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Published: February 2010Print Record of Viewing
Dr. Lieske reviews the current approach to identification and follow-up of kidney stones and related conditions.
Presenter: John C. Lieske, MD
Welcome to Mayo Medical Laboratories Hot Topics. These presentations provide short discussion of current topics and may be helpful to you in your practice.
Our speaker for this program is John C. Lieske, MD, Professor of Medicine, Medical Director of the Renal Function Laboratory, and Consultant in the Central Clinical Laboratory in the Department of Laboratory Medicine & Pathology at Mayo Clinic in Rochester, Minnesota. Dr. Lieske will review the current approach to identification and follow-up of kidney stones and related conditions.
Kidney stones are abnormal crystalline deposits that grow slowly in the kidney over many months to years. Typically they arise within the medullary regions of the kidney, where tubular fluid is most concentrated, and grow from microscopic deposits to eventually form true stones many millimeters in diameter.
While attached in the kidney stones are typically asymptomatic and do not cause pain. However, when they break free and enter the collecting system of the kidney they can cause obstruction. Swelling and spasm of the kidney and ureter are what cause the pain typically associated with a kidney stone attack, which is called renal colic.
Although kidney stones are not usually life threatening, we would really like to prevent them because they are very painful, very common occurring in up to 10% of males and 6% of females in their lifetime, tend to be recurrent, and are very costly to the health care system due to the medical care needed for patients with symptomatic stones.
Interestingly, the exact series of events that transpire during the formation of a kidney stone are poorly understood. Urine is almost always supersaturated in most humans, in some persons more so than others. However, there is likely more to stone formation that simple physical chemistry. Although tubular fluid along a nephron is saturated as early as the thin limb of the loop of Henle, any crystals that nucleate there are not likely to grow big enough to block a tubular lumen and grow into a stone. Therefore, these smaller crystals must aggregate together to form a larger mass, adhere to a tubular cell, or perhaps they even nucleate directly in the renal interstitium and grow into a stone precursor lesion there.
There is evidence to suggest all of these processes occur in certain circumstances and are under the control of various proteins and cell biologic processes. However, as of 2009, we know most about the factors that drive urinary supersaturation and how to treat it. Therefore, the diagnosis and treatment of stone formers is tightly focused on urinary supersaturation, and what factors might be addressed to improve it in individual patients.
This slide depicts the way that genes and environment both contribute to kidney stone disease. Important environmental factors include causes of insensible fluid loss, as well as the composition of the diet. How dietary components are absorbed and then excreted by the kidneys can be influenced by genetics. These processes in turn determine the overall urinary supersaturation. Other genetic factors likely influence how this supersaturation translates into kidney stone growth, such as the functional capacity of urinary inhibitors.
It's important to recognize that not all kidney stones are the same, and that the pathophysiology of each type of stone is very different. The most common group of stones contains a majority of calcium oxalate, and account for about 70% of the total stones in the United States. The pathophysiology of this type of stone, commonly referred to as "idiopathic calcium oxalate stone disease," is the most complex of those listed, as we will subsequently discuss. Other common types of stones include uric acid, calcium phosphate and struvite, each accounting for another 10% of the total. Cystine stones are rarer and due to a specific genetic disorder. Finally certain drugs can precipitate in the urinary tract and form true drug stones.
The laboratory workup of patients with stones includes a baseline assessment of blood electrolytes and renal function. Low serum bicarbonate can indicate renal tubular acidosis or diarrhea, which can each contribute to stones. Baseline creatinine and potassium are important for drug choice and to monitor after initiation of therapy, especially if thiazides or potassium citrate are under consideration. Looking for hypercalcemia is an important screen for hyperparathyroidism, while hyperuricemia if present might make allopurinol a good treatment choice, especially if the patient also has gout.
This slide pictorially depicts the concept of supersaturation. Supersaturation always exists in relationship to a specific crystal type. A solution is saturated for a specific phase if a crystal of that type neither dissolves nor grows when placed into the solution. The solution is under saturated if the crystal dissolves, and supersaturated if it grows.
In practice, we use a computer program called Equil2 to calculate the theoretic supersaturation of urine in relationship to crystals that can produce kidney stones. Equil2 has the binding coefficients for all common ion pairs that exist in urine, and the program goes through an iterative process to satisfy all of these binding pairs at once, each to the greatest extent possible. Equil2 reports in two scales. One is the relative supersaturation (or RSS scale). In this scale an RSS of 1 indicates a solution is exactly at saturation. The other scale is the exponential DG scale; DG is an abbreviation for a delta Gibbs free energy term. In this scale a DG value of 0 indicates an exactly saturated solution.
This slide lists all the urine analytes that are measured as part of the Mayo Supersaturation profile. Those in blue and green are required by EQUIL2 to perform the supersaturation calculations. Urinary creatinine is included since it can be used to assess completeness of collection. Analytes in blue are important urine factors that influence supersaturation and are potential treatment targets, using diet and/or drugs.
Large studies have validated urinary supersaturation as calculated by EQUIL2 for 3 different aspects (1) supersaturation predicts kidney stone risk; (2) supersaturation can predict risk of stone recurrence; and (3) supersaturation correlates with stone type. The last feature can be particularly helpful if you do not have a stone analysis.
You will initially review urinary risk factors that are associated with idiopathic calcium oxalate stones. Increased urinary amounts of calcium, uric acid, and oxalate, as well as reduced citrate are often present and drive an increase calcium oxalate supersaturation. A sizable minority have no clear metabolic abnormality, except for perhaps reduced urinary volume. Many patients will have more than one risk factor, for example high calcium and low volume.
On this slide are listed the general dietary guidelines that are applicable for patients with idiopathic calcium oxalate stones. Those with an asterisk have clinical trails to support their use, at least to some degree. Urinary volume is an important determinant of the concentration of urinary lithogenic substances such as calcium, and is largely determined by how much fluid one drinks. Therefore, all stone patients are encouraged to drink enough to have a urine volume of at least 2 liters. This requires 64-96 ounces per day. About half should be water. Low dietary calcium has been associated with increased stone risk, while the use of calcium pills may slightly increase kidney stone incidence. Therefore, patients are encouraged to get their recommended daily allowance of calcium, but from food and dairy sources and not pills.
High protein diets do many things that might increase kidney stone risk, such as increase urinary uric acid and reduce urinary citrate. Therefore a modest intake of 8 ounces or less of protein is advised. Lower sodium excretion will reduce urinary calcium levels, and also make thiazides more effective for reducing urinary calcium excretion. Finally, a lower oxalate intake will reduce the need for urinary elimination of oxalate. Dietary oxalate restriction is particularly important for patients with fat malabsorption and enteric hyperoxaluria, who absorb a higher percentage of oxalate from foods.
Hypercalciuria is the most common urine finding in patients with calcium oxalate stones. Most of these patients have hypercalciuria due to genetic causes, which was previously called idiopathic hypercalciuria. It's important to think about primary hyperparathyroidism, which is a correctable cause of stones. Fortunately, a normal fasting serum calcium is a very good screen to rule this out, and we do not recommend routinely checking a PTH level unless the patient is hypercalcemic. Other causes of hypercalciuria listed here are more unusual, and can be detected by considering other features of the history and/or physical exam.
Idiopathic hypercalciuria is clearly genetic. It tends to run in families, affecting 50% of first degree relatives. Many of these patients behave as if they have vitamin D excess, although vitamin D levels are normal. Although these patients have a genetic cause for hypercalciuria, tubular calcium handling is further influenced by diet including sodium, protein, and sucrose. Low bone mineral density is also often present in this group of individuals, perhaps due to systemic defects in calcium handling. Although a few rare monogenic causes have been identified, as listed here, the causative gene or genes remain to be identified for the majority of affected individuals.
The most effective treatment for hypercalciuria is a thiazide diuretic, which increases renal calcium reabsorption. Large doses of orthophosphate can also reduce urinary calcium excretion, perhaps due to suppressed vitamin D production, but this drug is not as well tolerated due to GI side effects. Potassium citrate can also be used and may help by effects on bone and/or simply by increasing urinary levels of citrate which is a crystallization inhibitor.
Increased urinary oxalate is another important risk factor for calcium oxalate stones. Oxalate is a small molecule composed of 2 carbons and 4 oxygens. Since humans have no enzyme to degrade oxalate, it must be eliminated by the urinary or GI tract. The major issue in the urine is that oxalate likes to bind calcium, and calcium oxalate is fairly insoluble. And these calcium oxalate crystals can grow into stones. Certain plants are high in oxalate, such as rhubarb, spinach, and nuts. However, a larger percentage of dietary oxalate comes from foods that are more moderate in oxalate content but eaten in greater amounts, such as potatoes.
The level of urinary oxalate can vary greatly depending on the underlying disease. In idiopathic calcium oxalate stone formers urinary oxalate is typically only modestly above the reference range of 40 mg/day. Higher levels, up to twice normal, are more typical of patients with malabasorptive disorders and enteric hyperoxaluria. Levels more than 100 mg/day are more typical of rare causes of hyperoxaluria, and should therefore prompt evaluation for primary hyperoxaluria.
Much of the oxalate in foods is not readily absorbed, most likely because it is complexed with calcium. An average value for net oxalate absorption might be 10%, as shown on this slide. The remainder comes from liver production of oxalate, which is an end product of metabolism that must be renally eliminated. Liver production increases markedly in patients with the genetic disorders primary hyperoxaluria.
This slide depicts the pathways that mediate enteric hyperoxaluria. One reason oxalate is not usually readily absorbed from the gut is that it is complexed with calcium, to a large degree. Ordinarily, little fat reaches the colon. However, in fat malabasorptive states fatty acids reach the colon and bind calcium, thus freeing up oxalate for absorption. Bile acid malabsorption might also contribute by injuring intestinal cells and increasing colonic permeability. Common causes of enteric hyperoxaluria include the now historical jejunoileal bypass, as well as the modern bariatric procedure Roux en Y bypass. Patients with inflammatory bowel disease, pancreatic insufficiency, and intestinal resection for any cause can also develop enteric hyperoxaluria, if the colon is intact. Even the lipid lowering drug Zetia, which blocks intestinal cholesterol absorption, has been associated with increased urinary oxalate levels.
Treatment for enteric hyperoxaluria includes adequate hydration, since these patients often have some degree of diarrhea and gastrointestinal losses; a low fat, low oxalate diet; and calcium dosed with meals to bind up oxalate. Cholestryamine or other bile acid sequestrants might be helpful in some patients. Urinary citrate is also often low due to gastrointestinal alkali losses, and should also be repleted.
Urinary citrate levels are largely determined at the level of the proximal tubule. Filtered citrate can be reabsorbed there, enter the citric acid cycle, and be broken down to generate bicarbonate ions. Control of these events is driven largely by systemic acid base status, which in turn affects intracellular pH. This makes sense, since the net result is to regenerate bicarbonate and help correct the acidosis.
Therefore, causes of a low citrate include diarrhea or renal tubular acidosis, both of which cause some degree of systemic acidosis. Proteins are the major dietary source of acid, and hence protein rich diets will reduce urinary citrate. Magnesium and potassium depletion both alter proximal tubular citrate handling, and therefore should be repleted in all patients with stone disease.
Some patients have no identifiable cause of a low urinary citrate. The treatment is straightforward, namely oral potassium citrate which comes in liquid or pill forms.
Increased urinary uric acid excretion has also been identified as a risk factor for calcium oxalate stones. The mechanism is not entirely clear, and at least 3 hypotheses have been put forth. Increased urinary uric acid may serve to salt out calcium oxalate, which is already almost always supersaturated in the urine. Uric acid crystals could also serve as heterogeneous nucleation sites for calcium oxalate. Finally, uric acid and/or uric acid crystals could bind and inactivate urinary macromolecular inhibitors. Varying degrees of evidence exist for each of these possibilities. Treatment for this subgroup of patients includes allopurinol, which blocks uric acid production, as well as potassium citrate, which presumably acts to block uric acid precipitation in the urine.
We will now briefly discuss other types of kidney stones. Fortunately, the urinary risk factors for each of these is more straightforward. Uric acid is very insoluble in urine with a pH less that 5.3. Hence, uric acid stones are all about having an acidic urine. Causes of acidic urine include excessive gastrointestinal losses of bicarbonate from diarrhea or illeostomies or a relatively protein rich diet such as the Atkins diet. More recently, it has been demonstrated that patients with insulin resistance or diabetes tend to have very acidic urine. The mechanism here seems to involve, at least in part, decreased renal ammoniagenesis and hence increased excretion of the daily acid load in the form of titratable acid. Treatment is fairly gratifying in that urinary alkalinization to a pH> 6 to 6.5 with oral citrate will effectively prevent uric acid crystallization, and even dissolve some pre existing uric acid stones.
Calcium phosphate stones are the exact opposite, since calcium phosphate precipitates in urine with an alkaline pH > 6.3. Many of these patients have a defect in renal acidification, or renal tubular acidosis.
Causes include autoimmune diseases affecting the kidney such as Sjogrens disease, monoclonal protein diseases with peritubular deposits, and certain drugs (for example toperimate or acetazolamide which both block carbonic anhydrase).
In patients with renal tubular acidosis, in addition to a high urinary pH, they also develop hypocitraturia because of the associated systemic acidosis, as well as hypercalciuria, probably due to effects of bone buffering of the acid load. All of these also favor calcium phosphate precipitation.
Treatment often consists of citrate repletion with potassium citrate, although this can potentially make things worse if the urinary pH goes up further. Therefore, it is very important to watch serial urinary supersaturation profiles to monitor treatment effect in these patients.
Cystine stones are only seen in patients with cystinuria, a genetic disorder in which transporters in the proximal tubular which reabsorbed filtered amino acids are not functioning normally. Although urinary levels of other dibasic amino acids are also high, the patients develop cystine stones because cystine is not very soluble in urine.
The mainstay of treatment is forced diuresis by drinking copious amounts of fluids. Low sodium and protein intake can marginally reduce urinary cystine excretion, and cystine is somewhat more soluble in alkaline urine. D-penicillamine and thiola are 2 drugs which can complex cystine to increase its solubility. However, both have potential side effects so are reserved for patients that fail other more conservative measures.
Finally, struvite stones require a unique set of urinary conditions to grow: a high urinary pH and high levels of ammonium. This occurs only when the urine is infected with a urease producing organism such as a proteus species.
Therefore, treatment starts with identification and treatment of the infection. The stones are colonized and usually cannot be sterilized with antibiotics alone. Therefore, all stones must be surgically removed. Quite often, these patients have an underlying stone disorder, and a preexisting calcium stone that became colonized with the urease positive organism that in turn led to overgrowth with struvite. Therefore, these patients should undergo metabolic workup for stone risk factors once the infected stone is removed. They often need suppressive antibiotics for 3-6 months postoperatively, with longer term follow-up to be sure they are clear of infection.