NephrolithiasisTeaching Module

2008-9

By

Tejas Desai, MD

Darina Stankeyeva, MD

Arlene Chapman, MD

James Bailey, MD

Division of Nephrology and Hypertension

Emory University School of Medicine

Module Format

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Module Format (continued)

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Reference

Table of Contents: This is a nested TOC that allows you to jump from one section (and subsection) to another. Clicking on the main section (e.g., Pathogenesis) will display the subsections for that area of study.

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Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

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Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Epidemiology

Table of Contents

Epidemiology

Race

Geography

Gender

Body Size

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

1988-1994

1976-1980

• Between the ages of 20-74, the lifetime US prevalence of kidney stones has increased

• 1976: 3.2%

• 1994: 5.2%

• This graph shows the prevalence by age

• As we age, regardless of gender, our risk ofdeveloping kidney stones increases

Epidemiology: Race

Table of Contents

Epidemiology

Race

Geography

Gender

Body Size

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Reference

1988-1994

1976-1980

• Within each age range, white patients have a greater likelihood of kidney stone formation than their black counterparts

• Repeated studies (not shown) indicate the same pattern

• We will discuss a possible explanation for racial differences later on

Epidemiology: GeographyReference

• The Southeast consistently shows the greatest prevalence of kidney stones, regardless of age or gender

Table of Contents

Epidemiology

Race

Geography

Gender

Body Size

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Epidemiology: Geography (cont’d)Reference

• Possible explanations for why the Southeast has a high prevalence of stones include:

1) Greater likelihood of concentrated urine because of hot climate

2) Increased sunlight leads to greater concentrations of activated vitamin D3, which may increase urinary calcium concentrations

• this was shown in a 1975 study of soldiers who had greater amounts of urinary calcium & oxalate when deployed to a sunny climate

Table of Contents

Epidemiology

Race

Geography

Gender

Body Size

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Epidemiology: GenderReference

Males

Females

• Although this graph shows a greater prevalence for stones in white men vs. women of all ages, there is consensus that this trend is seen in other races as well

Table of Contents

Epidemiology

Race

Geography

Gender

Body Size

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Epidemiology: Body SizeReference

• The greater your BMI (relative to 21-22.9), the more likely you will have kidney stones

• One explanation: obese patients are hyperinsulinemic & this feature could promote increase urinary calcium excretion• Another explanation: men weighing > 120kg had a 13% greater urinary UA excretion than those weighing < 100kg

• as you will see, UA excretion increases the likelihood of calcium-based stone formation

Table of Contents

Epidemiology

Race

Geography

Gender

Body Size

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

PathogenesisTable of Contents

Epidemiology

Pathogenesis

Saturation

Nucleation

Inhibitors

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

• In this section, we will simplify the molecular mechanisms that occur within the urine to develop kidney stones.

• We will discuss the following topics:

• Saturation

• Metastable solutions

• Nucleation

• Intrinsic inhibitors of crystallization

• Don’t worry…all of these terms will be defined repeatedly

• Advance to the next slide by using your keyboard’s arrow key

Pathogenesis: Saturation

Table of Contents

Epidemiology

Pathogenesis

Saturation

Metastable

ULM

Normal Urine

Nucleation

Inhibitors

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Reference

• Think of the urine as a solution containing calcium and oxalate ions

• The [Ca2+]*[C2O42-] = solubility product

• The lower the solubility product, the more undersaturated the urine (or solution) is

• Now imagine that you add more Ca2+ or oxalate2- to your solution

No crystals in solution because we have a low solubility product

Pathogenesis: Saturation (cont’d)Reference

• The solubility product increases as the ion concentrations increase

• But, crystals do not form de novo

• Crystals that existed previously would grow, but no new crystals would be formed

• The solution you have created is metastable

• These are solutions that have increased solubility products such that pre-existing crystals/surfaces can facilitate further crystal growth, but the solution itself does not have a high enough solubility product to produce native crystals

A metastable solution

+ a pre-existing surface or crystal

A precipitated solution

Table of Contents

Epidemiology

Pathogenesis

Saturation

Metastable

ULM

Normal Urine

Nucleation

Inhibitors

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Pathogenesis: Saturation (cont’d)Reference

• If you continue to add ions to the solution, you will traverse the metastable range and reach the upper limit of metastability

• ULM: the solubility product beyond which de novo crystallization can occur

• Studies show that stone formers have a higher solubility product than non-stone formers

• Stone formers are more likely to have urine at the ULM or greater

Y-axis: SP for Calcium Oxalate

Table of Contents

Epidemiology

Pathogenesis

Saturation

Metastable

ULM

Normal Urine

Nucleation

Inhibitors

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Pathogenesis: Saturation (cont’d)

• Surprisingly, non-stone formers produce urine within the metastable range

• The figure on the previous slide shows that even healthy subjects produce urine that can easily form crystals if a pre-existing crystal were present

• These findings are replicated in two additional scientific studies that look at women and men

Table of Contents

Epidemiology

Pathogenesis

Saturation

Metastable

ULM

Normal Urine

Nucleation

Inhibitors

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Pathogenesis: Nucleation

Table of Contents

Epidemiology

Pathogenesis

Saturation

Nucleation

Fixed Particle Theory

Inhibitors

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

• Metastable solutions form crystals by heterogeneous nucleation

• Heterogeneous nucleation: the process of forming crystals onto pre-existing surfaces

• Homogeneous nucleation: the spontaneous formation of crystals

• Since the normal urine sample is a metastable solution, it is easier for heterogeneous nucleation to occur

• Randall plaque helps facilitate heterogeneous nucleation

• the plaque can be found in the interstitium, at the level of the papilla

• When it expands into the urinary space, it facilitates heterogeneous nucleation by acting as a pre-existing surface

Reference

Pathogenesis: Nucleation (cont’d)Reference

• Some studies suggest that crystals cannot form in the lumen without an anchor

• It is thought that the transit time through the nephron and urothelial space is too short for crystals to form without an anchor point

• one such anchor point would be the Randall plaque

• this is known as the Fixed Particle Theory

• However, not all stone formers have a Randall plaque

• in these cases, it is theorized that the epithelial cells adhere to or uptake the crystal to form an anchor point for nucleation and growth

Table of Contents

Epidemiology

Pathogenesis

Saturation

Nucleation

Fixed Particle Theory

Inhibitors

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Pathogenesis: Inhibitors

Table of Contents

Epidemiology

Pathogenesis

Saturation

Nucleation

Inhibitors

Mg2+ and Citrate

Osteopontin

Tamm-Horsfall P

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

• Because normal urine is metastable, there must be some intrinsic inhibitors to keep urine in normal patients from crystallizing

• These inhibitors increase the ULM so that it is harder for crystallization to occur

• There are 4 main intrinsic inhibitors of crystallization

• multivalent cations

• organic anions

• inorganic anions

• macromolecules

• We will discuss each in brief…

Reference

Pathogenesis: Inhibitors (cont’d)

Table of Contents

Epidemiology

Pathogenesis

Saturation

Nucleation

Inhibitors

Mg2+ and Citrate

Osteopontin

Tamm-Horsfall P

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

• Mg2+: scientific trials are mixed about the efficacy of stone prevention by Magnesium supplementation. A 2005 review highlights these varied results, but it is thought that hypomagnesuria can predispose patients to calcium oxalate crystallization

• Citrate: known to inhibit crystallization and nucleation by raising the ULM

Pathogenesis: Inhibitors (cont’d)

Table of Contents

Epidemiology

Pathogenesis

Saturation

Nucleation

Inhibitors

Mg2+ and Citrate

Osteopontin

Tamm-Horsfall P

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

• Osteopontin: a glycoprotein found in bone

• it inhibits hydroxyapatite formation

• However, it is also found in the TALH and DCT

• In osteopontin-knockout mice, there is a greater propensity for calcium oxalate crystallization

• The schematic to the right is a proposed theory of how osteopontin works in the nephron

Legend:

- inhibitory effects of osteopontin

+ stimulatory effects of osteopontin

COM calcium oxalate monohydrate

COD calcium oxalate dihydrate

Pathogenesis: Inhibitors (cont’d)

• The Tamm-Horsfall protein (THP) is synthesized by the TALH

• It is the most abundant urinary protein

• In THP-knockout mice, there is greater likelihood of forming calcium-based crystals

Reference

Table of Contents

Epidemiology

Pathogenesis

Saturation

Nucleation

Inhibitors

Mg2+ and Citrate

Osteopontin

Tamm-Horsfall P

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Clinical ManifestationsReference

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

LPHS

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

• Flank pain is a common symptom

• the pain is caused by stretching of the renal capsule as the stone causes urinary obstruction

• pain can sometimes radiate anteriorly and inferiorly towards the bladder

• Stone size is directly proportional to the likelihood of spontaneous passage

• Hematuria is related to stone size

• Macroscopic hematuria usually occurs with larger stone sizes

Clinical Manifestations (cont’d)

Reference

• Loin Pain Hematuria Syndrome: mimics nephrolithiasis in that patients present with recurrent macro/microscopic hematuria & loin pain

• Most patients do not have stones; it is not clear if there is a causal relationship between stone-formers and LPHS

• Patients are usually young or middle-aged females

• A prospective biopsy study shows that the hematuria is glomerular in origin

• 66.5% of patients with LPHS displayed an abnormally thin or thickened basement membrane

• The mechanisms that lead to loin pain are still not clarified

• 21% of patients with LPHS were ultimately diagnosed with IgA nephropathy

• this diagnosis should be considered a secondary cause of LPHS

• Clinical significance of LPHS is not clear

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

LPHS

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

EvaluationReference

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

1st-time Stone Formers

Data

Stone Analysis (1, 2)

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

• Nephrolithiasis itself is not an etiology

• Many metabolic disorders can cause nephrolithiasis

• Therefore, once the diagnosis of nephrolithiasis is made, further evaluation must be conducted to determine the underlying metabolic disorder

• Should a workup be conducted after the first kidney stone?

• This is a debatable question, primarily because 50% of first-time stone formers will have a second episode within 10 years

• Some physicians argue that a workup should not be conducted until the second episode of nephrolithiasis, because 50% of first time stone formers will not form another stone in 10 years

Evaluation (cont’d)

Reference

Men

WomenRecurrence Free Rate

Recurrence Free Rate

Uric Acid + Calcium

Cystine

Struvite

Uric Acid or Calcium

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

1st-time Stone Formers

Data

Stone Analysis (1, 2)

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Evaluation (cont’d)

• The history should focus on symptoms as well as diet and volume status

• Urine crystals are minimally helpful because they can exist in the absence of kidney stones

• However, their presence can narrow the workup

• Specific gravity and urine osmolalilty can help assess hydration status

• Urine pH, measured directly (not via dipstick analysis) can offer clues as well

• Basic serum tests include: standard chemistry panel, Ca2+, PO4

3-, PTH

• 24-hour urine collections for Ca2+, PO43-, oxalate, uric acid,

Na+, K+, pH, bicarbonate, citrate, creatinine

• supersaturation ratios for calcium oxalate, calcium phosphate, monosodium urate can be determined as well

Reference

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

1st-time Stone Formers

Data

Stone Analysis (1, 2)

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Evaluation (cont’d)

Reference

• Analyzing the passed stone gives us considerable insight into the possible underlying metabolic defects

• For calcareous stones, the majority of patients have hypocitraturia (44-62%)

• The next most-prevalent metabolic disturbance is absorptive hypercalciuria (38-49%)

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

1st-time Stone Formers

Data

Stone Analysis (1, 2)

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Evaluation (cont’d)

Reference

• Patients with uric acid stones commonly have gouty diatheses, followed by hypocitraturia (84% and 36% respectively)

• Although not shown here, most patients have low urinary pH

• Patients with mixed UA/Ca stones follow the same pattern (75% gouty diatheses, 38% hypocitraturia)

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

1st-time Stone Formers

Data

Stone Analysis (1, 2)

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

General TherapyTable of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Fluid Intake (1, 2)

Sodium Intake

Animal Protein

Calcium Intake (1, 2)

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

• Because many physicians feel that the first kidney stone does not require a workup, only general therapeutic measures are employed

• These non-specific strategies are aimed at increasing the ULM to lower the likelihood of crystallization

• These strategies are known as “the stone clinic effect” and are summarized in this section

• increasing fluid intake

• decreasing sodium intake

• decreasing animal protein intake

• age and gender appropriate calcium intake

• We will discuss each of these non-specific strategies in this section, and focus on specific strategies in the next sections

General Therapy - FluidReference

• A landmark randomized prospective clinical trial showed that increasing fluid intake could decrease the risk of a 2nd calcareous stone

• At baseline, stone formers (white columns) form less urine than their healthy counterparts

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Fluid Intake (1, 2)

Sodium Intake

Animal Protein

Calcium Intake (1, 2)

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

General Therapy - Fluid (cont’d)

Reference

• 2 groups of patients were created, with Group 1 treated with higher water intake

• Without changing any other diet parameter, the group with the greater water intake had a lower risk of recurrent kidney stones

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Fluid Intake (1, 2)

Sodium Intake

Animal Protein

Calcium Intake (1, 2)

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

General Therapy - Sodium

• One of the earliest animal trials showed that increased urinary sodium excretion leads to a proportional increase in urinary calcium excretion

• More recent trials show similar findings

• Increasing sodium intake leads to increased sodium and calcium urinary excretion

• The likelihood of saturation for calcareous stones increases with higher levels of urinary calcium excretion

Reference

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Fluid Intake (1, 2)

Sodium Intake

Animal Protein

Calcium Intake (1, 2)

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

General Therapy - ProteinReference

• Animal proteins influence kidney stone development through a variety of mechanisms

• increasing the acid load causes a greater release of Ca2+ from bone, which results in a greater filtered load of Ca2+ and an increase in the solubility product

• the increased acid load stimulates increased citrate resorption by the PCT, thereby decreasing a necessary inhibitor of crystallization

• animal protein intake results in increased uric acid excretion and decreases uric acid solubility in the urine by decreasing urinary pH

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Fluid Intake (1, 2)

Sodium Intake

Animal Protein

Calcium Intake (1, 2)

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

General Therapy - CalciumReference

• Paradoxically, patients who had a calcareous stone were more likely to develop a 2nd stone if their calcium intake decreased

• Decreasing calcium intake actually increases dietary oxalate absorption because dietary oxalate is not sequestered in the small intestine

• As a result, urinary oxalate excretion would increase and the solubility product of calcium oxalate would favor crystallization

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Fluid Intake (1, 2)

Sodium Intake

Animal Protein

Calcium Intake (1, 2)

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

General Therapy - Calcium (cont’d)

Reference

Both groups of patients were told to increase oral water intake and decrease oxalate intake

• Patients with the low calcium diet had a 50% increase in recurrent stone formation at 5 years

• Experts in the field now recommend an age/gender appropriate calcium intake to limit bone demineralization but maintain enough dietary calcium to prevent oxalate absorption

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Fluid Intake (1, 2)

Sodium Intake

Animal Protein

Calcium Intake (1, 2)

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium StonesTable of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

• Calcium homeostasis is regulated by three organs: bone, kidney, small intestine

• The schematic shows the daily interactions amongst these three organs for a person in calcium balance

• A defect in any one organ leads to compensatory mechanisms in the remaining two

(Extracellular pool)

Reference

Calcium Stones - PhysiologyReference

• Intestinal calcium handling occurs by the transcellular and paracellular pathways

• In the proximal small intestine, absorption is transcellularly

• In the distal portions, absorption is paracellularly

• Only ionized Ca2+ can be absorbed (through either pathway)

• Ca2+ that is complexed to organic anions is not absorbed

• Theoretically, Ca2+ absorption should be linear despite a saturation in the transcellular pathway

• Experimentally, however, the relationship between Ca2+ absorption and luminal Ca2+ concentration is not linear (a plateau is reached)

• This suggests that the main pathway used by the small intestine to absorb Ca2+ is via the transcellular pathway

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - Physiology (cont’d)

Reference

• Approximately 85% of filtered Ca2+ is absorbed by the PCT through the paracellular pathway

• The main regulating factors are Na+ and fluid absorption

• When Na+ intake is high, Na+ reabsorption is decreased and Ca2+

reabsorption also decreases

• In the TALH, Ca2+ reabsorption is regulated by the Calcium-sensing receptor (CaSR)

• In the DCT, reabsorption occurs via the transcellular pathway, and is under the same regulatory influences that are seen in the proximal small intestine

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - Calcium OxalateReference

• Most calcium oxalate stone formers have idiopathic hypercalciuria

• Much of the urinary calcium is from the bone

• A review of the NHANES III data showed that men with idiopathic hypercalciuria ( calcium oxalate stones) had lower bone mineral densities than age-matched controls

• Almost all calcium oxalate stones form on the Randall plaque

• The size of the Randall plaque is directly proportional to the amount of urinary calcium and inversely related to the urinary pH and volume

• These graphs show a general trend that is outlined

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - Calcium Oxalate (cont’d)

• Specific treatment of calcium oxalate stones due to idiopathic hypercalciuria should focus on decreasing the growth of the Randall plaque

• Click General Therapy to review non-specific recommendations

• Increasing urinary volume and decreasing urinary calcium are specific strategies that one should employ

• A scientific trial used chlorthalidone (25-50 mg doses) to decrease urinary calcium and showed a 90.1% reduction in the number of calcium oxalate stones formed

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - PTHReference

• PTH exerts its influence on Ca2+ reabsorption primarily at the DCT

• PTH also stimulates osteoblastic activity

• PTH also stimulates activated vitamin D3 synthesis to increase intestinal Ca2+ absorption

• How does PTH cause hypercalciuria?

• These actions cause hypercalcemia

• It is theorized that the hypercalcemia which results from hyperparathyroidism increases the filtered load of Ca2+

• Also, elevated PTH increases activation of the CaSR

• Treatment for primary hyperparathyroidism includes: treatment strategies for hypercalciuria, bisphosphonate therapy, and if needed, parathyroidectomy

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2) 1* Hyperparathyroidism

Hyperoxaluria

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - HyperoxaluriaTable of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Intestinal Handling

Renal Handling

Enteric Hyperoxaluria

Treatment

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Reference

• Hyperoxaluria is equally as important as hypercalciuria in the development of calcareous kidney stones

• This data shows that the relative saturation ratio of calcium oxalate (RSR) is proportional to both the calcium and oxalate concentrations

Calcium Stones - Hyperoxaluria - Intestinal Handling

• Oxalate absorption occurs by both paracellular and transcellular pathways

• Contrary to previous reports, there does not appear to be evidence that oxalate is synthesized intra-intestinally

• However, there are native bacterial organisms in the intestine, specifically Oxalobacter formigenes, that utilize dietary oxalate for growth

• There is evidence that growth of this bacterium decreases urinary oxalate

Reference

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Intestinal Handling

Renal Handling

Enteric Hyperoxaluria

Treatment

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - Hyperoxaluria - Renal HandlingReference

• The kidneys are able to secrete and reabsorb oxalate

• However, the exact molecular mechanisms, including external factors that influence secretion or reabsorption, are not clear

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Intestinal Handling

Renal Handling

Enteric Hyperoxaluria

Treatment

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - Enteric HyperoxaluriaReference

• Hyperoxaluria commonly occurs from increased gastrointestinal oxalate absorption

• A common etiology that leads to increased bowel absorption are the malabsorption syndromes (10-100 times greater)

• In these cases, the inability to absorb free fatty acids leads to increased oxalate absorption by mechanisms illustrated below

• Malabsorption facilitates colonic absorption of oxalate

• Malabsorption decreases intestinal calcium oxalate (non-absorbable) formation by a saponification-like process

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Intestinal Handling

Renal Handling

Enteric Hyperoxaluria

Treatment

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - Enteric Hyperoxaluria (cont’d)Reference

• Treatment of hyperoxaluria focuses on decreasing enteric concentration and absorption of oxalate

• Because the exact mechanisms of renal secretion and reabsorption are not clear, no specific therapies exist to modify these processes

• The table above outlines the strategies to decrease intestinal oxalate

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Intestinal Handling

Renal Handling

Enteric Hyperoxaluria

Treatment

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - Hypocitraturia

• The 2 main functions of urinary citrate are: 1) chelate urinary Ca2+, and 2) act as a urinary buffer

• Ca-citrate is a very soluble complex; chelating Ca2+ prevents it from forming insoluble complexes (e.g., Ca-oxalate)

• Citrate may also increase the inhibitory activity of the Tamm-Horsfall Protein (click here to re-learn the intrinsic inhibitors of stone formation, including THP)

• Amount of urinary citrate depends, primarily, on the amount reabsorbed by the PCT

• and PCT absorption depends directly on the serum pH

• that is, a low serum pH (acidemia) stimulates reabsorption of citrate

• Most stone formers who have hypocitraturia also have another metabolic disturbance (e.g., hypercalciuria, hyperoxaluria)

• Common etiologies of hypocitraturia: any process that decreases serum pH

Reference

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Intestinal Handling

Renal Handling

Enteric Hyperoxaluria

Treatment

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - Hypocitraturia (cont’d)

• Treatment consists of mitigating serum acidemia (eliminate the factors that increase proximal tubular reabsorption of citrate)

• Provide supplemental citrate

• Journal of Urology 1993: in a RCT of K-citrate vs. placebo for recurrent stone formers with hypocitraturia, rate of subsequent stone formation was significantly less in the K-citrate group

• Journal of Urology 1999: a prospective double-blind trial comparing K-Mg-citrate to placebo in prevention of stone recurrence showed a 63% incidence in the placebo arm and a 12% incidence in the treatment arm.

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Intestinal Handling

Renal Handling

Enteric Hyperoxaluria

Treatment

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - HyperuricosuriaReference

• Defined as approximately > 750 mg/d urinary excretion of uric acid or urate (although the amount of uric acid/urate excreted fluctuates based on diet, for example)

• Elevated urinary UA levels is a risk factor for both uric acid stones and calcareous stones

• It is believed that hyperuricosuria facilitates heterogeneous nucleation for calcareous stone formation

• Also, elevated urinary uric acid levels may decrease intrinsic inhibitors of stone formation

• Etiologies of hyperuricosuria: increased purine-rich diet, tissue breakdown/lysis, medications that facilitate UA secretion

• Treatment: dietary modification, allopurinol or other xanthine oxidase inhibitors, and therapies to decrease calcium-oxalate stone formation

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Intestinal Handling

Renal Handling

Enteric Hyperoxaluria

Treatment

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - Calcium PhosphateReference

• Calcium phosphate stones, unlike the more prevalent calcium oxalate stone, are more likely to form in alkaline urine

• The alkaline urine decreases the solubility of calcium phosphate crystals

• This can explain why patients with distal renal tubular acidoses (type I) have a higher propensity for calcium phosphate crystallization

• Aggressively alkalinizing the urine in the treatment of calcium oxalate or uric acid stones can also precipitate calcium phosphate stones

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Intestinal Handling

Renal Handling

Enteric Hyperoxaluria

Treatment

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Calcium Stones - Calcium Phosphate (cont’d)

• Most treatment options take advantage of the fact that calcium phosphate stone formers are also hypercalciuric

• Strategies to diminish calcium excretion can be found by clicking here

• General therapeutic strategies are also employed, which can be reviewed by clicking here

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Basic Physiology (1, 2)

Idiopathic Ca-Ox Stones (1, 2)

1* Hyperparathyroidism

Hyperoxaluria

Intestinal Handling

Renal Handling

Enteric Hyperoxaluria

Treatment

Hypocitraturia (1, 2)

Hyperuricosuria

Calcium Phosphate (1, 2)

Uric Acid Stones

Struvite Stones

Cystine Stones

Uric Acid StonesTable of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Urine pH (1, 2, 3)

Diagnosis & Eval.

Treatment

Struvite Stones

Cystine Stones

Reference

• Most uric acid stone formers do not have hyperuricosuria

• Although hyperuricosuria predisposes a person to uric acid stones, most patients with elevated urinary uric acid form calcium oxalate stones (click here for further information)

• Uric acid stone formers generally have a low urine pH as their main risk factor

• These patients have an underlying defect in NH3 generation such that their urine must be low in order to excrete the daily acid load

• 8-10% of all kidney stones in the US are pure uric acid stones

• Amongst patients who develop pure uric acid stones, type 2 diabetics and obese patients are more predisposed to such stone formation

Uric Acid Stones - Urine pH Reference

Limit of solubility of uric acid

• pH 5.0

• pH 6.5

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Urine pH (1, 2, 3)

Diagnosis & Eval.

Treatment

Struvite Stones

Cystine Stones

Uric Acid Stones - Urine pH (cont’d)Reference

• Most uric acid stone formers maintain a lower urinary pH than their normal counterparts

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Urine pH (1, 2, 3)

Diagnosis & Eval.

Treatment

Struvite Stones

Cystine Stones

Uric Acid Stones - Urine pH (cont’d)Reference

• Presented below is a simplified algorithm outlining the risk factors for uric acid stone formation

• The most important risk factor, that is consistently found in uric acid stone formers, is low urinary pH

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Urine pH (1, 2, 3)

Diagnosis & Eval.

Treatment

Struvite Stones

Cystine Stones

Uric Acid Stones - Diagnosis and Evaluation Reference

• Complete history and physical examination (as always)

• X-rays are generally not helpful (CT’s are better)

• Uric acid stones are radiolucent on XR

• They are radio-opaque (or radiodense) with CT

• A lower urinary pH predisposes patients to uric acid stones

• 24-hour markers to indicate excess acid excretion

• e.g., elevated urine urea nitrogen, low urinary citrate, increased urinary sulfate

• Although increased urinary uric acid can predispose to uric acid stones, it is more likely to predispose to calcareous stones

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Urine pH (1, 2, 3)

Diagnosis & Eval.

Treatment

Struvite Stones

Cystine Stones

Uric Acid Stones – Treatment

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Urine pH (1, 2, 3)

Diagnosis & Eval.

Treatment

Struvite Stones

Cystine Stones

• Please review the “General Therapies Slide” for non-specific treatment options

• Although most uric acid stone formers have normal urinary uric acid, it is still recommended to limit dietary protein intake

• If urinary uric acid is high, xanthine oxidase inhibitors can be used

• Uric acid stones are the only stones that can dissolve in-situ, by raising urinary pH

• titrate for a urinary pH > 6.1 (but < 7.0 to decrease the risk of calcium phosphate stone formation)

• carbonic anhydrase inhibitors can raise urinary pH

• Orange and grapefruit juices – these will increase urinary pH but also contain a high amount of oxalate, so one must balance the risks and benefits

Reference

Struvite StonesTable of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Pathogenesis

Urease Organisms

Therapy

Cystine Stones

• Struvite is MgNH4PO46H2O; it comprises 10-15% of all stones

• These stones form only in urine that contains urea-splitting organisms

• The stone that forms is an infected stone

• Therefore, successful treatment requires complete removal

of the entire stone

• Because struvite stones have a propensity to form in patients with

urinary tract infections, this is the only stone type that is more common

in females than males

• On the next slide you will learn how urea-splitting organisms cause

stone formation

Reference

Struvite Stones - Pathogenesis

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Pathogenesis

Urease Organisms

Therapy

Cystine Stones

Reference

Urea

+ Urease

+ H2O

+ Mg2+ (found in urine normally)

+ PO43- (found

in urine normally)

Struvite

• Struvite stones can adhere to the urothelium without a previous nucleus (such as the Randall plaque)

Struvite Stones – Urease Organisms

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Pathogenesis

Urease Organisms

Therapy

Cystine Stones

Reference

• There are many gram positive and negative

organisms that contain urease

• Urease is necessary for these organisms to

convert urinary urea into NH3 for glutamine

synthesis

• Common organisms: Proteus mirabilis,

Ureaplasma, Corynebacterium, Haemophilis

• E. coli, a common cause of urinary tract

infections, does not possess urease

Struvite Stones – Therapy

Table of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Pathogenesis

Urease Organisms

Therapy

Cystine Stones

Reference

• Because these stones are considered infected, surgical removal is

necessary in any treatment regimen

• Percutaneous nephrolithotomy is successful, with 90% stone-

free rates after 5 years of follow-up

• Lithotripsy and ureteral stents only offer 50-75% stone free rates

• Antibiotics are also necessary to prevent further stone growth

• Conventionally, after urine cultures are obtained, antibiotics are

given until 3 consecutive urine cultures are negative

• Fluoroquinolones, ampicillin are commonly used agents

• Urease inhibitors: these agents will not dissolve existing stones, but

help in preventing further stone growth or new stone formation

• acetohydroxamic acid, hydroxyurea are examples

• most of these agents have terrible side effects and pertinent

contraindications

Cystine StonesTable of Contents

Epidemiology

Pathogenesis

Clinical Manifestations

Evaluation

General Therapy

Calcium Stones

Uric Acid Stones

Struvite Stones

Cystine Stones

Reference

• These stones form because of an inherited defect of an amino

acid transporter

• This transporter defect causes amino aciduria, of which

cystine is the most insoluble

• Cystine solubility increases as urinary pH increases above 6.5

• Therefore, strategies to reduce cystine stones include

increasing urinary pH

• be careful, however, to ensure that that Calcium

phosphate stones do not form as a result of excessive over

alkalanization

Thank you for viewing the 2008-9teaching module in Nephrolithiasis.

Please complete the post-module examination and the brief questionnaire. The questionnairewill be used to improve the design and content of future teaching modules for the Emory Renal Fellowship program.

Both can befound in the same folder as this module.