Physiology of Renal Calculi (Nephrolithiasis)

Overview

1. Stone Composition and Frequency

2. Core Physiological Mechanism: Supersaturation

• Supersaturation creates a thermodynamic driving force for crystal nucleation and growth.
• The calculated supersaturation value does not perfectly predict stone formation because crystallization inhibitors in normal urine prevent stone formation in most people.
• Supersaturation depends on urinary concentrations of the relevant ions, urine pH, ionic strength, and the concentrations of complexing agents.

3. Randall's Plaque - The Initiation Site

• Calcium phosphate deposits in the renal interstitium (at the thin limb of the loop of Henle) extend down to the papilla and erode through the papillary epithelium.
• This exposed calcium phosphate deposit at the tip of the renal papilla is called Randall's plaque, and it serves as a nidus for calcium oxalate and calcium phosphate crystal deposition.
• Most calcium oxalate stones grow on Randall's plaque.
• Tubular plugs of calcium phosphate may initiate calcium phosphate stone development separately.
• Stone formation may therefore begin years before a clinically detectable stone is identified. - Harrison's, p. 2492

4. Types of Stones - Specific Physiology

A. Calcium Oxalate Stones (most common)

• Absorptive hypercalciuria: Increased intestinal calcium absorption (often linked to excess 1,25-dihydroxyvitamin D or altered calcium-sensing receptor [CaSR] function). The CaSR in the kidney responds to elevated ionized calcium and reduces tubular calcium reabsorption in the thick ascending limb (TAL) and distal convoluted tubule (DCT).
• Resorptive hypercalciuria: Enhanced calcium mobilization from bone - most commonly from primary hyperparathyroidism (stones in 2-8% of PHPT patients). PTH increases skeletal calcium release and renal 1,25(OH)2D synthesis, amplifying intestinal absorption.
• Renal leak hypercalciuria: Defective tubular reabsorption of calcium, leading to secondary hyperparathyroidism and bone resorption. Tight junction proteins of the claudin family (claudin-16, claudin-19) regulate paracellular Ca²⁺ reabsorption in the TAL; mutations or dysregulation impair this. - Brenner & Rector's Kidney

• Urinary oxalate derives from both endogenous production (liver) and dietary absorption.
• Oxalate is a stronger lithogenic risk factor than urinary calcium, gram for gram.
• Low dietary calcium paradoxically increases oxalate absorption (less calcium in the gut to bind oxalate), explaining why low-calcium diets increase stone risk.
• High-dose Vitamin C supplements increase urinary oxalate (ascorbate is metabolized to oxalate).

• Citrate is the most important inhibitor of calcium stone formation.
• It complexes with calcium in urine, reducing free ionic calcium available for crystallization.
• It also directly inhibits calcium oxalate and calcium phosphate crystal growth and aggregation.
• Low citrate is caused by: metabolic acidosis, hypokalemia, chronic diarrhea, renal tubular acidosis (distal RTA), high animal protein intake.

B. Calcium Phosphate Stones

• Form when urine is persistently alkaline (high pH) combined with hypercalciuria.
• Classic setting: distal renal tubular acidosis (dRTA) - the distal tubule fails to acidify urine, leading to persistently alkaline urine, hypocitraturia, and hypercalciuria simultaneously.
• Also associated with primary hyperparathyroidism.

C. Uric Acid Stones (~8%)

• Uric acid is the end product of purine metabolism (xanthine oxidase pathway).
• The pKa of uric acid is 5.5 - at pH below 5.5, uric acid is mostly undissociated and insoluble.
• Low urine pH (persistently acidic urine) is the single most important risk factor, more so than hyperuricosuria.
• Causes: insulin resistance/metabolic syndrome (defective ammoniagenesis leads to acid urine), gout, high purine intake, high animal protein.
• Uric acid stones are radiolucent on plain X-ray (unlike calcium stones).

D. Struvite Stones (Magnesium Ammonium Phosphate)

• Form in the presence of urease-producing bacteria (Proteus, Klebsiella, Pseudomonas).
• Urease splits urea into NH₃ + CO₂, raising urinary pH and increasing ammonium and carbonate concentrations.
• Alkaline urine + high ammonia supersaturates struvite.
• These are "infection stones" and can grow rapidly into staghorn calculi filling the renal pelvis.

E. Cystine Stones

• Result from an autosomal recessive defect in the SLC3A1 or SLC7A9 gene - the dibasic amino acid transporter in the proximal tubule.
• Impaired reabsorption of cystine, ornithine, lysine, arginine (COLA) in the proximal tubule.
• Cystine has very low solubility, particularly at acidic pH.
• Stone formation requires urinary cystine excretion typically >250 mg/g creatinine.

5. Key Protective Factors Against Stone Formation

6. Dietary Physiological Relationships (Summary)

• Harrison's Principles of Internal Medicine 22E, Chapter 330

Quick-Reference Summary

Supersaturation → Nucleation → Crystal growth → Aggregation → Stone
                    ↑                                     ↓
              Randall's plaque                    Inhibitors prevent this
              (CaPO₄ in papilla)                (citrate, TH protein, Mg)