Update on Nephrolithiasis Part 1: Pathogenic Factors and Treatment [Hot Topic]

LieskeJohn
John Lieske, M.D.

There are several causes of kidney stones, ranging from diet to genetics. In Part 1, we examine the causes of stones and the need for stone analysis. Understanding the stone’s composition can support a diagnosis and help guide treatment plans and prevention options.

Presenter and Credentials:
John Lieske, M.D., Professor of Medicine at Mayo Clinic, Medical Director of the Renal Testing Laboratory in the Department of Laboratory Medicine and Pathology, and a Consultant in the Division of Nephrology and Hypertension at Mayo Clinic in Rochester, Minn.

 

Transcript

Thank you, Cara.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 Dr. John Lieske, Professor of Medicine at Mayo Clinic, Medical Director of the Renal Testing Laboratory in the Department of Laboratory Medicine and Pathology, and a Consultant in the Division of Nephrology and Hypertension at Mayo Clinic in Rochester, Minnesota. Dr. Lieske provides a 2-part update on kidney stones. Part 1 discusses the causes and treatments for kidney stones and related conditions.

I have the following disclosures; our work described here has funding from National Institute of Diabetes and Digestive and Kidney Diseases, the Rare Diseases Clinical Research Network and then also the National Center for Advancing Translational Sciences.

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, they are very common occurring in up to 10% of males and 6% of females in their lifetime, they tend to be recurrent, and they are very costly to the health system due to the medical care needed for patients with symptomatic stones.  Although kidney stones are very common, the types of stones vary greatly depending on your age and sex.

The first theme for today is that certain individuals are at more likely to form different kinds of stones.

To study stone types, we looked at all stones submitted to Mayo Medical Labs over 1 year. We classified by stone type in the order shown here: any struvite (or infection stone), any cystine, any uric acid, any brushite, mostly calcium oxalate, mostly hydroxyapatite, and then others.

As has been previously reported, most, approximately83%, contained majority calcium oxalate or hydroxyapatite.

However, when viewed by age, some striking trends emerged. Calcium oxalate were the most common in middle age (40-50 years old). However, hydroxyapatite were most common in younger persons (ages 10-30). Uric acid were progressively more common with age over 50.

When broken down by sex, trends were even more obvious. Younger women (ages 10-30) were particularly likely to have hydroxyapatite stones. And older persons of both sexes had more uric acid stones. Struvite were most common in older women. These observations suggest some potential hypotheses related to stone risk that could be investigated. Most striking would be why young women get calcium phosphate stones. Why do older persons of both sexes get uric acid 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 stone precursor lesions 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 2015 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 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 undersaturated 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 results in 2 scales. One is the relative superstation (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 at the top 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 black are important urine factors that influence urine 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.

We 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 perhaps for reduced urinary volume. Many patients will have more than one risk factor, for example high calcium and low volume.

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 is 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.

The vast majority of patients with hyperparathyroidism will have hypercalcemia.  Many will also have hypophosphatemia (at least mild). Hence a PTH level is not recommended for normocalcemic stone patients. Indeed, the values are hard to interpret unless the patient is hypercalcemic.

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 handing 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 and 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 in the urinary or GI tract. The major issue in the urine is that oxalate likes to bind calcium, and that calcium oxalate is fairly insoluble. And these calcium oxalate crystals can grow into kidney 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 genetic 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%. 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 disorder 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 jejuno-illeal 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.

A common cause of enteric hyperoxaluria in current practice is bariatric surgeries as a treatment for medially complicated obesity. We recently looked at the risk of stones after this surgery in a large cohort of patients and matched obese controls. As shown in this slide, the risk of stones is roughly twice those of persons who do not have the surgery. Malabsorptive procedures are reserved for those who need to lose more weight and causes more fat malabsorption.  Perhaps not surprisingly, those persons have even more stones.

Treatment for enteric hyperoxaluria includes adequate hydration, since these patients often have some degree of diarrhea and gastrointestinal losses, a low-fat diet, a 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 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 to help correct the acidosis.

Therefore, causes of a low urine 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.

In general, the level of citrate in the urine correlates with the amount of acid or base in the diet, together with the levels of absorption. For example a high-protein diet or chronic diarrhea can cause a low urine citrate. 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, as shown here. 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.

Hyperuricosuria is largely related to dietary purine intake, as shown here. In general, purines are associated with a high-protein diet.

The treatment for this subgroup of calcium oxalate stone patients with high urinary uric acid excretion includes allopurinol, which blocks uric acid production, as well as potassium citrate, which presumably acts to block uric acid precipitation in the urine. A randomized trial, shown here supports the effectiveness of this approach.

Nevertheless, a recent analysis of first time stone formers suggests that high urine uric acid was associated with decreased stone risk. Thus, the role of uric acid in calcium oxalate stones is yet to be fully defined.

We will now briefly discuss the other types of kidney stones. Fortunately, the urinary risk factors for each of these are more straightforward. Uric acid is very insoluble in urine with a pH less than 5.3. Hence, uric acid stones are all about having acidic urine. Causes 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 a very acidic urine. The mechanism 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 preexisting uric acid kidney 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 Sjögren’s disease, monoclonal protein diseases with peritubular deposits, and certain drugs (for example topiramate 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 the acid load. All 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.

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