor glycemic control and elevated BP

Detection of Micro albuminuria: 24 hour urine collection Normal urine protein excretion : <150mg (20% of this is albumin) Therefore, normal urinary albumin excretion is < 30 mg/day Microalbuminuria :urinary albumin excretion 30-300 mg/day

Microalbuminuria :Detection by Spot Urine Albumin to Urine Creatinine ratio Easier than cumbersome 24 hr.collection If we assume daily creatinine excretion to be 1000 mg and normal urine albumin excretion <30 mg; albumin / creatinine ratio should be less than 0.03 or 30mg/g creatinine Thus case 1 has micro albuminuria which is likely due to diabetic nephropathy.How would you manage him now?

Why and When to Screen Patients for Microalbuminuria ? BP control with Ace_I and ARB’s have been known to reduce microalbuminuria and delay the progression of kidney disease in diabetics IDDM patients should be screened yearly,beginning 5 years after the onset of disease Patients with NIDDM should be screened at presentation

Proteinuria Case 2 A70 year- old male is referred for chronic azotemia PMH: unremarkable GPE: BP120/60 , LE edema Labs: U/A SG 1.010 pH 6.0 , protein neg, glucose 2+, Uprotein /U creatinine ratio 4 BUN 30mg/dl creat.3.0, Blood Sugar 78mg/dl albumin 2.8, Hb 10 gm What other tests would you order to diagnose cause of his renal dysfunction ? UPEP,why?

Clinical Assessment of Renal Function: Glomerular Filtration Rate(GFR) Parameters used Blood urea nitrogen Serum creatinine Endogenous creatinine clearance 29

Case 3 Azotemia A 55 year old diabetic female is admitted with intractable vomiting and low urine output Exam: BP 120/60 with postural hypotension Labs: BUN 60, Creat. 2.0 mg/dl ( baseline 1.0mg/dl), Hb 16gm ,U/A: SG 1.020, sediment: hyaline casts,UNa: 10 mmol/L,UOsm: 600 mosm/kg,Ucreat.150mg/dl ,Fe Na < 0.5 Q.What is the cause of her high BUN to creatinine ratio and her renal failure? What are the other causes of high BUN to creatinine ratio

Blood Urea Nitrogen (BUN) Catabolism of aminoacids generates NH3 NH2 2 NH3 + CO2 = C = 0 + H2O Urea Mol wt : 60 BUN Mol wt. : 28 Normal BUN 10-20 mg/dl After filtration › 50% is reabsorbed by the tubule BUN level is related to: Renal function, protein intake, and liver function 31

Creatinine Formed at a constant rate by dehydration of muscle creatine Normally 1–2% of muscle creatine is broken into creatinine Mol. Wt. 113 Creatinine is freely filtered by the glomerulii and is not reabsorbed 10–15% is secreted into proximal tubule

Creatinine Normal serum level 1–2 mg/dl 24 hour creatinine excretion 20 mg/kg/day for males 15 mg/kg/day for females Children, females, elderly, spinal cord injured have low serum and urine creatinine 40

BUN/Creatinine ratio 10:1 Normal Chronic renal failure 41

D/D in Case 3 with BUN Creatinine ratio >10:1 Decreased perfusion Hypovolemia Congestive heart failure Increased urea load GI bleed Glucocorticoids -Tetracycline Hyper catabolic states High Protein diet Obstructive uropathy Decreased muscle mass

Pathophysiology of Pre-renal Azotemia in Case 3 Decreased “Effective” Intravascular ADH Volume + Renal Hypoperfusion activation of RAS Diminished GFR aldosterone Low urine volume and U sodium and high Uosmolality

Case 3 :Diabetic patient continued.. Vomiting stopped ,BP improved and BUN/creat lowered to 35/1.8mg/dl. 24 hours later she developed UTI, trimethaprim/sulfamethoxazole was started Next day 24 hr urine output 800 mL Exam: Unremarkable BUN: 20 mg/dl Creat: 3.0 mg/dl Uosm: 600 mosm/kg ,UNa: 10 mom/l, FeNa: <1% Urine Sediment: Hyaline casts What is the cause of < 10: 1 ,BUN to creat ratio now?

BUN/Creatinine ratio ‹ 10:1 Decreased urea load Low protein diet Liver failure Inhibition of creatinine secretion Cimetidine Trimethoprim Probenecid Increased removal: Dialysis 44

BUN/Creatinine ratio ‹ 10:1 Increased creatinine load Ingestion of cooked meat Rhabdomyolysis Interference with creatinine measurement Ketosis Cefoxitin Increased muscle mass Anabolic steroids Muscular development 46

Case 3 continued… 6 months later Pt was discharged with normal BUN and creatinine,6 months later she is admitted with vague abdominal pain, an US done shows 6 cm abdominal aortic aneurysm, she undergoes resection with cross-clamping of aorta for 2 hours. Post surgery she is oliguric (u/o less than 70ml in 8 hours).On exam well hydrated. U/A: SG 1.015 ,”Dirty brown sediment “U Na 40 mEq /L U osmolality 350 mOsm/l ,Fe Na 2% What is your diagnosis after reviewing the lab data ? How would you manage?

“Dirty Brown” Sediment in ATN

Urinary Indices in Diagnosis of Acute Renal Failure Pre renal ATN Uosm(mosm/kgH20) >500 <350 Urine sodium (mmol/l) <20 >40 Urine/plasma urea nitrogen >8 <3 Urine/Plasma Creatinine >40 <20 Fractional Excretion of Sodium<1% >1% Sediment normal “dirty brown”

Fractional Excretion of filtered Sodium(FeNa) FeNa= Amount of Na excreted Amount of Na filtered FeNa=UNa x Urine volume PNa x GFR FeNa = UNa x V PNa x[(UCr x V) /PCr] FeNa % =UNa x PCr X 100 PNa x UCr

Case 4 20 y/o male is seen at West point ,on admission physical : wt 70Kg , BUN 10mg/dl, serum creatinine 1.0mg/dl, GFR was 100ml/min and he excreted 1500mg creatinine /day in the urine. 2 months later he develops acute glomerulonephritis with RBC and fatty casts.His serum creatinine increases to 2mg/dl and remains at 2mg/dl at 1 year follow up .Wt is 72kg What is his estimated GFR by Cockcroft and Gault formula and by serum creatinine? What would be the creatinine excretion now at 1 year ?

Concept of Clearance ? Measurement of GFR by Creatinine Clearance(Ccr) Urine is collected for 24 hours and plasma creatinine is measured the next day 1. Filtered creatinine = Excreted creatinine 2. GFR x Pcr = Ucr x Volume 3. GFR = Ucr. mg/dl x V ml Pcr.mg/dl Normal GFR = 100 ml/min GFR declines by 1 ml/min/year after age 40 52

GFR Estimation by Plasma Creatinine Cockcroft and Gault Formula* Calculated creatinine clearance = (140–age) x wt (kg) 72 X serum creatinine(mg/dl) For females, subtract 15% (or multiply by 0.85); for paraplegics multiply by 0.8, for quadriplegics, multiply by 0.6 Est GFR for this pt is .. (140-20)x70 72x2 *Applicable only when patient is in a steady state, not edematous and not obese

GFR Estimation by Plasma Creatinine(Pcr) In steady state Creatinine excretion = creatinine production=constant Creatinine excretion =Urine creatinine x Urine volume Filtered creatinine =GFR x Plasma creatinine As creatinine production is a function of muscle mass and remains constant Thus plasma creatinine values vary inversely with GFR GFR1/2 X 2 Pcr = GFR x Pcr = constant A rise in Pcr almost always represents a fall in GFR 55

In case 4 ,serum creatinine increased from from 1 to 2 mg/dl and remained at that level, his 24urine creatinine will remain the same Another example :70 kg man with serum creat. of 1 mg/dl and GFR of 100 ml/min was excreting 1500 mg creatinine/day,if you remove his one kidney , next day his GFR will be 50ml/min,urine creatinine excretion will be 750 mg /day.Over the next few days creatinine will accumulate in the blood and level will increase to 2 mg /dl and thus filtered and excreted amount will be the same

Summary How to evaluate a patient with renal disease How to interpret u/a,urine protein to creatinine ratios Interpretation of urea nitrogen and creatinine ratios Estimation and measurement of GFR& to see when a patient would need renal replacement therapy Interpret urine indices in evaluation of various causes of ARF