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Renal Functions

and

Laboratory Assessment-II

Serkan SAYINER, DVM PhD. Assist. Prof.

Near East University, Faculty of Veterinary Medicine, Department of Biochemistry serkan.sayiner@neu.edu.tr

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Indirect Tests of Glomerular Function

▪ Cystatin C

• Cystatin C is a small constitutive protein synthesized by all nucleated cells and only cleared by glomerular filtration.

• After filtration, it completely reabsorbed by the proximal tubule and degraded. So the amount in urine is very low. Increase in urine

can be evaluated as a sign of proximal tubule injury.

• In the case of GFR decline, the amount of serum will increase as the excretion decreases. Correlation with plasma creatinine and GFR is very good in both healthy and GFR-depleted dogs and is a superior GFR marker than creatinine.

• However, depending on the extra-renal causes, it may increase in serum.

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Indirect Tests of Glomerular Function

• It is considered the most sensitive marker of renal failure in humans.

• It can be measured with reagents used in humans in plasma (especially for dogs)

• It can be measured in serum and urine.

• Absolutely must be taken after 12 hours fasting. Because plasma levels after feeding are reduced by 50%.

• It is stable 2 days at +4 °C and 1 month at -20 °C.

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Indirect Tests of Glomerular Function

• Studies in dogs have been revealed that it is more closely related to GFR and more sensitivethancreatinine for renal diseases.

• Nevertheless, it is not certain whether there will be an increase due to prerenal azotemia.

• Cystatin C concentration in cats with chronic kidney disease and healthy cats may overlap.

• On the other hand, clinically healthy cats are likely to have subclinical renal disease.

• Increased levels in the urine may be a sign of proximal tubular injury.

• Further research is needed.

• It is not affected by muscle mass like creatinine.

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Indirect Tests of Glomerular Function

• Reference values reported in cats and dogs are 0.4-1.6 mg/L and 0.4-1.0 mg/L, respectively.

• Increased Serum levels: Is used as a sensitive indicator for decreased GFR.

• Prerenal Azotemia: The effect is not certain.

• Non-renal diseases: Increased in cats with hyperthyroidism.

• Acute kidney damage: Needs work.

• Chronic Kidney Disease: Increased. However, the use of creatinine is still preferred when the disease is graded.

• Increased urine levels: Potential indication of proximal renal

damage. Proteinuria may mask the result. It is therefore advisable to look at urine with protein and creatinine.

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Indirect Tests of Glomerular Function

▪ SDMA (Symmetrical dimethylarginine)

• SDMA (symmetric dimethylarginine) is the amino acid, arginine, that contains two methyl groups (dimethyl) in a symmetrical orientation.

• It is the structural isomer of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA).

• SDMA is a relatively newly discovered renal biomarker. SDMA is primarily eliminated by renal excretion. Therefore, it is an

endogenous marker of GFR.

• It is not influenced by muscle mass, which is an advantage in comparison with creatinine.

• It has been used successfully to diagnose CKD in dogs and cats;

particularly in the early stage.

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Direct Tests of Glomerular Function

▪ The determination of glomerular filtration rate (GFR) is considered the best way to evaluate kidney function.

▪ GFR is the volume of ultrafiltrate produced per unit of time by glomerular filtration.

• It is 3-6 ml/minute/kg healthy dogs and 2-4 ml/minute/kg in cats.

▪ The surviving nephrons of the diseased kidney largely retain their essential functional integrity and retain a remarkably

uniform relationship between glomerular and tubular function.

▪ GFR may vary depending on the size of the animal.

Therefore, weight and surface area of the body is important

in the calculation.

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Direct Tests of Glomerular Function

▪ There is no easy method for determining GFR from a sin- gle blood or urine specimen.

▪ In humans, there are equations to estimate GFR from plasma

creatinine, gender, weight, and age. The most frequently used are the Cockroft-Gault’s equations, but these are imprecise and the results depend on the techniques used for P-Creatinine.

• This equation has been tested in dogs, but its use has not been determined appropriately.

▪ The accepted reference for GFR determination is the urinary clearance of inulin.

• GFR= (Urine volume) x (Urine inulin) : (Plasma inulin) x t

▪ Decreased GFR is the gold standard for the diagnosis of

renal failure.

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Tests of Tubule Function

▪ Urine Osmolality versus Urine-Specific Gravity (Density)

• Urine concentration is best evaluated by osmolality.

• The urine concentration is determined in routine tests from the specific gravity (SG). Urine osmolality and specific gravity were highly correlated in dogs, sheep and cats; weaker in calves.

• It may vary depending on diet, physical exercise, environmental conditions, medications, anesthetics, breed, sex, age, individual differences, and biological rhythms.

• Measuring osmolality requires expensive equipment. Thus, SG can be measured with the refractometer. In routine, test strips are used.

• Repeated measurements are recommended due to variations in healthy animals.

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Species Amount of Daily Urine

Specific Gravity

pH

Mean Min-Max

Horse 3 – 10 L 1040 1025-1060 6,8 – 8,4

Cattle 6 – 25 L 1032 1030-1045 6,0 – 8,7

Sheep/Goat 1 – 1,5 L 1030 1015-1045 6,0 – 7,0

Dog 0,5 – 2,0 L 1025 1016-1060 6,1

Cat 75 – 200 mL 1030 1020-1040 6,0

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Tests of Tubule Function

▪ Urine Excretion of Ions; Fractional Excretion (FE)

• Many electrolytes are intensely reabsorbed after filtration, mainly in the proximal tubule; their excretion is thus increased when tubule dysfunction occurs.

• Urine electrolyte concentrations also depend on the alimentary supply as the homeostatic mechanisms aimed to stabilize plasma

concentration modulate tubule reabsorption. The most meaningful information would be obtained from daily urine excretion, which is often impossible to obtain because of the difficulties associated with urine collection.

• Expressing the urinary elimination of a solute as the ratio of the filtered load that is found in urine has been proposed, whence the name fractional excretion (FE).

• FEX = (Urine-X x Urine Volume) : (Plasma-X x GFR)

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Tests of Tubule Function

• If creatinine clearance is used as a measurement of GFR, it can be demonstrated that FE is equal to the ratio of the solute clearance to creatinine clearance.

• FEX = (Urine-X : Plasma-X) x (Plasma-Creatinine : Urine Creatinine)

• Such spot measurements are often well correlated with daily elimination.

• It shows high variation in cats.

• Na, Cl, K, Pi can be used for this purpose. There are differences between animals.

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Tests of Tubule Function

• It may vary depending on diet, physical exercise, environmental

conditions, medications (especially fluid therapy), anesthetics, breed, sex, age, individual differences, and biological rhythms.

• Analytically, plasma techniques can be used in the urine (dilutions may be needed). Attention should be paid to the substances that create interferences.

• Especially in sheep, cattle, horses and cattle, an erroneous low K may be determined.

• The greatest difficulty in evaluating FE is that it varies with a number of non-renal problems. For this reason, more appropriate results can be obtained with controlled and repeated measurements.

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Tests of Tubule Function

▪ Urine Excretion of Ions; Fractional Excretion (FE)

FE

X

Dog Cat

Na < 1 < 1

K < 6-20 < 6-20

Cl < 1 < 1.5

P < 20 < 73

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Tests of Renal

Damage

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Glomerular Damage

▪ Proteinuria

• It is the most common abnormal condition in routine urine analysis.

• Although glomerular damage is the cause of the most intense

proteinurias, it can also originate from the tubules and their cause may be pre- or postrenal.

• The following systematic approach is required in cases of confirmed proteinuria.

1. Is it persistent?

2. Evaluate the magnitude.

3. Localize the origin.

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Glomerular Damage

• In glomerular filtrate, plasma proteins are either not found or in trace amounts.

• The molecular weight of albumin is closest to the filtration

threshold, so this is the first plasma protein to escape into urine in the case of glomerular disturbance.

• Almost all of the filtered proteins are reabsorbed in the tubule, and the remaining molecules which are degraded, are then discarded in the urine. This may lead to underestimation of urinary proteins with certain techniques (e.g. Biuret test) (<LOD).

• Protein concentration in spot urine may vary considerably

depending on urine concentration. Therefore, better estimates of proteinuria would be obtained by measuring total daily excretion;

need to collect urine for 24-hour, which is difficult.

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Glomerular Damage

• The concentration of creatinine, which is inversely related to urine dilution, is used as a correction in spot samples as its excretion in a given animal is supposed to be fairly constant.

• It is an accepted equation today (mainly by IRIS).

• The U-P/C ratio in spot urines is well correlated with 24-h urine excretion in healthy and chronic renal failure dogs and cats.

Urinary Protein/Creatinine Ratio (U-P/C) =

Urine Protein (mg/L) Urine Creatinine (mg/L)

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Glomerular Damage

• Variations in U-P/C values can be seen depending on the sample, diet, physical exercise, medication, sex, age, individual differences and biological rhythms.

• Proteinuria detection is most often based on the use of test strips, the detection limit being 0.25 to 0.30g/L for albumin.

Quantifications cannot be done.

• Alkaline urine can give erroneous results. The result must be evaluated together with the density.

• For quantitative results, methods such as Ponceau S, Coomassie Blue and Pyrogallol Red should be used.

• The biuret reaction cannot be used as its quantification limit (ŞOQ) is too high (~0,2 g/dL = 20 g/L).

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Glomerular Damage

• Borderline result should be repeated and re-evaluated within two months.

• Non-proteinuric or borderline values can also be considered as

«microalbuminuric».

• Proteinuria may decrease as renal dysfunction increases.

• The treatment can be followed by U-P/C.

U-P/C Value

Assessment

Dog Cat

<0,2 <0,2 Non-Proteinuric

0,2 - 0,5 0,2 - 0,4 Borderline proteinuric

>0,5 >0,4 Proteinuric

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Glomerular Damage

▪ Albuminuria-Microalbuminuria

• More than 99% of filtered albumin is reabsorbed in the proximal tubule.

• The word microalbuminuria is used to qualify the urinary elimination of traces of albumin.

• It can be used for early diagnosis in humans.

• Methods used for human can not be used for cats and dogs.

Semi-quantitative commercial test kits for dogs are available.

• Microalbuminuria was observed in a large proportion of dogs

without any clinical sign of renal disease. However, more studies are required.

▪ Urine Protein Electrophoresis

• Routine use in animals is rare.

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Tubule Damage

▪ Urine Enzyme Activities

• Enzymes found in urine have two sources. Those with a small molecular weight may leak from the glomerulus, many of which are absorbed. The second source is urine leakage due to tubular cell damage. Most originate from the proximal tubule.

• Renal damage causes their excretion into urine to increase, but there are no increases in plasma enzyme activity (except in

severe cases).

• ALP, GGT, LDH, GLDH, NAG

• Increased urine enzyme activities indicate acute kidney damage regardless of the cause (not dysfunction). In many cases, enzyme activities increase before function parameters (sometimes function parameters may not increase).

• Enzyme activities may also increase depending on the secondary causes. Ex. Canine Leishmaniasis and pyometra.

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Tubule Damage

▪ Blood: Hematuria

• It can originate from any part of the kidney or urinary tract.

• It is detected by the color of the urine, ranging from light pink to red in macrohematuria, or more frequently by rou- tine urinalysis for invisible microhematuria.

• The limit of detection of hemoproteins is low, so that occult blood can be detected in the absence of a positive reaction for proteins (peroxidase activity).

• Depending on the sampling technique, blood can be seen in urine (especially in catheterization).

• It can also be detected with a microscope examination.

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Your Questions?

Send to serkan.sayiner@neu.edu.tr

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References

▪ ECLINPATH. http://www.eclinpath.com/chemistry/kidney/cystatin-c/Access Date: 8.5.2018

▪ Dahlem DP, Neiger R, Schweighauser A, et al. (2017). Plasma Symmetric Dimethylarginine Concentration in Dogs with Acute Kidney Injury and Chronic Kidney Disease. Journal of Veterinary Internal Medicine, 31(3):799-804. Doi:10.1111/jvim.14694.

Karagül H, Altıntaş A, Fidancı UR, Sel T, 2000. Klinik Biyokimya. Medisan, Ankara

▪ Kaneko JJ, Harvey JW, Bruss ML, 2008. Clinical Biochemistry of Domestic Animals, 6th edi. Academic Press-Elsevier

▪ Thrall MA, Weiser G, Allison RW, Campbell TW, 2012. Veterinary Hematology and Clinical Biochemistry, 2nd edi. Wiley-Blackwell

▪ Turkish Society of Nephrology. http://www.nefroloji.org.tr/folders/file/bobrek_yetmezligi.pdf Erişim Tarihi: 8.5.2018

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