What is the pathophysiology of nephrolithiasis?

Pathophysiology of Nephrolithiasis

Core Mechanism

Nephrolithiasis occurs when kidney stones form from crystals precipitating from urine within the urinary tract, driven by an imbalance between high urinary concentrations of crystal-forming substances and low concentrations of substances that inhibit stone formation. 1

Multi-Step Formation Process

Stone formation is a complex, multi-step process involving several sequential events 2, 3:

• Supersaturation is the essential first step, where urine becomes oversaturated with stone-forming salts, though supersaturation alone does not guarantee stone formation 2
• Nucleation occurs when crystal-forming substances reach critical concentrations and begin to aggregate into microscopic crystals 2, 3
• Crystal growth follows as additional ions deposit onto existing crystal nuclei, enlarging the crystalline structure 2, 4
• Crystal aggregation involves multiple crystals clumping together to form larger masses that are more likely to be retained 2, 3
• Crystal retention is the final critical step where crystals adhere to renal tubular epithelium or become trapped, allowing continued growth into clinically significant stones 2, 3

All these processes must occur within the short urinary transit time through the kidney, which is only a few minutes 3

Anatomical Origins of Calcareous Stones

Calcium-containing stones, which represent approximately 80% of all kidney stones, originate from two distinct anatomical locations 1, 5:

• Interstitial subepithelial calcified plaques (Randall's plaques) form in the renal interstitium and eventually erode through the epithelium to contact urine in the renal pelvis, serving as a nidus for stone growth 5
• Calcified blockages in the openings of collecting ducts can also serve as initial sites for crystal deposition and subsequent stone formation 5

Stone Composition

The predominant stone types reflect different pathophysiologic mechanisms 1:

• Calcium oxalate and calcium phosphate comprise approximately 80% of stones in adults, forming when urinary calcium and oxalate or phosphate concentrations exceed solubility thresholds 1
• Struvite stones form in the presence of urease-producing bacteria that alkalinize urine 1
• Uric acid stones develop when urine pH is low and uric acid concentrations are elevated 1
• Cystine stones occur in patients with genetic defects in cystine reabsorption 1

Promoters of Stone Formation

Multiple urinary factors actively promote crystallization and stone formation 2, 4:

• Low urine volume concentrates all stone-forming substances, increasing supersaturation 2
• High urinary calcium increases calcium salt supersaturation and is the hallmark of idiopathic hypercalciuria, the most common metabolic abnormality in calcium stone formers 2, 4
• High urinary oxalate dramatically increases calcium oxalate supersaturation, as oxalate has a more potent effect than calcium on supersaturation 2
• High urinary uric acid can promote calcium oxalate crystallization through heterogeneous nucleation 2
• High urinary sodium increases calcium excretion by reducing proximal tubular calcium reabsorption 1
• Low urine pH promotes uric acid stone formation by reducing uric acid solubility 2

Inhibitors of Stone Formation

The body produces multiple substances that inhibit various steps of stone formation 2, 3:

• Citrate is the most important urinary inhibitor, chelating calcium to reduce supersaturation and directly inhibiting crystal nucleation and growth 2, 4
• Magnesium complexes with oxalate, reducing calcium oxalate supersaturation 2
• Nephrocalcin is an organic macromolecule that inhibits calcium oxalate crystal aggregation 2
• Urinary prothrombin fragment-1 inhibits calcium oxalate crystallization 2
• Osteopontin modulates crystal-cell interactions and inhibits crystal growth 2

Critical Pathophysiologic Insight

Supersaturation alone does not explain stone formation, as normal individuals regularly have urine supersaturated with respect to calcium oxalate without forming stones. 6 This indicates that the balance between promoters and inhibitors, along with anatomical factors affecting crystal retention, determines whether clinically significant stones develop 2, 6

Genetic and Environmental Interaction

Stone formation results from an interaction between genetic predisposition and environmental exposures, with a lifetime prevalence of 13% for men and 7% for women 1 The 5-year recurrence rate after an initial stone event is 35% to 50% without treatment, reflecting the chronic nature of the underlying pathophysiologic abnormalities 1

Role of Oxidative Stress and Inflammation

Both pathways of stone formation (interstitial and tubular) share common mechanisms 5:

• Oxidative stress damages tubular epithelial cells, promoting crystal adhesion 5
• Inflammatory processes alter the local environment to favor crystallization and retention 5
• Imbalance between inhibitors and promoters shifts the equilibrium toward stone formation 5