1 - Kidney Stones / Nephrolithiasis

What is a kidney stone?

A hard stone/pebble-like deposit that forms in urine

Can build up in the kidneys, renal pelvis, or ureters

What happens when kidney stones are small vs. large?

Small stones → May pass through the urinary tract and leave the body on their own

Large stones → May get stuck in the kidney or ureter

How much fluid do the kidneys filter vs. produce as urine daily?

Filter about → 120–150 quarts of blood

Produce about → 1–2 quarts of urine

What are ureters?

Thin tubes of muscle, one on each side of the bladder

They carry urine from each of the kidneys to the bladder

What is the function of the urinary tract?

Filters wastes and excess fluid from the blood

Removes them from the body as urine

How do kidney stones begin to form?

Urine contains water and dissolved substances

When salts or other molecules become supersaturated → (too concentrated for the amount of water) → they precipitate and form crystals

Crystals can grow into kidney stones

What is a universal way to prevent kidney stones?

Increase hydration!!!

It will dilute urine and reduce crystal formation

Any other ways of prevention require → knowing the specific type of stone

How common are kidney stones?

Relatively common

Affecting 9% of women and 11% of men in the US

What affects the amount of urine a person produces and the pH of it?

1. The amount of liquids/food a person consumes

2. Amount of fluid lost via sweating/breathing

3. Certain meds, conditions, and types of food/drink

4. Alcohol

5. Effects of caffeine

How does the amount of fluid lost through sweat/breathing affect the amount of urine produced?

More fluid loss → less, more concentrated urine

Fluid loss depends on temperature, activity level, and individual differences

So more sweat = more concentrated urine

What kind of certain medications can affect the amount of urine produced?

Diuretics and other drugs that impact urine production

What is ADH / Vasopressin ?

Antidiuretic hormone that signals the kidneys to retain water

Increases water reabsorption → decreases urine production

Released from the posterior pituitary → increases during dehydration

How does alcohol affect the amount of urine a person produces?

Ingested alcohol decreases ADH production

This decreases water reabsorption and increases the amount of urine produced

Overall → body loses more water than normal via increases in urination

How does caffeine affect the amount of urine a person produces?

Increases GFR → Blocks adenosine receptors, reducing afferent arteriole vasoconstriction

Decreases Na⁺ reabsorption in proximal tubules → more salt stays in urine, and water follows

Large amounts of caffeine are generally needed to cause significant dehydration

How can distal renal tubular acidosis (dRTA) affect kidney stone formation?

Inherited or acquired metabolic acidosis that increases the risk of kidney stone formation

When can crystals form in urine?

Low urine volume + high solute concentration → salts and compounds can form solid crystals in the kidneys

What is crystal nephropathy?

Kidney damage caused by crystals forming in the kidney tubules or tissues

What drugs can cause drug-induced crystal nephropathy?

Sulfadiazine → sulfonamide antibiotics

Acyclovir and Indinavir → two nucleoside-mimicking antivirals

Triamterene → diuretic used to reduce blood pressure and edema

Methotrexate → anti-cancer and anti-rheumatic arthritis uses

What is acute uric acid nephropathy?

Uric acid crystals forming in kidney tubules and tissues

Sometimes following certain types of cancer chemotherapy

What is nucleation in kidney stone formation?

The formation of a solid crystal nidus of an insoluble component formed from a precipitated solute

Basically → A dissolved substance forms a tiny solid crystal that becomes the starting point of a kidney stone

Homo-nucleation vs. hetero-nucleation?

Homo-nucleation → Crystal forms from the same substance

Hetero-nucleation → Crystal forms around a different substance

What happens after a solid crystal nidus forms?

Crystals deposit at the renal papilla and grow/aggregate over time

If displaced, the stone travels → ureter → bladder → urethra

If too large, it can block the ureter → causing pain and obstruction

What is the main treatment goal for most kidney stones?

Prevention!

Most stones cannot be dissolved with medication, especially once large and established

What is the exception to kidney stones that can be dissolved with medication?

Uric acid stones

Alkalinize the urine → make it less acidic → to help dissolve them

Endoscopic kidney stone removal/surgery ?

Physically removes stones from the urethra, bladder, or ureter

Used when the stone has moved out of the kidney and into the urinary tract

Shock Wave Lithotripsy (SWL)?

Uses targeted shock waves to break an established stone into tiny pieces

The pieces pass through the ureter → bladder → urethra

Common treatment for stones that have formed and are not passing on their own!

What is the goal of treatment after shock wave lithotripsy (SWL)?

Help pass the small stone pieces through urine

Chemolytic agents may dissolve or further shrink fragments, depending on stone type

Prevent new kidney stones from forming

What types of pharmacotherapy can be used to help pass stones?

Pain Relievers

Alpha-blockers → muscle relaxants

Pain reliever pharmacotherapy to help pass stones?

OTC

Can be prescription when needed → percocet, acetaminophen/oxycodone

Alpha blocker pharmacotherapy to help pass stones?

Muscle relaxants

Selective alpha-1 adrenergic receptor antagonists

Selectively relax smooth muscle in bladder, neck, and prostate → which typically restricts resistance to urine flow

How do alpha-1 blockers affect ureter smooth muscle and pressure?

Reduce basal tone → Relax baseline muscle tightness

Reduce peristaltic amplitude and frequency → Make ureter contractions weaker and less frequent

Decrease intraluminal pressure → Lower pressure inside the ureter

How do alpha-1 blockers help move a kidney stone through the ureter?

Increase fluid transport → Increase the rate of urine flow

Increase the intra-ureteral pressure gradient around the stone → creates a pressure difference that helps propel the stone out

What is Flomax / Tamsulosin ?

Uroselective for blocker for → α1A and α1D receptors

Relaxes smooth muscle in the lower ureter → helping the stone pass

Helps relieve stone-related pain

Used in all genders

What is Uroxatral / Alfuzosin ?

Less selective for α1A and α1D receptors than Flomax

Used less often for kidney stone passage across genders → typically used in men

Tamsulosin/Flomax VS Alfuzosin/Uroxatral ?

Head-to-head trials found no significant difference in stone-passage outcomes

Flomax is used more often and has good outcomes with a better safety profile

What is Tamsulosin/Flomax and Alfuzosin/Uroxatral also used for?

To treat benign prostatic hyperplasia

Symptoms of enlarged prostate

Calcium oxalate stones?

Most common

Have black/dark brown appearance

Radiopaque → shows up on x-rays as a white spot

When are calcium oxalate stones more likely to form?

In acidic urine

Use urine alkalinization and increasing urine volume to prevent !!!

Hyperoxaluria?

Can occur by:

Genetic defects → Increase oxalate excretion into urine

Liver metabolism defects → Cause increased oxalate in urine

High-oxalate diet → Foods such as chocolate, nuts, and beer can increase oxalate intake

Complications of hyperoxaluria?

Can cause formation of calcium oxalate stones

Calcium phosphate stones?

Grungy white in color

Radiopaque → shows up on x-rays as a white spot

When are calcium phosphate stones more likely to form?

In alkaline urine

Use urine acidification and increased urine volume to prevent !!!

What factors can increase calcium levels in urine and promote stone formation of calcium-based stones?

Impaired renal tubular reabsorption of calcium → Less calcium is reabsorbed into the blood, so more remains in urine

This can promote both types of calcium-based stones

How can hyperparathyroidism contribute to calcium-based kidney stones?

Excess PTH can disrupt calcium regulation and increase urinary calcium

This increases the risk of calcium-based stone formation!!!

How are blood calcium, PTH, and calcium kidney stones related?

Low blood Ca²⁺ → increased PTH release

High blood Ca²⁺ → decreased PTH release

Excess PTH can increase calcium released from bones and increase urinary calcium

More urinary calcium → increased risk of calcium-based kidney stones

Uric acid stones?

10% of all kidney stones

Red/Brown color

Radiolucent → does not show up in x-rays

Composed of significant amounts of urate

How can uric acid crystals contribute to calcium oxalate stones?

Uric acid crystals act as a starting surface (seed) for calcium oxalate crystals to form and grow

This can promote calcium oxalate kidney stone formation!

What is uric acid, and how does the body eliminate it?

Is a waste product that is normally removed from the body through urine

What is the main risk factor for uric acid stones?

Low urine pH (below 5.5) → promotes uric acid crystallization

Other factors like → diet high in red meat/shellfish, low urine output

How to treat uric acid stones?

Uric acid is less water-soluble than its salt form (urate) when pH is below 6

Need to make urine more basic !! → alkalization

What is used for urine alkalization of uric acid stones?

Potassium citrate or sodium bicarbonate are highly effective → potassium citrate is treatment of choice for prevention of recurrence

Bring pH values between 6.2—6.8

One of the few stones that can be dissolved successfully !!!

Allopurinol / Zyloprim?

Prescription treatment that reduces the frequency of stone formation in hyperuricosuria patients with recurrent uric acid stones and/or gout

Combined with urine-alkalinizing agents → sodium bicarbonate / potassium citrate

MOA of Allopurinol / Zyloprim ?

Blocks xanthine oxidase → so blocks productions of uric acid from xanthine and hypoxanthine in the liver

Basically → decreases productions of uric acid in the liver, which is the primary source of uric acid in the body/joints/urine/etc.

Struvite / Infection stones?

Grungy white in color

Radiopaque → shows up on x-rays as a white spot

Struvite → magnesium ammonium phosphate, a phosphate mineral with the formula NH4MgPO4∙6H2O

How do bacteria cause struvite kidney stones?

UTI bacteria produce urease → which breaks down urea into carbon dioxide and ammonia

Ammonia raises urine pH → makes urine more alkaline

Alkaline urine promotes precipitation of magnesium, ammonium, and phosphate → struvite stones

Cystinuria?

Inadequate reabsorption of cystine in the proximal tubules

Causing excess cystine in the urine that can precipitate in neutral or acidic urine and form stones

What is cystine, and what normally happens to it in the kidneys?

It is disulfide dimer of two L-cysteine molecules

It is formed under normal physiological conditions and normally reabsorbed after glomerular filtration

When do cystine kidney stones form?

When urinary cystine exceeds its solubility limit → about 250 mg/L

Causing cystine to precipitate and form crystals

What causes cystinuria?

Mutations in SLC3A1 or SLC7A9

This impairs reabsorption of cystine and basic amino acids → causing buildup in urine, only cystine forms stones

Males tend to develop stones more than females with the same genetic predisposition

What are the major risk factors for kidney stone formation?

Dehydration → #1 environmental risk; lowers urine volume.

High-sodium diet → Doubles risk; increases urinary calcium and decreases citrate

High animal-protein diet → Increases uric acid and decreases urinary citrate

Medications → Acetazolamide, ephedrine, guaifenesin, topiramate, and triamterene

How does magnesium help prevent kidney stones?

Magnesium binds oxalate and phosphate to form highly soluble complexes

Reducing their binding with calcium and lowering stone formation risk

How does citrate prevent calcium kidney stones?

Citrate binds Ca²⁺ more tightly than Na or K

Reducing calcium available to bind oxalate or phosphate

It inhibits crystal formation and alkalinizes urine

How do urinary stone inhibitors prevent kidney stones?

They bind stone-forming ions to slow crystal formation, growth, and clumping; low inhibitor levels increase stone risk

Ex → magnesium, citrate, glycosaminoglycans, and some proteins

What inherited disorders can cause hypercalciuria and calcium kidney stones?

Distal RTA → defective acid secretion → metabolic acidosis and increased urinary calcium.

Dent disease → X-linked recessive disorder → increased urinary calcium.

Bartter syndrome (types III/IV) → Ion-transport gene mutations → may increase urinary calcium.

Autosomal dominant hypocalcemic hypercalciuria → CASR mutation → low blood calcium and high urinary calcium

What genetic defects promote kidney stones through non-calcium mechanisms?

Hypocitraturia → Low urinary citrate → less stone inhibition

Primary hyperoxaluria → Excess oxalate production → calcium oxalate stones

Cystinuria → Defective kidney reabsorption transporter → excess urinary cystine → cystine stones

What diet and lifestyle changes prevent calcium oxalate and calcium phosphate stones?

Increase fluids and citrus consumption

Maintain citrate, magnesium, and normal dietary calcium intake.

Limit excess sodium, animal protein, and high-oxalate foods → spinach, beets, chocolate, nuts, seeds, potatoes

Avoid stone-promoting drugs and conditions

Eat calcium-rich foods with oxalate-rich foods to reduce oxalate absorption in the gut

How are diuretics used with calcium containing stones?

Thiazides block the NaCl symporter in the distal convoluted tubule → decreases urinary calcium excretion → reduce calcium stone formation

Works best for → Renal leak hypercalciuria (a kidney defect causing high urinary calcium)

How do NaCl symporter inhibitors affect kidney function and urination?

They increase sodium excretion and decrease urinary calcium

Does not affecting renal blood flow and only variably decreasing GFR

Increased urination occurs as the kidneys excrete more sodium and water

How does tiopronin/Thiola prevent cystine stones?

Tiopronin is a prescription chelating agent used when hydration and other measures fail or cystine levels are very high

It forms hetero-disulfides with cysteine to prevent cystine stone formation

Tiopronin / Thiola ?

Orphan drug

Forms a tiopronin-cysteine dimer that is more water-soluble than cystine

Helping prevent crystal and stone formation

Alkalinization of urine?

The target urine pH is around 6.5

pH above 7.0 increases the risk of calcium phosphate stones

Also increases urinary citrate level → helpful to reduce aggregation of calcium oxlate stones

Examples of alkalinization agents → Sodium bicarbonate, potassium citrate, magnesium citrate, or Bicitra

Potassium citrate?

Is an alkaline citrate load that increases urinary pH and raises urinary citrate

Also increase urinary potassium → can contribute to transient reduction in urinary calcium

pKa → 8.5

Potassium citrate supplement?

Cheap / available as a supple → but does not provide the longevity of excretion in urine needed to control stone formation unless a very regular dosing regime is followed

Urocit-K?

Extended-release citrate tablets

Ghost in the stool → citrate slowly diffuses out of the large wax matrix table while the tablet itself can then be excreted in the stool otherwise unchanged