This document discusses urinary stone disease (kidney stones). It reviews the epidemiology, risk factors, pathogenesis and types of kidney stones. It also reviews guidelines for management from the American Urological Association. The main points are: - Kidney stone prevalence is increasing worldwide, especially for calcium stones. Risk factors include metabolic syndrome, obesity, diabetes and cardiovascular disease. - The major stone types are calcium oxalate, calcium phosphate, uric acid and struvite. Composition depends on urine composition and risk factors. - Pathogenesis involves supersaturation of urine leading to crystallization of stone-forming substances. Hypocitraturia and hyperoxaluria are common contributing factors. -

1. Urinary Stone Disease
Christos Argyropoulos MD, PhD, FASN

2. Learning Objectives
• Review the epidemiology and risk factors of urinary
stone disease
• Review the pathogenesis and the types of the
various renal stones
• Review the American Urological Association
guidelines for the management of stones and their
evidence basis
• Clinical approach to the stone former

3. Epidemiology and Risk
Factors of Urinary Stone
Disease

4. Epidemiological concepts relevant
to Urinary Stone Disease
• Incidence: Number of new stone episodes in the
population over a defined period of time
• Prevalence: Number of stones present in a given
population at any point in time
• Lifetime Prevalence: Presence of stones at any
point in a patient’s history
• What is the quantity measured in a survey that asks
if a patient has “ever had a kidney stone”?

5. Worldwide trends in the
epidemiology of nephrolithiasis
Iran J Kidney Dis. 2016 Mar;10(2):51-61
Dtsch Arztebl Int. 2015 Feb; 112(6): 83–91
In the US (and around the globe):
• M>F (but sex differences ↓)
• Struvite is decreasing
• Calcium stones are increasing (in
both the developed world and
developing world)
• Uric acid stones continue to be
more prevalent outside USA
Prevalence
Incidence

6. The burden of kidney stones on
individuals and the healthcare system
• Lifetime prevalence: 13% (men) and 7% in women
• 5-year risk of recurrence: 35-50%
• Risk is time dependent:
• Estimated costs (2000 data – 25 largest employers):
• 2.1-4.5 Billion dollars (direct costs)
• 0.78 Billion dollars (indirect costs)
• Incremental costs for nephrolithiasis: $3,500
Transl Androl Urol. 2014 Sep; 3(3): 278–283.
J Am Soc Nephrol. 2014 Dec;25(12):2878-86.
Time 2 years 5 years 10 years 15 years
Recurrence 11 % 20% 31% 39%

7. Risk factors for urinary stone
disease – The New Epidemiology
• Southeas v.s. Northwest US: x1.8
• Nephrolithiasis as a systemic dz:
• Metabolic syndrome and stones:
• Obesity and stones:
• 220lbs vs <150 lbs (x 1.44 M, x 1.90 F)
• Weight gain > 35lbs : x1.39 M – 1.89 F
• Diabetes and stones:
• 1.4 (both conditions are risk for each other)
• CVD: x 1.18-1.48 risk for revascularization in women
• CKD-ESRD: x 1.5-2.37
Advances in Chronic Kidney Disease, Vol 22, No 4 (July), 2015: pp 273-278
Diet
0 traits 3 traits 5 traits
3% 7.5% 9.8%

8. Pathogenesis and
Pathophysiology

9. Types of stones, frequency and
composition
http://www.ncbi.nlm.nih.gov/books/NBK279069/

10. Manifestation of stones by
composition
http://www.ncbi.nlm.nih.gov/books/NBK279069/

11. Citrate and Urinary Stones
• Most important inhibitor of stone formation
• Several mechanisms of action:
Complexes with calcium
Limits the availability of calcium to bind to oxalate
and phosphate
Inhibits spontaneous precipitation of CaOx
Prevents agglomeration of CaOx
Reduces CaP crystal growth
Prevents heterogeneous nucleation of CaOx by
uric acid

12. Pathogenesis: the interplay between physical
chemistry and molecular cell biology
World J Nephrol. 2014 Nov 6;3(4):256-67.
http://dx.doi.org/10.1155/2013/292953
Am J Nephrol 2014;40:499-506
Two different pathways for Ca stones
• Calcium-phosphate stone may develop
from crystal aggregates deposited at the
tip of the Bellini duct
• Calcium-oxalate stones may result from
urinary calcium-oxalate precipitation on
the Randall's plaque, which is a
hydroxyapatite deposit in the interstitium
of the kidney medulla

13. Randall Plaque and Calcium Stones
– An Integrative Hypothesis
doi:10.1016/j.afju.2014.06.001

14. Tipping the balance
[Nephrology Reviews 2012; 4:e14

15. Randall Plaque
http://eu-acme.org/europeanurology/upload_articles/Knoll%20T.pdf

16. Citrate Metabolism
Renal Citrate Handling Citrate Basics
• Citric Acid synthesized in
the mitochondria
• Constant concentration in
serum
• Freely filtered
• 65-90% reabsorbed in the
proximal tubule
• 95-98% absorbed in the
gut
• NaDC-1 transporter
selects divalent over
trivalent citrate
• NaDC-1 also present in
the intestine
Rev Urol. 2009 Summer; 11(3): 134–144.
• Low pH will shift the equilibrium towards
the trivalent species => hypocitraturia
• Acidosis & hypoK also↓ cell CA levels (↑
gradient for reabsorption)

17. Hypocitraturia – Causes and Mechanisms
Rev Urol. 2009 Summer; 11(3): 134–144.
Acidosis is the most important determinant of urinary citrate
excretion and explains many associations
• Complete RTA-I > incomplete
• Incomplete RTA-I may underline many idiopathic
hypocitraturic cases
• RTA-II not associated with hypocitraturia
• RTA-IV may even be protective (less UCa and UA)
• HypoK+ : intracellular acidosis and ↓ tubular pH
• GI disorders: GI HCO3- wasting
• Animal based diets: mild systemic acidosis, urinary
acidosis and hypocitraturia
• Worse with ketogenic diets (e.g. Atkins)
• High Na intake: expansion acidosis
• Carbonic anhydrase inhibition
VDR polymorphisms: direct effect on NaDC-1
Drug effects:
• ACEi: ↓ citrate lyase activity
• Thiazides: hypokalemia
• Lithium: ↑ urinary citrate

18. Hyperoxaluria
• Raises urinary CaOx supersaturation
• Due to:
• Oxalate overproduction (type I: alanine glyoxalate trasferase, type
II: glyoxalate reducate, type III aldolase)
• Increased dietary intake
• Increased oxalate production (altered Oxalobacter formigenes
flora)
• Malabsorptive syndromes (enteric oxaluria – multiple risk factors
for stones)
• SLC26A6 interaction with the the NaDC-1 in the proximal tubule
J Clin Endocrinol Metab. 2012 Jun; 97(6): 1847–1860
Kidney International (2013) 83, 1144–1149

19. Pathogenesis of non-calcium stones
J Clin Endocrinol Metab. 2012 Jun; 97(6): 1847–1860

20. Hyperuricosuria & Uric acid stones
• Solubility greatly reduced in acidic pH
• “Salting out” phenomenon: decreased solubility of
Calcium oxalate in the presence of monosodium
urate
• Clinical associations & pathogenesis:
• Acidic pH: high animal protein diet, diarrhea, insulin
resistance
• Low urine volume: diarrhea
• Increased production:
• High purine diet
• Increased endogenous production of uric acid
(myeloproliferative, Lesch Nyhan, Tumor Lysis, PV, sickle
cell disease)
J Clin Endocrinol Metab. 2012 Jun; 97(6): 1847–1860

21. Distribution of calcium and UA stones with respect to body mass index (in kg/m 2 )
and diabetes mellitus status. BMI, body mass index; DM, diabetes mellitus.
Calcium stones UA stones.
Seminars in Nephrology Volume 28, Issue 2 2008 174 - 180
Metabolic syndrome and uric acid
stone

22. Types of kidney stones

23. Staghorn Calculi
• Stones that involve the renal pelvis and extend into at
least 2 calyces
• All types of urinary stones can potentially form staghorn
calculi
• About 75% are composed of a struvite: magnesium
ammonium phosphate
• These stones are often referred to as 'infection stones'
since they are strongly associated with infections with
urea splitting organisms

24. Struvite stones
• Two conditions must coexist for the formation of struvite calculi:
(1) alkaline urine (pH >7.2)
(2) the presence of ammonia in the urine
• Invariably associated with infection with urease-producing bacteria:
- Ureaplasma urealyticum
- Proteus species
- Staphylococcus species
- Klebsiella species
- Providencia species
- Pseudomonas species
• Magnesium ammonium phosphate crystals (MgNH4 PO4 •6H2 O) are admixed with carbonate
apatite (Ca10 (PO4) 6•CO3) in varying proportions along with matrix
• The proportion of matrix, typically low molecular weight mucoproteins, is greater than in other
types of calcium-based stones and is thought to protect the bacteria from antimicrobials

25. Calcium Phosphate Stones
• Kidney stones composed predominantly (50% or more) of calcium
phosphate constitute up to 10% of all stones and 15%–20% of
calcium stones
• Calcium phosphate is a minor component of 30% of Ca oxalate
stones
• There are several forms of calcium phosphate that appear in
kidney stones:
- Hydroxyapatite (Ca5(PO4)3(OH) ): most common, the same crystal
form that composes bones
- Brushite (CaHPO4-2H2O): less stable crystal formation
- Carbonate apatite (Ca5(PO4,CO3)3(F, OH, Cl) ): UTI should be ruled
out

26. Calcium Phosphate Stones
• A higher urine pH distinguishes calcium phosphate
stone formers from calcium oxalate stone formers
• At higher urine pH:
H2PO4
− → HPO4
= → more prone to combine with Ca⁺⁺
• Patients with calcium phosphate stones usually have
more profound hypocitraturia
• Females are more likely to have calcium phosphate
stones

27. Mechanisms Underlying Medication
Associated Nephrolithiasis
• Calcium stones: loop diuretics, vitamin D and C,
glucocorticoids, calcium supplements, theyphylline,
CA-inhibitors, amphotericin-B
• Uric acid stones: salicylates, probenecid,
allopurinol (xanthine/oxypurinol stones)
• Medications that precipitate into stones:
sulfonamides, ceftriaxone, floroquinolones,
nitrofurantoin, protease inhibitors, ephedrine,
guanafecine, triamterene (avoid in patients with
h/o nephrolithiasis, esp uric acid lithiasis)

28. Calcium Oxalate Calcium Phosphate
Uric Acid (10-15%) Struvite (10-15%)
(60-70%)
Stone
types
http://www.herringlab.com/photos/index.html

29. Calcium Carbonate
Calcium Citrate
Ammonium Urate
(laxative abuse)
Uncommon types
of Stones
http://www.herringlab.com/photos/index.html

30. Xanthine
2,8-dihydroxyadenine
adenine phosphoribosyltransferase (APRT)
Cystine (1%)
dibasic AA transporter
Alcaptonuria
homogentisate 1,2-dioxygenase
Hereditary
Disorders
• Polycystic kidney Disease
• Medullary Sponge Kidney
• Horseshoe kidney

31. Ciprofloxacin
Indinavir
Triamterene
Sulfamethoxazole
Oxypurinol
Phenazopyridine Phenytoin
Aminophylline
Drugs & Metabolites
(<1%)
Amoxicillin
herringlab.com

32. Amorphous silica
Methylglucamine
Iothalamate
Guaifenesin
Metabolite
Drugs & Metabolites
(<1%)
(magnesium trisilicate)
herringlab.com

33. American Urologic
Association Guidelines
https://www.auanet.org/common/pdf/education/clinical-
guidance/Medical-Management-of-Kidney-Stones.pdf

34. The war of guidelines ACP v.s. AUA
• There are some dis-agreements especially with respect to
fluids, use of drugs and the monitoring of therapy
• I consider the criticism against the ACP guidelines valid e.g.
see
• http://kidneystones.uchicago.edu/acp-guideline-on-medication/
• http://kidneystones.uchicago.edu/an-expert-rebukes-defective-acp-
guidelines/
Or one could choose instead to acknowledge that in the absence of RCT data, writing
guidelines based on “expert opinion” is preferable to nothing, given the clinical need. That
is what the American Urological Association’s committee on Medical Management of
Kidney Stones decided.
It is rather frustrating to read these ACP guidelines in the context of what my goals as a
kidney stone doctor are. I try to advance the idea that kidney stones cause significant
pain, misery and cost and that they are preventable. The ACP guidelines offer no practical
advice that advances this goal. The guidelines do not achieve any utility with respect to
diagnosis, evaluation or therapy. As a result they have no pedagogical value: I would not
distribute the paper to a resident or a fellow if instruction in the care of patients were the
goal.

35. Evaluation I
1. A clinician should perform a screening evaluation
consisting of a detailed medical and dietary history,
serum chemistries and urinalysis on a patient newly
diagnosed with kidney or ureteral stones. (Clinical
Principle)
2. Clinicians should obtain serum intact parathyroid
hormone (PTH) level as part of the screening evaluation
if primary hyperparathyroidism is suspected. (Clinical
Principle)
3. When a stone is available, clinicians should obtain a
stone analysis at least once. (Clinical Principle)
4. Clinicians should obtain or review available imaging
studies to quantify stone burden. (Clinical Principle)

36. Evaluation II
5. Clinicians should perform additional metabolic
testing in high-risk or interested first-time stone
formers and recurrent stone formers. (Standard;
Evidence Strength: Grade B)
6. Metabolic testing should consist of one or two 24-
hour urine collections obtained on a random diet
and analyzed at minimum for total volume, pH,
calcium, oxalate, uric acid, citrate, sodium,
potassium and creatinine. (Expert Opinion)
7. Clinicians should not routinely perform “fast and
calcium load” testing to distinguish among types of
hypercalciuria. (Recommendation; Evidence
Strength: Grade C)

37. Diet Therapies
8. Clinicians should recommend to all stone formers a fluid intake
that will achieve a urine volume of at least 2.5 liters daily.
(Standard; Evidence Strength: Grade B)
9. Clinicians should counsel patients with calcium stones and
relatively high urinary calcium to limit sodium intake and consume
1,000-1,200 mg per day of dietary calcium. (Standard; Evidence
Strength Grade: B)
10. Clinicians should counsel patients with calcium oxalate stones
and relatively high urinary oxalate to limit intake of oxalate-rich
foods and maintain normal calcium consumption. (Expert Opinion)
11. Clinicians should encourage patients with calcium stones and
relatively low urinary citrate to increase their intake of fruits and
vegetables and limit non-dairy animal protein. (Expert Opinion)
12. Clinicians should counsel patients with uric acid stones or
calcium stones and relatively high urinary uric acid to limit intake of
non-dairy animal protein. (Expert Opinion)
13. Clinicians should counsel patients with cystine stones to limit
sodium and protein intake. (Expert Opinion)

38. Pharmacological Therapies I
14. Clinicians should offer thiazide diuretics to patients with
high or relatively high urine calcium and recurrent calcium
stones. (Standard; Evidence Strength Grade B)
15. Clinicians should offer potassium citrate therapy to
patients with recurrent calcium stones and low or relatively
low urinary citrate. (Standard; Evidence Strength Grade B)
16. Clinicians should offer allopurinol to patients with
recurrent calcium oxalate stones who have hyperuricosuria
and normal urinary calcium. (Standard; Evidence Strength
Grade B)
17. Clinicians should offer thiazide diuretics and/or
potassium citrate to patients with recurrent calcium stones in
whom other metabolic abnormalities are absent or have
been appropriately addressed and stone formation persists.
(Standard; Evidence Strength Grade B)

39. Pharmacological Therapies II
18. Clinicians should offer potassium citrate to patients
with uric acid and cystine stones to raise urinary pH to
an optimal level. (Expert Opinion)
19. Clinicians should not routinely offer allopurinol as
first-line therapy to patients with uric acid stones.
(Expert Opinion)
20. Clinicians should offer cystine-binding thiol drugs,
such as alpha-mercaptopropionylglycine (tiopronin), to
patients with cystine stones who are unresponsive to
dietary modifications and urinary alkalinization, or have
large recurrent stone burdens. (Expert Opinion)
21. Clinicians may offer acetohydroxamic acid (AHA) to
patients with residual or recurrent struvite stones only
after surgical options have been exhausted. (Option;
Evidence Strength Grade B)

40. Follow up I
22. Clinicians should obtain a single 24-hour urine
specimen for stone risk factors within six months of
the initiation of treatment to assess response to
dietary and/or medical therapy. (Expert Opinion)
23. After the initial follow-up, clinicians should obtain
a single 24-hour urine specimen annually or with
greater frequency, depending on stone activity, to
assess patient adherence and metabolic response.
(Expert Opinion)
24. Clinicians should obtain periodic blood testing to
assess for adverse effects in patients on
pharmacological therapy. (Standard; Evidence
Strength Grade: A)

41. Follow up II
25. Clinicians should obtain a repeat stone analysis,
when available, especially in patients not responding
to treatment. (Expert Opinion)
26. Clinicians should monitor patients with struvite
stones for reinfection with urease-producing
organisms and utilize strategies to prevent such
occurrences. (Expert Opinion)
27. Clinicians should periodically obtain follow-up
imaging studies to assess for stone growth or new
stone formation based on stone activity (plain
abdominal imaging, renal ultrasonography or low
dose computed tomography [CT]). (Expert Opinion)

42. The Clinical
Management of the
Stone Former
Implementing the guidelines in clinical practice

43. Evaluation components:
Past Medical History
• Obesity
• Hyperthyroidism
• Gout
• RTA I
• DM
• Known bone disease (osteoporosis, rickets)
• Primary Hyperparathyroidism
• Primary or surgical (bariatric Sx) enteric
malabsorption
• Pancreatic disease

44. Evaluation components:
Nutritional and Dietary History
• Low calcium intake (below RDA): ask about milk
& cheese
• Fluid intake (# of glasses of ALL fluids, not just
H2O – but note that cola drinks may ↑ risk)
• High sodium intake (added Na in home cooked
meals, prepared meals/dine-outs)
• Low intake of fruits and vegetables (natural
source of citrate)
• Consumption of meat (source of purines)

45. Evaluation components:
Medication History
• HIV protease inhibitors
(indinavir, atazanavir and
increasingly darunavir)
• Probenecid
• Vitamin D AND Vitamin C
• Extra large doses of
calcium supplements
(usually with vitamin C)
• Carbonic anhydrase
inhibitors:
• Acetazolamide
• Topiramate
• Zonisamide
Indinavir
Atazanavir
http://dx.doi.org/10.1155/2015/106954

46. Evaluation components:
Laboratory (Basic Evaluation)
• Chem 7
• Calcium
• Uric acid
• Dipstick
• Urine microscopy (crystals)
• Urine culture (UTI in UA or recurrent UTIs)
• Also consider when pH>7.0
• PTH:
• When serum calcium is high or normal high
• Calcium phosphate stone composition
• Consider simultaneous measurement of vitD

47. Evaluation components:
Stone Analysis And Imaging
• Stone Analysis:
• Uric acid, cystine, struvite: specific genetic, metabolic
analyses
• Calcium phosphate: RTA-I, 1o HPT, CA-inhibitors,
Medullary Sponge Kidney (MSK)
• Imaging:
• Stone burden (location, size)
• Risk for recurrence (multiple stones)
• Clinical risk (stones in solitary kidney)
• Nephrocalcinosis (RTA-I, 1o HPT, 1o hyper-oxaluria (MSK)

48. Evaluation components:
Expanded Metabolic Testing
• Geared towards identifying metabolic abnormalities upon diagnosis,
assessing recurrence risk and monitoring therapy response & adherence
• One or two 24hr collections (preferable)
Optimal parameters in a 24hr collection
• Volume > 2.5L
• Calcium < 4mg/kgr (250 mg in F, 300 mg
in men)
• Oxalate < 40mg (suspect 1o if > 75mg/d)
• Uric Acid < 750 mg
• Citrate > 320 mg
• Sodium < 3000mg
• Phosphorus < 1100 mg
• Creatinine (completeness of collection)
• CalOx supersaturation: < 5
• CaP supersaturation : 0.5 -2
• UA supersaturation: 0-1
http://www.litholink.com/downloads/StonePatientReportSample-2.pdf
… BUT risk is continuous
Additional tests in the 24hr collection
• Markers of protein intake (sulfate, urinary
nitrogen => animal protein intake)
• Urinary potassium (adherence to therapy
• Cystine (family hx, known cystine stones)

49. Conceptualizing Metabolic Screening
Things you measure in all patients
Things you calculate in (almost) all patients
Don’t try this at home
Clin Cases Miner Bone Metab. 2008 May-Aug; 5(2): 127–130.

50. Calcium intake and stone disease
• A lower calcium intake is associated with higher risk
• In prospective, observational studies, calcium intake within the RDA of 1,000-1,200mg/d is
associated with lower risk, irrespective of the source of calcium, age, body size, dietary
factors, fluid intake and supplemental calcium
• But excessive supplementation may increase risk (measure SS on and off supplements)
• In enteric oxaluria calcium timed with meals may serve as oxalate binder
J Urol. 2013
Oct;190(4):1255-9. doi:
10.1016/j.juro.2013.03.0
74

51. Vitamin C intake is associated with
higher risk for incident stones
• No significant risk in women
• Risk is significant in men (>700mg/day)
Am J Kidney Dis. 2016
Mar;67(3):400-7. doi:
10.1053/j.ajkd.2015.09.005.

52. Restriction of Na and animal fat but
not calcium reduces recurrence risk
N Engl J Med. 2002 Jan 10;346(2):77-84.
All patients Recurrence by baseline risk
A five-year randomized trial comparing the
effect of two diets in 120 men with recurrent
calcium oxalate stones and hypercalciuria.
Do not restrict calcium below
RDA of 1,000-1,200 mg/day
Restrict Na to <2,300 mg/day

53. Thiazide diuretics in patients with high
urine calcium and recurrent calcium stones
Thiazide trials in secondary prevention of lithiasis
Clin J Am Soc Nephrol 5: 1893–1903, 201
Br J Urol. 1996 Aug;78(2):176-8
Indapamide does not ↑
serum uric acid
Doses are x2 those used in
the treatment of HTN
• HCTZ 25 mg po BID
• HCTZ 50 mg po QD
• Chlorothalidone 25mg
po QD
• Indapamide 2.5 mg QD
Used in evidence based
doses only 1/3 of the time
Treat hypoK with
supplements or amiloride
or spironolactone
Urinary calcium
(mmol)
Urinary Citrate (mmol)
Before After Before After
Indapamide 2.5 mg 6.06± 2.68 3.37± 2.00 1.19 ± 0.71 1.18 ±0.79
HCTZ 50 mg 5.58 ± 1.98 3.93±2.35 1.41 ± 1.05 1.00 ± 0.71

54. Potassium Citrate Therapy in patients with
recurrent Ca stones and hypocitraturia
 Potassium citrate will
not only correct
hypocitraturia but
also decrease urinary
sodium and calcium
 Alternatives in pts at
risk for hyperK:
NaHCO3 *Na-citrate
(no effect on Uca) Urology. 2013 Jul;82(1):33-7 Rev Urol. 2009 Summer; 11(3): 134–144.

55. Miscellaneous use of citrate and
diuretics in urolithiasis
• Recurrent stone formation in patients with
“normal” urine metabolic profiles
• Rationale: they have been show to prevent recurrent
episodes in patients with normal range urinary calcium
and citrate
• Use citrate first and thiazides subsequently
• Patients with uric acid acid or cystine stones
• Low pH is an important abnormality driving stone
formation by decreasing solubility
• Target pH of
6.0 (uric acid)
7.0 (cysteine)

56. Practical aspects of citrate (alkali)
therapy for urinary stone disease
• Initial dose
• Urinary citrate <150 mg/day: 60 mEq/day PO (20 mEq with each
meal) OR
• Urinary citrate >150 mg/day: 30 mEq/day PO (10 mEq with each
meal)
• Maintenance
• Target urinary citrate 320-640 mg/day & urinary pH 6.0-7.0 (maximum dose
100 mEq/day)
• Side effects: (mostly GI) bloating, nausea, vomiting,
diarrhea. More common with liquid than tablets
• Citrate in tablets may not be as bio-available as the liquid in GI
disease
• Monitoring: serum electrolytes, urine pH & 24hr
metabolic parameters
• Watch for alkalotic pH (>7) which may ↑ risk for phosphate
stones

57. Citrate “Dietotherapy”
• Citrate containing juices as alternatives for patients who
are intolerant or cannot afford K-citrate
• 1.2L of orange juice v.s. 60meq K-citrate
• Equivalent ↑ in upH, but juice did not ↓ UCa & CaOxSS
• 120mL of concentrate lemonade (diluted to 2L v.s. 40
meq of K-citrate
• Lemonade did not ↑ upH & was less effective in ↑ citrate
• Among low calorie beverages Crystal Light® had the
highest citrate
• Grape juice > lemon juice > orange juice in terms of
citrate content
Rev Urol. 2009 Summer; 11(3): 134–144.

58. Allopurinol in the treatment of
nephrolithiasis
• Do offer it: recurrent oxalate stones with
hyperuricosuria (>800mg/d) and normocalciuria
• Not tested in hyperuricosuria with calciuria
• Alternative to allopurinol (febuxostat): no outcomes trial,
only biochemical ones
• Do not routinely offer it: in uric acid stones
• Most of these patients have low urine pH rather than
hyperuricosuria
• Alkalinization is 1st line therapy
• Allopurinol is adjunct when alkalinization is not successful (GI
disorders) or when stones form despite successful
alkalinization

59. Monitoring of therapy
• 24hr metabolic profile: effectiveness, adherence, dose
escalation: 6 months and yearly thereafter
• Blood based measurements: adverse effects of Rx
• Thiazides: glucose intolerance, hypokalemia, hypercalcemia
(unmasking 1o HPT), hyperuricemia (likely not with
indapamide)
• Allopurinol, Tiopronin: elevated LFTs
• Acetohydroxamic: anemia
• Potassium Citrate: hyperkalemia
• Repeat stone analysis: change in stone composition
• Calcium Oxalate to Calcium Phosphate
• Cystine and uric acid stones: composite “rocks”
• Surveillance urine cultures: struvite stones
• Imaging: assess stone activity and burden

60. Therapy at a glance: calcium stones
J Clin Endocrinol Metab. 2012 Jun; 97(6): 1847–1860

61. Therapy at a glance: non- calcium stones
J Clin Endocrinol Metab. 2012 Jun; 97(6): 1847–1860

62. Special Topics
What I could not fit elsewhere, I just put here

63. Algorithm for the management of
acute renal colic

64. Expectant management of stones
• 75% of distal, 45% of midureteral but only 25% of proximal stones will pass
spontaneously
• A ureteral stone that has not passed spontaneously within 1-2 months it is
unlikely to do so with further management
• Patients with stones < 5mm with minimal symptoms, no infection and stable
renal function may be followed clinically
• Symptomatic patients should be followed closely with renal fx tests and
imaging to assess development of infection, stone growth or obstruction
• Spontaneous stone passage of distal urinary stones may be facilitated with
alpha-blockers (Medical Expulsion Therapy). In meta-analysis:
• Stone expulsion time: shorter by 2.91 days (95%CI 1.81 – 4)
• Increased Rate of passage: 1.48x (95% 1.33x – 1.54 x)
• Decreased pain, hospitalization, need for analgesics but ↑ mild AEs
Cochrane Database Syst Rev. 2014 Apr 2;4:CD008509.

65. Options for Stone Intervention
• Oral stone dissolution:
effective in uric acid stones
with alkalinization
• ESWL: calculi < 3cm in
diameter (1st line in 75% - not
as effective for lower pole
• PCNL: > 3cm, cysteine, CaOx
monohydrate
• Struvite stones: need for
complete removal to prevent
reinfection makes ESWL a
poor choice
Success rates in surgical stone
management

66. Genetic nephrolithiasis
Nephrol. Dial. Transplant. (2013) doi: 10.1093/ndt/gfs54
Monogenetic stone disorders

67. “Red flags” for genetic nephrolithiasis
Nephrol. Dial. Transplant. (2013) doi: 10.1093/ndt/gfs54
Pre-test probability
Clinical Associations

68. Nephrocalcinosis
• Calcium deposition within the kidney:
• Cortical (rare: 3%): cortical necrosis, transplant rejection,
chronic glomerulonephritis, tuberculosis, oxalosis
• Medullary (97%)
Kidney Int. 2015 Jul;88(1):35-43.
Modern theories of pathogenesis and genetic rodent models
suggest that aberrant interstitial calcification (Randal’s plaque) is
the initiating event

69. Genetic syndromes associated with
nephrocalcinosis I

70. Genetic syndromes associated with
nephrocalcinosis II
Kidney Int. 2015 Jul;88(1):35-43.

71. Stone formation after bariatric surgery
• Higher incidence in obese pts undergoing bariatric
surgery (11%) v.s. those not undergoing surgery (4%)
• RR for patients undergoing standard RY is 2.15 but
increases to 4.15 for those undergoing more
malabsorptive procedures
Nat Rev Urol. 2015 May;12(5):263-70.

72. Percentage of abnormal laboratory and 24-hour
urine values before and after surgery
Journal of Urology. 182(5):2334-2339, November 2009
Metabolic changes after bariatric
surgery
• 4639 RYGB patients
• 3 year follow-up
• 7.65% in bypass
patients
• 4.63% in control (p <
0.0001)
J Urol 2009; 181:2573–2577

73. Timeline and pathogenesis of stone
formation after bariatric surgery
• First stone episode : 1.5 – 2 years after surgery
• Risk persists up to 10 years (cumulative incidence 20%)
• Hyperoxaluria and hypocitraturia occur early and may
even worsen over time
• Pathogenesis involves malabsorption of calcium, leading
to enhanced oxalate absorption, increased colonic oxalate
permeability (due to bile acids and systemic acidosis)
• Malabsorptive procedures may even increase the risk of
ESRD (HR: 1.96) and even lead to oxalate nephropathy
Nat Rev Urol. 2015 May;12(5):263-70.

74. Preventive management of stones
after bariatric surgery
Nat Rev Urol. 2015 May;12(5):263-70.

75. Primary Hyperparathyroidism and
Nephrolithiasis
Nephrolithiasis is extremely
common in 1o HPT
Rates of asymptomatic urinary stones
increased 4.3x – 5.3x
J Clin Endocrinol Metab. 2011 Aug;96(8):2377-85
Risk may persist years after surgery

76. Indications for surgery in 1o HPT: 4th
International Workshop Consensus Statement
J Clin Endocrinol Metab, October 2014, 99(10):3561–356
Kidney stones are an indication for surgery either upon presentation or during
follow up (symptomatic stone or detected during imaging

77. Predicting recurrence of kidney
stones (ROKS nomogram)
• Based on 2239 first-time adult kidney stone formers in Olmsted county
• Modeling on clinical variables ascertained within 90 days of initial episode
• An 11-variable model was effective in predicting recurrence (AUC 0.661)
J Am Soc Nephrol. 2014 Dec;25(12):2878-86. doi: 10.1681/ASN.2013091011
Area Under The Curve (AUC):
.90-1.0 = excellent (A)
.80-.90 = good (B)
.70-.80 = fair (C)
.60-.70 = poor (D)
.50-.60 = fail (F)
The best model that currently exists – but
performance is still suboptimal

78. Stone disease in pregnancy
• 1:200 – 1:1500 pregnancies
• 2nd and 3rd trimester
• Mechanisms:
• CaP ( Octacalcium phosphate pentahydrate, a transitional
molecule) Ca8H2(PO4)6*5H2O
• Hydroureter
• Supra-normal GFR
• Increase urine pH
• Hypercalciuria
• Diet
• Placental production of calcitriol
herringlab.com

79. Stone disease in pregnancy:
Complications
• Colic, obstruction, pyelonephritis, sepsis
• Premature membrane rupture, pre-term labor,
preeclampsia
• Recurrent abortions, hypertension, gestational
diabetes, Cesarean section

80. • Ultrasound, low dose non-contrast CT, HASTE MRI
• Conservative approach
• Stone passage rate is double the non-pregnant women
• Urologic interventions
• Ureteroscopy vs. drainage procedure
Stone disease in pregnancy:
Diagnosis and Management

81. Stone and CKD
Rule A D et al. CJASN 2011;6 (8) 2069-2075
Risk for a clinical diagnosis of CKD between stone
formers and control subjects in Olmsted County.
Brushite (Br), calcium oxalate (CaOx), apatite (Apa), struvite
(Str), uric acid (Ua), and cystine (Cys).
Worcester EM J Urol. 2006 Aug;176(2):600-3
Initial creatinine clearance in 1,856 stone formers and
153 normal individuals

82. Urinary stones after renal transplant
• Largest most recent series from Cornell (849
transplants)
• Incidence 1.8% (range in studies 0.4-1%, USRDS 0.11%)
• Diagnosed 3-109 months after transplant (mean 17.8)
• Most in kidney or bladder
• Tertiary hyperpara in >50% of patients
• Recurrent UTIs 1/3
• Hypocitraturia in 25%
• Symptomatic renal colic rare (organ is denervated)
• Management:
• Small stones may be followed if renal fx is stable
• Acute obstruction: usually stent
• After decompression: ESWL or URS for stones <1.5cm,
otherwise percutaneous nephrolithotomy
Korean J Intern Med. 2001 Jun; 16(2): 118–122
Patients usually had
> 1 risk factors

83. Drink Water
?