Kidney Stone: Current Status in the

Northeast of Thailand Piyaratana Tosukhowong Wattanachai Ungjaroenwattana Tasanee Klinhom Darunee Boongthong Thasinas Dissayabutra Chanchai Boonla

Current trend of urolithiasis (nephrolithiasis,

Renal stone, Kidney stone) or in Northeast Thailand

Epidemiology

• Incidence

• Demographic data (gender and age)

• Climate and season

Stone comorbidities

• Metabolic syndrome

• Cardiovascular disease

• Chronic kidney disease

• Oxidative stress

• Inflammation

Incidence of urolithiasis IPD in Thailand

ป พ.ศ. จ ำนวนผปวยในทงประเทศ

อบตกำรณ (ตอ 100,000

คน)

ป พ.ศ.

จ ำนวนผปวยในทงประเทศ

อบตกำรณ (ตอ 100,000

คน)

2545 49,706 79.15 2551 61,800 97.49

2546 54,570 86.51 2552 62,239 97.39

2547 55,086 88.89 2553 65,888 103.4

2548 60,668 97.20 2554 57,758 89.99

2549 57,384 91.33 2555 63,558 98.90

2550 57,960 91.94 2556 60,852 93.44 ขอมลโดยส ำนกงำนปลดกระทรวงสำธำรณสข กระทรวงสำธำรณสข

เฉพำะผปวยทเขำรบกำรรกษำในโรงพยำบำลทวประเทศ และ รอยละ 48 เปนผปวยในภำคตะวนออกเฉยงเหนอ (รมว.สธ. 2556)

Urolithiasis: gender

• งำนวจยตำงๆ บงชไปในทำงเดยวกนวำเพศชำยเสยงตอกำรเกดนวสงกวำเพศหญง – สนอง อนำกล (2504) ผปวยโรคนวทวประเทศในป 2496-2502 (26,101 คน) พบเปนชำย:หญง 8:1

– ชวนะ เอยมเพชรำพงศ (2523) ผปวยโรคนวท รพ.สรรพสทธประสงค เปนชำย:หญง 3:1

– ชยณรงค บรตน (2540) รำยงำนผปวยโรคนวท รพ.สรรพสทธประสงค ในป พ.ศ. 2538 (990 คน) เปนชำย:หญง 1.57:1

• จำกรำยงำนของกระทรวงสำธำรณสข สดสวนผปวยโรคนวเพศชำย: เพศหญง ในป พ.ศ. 2549 คอ 1.44:1 และในป พ.ศ. 2556 คอ 1.60:1

Urolithiasis: age

• อำยทมควำมเสยงสงสด คอ 40-50 ป

– ชวนะ เอยมเพชรำพงศ (2523) ผปวยโรคนวท รพ.สรรพสทธประสงค ชวงอำยตงแต 30-60 ป

– ชยณรงค บรตน (2540) รำยงำนผปวยโรคนวท รพ.สรรพสทธประสงค ในป พ.ศ. 2538 (990 คน) มอำยเฉลย 45+14.2 ป

– วฒนชย องเจรญวฒนำ (2556) รำยงำนอำยเฉลยผปวยโรคนวไต โรงพยำบำลสรรพสทธประสงค คอ 46±9.8 ป

Kidney stone disease in Thailand Age & gender

o M:F 2:1 o Age 40-49years

Tosukhowong P, et al. Asian Biomedicine 2007.

Urolithiasis: climate & season

• สนอง อนำกล (สำรศรรำช 1961) ศกษำผปวยนวทำงเดนปสสำวะ 26,101 คน พบวำมผปวยมำกทสดในชวงฤดรอน (เมษำยน-มถนำยน) และนอยทสดในฤดหนำว (พฤศจกำยน-ธนวำคม)

• Tom H (2008) แสดงควำมชกของโรคนวทำงเดนปสสำวะเพมสงขนเมออณหภมสงแวดลอมเพมขน และท ำนำยกำรเพมขนของควำมชกโรคนวในอนำคต

(Proc Natl Acad 2008)

ดงนนคนไทยมโอกำส เกดโรคนวเพมขน

Tosukhowong P, et al. Asian Biomedicine 2007; 1: 94-97.

80.86 % were Calcium oxalate stone

Stone: composition

MAP (1.2 %)

Isolated CaOx (21.0%)

CaOx+CaPO4 (27.2%)

CaOx, CaCO3+MAP (22.5%)

CaOx+Uric acid (16.0%)

CaPO4 (9.7 %)

Isolated CaP (2.5%)

CaPO4, Uric acid, MAP (7.2%)

Uric acid (2.4 %)

Isolated Uric acid (1.2 %)

Uric acid + MAP (1.2%)

CaOx (86.3 %)

from Sunpasit Prasong Hospital(2015) From 4 regions of Thailand

สำเหตของกำรเกดโรคนวมอะไรบำง?

แคลเซยม ออกซำเลต ฟอสเฟต กรดยรก

สำรยบยงนวนอย ซเทรต โพแทสเซยม แมกนเซยม

สำรกอนวมำก

กำรสรำงผลกนว

MS-ภำวะอวน โรคเรอรงอนๆ

ภำวะเครยดจำกออกซเดชน และกำรอกเสบทเนอไต

กระตน

อมตวยงยวด

กำรเตบโตของผลก กอนนว

บรโภคสำรตำนอนมลอสระและพฤกษเคมจำกผลไม

และผกนอย ดมน ำนอย

บรโภคนอยและสญเสยจำก

กำรปรงอำหำร

Stone comorbidities • Common complications: hematuria, flank pain,

urinary tract infection

• Recurrence

• Metabolic syndrome

– Hypertension

– Dyslipidemia

– Obesity

– Insulin resistance/diabetes mellitus type 2

• Cardiovascular disease

• Chronic kidney disease and proteinuria

• Oxidative stress and inflammation

Metabolic syndrome

Kidney stone

Ox

ida

tiv

e s

tre

ss

Infl

am

ma

tio

n

11

Obesity

Hypertriglyceridemia

Low HDL

Hyperglycemia

Hypertension

Cardiovascular disease

Metabolic syndrome and kidney stone disease

Metabolic

abnormalities

Chronic kidney

disease (CKD)

Metabolic syndrome(MS) is associated with the risk of nephrolithiasis

-Association between NL and systemic diseases Diabetes mellitus, Obese, Hypertension, Dyslipidemia, Cardiovascular disease (CVD) risk factors grouped as the MS

Obesity and overweight increase the

risk of kidney stone formation.

Dyslipidemia and Kidney Stone Risks

-Increase the level of total cholesterol, triglyceride LDL and decrease the level of HDL -Hypercholesterol patients have higher urinary K and Ca level -Low HDL and hypertriacylglycerol patients have lower urinary pH and higher urinary Na, oxalate and uric acid level

Dyslipidemia is associated with an increased risk of nephrolithiasis Masterson JH et al ,Urolithiasis. 2015 February ; 43(1): 49–53.

Hypertriglyceride patients have higher urinary Ca, Na, uric acid, Mg and K

14

Kidney stone/ Urolithiasis Metabolic syndrome

Patients treated for urolithiasis with shockwave

lithotripsy, have increased in the prevalence of

diabetes and hypertension.

Diabetes mellitus Hypertension

Kidney stone

formers are at

increased risk

for myocardial

infarction.

15

Urolithiasis Cardiovascular disease

Urolithiasis and metabolic syndrome in Thailand

• Wattanachai U. reported that in 308,185 participants visiting Ubonratchathani project during 2006-2007, 593 had urinary stone.

• Urolithiasis patients were strongly that associated with high blood pressure, diabetes mellitus, hypertension, heart disease, central obesity, and high cholesterol level.

Characteristics of study patients :102 NL patients from

Sunpasit Prasong Hospital in Ubon Ratchathani Province. (2013-2015)

Characteristics of study patients % Sex Male (60) 59.4

Age (years) 46 ± 9.8

BMI (kg/m2) 23.5 ± 3.9 36.3

Lipid profile, Dyslipidemia status and abnormalities (%)

- Triglyceride (mg/dl) 161.6 ± 119.2 41.2

- Cholesterol (mg/dl) 186.1 ± 47.5 38.2

- LDL (mg/dl) 111.6 ± 40.1 30.4

- HDL (mg/dl) 34.3 ± 10.7 79.4

Lipid Profiles and Urinary Lithogenic Promoters

Triacyglycerol Cholesterol LDL HDL

Normo TG

Hyper TG

Normo Chol

Hyper Chol

Normo LDL

High LDL

Normo HDL

Low HDL

Ca 79.8 ±

47.7

104.0±

54.5

82.52 ±

48.08

90.77 ±

52.44

92.05 ±

54.54

84.66 ±

45.14

89.85 ±

53.47

89.59 ±

45.74

Uric 1023.6 ±

376.3

987.1 ±

471.5

1006.2 ±

388.8

1009.3 ±

485.1

1036.2 ±

436.9

907.0 ±

341.0

1030.0 ±

428.3

906.1 ±

371.0

Na 166.6 ±

75.7

183.0 ±

81.5

175.47 ±

82.93

166.97 ±

70.68

174.6 ±

62.1

163.6 ±

84.6

177.4 ±

835

157.6 ±

51.1

ผปวยทมภำวะ triacylglycerol สง จะพบระดบแคลเซยมในปสสำวะสงกวาผทมระดบ triacylglycerol ปกต อยางมนยส าคญทางสถต

Lipid Profiles and Urinary Lithogenic Inhibitors

Triacyglycerol Cholesterol LDL HDL

Normo TG

Hyper TG

Normo Chol

Hyper Chol

Normo LDL

High LDL

Normo HDL

Low HDL

Citrate 175.42 ±

155.92

150,18 ±

145.67

170.10±

154.43

155.38±

148.27

169.07

±

144.24

155.75

±

169.28

168.21±

155.67

152.75

± 137.34

K 39.7 ±

19.7

42.3 ±

20.6

41.3 ±

18.1

39.9 ±

23.0

41.3 ±

20.2

39.6 ±

19.8

40.6 ±

19.7

41.4 ±

21.5

Mg 40.1 ±

29.0

51.0 ±

29.6

46.7 ±

30.8

41.2 ±

27.6

45.9 ±

31.1

41.6 ±

26.1

47.2 ±

31.1

34.4 ±

20.3

ผปวยทมระดบ HDL ต ำ จะพบระดบ Mg ต ำกวำผปวยทมระดบ HDL สง อยำงมนยส ำคญทำงสถต

BMI and Urinary Lithogenic Biomarkers

BMI

normal Over-weight

Ca 81.8 ±

47.5

104.7 ±

56.1

Uric 892.6±

401.5

1188.3±38

5.5

Na 160.7 ±

78.4

195.8 ±

74.6

BMI

normal Over-weight

Citrate 159.44±

130.62

175.53±

164.20

K 38.0 ±

19.1

45.5 ±

21.2

Mg 41.6 ±

28.5

49.1 ±

31.4

Lithogenic promoters Lithogenic inhibitors

ผปวยทม BMI สง จะพบระดบ U-Ca,Na และ uric acid สงกวำผทมระดบ BMI ปกต อยำงมนยส ำคญทำงสถต

Clinicians should consider obtaining lipid levels with the intent that treatment (life style changes) could potentially not only mitigate atherosclerotic disease but also decrease kidney stone risk.

Patients with dyslipidemia 7,742 HLD patients

(4,099 men, 3,643 women)

Statin treatment

reduced the incidence of nephrolithiasis (25% for men and 50% for women)

Do statin medications reduce the incidence of

nephrolithiasis in patients with hyperlipidemia?

Metabolic syndrome

Kidney stone

Ox

ida

tiv

e s

tre

ss

Infl

am

ma

tio

n

22

Obesity

Hypertriglyceridemia

Low HDL

Hyperglycemia

Hypertension

Cardiovascular disease

Metabolic syndrome and kidney stone disease

Metabolic

abnormalities

Chronic kidney

disease (CKD)

The Markers for CKD

23

GFR - assess the filtration

function of glomerulus

- GFR of healthy kidney is ≥90 ml/min

Urine ACR (Urine albumin:creatinine ratio)

- To assess the glomerular

integrity

- The ratio of protein and

creatinine in urine.

- ACR increases in early stage

kidney disease.

In recent years kidney stone have been associated

with increased risk of CKD and ESRD .

Impact of nephrolithiasis on kidney

functions

24

2. Vaka K. et al BMC Nephrology 2015: Impact of nephrolithiasis on kidney function.

The prevalence of CKD was 9.3 % among stone formers compared with 1.3 % in the control group.

1. Ziad M. et al. CJASN 2012 .Urolithiasis and the Risk of ESRD. Stone formers are at increased risk for ESRD independent of several cardiovascular risk factors

3.Lorenz EC, et al. Nephrol Dial Transplant 2011. Clinical Characteristics of potential kidney donors with asymptomatic kidney stones.

Increased prevalence of albuminuria (13% among asymptomatic stone formers) compared with 3.5% in control group.

Impact of nephrolithiasis on kidney functions Corrected CCr in nephrolithiasis patients was significantly lower than that in healthy controls and there was not significant difference of kidney function between stone types

Fibrosis and evidence for epithelial mesenchymal transition in the kidneys of patients with staghorn calculi Chanchai Boonla, Kerstin Krieglstein , Sombat Bovornpadungkitti Frank Strutz Björn Spittau, Chagkrapan Predanon and Piyaratana Tosukhowong

P < 0.001

P =0.453

BJUI 2011

CaOx(21), CaP (five), UA(nine), magnesium ammonium phosphate (MAP, three).

Tosukhowong P, et al, 2015

Impact of nephrolithiasis on kidney functions

ปรมำณโปรตนในปสสำวะของผปวยโรคนวไต มปรมำณสงกวำคนปกต และมระดบลดลงหลงจำกไดรบสตรยำมะนำวผง เปนเวลำ 6 เดอน

Citrate

ยบยงกำรเกดนวโดยกำรจบกบแคลเซยม, ยบยงกำรเกด

ภำวะอมตวยงยวดของแคลเซยม เพมประสทธภำพของ

กลำมเนอในกำรออกก ำลงกำยระยะยำว

ลดภำวะตอกระจกและลดระดบโปรตนในปสสำวะได ในหนทดลองทเปน

โรคเบำหวำน

ลดกำรเกดปฏกรยำออกซเดชนของลพด, กำรเกด DNA damage ในสมอง และกำรเกดภำวะเครยดจำกออกซเดชนในตบ ในหนทดลอง

ทเปนนว

ลดภำวะกรดเกน โดยเพมควำมเปนดำง

ลดควำมผดปกตและกำรอกเสบ ของเซลลบหลอดเลอด ทถกกระตนโดยน ำตำล (hyperglycemia-induced human umbilical

vein endothelial cells)

ตำนทำนภำวะเครยดจำกออกซเดชน, กำรอกเสบและอำกำร

ออนเพลย

Citrate-new functions

Compared the efficacy of lime powder regimen (LPR) and potassium citrate containing equivalent concentrations of potassium (21 mEq) and citrate (63 mEq), on the improvement of metabolic risk factors, in nephrolithiasis

patients.

LPR n = 13

K-Cit. ,n = 11 Placebo, n= 7

LPR and K-Cit had ability to decrease stone-forming potential

by increasing urinary pH, K and citrate excretion. Piyaratana,et al. Urol Res. 2008

Urinary NAG activity and fractional excretion of magnesium were decreased only in patients treated with the LPR

(reduced renal tubular damage)

Lime powder K-Cit. Placebo

Cause of stone recurrence ผปวยเคยเปนโรคนวแลวสวนใหญ เกดนวซ ำบอยๆทำใหเกดโรคไตเร อรง สำเหตทพบมำก

มภำวะเครยดจำกออกซเดชนสง เกดกำรอกเสบ และกำรบำดเจบภำยในเน อไตและพงผดในเน อไต จำกกำรสลำยนว

ภาวะโลกรอน และขาดน าจากการเสยเหงอมาก

ขาดสารยบย งการเกดนวในปสสาวะ คอ ซเทรต รอยละ 90 โพแทสเซยม รอยละ 80 และแมกนเซยม รอยละ 60 มสารกอนวคอ ออกซาเลตในปสสาวะสง (รอยละ33)

Highly Recurrent rate lead to chronic kidney disease o 39% in 2 years at Khon Kaen H. (open surgery) o 25% in 3 years at King Chulalongkorn H.(ESWL)

Renal stone patients

*High oxidative stress

increase blood MDA

*Decrease glutathione

*Potassium citrate improved oxidative stress

Urolithiasis & Oxidative stress

31

CaOx and CaP crystals

increased production of

MCP-1.

IL-8 were significantly

increased in urolithiasis

patients

Urolithiasis & inflammation

32

Metabolic abnormalities found in urolithiasis (2014) Amaro CR et al.

The most prevalent metabolic abnormalities were hypercalciuria (50.8 %),hyperoxaluria (22.5%)and hypomagnesuria (50.1 %).

The etiology of kidney stone disease

55 84.66

47 72.45

8 12.31

22 33.8

Metabolic abnormalities found in urolithiasis (2014-2015)

NL patients from Sunpasit Prasong Hospital

The most prevalent metabolic abnormalities were hypocitraturia and hyperoxaluria.

Hyperoxaluria cause nephrolithiasis characterized by deposition of calcium oxalate crystals throughout the renal parenchyma, profound tubular damage and interstitial inflammation and fibrosis.

Dietary oxalate

Endogenous production of oxalate

Urinary excretion of oxalate

Historically, the contribution of dietary oxalate to urinary oxalate was presumed to be no greater than 10%. Holmes et al (2001) reported dietary oxalate contributes to about 50% of the urinary oxalate.

Hyperoxaluria, Hypercalciuria, Hypocitraturia and Hypomagnesiuria

36

High oxalate consumption and risk of kidney stone

High oxalate consumption and risk of kidney stone

37

-Safarinejad M (2007) Regular black tea consumption is a cultural tradition in Iran, a country with an estimated 5.7 % prevalence of urolithiasis

High dietary intake of oxalate. can cause renal disease(not only nephrolithiasis and nephrocalcinosis, but also AKI, CKD and ESRD) -Fahd Syed (2015) N Engl J Med .Excessive tea consumption lead to nephropathy. A case of the patient who drinking sixteen 8-oz glasses of iced tea daily cause renal failure . Renal biopsy was performed, which showed many oxalate crystals, interstitial inflammation with eosinophils and abundant oxalate crystals are present in urine sediment .

Oxalate in foods

Low oxalate foods

Oxalate is naturally found in many foods, including vegetables, fruits, nuts, seeds, grains, even chocolate and tea.

Very high Oxalate foods

High oxalate foods

Extracted from Oxalate content of foods (available at : https://regepi.bwh.harvard.edu/health/Oxalate/files)

Red meats, fish, poultry,eggs and dairy products contain relatively small amountsof oxalate.

38

Cha-pu, star fruit Pak-paw Pak-nham

increase water intake

limit oxalate-rich foods Quick boil oxalate-rich foods and discard the boiling water to reduce their oxalate content. Many researcher suggested eat calcium and oxalate-rich foods together during a meal can reduce oxalate and urinary oxalate

increase citrate intake intake normal dietary Ca

Prevention of Recurrent Stone Formers in Northeast of Thailand by reduce supersaturation

39 Moderate protein and reduced dietary sodium

DASH-style diet reduces risk for kidney stone

Dietary Approaches to Stop Hypertension (DASH) diet reduces stone risk by Increase urinary stone inhibitors such as citrate, K , Mg, pH and volume Decrease supersaturations (SS) of calcium oxalate and uric acid

40

What is DASH diet ?

High in vitamin, mineral, citrate, K, Mg, fiber and MUFA but also high in oxalate and vitamin C

Low in Na and saturated fat

Food Group

(2000 Cal/day) Exchanges/day

1. Starch or Grains 6-8

2.Vegetables 4-5

3.Fruits 4-5

4.Low-fat dairy 2–3

5.Meats, poultry, fish <6

6.Nuts, seeds, legumes 4-5 per week

7.Fats and oils 2-3

Maximum sodium limit 2,300 mg/day

Source: National Heart, Lung, and Blood Institute, 2012. 41

The DASH eating plan-following amounts of food exchange from each food group:

1,2,3,6=1/2 cup cooked, 4=1 cup, 5=2Tbs, 7=tsp

DASH diet is high in fruits, vegetables, whole grains and low-fat dairy products and low in animal proteins and Na

LPR inhibited the growth of calcium oxalate monohydrate crystals, and inhibited the intracellular production of

reactive oxygen species (ROS) in COM-treated HK-2 cells

• Pajaree Chariyavilaskul · Poonsin Poungpairoj · Suchada Chaisawadi · Chanchai Boonla

· Thasinas Dissayabutra · Phisit Prapunwattana · Piyaratana Tosukhowong In vitro anti-lithogenic activity of lime powder regimen (LPR) and the effect of LPR on urinary risk factors for kidney stone formation in healthy volunteers. Urolithiasis (2015) 43:125–134

Lime powder regimen : reduces risk for kidney stone

Take home messages 1. Metabolic syndrome, CVS and CKD are associated with

kidney stone formation, therefore, to prevent stone onset patients with these underlying conditions should be normalized or corrected.

2. Main dietary risk factors of stone formation are still high consumption of oxalate-rich vegetables, low intake of citrus fruits and low fluid intake.

3. To eradicate kidney stone in NE, it needs a good and effective healthcare team (including nurses, nutritionists, urologists, nephrologists) from all NE hospitals to work collaboratively in order to change a lifestyle-related to kidney stone formation permanently and sustainably.

THANK YOU FOR YOUR ATTENTION