Kidney stones

Abstract

Kidney stones are mineral deposits in the renal calyces and pelvis that are found free or attached to the renal papillae. They contain crystalline and organic components and are formed when the urine becomes supersaturated with respect to a mineral. Calcium oxalate is the main constituent of most stones, many of which form on a foundation of calcium phosphate called Randall's plaques, which are present on the renal papillary surface. Stone formation is highly prevalent, with rates of up to 14.8% and increasing, and a recurrence rate of up to 50% within the first 5 years of the initial stone episode. Obesity, diabetes, hypertension and metabolic syndrome are considered risk factors for stone formation, which, in turn, can lead to hypertension, chronic kidney disease and end-stage renal disease. Management of symptomatic kidney stones has evolved from open surgical lithotomy to minimally invasive endourological treatments leading to a reduction in patient morbidity, improved stone-free rates and better quality of life. Prevention of recurrence requires behavioural and nutritional interventions, as well as pharmacological treatments that are specific for the type of stone. There is a great need for recurrence prevention that requires a better understanding of the mechanisms involved in stone formation to facilitate the development of more-effective drugs.

Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1. Macroscopic and microscopic morphology of human kidneys and location of stones

a | According to the fixed-particle mechanism, stones begin as depositions of calcium phosphate (CaP) in the interstitium (apatite), grow outwards reaching the renal papillary surface, become exposed to the pelvic urine and establish a nucleus for the deposition of calcium oxalate (CaOx), leading to the formation of CaOx stones attached to a CaP base, known as Randall’s plaques. b | By contrast, in the free-particle mechanism, for example, CaP, uric acid or cystine crystals form in the renal tubules, move with the urine, aggregate and plug the terminal collecting ducts. These plugs, called Randall’s plugs or lesions, are exposed to the pelvic urine. Deposition of CaOx crystals on the CaP plugs leads to the formation of CaOx kidney stones.

Figure 2. Calcium oxalate kidney stones examined using scanning electron microscopy

a | A low magnification image showing the outer nodular appearance of a calcium oxalate (CaOx) monohydrate stone. b | The fractured surface showing CaOx monohydrate crystals organized in concentric laminations and radial striations. c | The surface of a stone with an outer layer of CaOx dihydrate crystals. Bipyramidal CaOx dihydrate crystals protruding on the surface are shown (arrows) and are powdered with tiny calcium phosphate crystals. d | The surface of a CaOx monohydrate stone. The tabular morphology of CaOx monohydrate crystals is clearly visible.

Figure 3. Scanning electron microscopy and transmission electron microscopy of kidney stones

These images demonstrate the ubiquitous nature of the organic matrix, and its intimate association with the crystalline components of the stone. Stone fragments were demineralized and then processed for electron microscopy. The stone and crystals maintained their architecture even after the removal of the crystalline components. a | A scanning electron microscopy image of the organic matrix of calcium oxalate (CaOx) dihydrate crystals in a CaOx stone. The organic matrix is organized in layers, but the overall bipyramidal architecture of the CaOx dihydrate crystal is maintained even after demineralization. b | The fractured surface of CaOx monohydrate crystal ‘ghosts’ showing internal spaces (arrows) created by a loss of plate-like CaOx monohydrate crystals. c | A transmission electron microscopy image of the organic matrix, showing at least two layers of radially organized CaOx monohydrate crystal ghosts. d | A higher magnification of the CaOx monohydrate crystal ghosts from part c stained with antibodies against osteopontin (black dots), demonstrating its substantial presence in the matrix.

Figure 4. The renal interstitium of a calcium oxalate stone former with Randall’s plaque

a | The tubular epithelium is separated from the interstitium by the basement membrane. The interstitium contains collagen fibres, spherulitic calcium phosphate (SCaP) reminiscent of membrane-bound vesicles with crystals, as well as dense and compacted calcium phosphate (CaP) crystals. There is a close association between collagen and dense CaP. b | A portion of the image in part a, but at a higher magnification. Collagen fibres are intimately associated with dense deposits of CaP.

Figure 5. The renal papillary surface of a calcium oxalate monohydrate stone former examined using scanning electron microscopy

a | A crystalline entity is protruding through the papillary surface, causing epithelial cells to be pushed apart (arrow). The protrusion is covered with fibrous material and surrounded by a layer of crystalline shell. b | Fibrous material covering the protrusion. c | An intact portion of the papillary surface epithelium.

Figure 6. Randall’s plaque and calcium oxalate stone formation

On the basis of experimental and available clinical data, one can surmise that stone formation is a multistep process, probably involving the formation of Randall’s plugs and plaques. For simplicity, we have separated out these steps, but a combination of factors probably contributes to stone formation and growth. a | In Randall’s plaque formation, supersaturation of tubular fluid with respect to calcium phosphate (CaP) and/or calcium oxalate (CaOx) occurs in renal tubules at the end of the loop of Henle and at the beginning of the colleting duct system (step 1). From here, two alternate pathways have been suggested. Supersaturation with respect to CaP leads to the deposition of CaP in the basement membrane of the loop of Henle (step 2), initiating the process of plaque formation (FIG. 1). Alternatively, crystal formation occurs in the renal tubules (step 3). CaP crystals translocate into the interstitium (step 4) or are internalized by the cells, dissolved and re-precipitated in the tubular basement membrane. Another possibility is that renal epithelial cells, when exposed to CaP and/or CaOx, produce reactive oxygen species and, probably, a range of factors associated with osteogenesis, such as Runt-related transcription factor 2 (RUNX2), osterix (also known as Sp7), bone morphogenetic protein 2 (BMP2), BMP7, BMP receptor type 2 (BMPR2), collagen and osteopontin. Epithelial cells produce matrix vesicles on the basal side (step 5) followed by their calcification (step 6; REFS 88,168). b | Once CaP crystals have been deposited in the basement membrane of the loop of Henle and/or collecting ducts, mineralization continues. Collagen fibres and membranous vesicles become calcified (step 1). The mineralization front reaches the renal papillary surface and a subepithelial plaque is established (step 2). The papillary surface epithelium is disrupted (step 3) and plaques rupture, exposing the CaP crystals to the pelvic urine metastable with respect to CaOx (step 4). Urinary macromolecules are deposited over the exposed CaP crystals, promoting the deposition of CaOx crystals on the CaP base (step 5).

Figure 7. Algorithm for the most common approaches to surgical treatment of kidney stones

The decision of which surgical strategy to use is dictated by the location of the stone (with lower-pole stones being more difficult to treat), stone size and stone density.

Figure 8. Potential methods to interfere with abnormal crystallization and stone formation

Oxidative stress in the proximal tubules might induce lipid peroxidation and damage to the brush border membrane at this level of the nephron. Released membrane fragments and vesicles containing phospholipids are considered important as promoters for both calcium phosphate (CaP) and calcium oxalate (CaOx) precipitation at supersaturation levels lower than those otherwise required for crystallization. Precipitation of CaOx higher in the nephron is only expected when very high concentrations of oxalate are available. Dilution of the urine at all levels of the nephron is most certainly associated with a reduced risk of intratubular, as well as interstitial, precipitation of CaP and CaOx. *Indicates that precipitation of CaOx at high nephron levels only occurs when very high concentrations of oxalate are available. AP, ion-activity product.