Kidney Stones

Introduction
Kidney stone disease is an illness associated with formation of crystal concrements in the kidneys, also known as stone kidneys. The spread of disease is increasing and affects approximately 12% of the world’s population. It is more frequent in men than in women at the the age of 20-49 years. The etiology is multifactorial, and the mechanism of stone formation is a complex process involving multiple physico-chemical reactions. The most frequent type of kidney stones is the calcium-oxalate concrements (Alelign 2018).
The prevalence of kidney stone disease, also called urolithiasis, is increasing in the last decades, in both developing countries and developed industrialized societies, and it is well accepted that the cause of this increase is a result of lifestyle changes – lack of physical activity and a shift in the dietary habits. In USA kidney stone disease affects 1 in every 11 individuals and it is estimated that approximately 600 000 Americans experience kidney stones (Alelign 2018).
The prevention of recurrent kidney stones is still a serious problem for human health and requires better understanding of the mechanisms for their formation. Kidney stones are associated with higher risk of chronic renal diseases, renal insufficiency, cardio-vascular diseases, diabetes, hypertension, metabolic syndrome. The prevalence of kidney stone disease and its recurrence is increasing worldwide, while the availability of effective pharmacological therapies is limited. If patients do not use metaphylaxis, the approximate recurrence frequency is 10-23% in 1 year, 50% in 5-10 years, and 75% in 20 years. Therefore, well-designed prophylaxis and metaphylaxis in patients with stones is essential for the management of this disease (Alelign 2018).

BACKGROUND

The Urinary Tract
The urinary tract, also known as the renal system, produces and eliminates urine and maintains the water-electrolytes balance in the human body. The waste products of the metabolisms are filtered to the urine and are eliminated with evacuation of urine (Zimmermann 2018).
The main organs of the urinary tract are the kidneys. Kidneys eliminate urea – a waste substance, formed in the degradation of proteins in blood, through small filtrating units, called nephrons. Urea, together with water and other waste products, form the urine while passing through the nephrons and renal tubules. From the kidneys urine reaches the urine bladder via two fine pipes, called ureters. From the urine bladder urine is eliminated from the body via the process of urination (Zimmermann 2018).

Kidney Stones
Kidney stones are formed when the levels of substances like calcium, oxalate, cysteine or uric acid in urine are high. Stones can also form when levels are within normal ranges, but the daily amount of urine is low. These substances form crystals, which are anchored in the kidneys and slowly grow, forming kidney stones of various size (Preminger 2018).
Kidney stones can contain different crystal and non-crystal materials. Awareness of the kidney stone composition is an important element in taking decisions for their subsequent removal and is an essential part in the selection of the preventive measures against their recurrence. Most frequently, the crystals in the kidney stones are calcium oxalate, calcium phosphate, uric acid end struvite. It is not unusual to have stones containing more than one type of crystal component. Non-crystal materials, found in kidney stones, include proteins and blood (Preminger 2018).

  • Calcium oxalate – the most frequently seen component, present in approximately 70% to 80% of kidney stones. The risk factors for calcium oxalate crystals formation are lower urinary volume, higher excretion of calcium in urine, higher excretion of oxalate and lower excretion of citrate (Curhan 2018).
  • Calcium phosphate – observed in approximately 15% of kidney stones pure or in combination with calcium oxalate or struvite. Calcium phosphate crystals in urine sediment are usually dark and amorphous. The risk factors for calcium phosphate stones are lower urinary volume, higher excretion of calcium in urine, excretion of citrate, higher pH of urine and potentially higher excretion of phosphate (Curhan 2018).
  • Uric acid – the most common crystal form containing urate. Rarely, urate crystals include sodium urate (present in joint liquid of patients with gout) and ammonium urate. Uric acid is present in about 8% of evaluated stones, sometimes in combination with calcium oxalate. The risk factors for the uric acid crystal formation are lower urinary volume, higher excretion of uric acid in urine, and most importantly lower pH of urine. pH of urine is much stronger promotor of uric acid crystal formation, than the amount of urine acid in urine (Curhan 2018).
  • Struvite (infectious stones) are concrements formed only in the presence of urease-producing bacteria (for example, Proteus mirabilis). Struvite is seen in approximately 1% of evaluated stones and much more frequently in women than men (due to the higher risk of urinary tract infections in women) (Curhan 2018).


Causes and Risk Factors
Multiple and various factors increase the risk of kidney stones formation. One of them is the dietary regimen – inadequate fluid intake, calcium-poor diet, use of calcium supplements, diets rich in animal proteins or sugars (saccharose, fructose), high sodium diet, frequent consumption of spinach (Curhan 2018). 
Other medical conditions, leading to kidney stone formation are: primary hyperparathyroidism, gout, diabetes mellitus, obesity, Crohn’s disease (Alelign 2018). Nephrolithiasis risk depends on the composition of urine, which is influenced by diseases and patient habits. Risk factors for calcium oxalate stones include elevated calcium in urine, increased oxalate and decreased citrate in urine, and dietary risk factors like lower intake of calcium, higher intake of oxalate, higher intake of proteins, lower intake of potassium, and lower liquid intake (Preminger 2018).

Oher factor potentially associated with increased risk of stone formation is a history of past nephrolithiasis. Patients with family history of kidney stones have 2-fold increase of the risk of nephrolithiasis (Preminger 2018). The risk increases in individuals with elevated oxalate absorption in the intestine. Less frequent causes are frequent upper urinary tract infections and administration of medications which can form crystals in urine (Preminger 2018).

  • Constantly acidic urine (pH ≤5.5) facilitates sedimentation of uric acid and leads to formation of concrements (Preminger 2018).
  • Struvite stones are formed only in patients with upper urinary tract infections cause by urease-producing microorganisms, like Proteus or Klebsiella. Classic symptoms of nephrolithiasis are uncommon. This diagnosis can be suspected in patients with recurrent urinary tract infections, mild flank pain or hematuria, sustained alkaline pH of urine (> 7.0), frequently magnesium-ammonium phosphate crystals in urine sediment (Preminger 2018).


Kidney stone symptoms
Symptoms of urolithiasis depend on the location of stones – in the kidney, the ureter or the urinary bladder. Initially, stone formation is asymptomatic. Later, nephrolithiasis presents with renal colic, back pain, hematuria (blood in urine), urinary tract infections, hydronephrosis (dilation of the kidneys). These conditions can lead to nausea and vomiting and severe pain (Alelign 2018).

Pain is the most frequent symptom of a kidney stone passing through the urinary tract. Most frequently pain is due to obstruction, preventing urine to flow freely from the kidneys to the urinary bladder. It can vary from mild, barely noticed pain, to severe discomfort requiring in-patient treatment with parenteral analgesics. Usually episodes of pain worsening are followed by episodes of improvement, however pain does not resolve completely. Episodes of severe pain, known as renal colic, usually last for 20-60 minutes. Pain can occur in the flank or the lower abdomen and can march to the groin (Preminger 2018).

The location of obstruction determines the location of pain. It can change with the stone migration. Many patients, familiar with the symptoms, can define when the stone has passed the ureter. Most patients with kidney stones also have blood in urine (hematuria). Urine can be pink or reddish, or blood can be seen only in urinalysis or urine microscopy. Other common symptoms include nausea, vomiting, dysuria, as well as urgency to urinate. The last two symptoms listed usually occur when the stone is located in the distal ureter. Complications – nephrolithiasis can lead to persistent renal insufficiency, resulting in terminal kidney injury, if it is not timely treated (Preminger 2018; Curhan 2018). 


Diagnosis of kidney stones 
Kidney stones are usually diagnosed based on the symptoms, physical examination and maging. Computed tomography and ultrasound are used to reveal kidney stones, although the ultrasound scan can fail to detect small stones or those in the ureters. Ultrasound, though, is referred in individuals who should avoid exposure to radiation, like pregnant women and children (Preminger 2018).
Performing a laboratory analysis of the stone composition after its removal, is an essential part of the adequate diagnosis. The knowledge of the stone type allows for planning specific treatment for prevention of stone recurrence (Preminger 2018).

Conventional treatment of kidney stones 
Approximately 10% to 20% of all kidney stones require surgical removal, and it is determined by the present symptoms, their size and location. Bigger stones and proximal ureteral stones are less likely to pass spontaneously. At the same time, asymptomatic stones, especially those smaller than 5 mm in diameter, do not require specific surgical treatment (Preminger 2018).

There are three minimally invasive surgical techniques mainly used for removal of stones (Preminger 2018):

  • Percutaneous nephrolithotomy (PNL)
  • Rigid and flexible ureteroscopy
  • Shock wave lithotripsy (SWL)

If you have severe pain or nausea, you should take potent pain killers and intravenous (IV) fluids, administered in in-patient setting. Apart from that, kidney stone patients with fever need to be urgently hospitalized to prevent life-threatening infection (Preminger 2018).

Home therapy – You can administer medications to alleviate pain, until the stone passes, but it is important that you consult your doctor first (Preminger 2018).

After the stone is eliminated with urine, you should provide it to your doctor for analysis of its composition (for example, calcium oxalate, uric acid, etc.). Having the composition analyzed, specific treatment can be prescribed and formation of new stones can be prevented (Preminger 2018; Curhan 2018).
Stones larger than 9-10 mm, rarely pass spontaneously and usually require a procedure to disintegrate or remove them. There are small stones, as well, which cannot pass (Preminger 2018; Curhan 2018).
There are several procedures use for the removal:

Ureteroscopy is a common endoscopic procedure, where a fine endoscope is use which passes through the urethra and the urinary bladder to the ureter and the kidney. This endoscope allows the urologist to visualize the stone and to remove it or to fragment it to smaller pieces which pass easier. Ureteroscopy is frequently used for removing stones which block the ureter, and sometimes for small stones in the kidneys (Preminger 2018; Curhan 2018).
Shock wave lithotripsy (SWL) – it uses high frequent sound waves targeted at the kidney stone. These sound waves pass through the skin and body fluids and release energy on the surface of the stone. This energy causes the stone to break up into smaller pieces, which can easily be eliminated with urine (Preminger 2018; Curhan 2018).
Percutaneous nephrolithotomy (PNL) – Particularly big or composite stones, or stones resistant to lithotripsy, may require minimally invasive surgical procedure for their removal. During this procedure a small endoscopic instrument penetrates through the skin on the back and reaches the kidneys, in order to remove the stones (Preminger 2018; Curhan 2018).
Treatment of asymptomatic kidney stones – If you have a kidney stone which does not cause any symptoms, the decision for its removal is based on the size and location of the stone, as well as your access to urgent treatment should symptoms occur. If there is a possibility that you will not receive urgent treatment (for example, if you travel frequently), it is more likely that you will be advised to remove the kidney stone (Preminger 2018; Curhan 2018).


Medical therapy
In more than 95% of kidney stone disease patients, a curable metabolic etiology of stone formation can be identified (Preminger 2018).
The various available therapies can correct the main metabolic defects responsible for stone formation, thus preventing their recurrence. Numerous controlled trials have proven the advantages of (Preminger 2018):

  • High liquids intake for all forms of kidney stone disease
  • Thiazide diuretic in hypercalciuria. These medications reduce the amount of calcium entering the bloodstream. They promote the production of urine, preventing calcium stones.
  • Allopurinol or potassium citrate in hyperuricosuria. This drug inhibits the breakdown of purines to uric acid, lowering the uric acid levels in the urine. Allopurinol is mostly used to prevent uric acid stones.
  • Potassium citrate in hypocitraturia and potassium citrate in urate stones due to persistent acidic urine. This lowers the acidity of the urine, improving its ability to dissolve salts. Potassium citrate  is used to prevent calcium stones, uric acid stones and cystine stones (www.ncbi.nlm.nih.gov).

Although it prevents recurrent formation of kidney stones, conventional therapy does not dissolve already formed calcium stones, but can facilitate their expulsion (Preminger 2018).

Facilitation of stone expulsion – the probability for a stone to pass the ureter spontaneously, is associated with both its size and location. Majority of the stones of ≤ 4 mm in diameter pass spontaneously (Preminger 2018).

Kidney stone prevention
After the renal colic related to stone passing is resolved, blood and urine tests should be done to determine whether there are health problems or dietary habits, which increase the risk of stone formation (Preminger 2018; Curhan 2018).

The stone should be preserved and its type analyzed. The physician can also request a 24-hour urine collection (the whole amount of urine which you produce for 24 hours), in order to determine the presence of main risk factors for kidney stones (Preminger 2018; Curhan 2018).

Based on the results of the assessment. The physician may recommend you to drink more liquids, in order to decrease the risk of stone recurrence. The aim is to increase the amount of urine which flows through the kidneys, as well as to decrease the concentration of substances, which favor stone formation (Preminger 2018; Curhan 2018).

Experts recommend drinking enough fluid that you make more than 2 liters of urine per day. You may need to change your diet; the recommended changes will depend on the type of the kidney stone you have and the results of the 24-hour urine analysis. You may also be advised to take medications to decrease the risk of stone formation in the future (Preminger 2018; Curhan 2018).

Natural substances with significant clinical data for the management of Kidney Stone Disease.
Some natural ingredients have significant amount of scientific data, demonstrating beneficial effects in preventing kidney stone formation and concrement expulsion:

Birch leaves extract (Betula pendula) possesses rich chemical composition, including flavonoids, terpenes and tannins which are important in the treatment of kidney stone disease. (EMA/HMPC/573240/2014). The flavonoid hyperoside in the content of the birch leaves extract has a marked diuretic effect. Potassium nitrate in the standardized extract potentiates the diuretic activity of flavonoids (Akiyama 1987). Flavonoids exert their anti-inflammatory activity by suppressing mast cell degranulation and thus inhibiting histamine release (Weng 2012; Akiyama 1987). The flavonoid quercetin suppresses the release of leukotrienes and other precursors of prostaglandins, which are important elements of the inflammatory process (Weng 2012). It has a pronounced spasmolytic activity on the smooth muscle relaxation (Doc. Ref. EMEA/HMPC/285759/2007). Birch leaves are a rich source of flavonoids, including quercetin.. (Costea 2015). Flavonoids in the content of the standardized birch leaves extract showed in vitro activity against a broad spectrum of microorganisms. They have a proven antibacterial and uroantiseptic activity – through the inhibition of receptors (tyrosine-kinase) in the bacterial cells which are responsible for important cellular processes (Cos 1997; Nagao 1999; Akiyama 1987). Terpenes are contained in plant essential oils (Kumari, 2014). They also exhibit moderate spasmolytic activity. Terpenes have lipophilic structure which allows them to destroy the cell membrane of several bacterial species. This property is the base for their antibacterial activity (Zengin 2014). Antibacterial activity of tannins is due to building strong hydrogen bonds with specific receptors on the cell wall surface different microorganisms. Tannins also exert anti-inflammatory action by stimulating phagocytosis and cell mediated immunity. Other well-known feature of tannins is the astringent action over the tissues along the urinary tract (Haslam 1996).

Elymus repens (Agropyron repens) contains 3-8% triticin (a compound similar to inulin). It also contains 3-4% fructose, and 2-3% sugar alcohols (mannitol, inositol), (Assessment report on Agropyron repens 2011). The BAS in the composition of Elymus repens have soothing diuretic effect (Al-Snafi 2015). Triticin from Elymus repens has a demulcent diuretic effect (Plitt 1928). The beneficial effect of producing a lubricant film over the urinary tract lining is due to the polysaccharide triticin. It is excreted in urine unchanged, it is not re-absorbed by the urinary tract mucosa and forms jelly-like film over the epithelium of ureters. This is particularly useful in cases of kidney stones, because it decreases the friction between the stone and the uroepithelium and favors its passing. In addition, the jelly-like film on the urinary tract lining acts as a mechanical barrier between the stone and the underlying tissue and decreases the irritation of nerve endings in the ureter, and as a result decreases the pain. Mannitol in the composition of the Elymus repens extract possesses diuretic effect exerted by increasing the osmolarity of kidney filtrate, which increases the urine volume (Al-Snafi 2015).

Herniaria glabra. The extract from Herniaria glabra has a pronounced diuretic effect and increases diuresis with over 50% by intensifying glomerular filtration. It also possesses the ability to reduce calcium oxalate crystalluria (Gaybullaev 2012). The extract from Herniaria glabra showed antilythogenic activity against calcium oxalate stones both in vitro and in vivo (Atmani 2000). Triterpene saponins in the composition of the extract from Herniaria negatively influence the risk factors for calcium oxalate lithiasis. They decrease the concentration of uric acid. Saponins decrease the size of oxalates and their ability to aggregate into larger crystals. The extract from Herniaria glabra increases the number of calcium oxalates stones, but reduces their size in kidneys in vivo (Atmani 2003). It also possesses antibacterial activity against E. coli (Wojnicz 2012).

Viburnum opulus. Viburnin – increases renal blood circulation and filtration rate. It also possesses moderate spasmolytic activity. Reduces the size of oxalates and their affinity to aggregate, which prevents formation of larger stones. In this way, the extract from Viburnum exerts its antilythogenic effect against calcium oxalate stones in vivo (Ilhan 2014). The extract from Viburnum opulus also possesses diuretic effect (Shikov 2014). The coumarin scopoletin and the glycoside viopudial have spasmolytic effect on smooth muscles. They interact with M-choline receptors on smooth muscles and cause their relaxation. Apart from this, scopoletin reduces the capillary permeability thus, along with the diuretic action of viburnin, exerts antiedematous activity and improves kidney drainage (Jarbo 1967; Nicholson 1972).

HIGHLIGHTS

Treatment of kidney stones varies depending on their type and the cause for their formation.

Majority of small kidney stones do not require invasive treatment. In these cases you may (www.mayoclinic.org):

  • Drink more water, the recommendation is about 2-3 liters a day, which will help to eliminate the small stones from kidneys.
  • Take analgesics. The passing of a small stone may cause some discomfort. To alleviate mild pain, your doctor may prescribe analgesics like ibuprofen, acetaminophen, etc.
  • Your doctor may prescribe a medication, which may help the stone to pass the urinary tract.

Kidney stones which cannot be treated conservatively, because they are too large to pass spontaneously, or cause bleeding, kidney injury or continuous urinary tract infections, may require other interventional treatment, like (www.mayoclinic.org):

  • Utilization of sound waves to break up the stone – lithotripsy (extracorporeal shock wave lithotripsy [ЕSWL])
  • Surgery for removal of particularly large kidney stones.
  • Ureteroscopy

Change of lifestyle for reducing the risk of kidney stone formation (www.mayoclinic.org):

  • Drink water throughout the day. Individuals with kidney stone history physicians usually recommend that urine volume be about 2.5 liters a day.
  • Consume less amounts of oxalate-rich food. If you are predisposed to forming calcium oxalate stones, your doctor may recommend to limit foods rich of oxalate.
  • Choose low salt and low animal protein diet. Reduce the amount of salt in your menu.


There are mediations which can control the concentration of minerals and salts in the urine and can be beneficial for individuals prone to forming specific types of stones (www.mayoclinic.org).

  • Calcium stones. To prevent formation of calium stones, your doctor may prescribe a thiazide diuretic or a compound containing phosphate (www.mayoclinic.org).
  • Urate stones. Your doctor may prescribe allopurinol, in order to reduce uric acid level in your blood and urine and a medication for maintaining alkaline urine (www.mayoclinic.org).
  • Struvite stones. In order to prevent subsequent formation of struvite stones, your doctor may recommend strategies for clearing your urine from bacteria which cause infections (www.mayoclinic.org).
  • Cystine stones. Cystine stones may be difficult to treat. Your doctor may recommend you to drink more liquids, in order to increase the volume of your urine (www.mayoclinic.org).


There is significant amount of scientific data for some natural substances demonstrating beneficial effects in preventing kidney stone formation and concernment expulsion. 
These are biologically active substances in the composition of plant extracts which can influence the formation, symptomatology and elimination of kidney stones. 
Some of the ingredients of these extracts play a role in the prevention of recurrent stone formation. 

In general, the activity of biologically active compounds in the extracts from Birch leaves, Herniaria glabra and Viburnum opulus and their effects in the treatment of kidneys tone disease can be summaried in the following main points:

  • A part of the BAS in the mentioned extracts facilitate the elimination of kidney stones
  • Due to their biolubricating action, diuretic and spasmolytic effect, the pharmacologically active ingredients of these extracts decrease the mechanical friction between the concrement and the tissues, increase the ureter lumen and facilitate stone expulsion with urination.
  • Antibacterial and uroantiseptic properties of the listed extracts protect the urinary tract from the development of a secondary infection.
  • Antilythogenic activity, resulting from the diuretic effect of mainly flavonoids and mannitol in the extracts, is re-enforced by the effects of vibunin, scopoletin and agropyrene in the composition of these plants.
  • The listed BAS possess various properties, which are relevant to the treatment of kidney stone disease.
  • These extracts have proven efficacy in decreasing the concentration of stone-forming compounds in urine by increasing the diuresis. For this reason they also prevent from formation of new stones, enlargement in size of existing ones and subsequent renal colic. 

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