Kidney function tests

The Zimnitsky Test

The Zimnitsky test is a classic, though less commonly used today, functional kidney test designed specifically to assess the kidney's ability to concentrate and dilute urine over a 24-hour period under normal living conditions.

Procedure

The test involves collecting urine in separate containers at specific time intervals over a full 24-hour cycle, typically every three hours (8 portions). The patient follows their normal diet and fluid intake routine (no specific water loading or restriction is imposed).

For each collected urine portion, the laboratory measures:

• Volume
• Relative density (Specific Gravity)

Sometimes, total solute excretion (like sodium chloride and urea) might be measured in pooled daytime and nighttime samples, but the core of the test focuses on volume and specific gravity fluctuations.

The total urine volume excreted over 24 hours is compared to the patient's recorded fluid intake during that period.

Interpretation

Normal kidney function is indicated by:

• Volume Variation: Significant fluctuation in the volume of individual urine portions throughout the day.
• Specific Gravity Variation: Wide fluctuation in specific gravity between different portions, demonstrating the ability to both concentrate and dilute. Typically ranges might span from below 1.005 (dilute) to above 1.020-1.025 (concentrated) in at least one sample.
• Day/Night Ratio: Daytime urine volume should significantly exceed nighttime volume (typically a ratio of 3:1 or 4:1).
• Concentration Ability: At least one sample should show good concentration (e.g., SG ≥ 1.018 or 1.020).
• Dilution Ability: At least one sample should show good dilution (e.g., SG ≤ 1.004 or 1.005).
• Total Volume: Total 24-hour urine output should appropriately reflect fluid intake (e.g., roughly 65-80% of intake).
• SG Range Difference: The difference between the highest and lowest specific gravity measured should be significant (e.g., ≥ 0.007 or often cited as ≥ 0.012-0.016).

Pathological findings suggestive of impaired renal concentrating/diluting ability include:

• Isosthenuria: Fixation of specific gravity in a narrow range, typically around 1.007–1.012 (similar to glomerular filtrate), indicating loss of both concentrating and diluting ability. Characteristic of advanced chronic kidney disease.
• Hyposthenuria: Persistently low specific gravity (< 1.010), indicating impaired concentrating ability (seen in diabetes insipidus, chronic pyelonephritis, early chronic renal failure).
• Nocturia: Predominance of nighttime urine volume over daytime volume, often an early sign of impaired concentrating ability or conditions like heart failure or BPH.
• Monotonous Volume/Density: Lack of significant variation in volume or specific gravity between portions.
• Polyuria: Consistently large volumes in each portion or overall (if not due to high intake).

While informative, the Zimnitsky test is cumbersome due to the multiple collections and has largely been replaced by simpler assessments like measuring specific gravity or osmolality on a first morning urine sample (for concentration) or after water loading (for dilution), and by GFR estimation.

Renal Clearance Concept

Renal clearance methods provide a more quantitative assessment of specific kidney functions, particularly glomerular filtration. Renal clearance of a substance represents the theoretical volume of plasma (or blood) from which that substance is completely removed (cleared) by the kidneys per unit of time (usually measured in ml/min).

Types of Renal Clearance

Depending on how the kidneys handle a substance, its clearance reflects different aspects of renal function:

1. Filtration Clearance: Measured using substances that are freely filtered by the glomeruli but are neither reabsorbed nor secreted by the tubules (e.g., inulin - the gold standard, or approximately, endogenous creatinine). This clearance value directly measures or estimates the Glomerular Filtration Rate (GFR).
2. Excretion Clearance (Renal Plasma Flow): Measured using substances that are both freely filtered and almost completely secreted by the tubules from the blood that *doesn't* get filtered (e.g., para-aminohippurate - PAH). This clearance approximates the Renal Plasma Flow (RPF).
3. Reabsorption Clearance: Substances freely filtered but then completely reabsorbed by the tubules (e.g., glucose under normal blood levels, most proteins). Their clearance is normally zero. When blood levels exceed the tubular reabsorptive capacity (Tm), the substance appears in the urine, and its clearance can be measured to assess maximal tubular reabsorption capacity.
4. Mixed Clearance: Substances that are filtered and then partially reabsorbed and/or partially secreted (e.g., urea). Their clearance reflects a combination of these processes and is less straightforward to interpret than pure filtration or excretion clearance.

Clearance Calculation

The standard formula to calculate the renal clearance (C) of a substance is:

C (ml/min) = [U × V] / P

Where:

• U = Concentration of the substance in urine (e.g., mg/ml or mg/dL)
• V = Urine flow rate (volume of urine produced per minute, ml/min) - calculated from a timed urine collection (e.g., 24-hour volume divided by 1440 minutes)
• P = Concentration of the substance in plasma (or serum) (in the same units as U, e.g., mg/ml or mg/dL)

Clearance values are influenced by age, sex, body size, and the extent of kidney damage.

Common Markers for Kidney Function

While various substances can be used for clearance studies, the most commonly measured endogenous markers in clinical practice to assess renal function (specifically GFR) are creatinine and, to a lesser extent, urea (BUN).

• Creatinine: Produced from muscle metabolism at a relatively constant rate, primarily cleared by glomerular filtration with some tubular secretion. Serum creatinine levels rise as GFR falls. Creatinine clearance approximates GFR but slightly overestimates it due to secretion, especially when GFR is low. eGFR formulas based on serum creatinine are widely used.
• Urea (BUN): End product of protein metabolism, cleared by filtration and significant tubular reabsorption (influenced by hydration). Serum BUN levels increase with decreased GFR but are also heavily influenced by protein intake, hydration status, and liver function, making it a less specific marker of GFR than creatinine alone.

Elevated serum creatinine and urea (BUN) levels are hallmarks of renal dysfunction and are key indicators of renal failure. Creatinine typically rises earlier and is considered a more reliable marker of GFR changes than urea.

References

1. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). (n.d.). The Kidneys and How They Work. NIH. Retrieved from https://www.niddk.nih.gov/health-information/kidney-disease/kidneys-how-they-work
2. Hall, J. E., & Guyton, A. C. (2020). *Guyton and Hall Textbook of Medical Physiology* (14th ed.). Elsevier. (Chapters on Renal Physiology and Urine Formation).
3. Rose, B. D., & Post, T. W. (2001). *Clinical Physiology of Acid-Base and Electrolyte Disorders* (5th ed.). McGraw-Hill. (Chapter on Renal Regulation of Water Balance).
4. Lamb, E. J., Jones, G. R. D., & Davison, A. M. (Eds.). (2010). *Clinical Biochemistry and Metabolic Medicine* (8th ed.). Hodder Arnold. (Chapter on Renal Function).
5. McPherson, R. A., & Pincus, M. R. (Eds.). (2017). *Henry's Clinical Diagnosis and Management by Laboratory Methods* (23rd ed.). Elsevier. (Chapter on Renal Function and Urinalysis).