WHAT CAUSES KIDNEY STONES (I)?

Kidney stone disease or nephrolithiasis (Nlith) is a commonly seen one. A study based upon the NHANES reported that 19 % of males & 9 % of females can

 

WHAT CAUSES KIDNEY STONES

 

 

 

List of abbreviations:

o   AB: Antibiotics.

o   ADH: antidiuretic hormone

o   ALK: alkaline phosphatase

o   Ca^+: Calcium

o   CAI: carbonic anhydrase inhibitors

o   DASH: Dietary Approaches to Stop HT.

o   FA: Fatty acids

o   FH: Family history 

o   GIT: Gastrointestinal tract

o   Hpara: hyperparathyroidism

o   K⁺: Potassium.

o   KCl: Potassium chloride

o   Mg⁺: Magnesium

o   Na⁺: Sodium

o   NaPi-IIa: Sodium-dependent phosphate transporter 2A

o   NaPi-IIa: Sodium-dependent phosphate transporter 2A

o   NC: nephrocalcinosis

o   NHANES: The National Health and Nutrition Examination Survey.

o   Nlith: Nephrolithiasis

o   Nlth: Nehrolithiasis = Kidney stone disease

o   Ox : Oxalate

o   PO⁴: Phosphate.

o   RTA: Renal tubular acidosis

o   UTI: Urinary tract infection

o   + ve: Positive

o   -ve: Negative

o   Vit.: Vitamin

Kidney stone disease or nephrolithiasis (Nlith) is a commonly seen one. A study based upon the NHANES reported that 19 % of males & 9 % of females can be observed with a kidney stone by the age of 70 ys. Another report showed that the prevalence elevated from 3.8 % in 1976-1980 to 5.2 % in 1988-1994. Prevalent stone disease increased in both sexes, in white & black ptns. The 2007-2010 NHANES data reported continued rise in prevalence to 8.8 % in US. Factors that may be implicated in rise in stone prevalence include increase in obesity, raised temperature, and progress in diagnostic technique applications:

1)    Age: Prevalence of having a stone increased with age. According to NHANES reports 2007-2016, prevalence = 5.1 % in males aged 20-39 ys, as compared to 19.7 % in males aged 80 ys & older. Moreover, prevalence was 5.8 % in female aged 20-39 y, as compared to 10.6 % in females aged 80 ys & older. Among males, incidence of kidney stone is about 2/1000/y below 40 ys, raised to about 4/1000/y in 40-60 ys of age, and then lowered with age. Among ladies, incidence is about 2/1000/y < 40 ys & declined with age to 1.5/1000/y. However, even an 80-y-old male or females may be seen with 1^st stone.

What is the impact of sex on kidney stones prevalence?

2)    Sex: Although the prevalence of a history of Nlith is similar among males & females < 40 ys, overall prevalence of stone disease is about twice as high in males in comparison to females. Incidence are also similar in males & femaes < 40 ys, but > 40 ys rates are higher in males than in ladies.

3)    Race/ethnicity: Stone disease is most commonly observed in non-Hispanic white ptns, followed by Hispanic white ptns, and is least commonly reported in black & Asian ptns.

4)    Geography: In the US, a north-south gradient as well as west-east gradient can be observed with the highest prevalence of stone disease in the southeastern US. Reason is uncertain.

5)    Stone composition: frequency of composition in adults is as follows:

o   Ca⁺ oxalate: 70-80 %

o   Ca⁺ phosphate: 15 %

o   Uric acid: 8 %

o   Cystine: 1-2 %

o   Struvite: 1 %

o   Miscellaneous: <1 %

Stone recurrence: Although how commonly Nlith is, high-quality & general data concerning stone recurrence rate still scarce. Rate of stone recurrence = 10-30 % at 3-5 ys in idiopathic Ca⁺ Ox stones. A higher rate of = 15 % at 1 y, 35-40 % at 5 ys, and 50 % at 10 ys was observed in another report and was higher in males than females. This variability may be attributed to difference in sensitivity of the imaging tools. Overall stone recurrence rate relied on factors e.g., prior stone history (including composition) & type of ttt.

Part I. MODIFIABLE RISK FACTORS

CALCIUM OXALATE STONE

URIC ACID STONE

I. Urinary factors: Certain biochemical alterations of urine contents have been related to kidney stone formation. Definition of "abnormal" may differ from study to another. Correction of biochemical alterations may help preventing recurrence of stone formation. Ca⁺ PO⁴ & Ca⁺ Ox may share other risk factors e.g., (1) low urine volume, (2) high urine Ca⁺, & (3) low urine Ctr. However, many definite risk factors for each type of stone, e.g., higher urine Ox is a risk factor for Ca⁺ Ox stone, while high urine pH is a risk factor for Ca⁺ PO⁴ stone. Low urine volume & its lower pH are risk factors for UA stone. As approach to stone prevention is primarily relied upon stone composition, it is crucial that any attempt to retrieve a passed or removed stone to be sent for analysis. Study: 1270 ptns in Texas > 15-y period of stone recurrence & reported their frequency of urine abnormalities. Many cases had > one risk factor:

o   Hypercalciuria: 61 %, including primary Hpara

o   Hyperuricosuric Ca⁺ stones: 36 %

o   Hypocitraturia: 28 % idiopathic & 3.3 % due to distal (type 1) RTA or chronic diarrhea

o   Hyperoxaluria: 8 %, enteric & primary types & marked rise in oxalate intake

o   Low urine volume (<1 L/d.): 15 %

[1] High urine Ca⁺: higher urine Ca⁺ excretion, with/without other risk factors, seen in up to ½ of idiopathic Ca⁺ stone formers:

Definition: Hypercalciuria has a variable defined, and each definition has limitations:

o   Urinary Ca⁺ excretion > 250 mg/d (6.24 mmol/d) in ladies & > 300 mg/d (7.49 mmol/d) in males were the common definitions.

o   Urinary Ca⁺ excretion > 4 mg/kg (0.1 mmol/kg)/d is another one. However, heavy subjects will have more urine Ca⁺  than lighter ones.  

 Mechanisms: Reasons increasing urine Ca⁺ in Ca⁺ stone ptns may include primary Hpara & chronic acidemia related to distal RTA. However, most Ca⁺ stone cases with high urine Ca⁺ may not have either of these diseases. High urinary Ca⁺ with no identifiable cause is usually referred to as idiopathic hypercalciuria. So, it is beneficial to consider 3 contributors to increased urine Ca⁺ excretion:

o   Enhanced GI absorption ("absorptive hypercalciuria"): raised intestinal Ca⁺ absorption. Of note, dietary Ca⁺ consumption typically should not be limited unless it’s >1000 mg/d.  

o   Higher bone resorption ("resorptive hypercalciuria"): source of extra Ca+ could be the bone.

o   Increased renal loss ("renal hypercalciuria"): renal defect in the renal tubular reabsorbed Ca⁺.

Most ptns with higher urine Ca⁺ may show more than one disorder. It has been suggested that idiopathic hypercalciuria is inherited as an autosomal dominant mode.

[2] High urine oxalate: Risk of Ca⁺ Ox stone can be increased with rise in urine oxalate. It was believed that a small rise in Ox excretion reflects a relatively high % change and, so, was more likely to induce Ca⁺ oxalate precipitates to a larger degree than absolute rise in Ca⁺ excretion.

Definition: Normal urinary Ox excretion = < 45 mg/d (0.5 mmol/d), generally < 20 % that of Ca⁺. Of note, the risk of stone formation starts to be higher significantly with urinary Ox > 25 mg/d. So, the risk of stone formation triggered with elevated urine Ox, even if the levels still within its "normal" levels.

Mechanisms: With general agreements that raised dietary Ox raises urinary Ox excretion, the magnitude of rise according to the type of food; the actual impact of dietary Ox on stone formation      seems to be little, but it is mainly controlled by concurrent Ca⁺ consumption, with the risk is rising with lowered Ca⁺ intake. Endogenous Ox is mainly derived from the metabolized glycine & ascorbic acid. Dietary Ox may exhibit more clear impact in subjects with idiopathic Ca⁺ Ox Nlith; they seem to show a high rate of Ox absorption (& urinary losses). Dietary Ca⁺ can limit Ox absorption in the gut by forming insoluble Ca⁺ Ox salt in GI lumen. Lowered Ca⁺ in the GI lumen to bind Ox, Ox absorption, & urinary Ox will increase, examples:

o   Low- Ca⁺ diet that is generally NOT advised for idiopathic Ca⁺ stones

o   Higher absorbed intestinal Ca⁺, as with cases with high urine Ca⁺

o   Malabsorption syndromes, (e.g., Crohn disease), resected/diverted bowel, e.g., jejunoileal bypass  in bariatric surgery, or cystic fibrosis.

This last disorder with malabsorption of FA & bile salts is the “enteric hyperoxaluria”. Raised Ox absorption & excretion can be attributed to both binding of free Ca⁺ to FA in GI lumen & to higher colonic permeability to smaller molecules e.g., Ox induced by colonic exposure to non-absorbable bile salts. Rate of hyperoxaluric stone production is increased with bariatric surgery. Altered GIT flora, e.g., may be observed with prolonged AB use (common in e.g., cystic fibrosis) may lead to diminished metabolism of Ox &, so, higher risk of hyperoxaluria. Lost bacterium, Oxalobacter formigenes that degrades Ox & may enhance enteric Ox secretion (thus decreasing urinary Ox excretion).

Mild hyperoxaluria can be genetic (autosomal dominant inheritance) in origin with higher activity of a Cl/Ox anion exchanger. This error has been observed in RBCs & with higher fractional Ox excretion that suggest a renal tubular defect. A defect in Ox secretion into GI lumen has been also suggested. Higher Ox production may increase the risk of Ca⁺ Ox stone formation with unclear mechanism. Increased Ox production is currently contributing to a high risk of stone formation in males as compared to females. Dramatic rise in Ox production can be seen with high-doses of vit. C and primary hyperoxaluria, a rarely seen disorder with enzymatic deficiency > overproduced Ox from glyoxylate.  

[3] Low urine citrate (Ctr): decreased excretion of urinary inhibitors of crystallization is an additional mechanism promoting evolution of kidney stones. One agent considered to be a vital inhibitor of stone formation is citrate. Low urine Ctr can be seen isolated in stone formers or combined with other urinary alterations including high urine Ca⁺ & high urine Ox:

Definition: Hypocitraturia can be defined as Ctr excretion < 320 mg/d.  

Mechanisms: Ctr acts within tubular lumen combined with Ca⁺ forming soluble complex. So, there’s low free Ca⁺ available to be combined with Ox. Moreover, Ctr can inhibit the vital process of crystal aggregation where individual Ca⁺ Ox crystals are combining to make a stone. One crucial factor limiting Ctr excretion via increasing proximal reabsorption is chronic metabolic acidosis created by (1) chronic diarrhea, (2) RTA, (3) CAI (e.g., topiramate & zonisamide), or (4) ureteral diversion.  

Decline in Ctr excretion can also be produced via a high animal protein diet, where acid generation is triggered. Higher-protein diet that is popular for losing weight, may induce substantial untoward effects on urine Ctr. Also, a diet lowered in fruits & vegetables may induce low urinary K⁺ that is parallel to urine Ctr excretion. In incomplete distal (type 1) RTA, a primary proximal tubular deficit, hypocitraturia can be seen with absence of evident metabolic acidosis. It can be suspected if [urine pH is > 5.3 + low or low-normal CO²], Dgx is confirmed by absent acidification of urine post ammonium Cl load.  

[4] High urine UA: Hyperuricosuria can be defined as 24-h urine UA excretion = > 750 mg (4.5 mmol) in women or > 800 mg (4.8 mmol) in men. A higher urine UA was considered promoting Ca⁺ Ox stone formation. One suggesed mechanism: uric acid crystals formed a nidus for subsequent Ca⁺ Ox.  

[5] Low urine volume: Nlith is a disease induced by urine concentration of lithogenic agents. So, a high urine volume is commonly associated with a decreased risk of kidney stone formation. An accepted target is at least 2.5 L. of urine/d. The main agent determining urine volume is total fluid intake, and, so, it is not surprising that higher fluid intake has been consistently found to be one of the other strongest protective factors against kidney stone formation.  

[6] Urine pH: Urine pH is contributing to the possibility of certain stones production. Acidic urine (in most subjects) enhances UA precipitation if pH is persistently 5.5 or lower. Despite UA crystallization was believed to form a nidus for Ca⁺ Ox stones, this was not proved in many reports. An alkaline urine (as with UTI & RTA & high alkali consumption) triggers Ca⁺ PO⁴ stone formation, typically if pH = 6.5 or more. Ca⁺ Ox stone is NOT pH-related in the physiologic values.

II. Dietary factors: they play a crucial role in stone formation, mainly via altering urine composition. Several elements play a vital role in many ptns: fluid, Ca⁺, Ox, K⁺, Na⁺, animal proteins, phytate, sucrose, fructose, & vit C intake. Lowered consumption of fluid, Ca⁺, K⁺, & phytate & higher use of oxalate, Na⁺, sucrose, fructose, vit. C, & animal proteins are commonly related to a higher risk for Ca⁺ stone formation. Type of beverage may also affect this risk. Impact of Ca⁺ intake is paradoxical, with a lowered risk with increased dietary Ca⁺ and a higher or no effect in risk with Ca⁺ supplementation. High intake of [animal proteins + low fruits & vegetables] increase the risk of UA stones by decreasing urine pH & increasing produced UA. Factors: BMI, fluids intake, DASH-style diet, Ca⁺ intake, & sugar-sweetened beverage are 5 modifiable risk factors representing > 50 % of incident stone formation.  

[1] Fluid intake:  lowered fluids intake > lower UO, > stone formation due to concentrated lithogenic agents e.g., Ca⁺ & Ox. Type of fluids:  examples of fluid impact on urine composition:

o   Data from 3 large studies reported: sugar-sweetened beverages (cola & non-cola beverage) are related to a higher risk of developing kidney stones development. Compared to non-users of these fluids, reported risk = 23 % higher with drinker with one or more sugar-sweetened colas / day and 33 % higher in those using one or more sugar-sweetened non-cola/d.

o   Coffee & tea was considered to provide high Ox levels. However, some reports were against. Actually, large amounts of tea seems to provide a little impact on urinary Ox. Study: higher tea & coffee (including decaffeinated one) showed a lowered risk of stone formation. Study (US): twins showed that coffee & perhaps tea were relatively protective.

Does beer cause kidney stones?

o   Beverages had been suggested to augment the risk of stones. However, studies: beer & wine were related to a lowered risk of stone formation, owing to inhibited ADH release.

o   Orange juice (containing K⁺ & Ctr) was related to a lowered risk of crystal formation (partially due to elevated urine Ctr excretion). Studies: orange juice was related to lowered risk stone formation.

o   Cranberry juice, suggested to have prophylactic effect against UTI recurrence, has been shown to increase/decrease urine saturation of Ca⁺ Ox and/or pH.  

[2] Calcium: consumed Ca⁺ absorption in the intestines will be excreted in the urine; the % absorbed is elevated with hypercalciuria that suggesting a diet with high Ca⁺ may promote stone disease, however, the opposite is observed, risk of stone formation seems to be decreased in both males & females. By contrary, Ca⁺ supplies may slightly raise the likelihood to stones formation particularly in old ladies. An explanation, risk depends upon the source of Ca⁺ in relation to timing of Ca⁺ intake:

o   Dietary Ca⁺ ingested with food-containing Ox, binds dietary Ox in gut > lowered Ox absorption & excretion. Decline in excreted Ox may exceed the rise in Ca⁺ excretion; the net result is decline in super-saturation of urine regarding Ca⁺ Ox.

o   Ca⁺ supply usually taken in the morning or before bedtime and not during meal; so, it may not be effective in binding dietary Ox and may lead to both keeping Ox excretion and, by keeping Ca⁺ free in the intestinal lumen, elevating Ca⁺ absorption & urinary excretion.

Other inhibitory factor (s) in dairy products that’re the main source of dietary Ca⁺ (risk is lower with high dietary Ca⁺ intake from non-dairy).  

Role of calcium oxalate in kidney stones formation?

[3] Oxalate: Ox present in types of food in small quantities. Ox can be generated from metabolized glycine, hydroxyl-proline, & vit C (ascorbic acid). Dietary Ox or that produced from endogenous metabolism is currently excreted in urine. It has been estimated that 10-50 % of urine oxalate is obtained from dietary Ox. Reliable assessments now exist for direct recognition of Ox in food. A clear list of > 200 food (s) recognized by the recently provided modern techniques.  

To evaluate the relation between stone risk & Ox consumption, 3 large studies: subjects with highest dietary Ox intake were compared to the lowest group > a mild rise in the risk of stones for males & older females. This risk was increased in males with lower dietary Ca⁺. Moreover, 8 or more servings of spinach per mo (= > 40 % of Ox intake) compared to less than one serving per mo was complicated with a similar rise in stone risk for older males and females. On contrary, dietary Ox & spinach intake cannot be related to a higher risk in younger ladies.

Dietary Ox consumption seems to be of a moderate risk factor for incident kidney stone with individual variation. Subject forming Ca⁺ Ox stones may absorb a high % of dietary Ox. Dietary studies: showed higher Ox consumption raised urinary Ox and consequently stone formation. However, other factors are contributing, e.g., higher Ca⁺ & Mg⁺ intake that may limit dietary Ox absorption. However, as the risk of stone formation augmented with rising urine Ox, a lowered use of dietary Ox and vitamin C appear to be wise. Challenge is in choosing a lower- Ox diet with no excessive restriction in fruits & vegetables consumption. Vigorous restriction of dietary Ox is inapplicable. Total 24-h urine Ox can be applied to recognize if restricted dietary Ox can be beneficial; if not, holding this maneuver is advised.

[4] Potassium: A higher dietary K⁺ intake was related to a decreased risk of incidental stone formation in male & females. A higher K⁺ intake can lower the risk of stone formation by decreasing urinary Ca⁺ excretion. Another mechanism: higher K⁺ intake may enhance urinary Ctr (as K⁺-rich food usually has a high alkali contents) so augmenting the inhibitory criteria of urine. Foods with high K⁺ content include fruits & vegetables. Generally, given that dietary  K⁺ is related to a lower risk and fruits & vegetables are a major source of dietary K⁺, enough evidence is available to permit intake of fruits & vegetables (with avoidance of food very high in Ox e.g., spinach, rhubarb, & potatoes).

[5] Sodium: A high Na⁺ consumption may enhance excretion of Ca⁺, partially due to reabsorbed Ca⁺ passively following that of Na⁺ & water in proximal tubule. So, any reduction in proximal reabsorbed Na⁺ given by volume expansion will result in parallel decrease in Ca⁺ transport & raised Ca⁺ excretion. Study: stone formers with idiopathic hypercalciuria, e.g., increasing Na⁺ intake from 80 to 200 mEq/d led to almost a 40 % rise in Ca⁺ excretion (from 278 to 384 mg/d [7-9.5 mmol/d.]). This rise in Ca⁺ excretion may induce -ve Ca⁺ balance promoting the evolution of osteopenia. Nurses' Health Study showed a relative risk for symptomatizing stones in ladies with higher Na⁺ intake as compared to the lowest quintile.  

[6] Protein: Different dietary proteins may show variable impact on the risk of kidney stones. High animal protein intake has been related to a slightly higher incidence of stone disease, at least in males; by contrast, vegetable protein has NOT been related to stone risk. Moreover, the risk of stones attributed to animal proteins may vary according to whether the source of this protein is dairy or nondairy. Study: higher non-dairy animal protein consumption was related to a moderate but non-significant rise in stone risk, whilst higher dairy proteins in young ladies was complicated with a lowered risk of stone formation.

High animal proteins (non-dairy & dairy) is related to increased urinary Ca⁺. Moreover, higher non-dairy, animal proteins is related to lowered urine Ctr, whilst higher dairy proteins can be related to higher urinary Ctr & lowered urine Ox excretion. Vegetable proteins has a much lower impact on Ca⁺, UA, & Ctr excretion as it has a low sulfur content & so less acid. Several factors have been implicated in elevating urinary Ca⁺ coming from higher animal protein consumption:

o   Prolonged high-protein diet > higher urinary Ca⁺ via increased renal calcitriol mediated by the increased renal mass.

o   Acid produced by high animal protein consumption (metabolized sulfur-containing AA) that’s buffered in part via bone salts > Ca⁺ release from bone & rise in urinary Ca⁺. However, the neutralized acid loads of the high-protein diet does not alleviate hypercalciuria.  

Ratio of non-dairy, animal proteins to K⁺ consumption that correlates net acid load, may also be contributing to the risk of kidney stone formation. Study: elevated animal protein-to- K⁺ ratio was related to a higher risk of stone formation, even with adjusting animal proteins & K⁺ intake.

[7] Phytate: Higher amounts of dietary phytate may lower the risk of stone formation. Study: 100,000 younger female participants in the Nurses' Health Study II, the adjusted relative risk of stone formation among those in the highest quintile of phytate intake, compared with those in the lowest, was 0.63. Although mechanism of action is unclear, Ca⁺ Ox crystal formation is strongly inhibited in vitro by phytate. Principal dietary sources of phytate in this population were cold cereal, dark bread, and beans.

[8] Sucrose: Higher sucrose intake is associated with an increased risk of stone formation in younger and older women. Nearly 40 years ago, Lemann showed that an oral glucose load increased urine calcium excretion. Although the mechanism is unknown, higher insulin levels may lead to higher urinary calcium excretion; however, some data are contradictory. Fructose intake should also be minimized, as higher fructose intake is associated with a higher risk of kidney stones.

Can too much vitamin C causes kidney stones?

[9] Vitamin C: High-dose vitamin C may lead to higher Ox production as vitamin C (ascorbic acid) is metabolized to Ox. Study: in stone formers: urinary Ox increased 6-13 mg/d for every 1000 mg vit C taken > 500 mg/d. Most clinicians recommended intake of vitamin C to be confined to the recommended dietary permission (90 mg/d) in ptns with PH of Ca⁺ Ox stones.

[10] Dietary patterns: Combined dietary elements may also contribute on stone risk. DASH diet is high in fruits & vegetables, moderate in low-fat dairy elements with low animal proteins. Adherent ptns to a DASH diet show a 40-45 % lowered risk for incidental kidney stones among males, older females, younger females, high-& low-BMI subjects. Mediterranean diet: healthy diet related to lowered risk of many conditions e.g. CVS & DM was found to result in a lowered risk of kidney stone formation.  

III. Medications: Several drugs can be related to higher risk of kidney stone formation:

1)    Topiramate,

2)    Acetazolamide,

3)    Prolonged steroid can induce kidney stone via metabolic alteration affecting urine composition.

4)    Indinavir, triamterene can crystallize in urine to become the primary constituent of kidney stone. Correction of metabolic defect or drug holding may limit the risk of stone formation.