Update in rare and common causes of kidney stones

Transcription

1 Update in rare and common causes of kidney stones John C. Lieske, MD, FACP, FASN SECOND INTERNATIONAL RENAL CONFERENCE BRUGGE 2018 March 16-17, MFMER slide-1

2 Nephrologists and kidney stones Kidneys are cool (but complicated) Only nephrologists really understand how they work Kidney stones are made in the kidneys and are also complicated Even today the pathogenesis is poorly defined, but clearly the renal physiology we are so familiar with is very important Thus, this area of great unmet need is uniquely suited for our specialty 2017 MFMER slide-2

3 Outline Common urine stones Urine chemistries and stone risk Influence of sex Influence of genetics Influence of environment Rarer stone types Diagnosis Treatment 2017 MFMER slide-3

4 All stones submitted to Mayo Medical Labs in 2010 (n=48,446) Number Percent Majority Calcium oxalate 29, % Majority Apatite % Uric Acid % Struvite % Artifact % Brushite % Other % Cystine % Ammonium urate % Drug % Rare 1 } 83.4% Ca 2017 MFMER slide-4

5 Stone type varies by age and sex 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Male Age group 80% 70% 60% 50% 40% 30% 20% 10% 0% Female Age group Uric Acid Apatite Brushite Struvite Cystine Sodium/Potassium Urate Other Artifact Drug Ammonium Urate Calcium Oxalate 2017 MFMER slide-5

6 How do Kidney Stones Form?

7 Supersaturation RSS <1 1 >1 * DG <0 0 >0 * EQUIL2: computer simulation of supersaturation for calcium oxalate, uric acid, calcium phosphate 2017 MFMER slide-7

8 Why do kidney stones form? Urine is supersaturated Some people more than others Most likely other factors But (in 2018) the supersaturation is what we can fix SS correlates with stone type and risk of recurrence Therefore, our job is to figure out: What is causing it and how best to fix it! 2017 MFMER slide-8

9 Key Risk Factors for idiopathic calcium oxalate stones directly related to urinary supersaturation 1. Low volume/ concentrated urine 2. Hypercalciuria 3. Hypocitraturia 4. Hyperoxaluria 5. Hyperuricosuria

10 Drinking water works! Parameter a Placebo Tolvaptan P* (n= 20) (n= 19 ) Serum Na (meq/l) 141±2 142± Serum K (meq/l) 4.1± ± Serum Cl (meq/l) 102±3 102± Serum Bicarb (meq/l) 28±3 27± Serum BUN (mg/dl) 15±4 14± Serum Cr (mg/dl) 0.9± ± Urine volume (ml/24h) 1833± ±2866 <0.001 Urine ph 6.3± ± Osmolarity, mosm/kg 529± ±96 <0.001 Ammonia (mmol/24h) 33±38 26± Calcium (mg/24h) 148± ± Chloride (mmol/24h) 108±72 91± Citrate (mg/24h) 413± ± Creatinine (mg/24h) 1096± ± Magnesium (mg/spec) 76±53 87± Oxalate (mg/24h) 15±8 23± Phosphate (mg/24h) 714± ± Potassium (mmol/24h) 46±46 51± Sodium (mmol/24h) 111±56 97± Uric acid (mg/24h) 473± ± Calcium oxalate SS (DG) 0.95± ±1.14 <0.001 Calcium phosphate (BR) SS (DG) -0.13± ±1.17 <0.001 Uric acid SS (DG) -2.05± ±

11 Drinking water works! Urine Volume 1.81 L 1.83 L 4.81 L Baseline Placebo Tolvaptan Urinary SS (DG) CaOx CaP (BR) UA

12 Thirst and urine flow differs by age and sex

13 Heritabilities of urinary traits Lieske et al: CJASN 2014

14 Systematic differences in calcium metabolism amongst first time stone formers

15 Systematic differences in calcium metabolism amongst first time stone : subtle shift in 1,25 vitamin D levels* Number of pe ersons 1,25 vitamin D 90% calcium oxalate *and serum calcium, PTH, and FGF 23

16 Variable effect of age on urine calcium and other stone risk factors

17 Idiopathic Hypercalciuria Genetic Hypercalciuria Familial: 50% of 1 st degree relatives affected On average, behave functionally as if in a state of vitamin D excess (increased dietary absorption) Renal reabsorption further influenced by diet (Na, protein, sucrose) Low bone mineral density Genetics likely to be complex.. Monogenic causes Bartter s syndrome Dents Soluble adenyl cyclase Ca sensing receptor Claudin 14 CYP24A1 (abnormal 24 vitamin D hyroxylation)

18 Heritabilities of dietary traits! Lieske et al: CJASN 2014

19 Case 1 50 yo gentleman 2 stones Removed ureteroscopically age 30 Removed percutaneously age 36 Neither analyzed Noted to have reduced GFR at age 30 (egfr ~40-50 ml/min/1.73 m 2 ) At a check-up age 49 had fallen to ~30 ml/min/1.73 m 2 Started on low sodium/low protein diet egfr trickled down to 20 s over the next months 2017 MFMER slide-19

20 Case 1 In early 2014 hospitalized with pneumonia Developed acute on chronic kidney injury A kidney biopsy revealed crystal deposition and an acute inflammatory reaction Peritoneal dialysis initiated soon thereafter No family history of kidney disease or stones (two siblings and twin sons) On exam he looks fit 2017 MFMER slide-20

21 Some test results 2017 MFMER slide-21

22 Some test results Plasma oxalate 23.2 µmol/l Urine oxalate 11 mg (Creatinine 447 mg) 1991 urine oxalate 42 mg U/A ph 7.0; trace protein 2017 MFMER slide-22

23 Urine microscopy 2017 MFMER slide-23

24 A DHA: Dihydroxyadenine B C D E COD * COM Cystine Calcium Oxalate Calcium Phosphate 2017 MFMER slide-24

25 Renal Biopsy Not everything that polarizes is calcium oxalate! 2017 MFMER slide-25

26 These are characteristic DHA crystals Confirmatory enzymatic testing on blood spot (UCSD) 2017 MFMER slide-26

27 Other confirmatory testing (research basis) APRT Genetic testing Urine DHA quantification Landspitali University Hospital Reykjavik Iceland 2017 MFMER slide-27

28 X Adenine APRT AMP IMP XDH Adenosine Inosine HPRT 2,8-Dihydroxyadenine Hypoxanthine XDH Xanthine XDH Uric acid Edvardsson et al, Pediatr Nephrol, 2013;28(10): MFMER slide-28

29 The APRT gene Located on chromosome 16q24 Approximately 50 pathogenic human APRT mutations reported all completely abolish enzyme function No genotype-phenotype correlations have been identified MFMER slide-29

30 Treatment Allopurinol? Febuxostat Kidney transplant No liver transplant! 2017 MFMER slide-30

31 Epidemiology The disorder described in all ethnic groups and the majority of reported cases have come from Japan, France, and Iceland. Estimated heterozygote frequency approximately 1% (1.25% in Iceland, whole genome sequencing data). 35 known cases in Iceland (prevalence,1:10,000); Calculated number = 52 based on gene frequency Less than 400 cases reported world wide. Lack of awareness is likely contributing to the low number of reported cases worldwide 2017 MFMER slide-31

32 Monitoring effectiveness of pharmacotherapy Current practice Absence of urinary DHA crystals has been considered indicative of adequate therapy. This approach has proven inadequate and a more reliable method to guide treatment is needed. Future A UPLC-MS/MS assay for the measurement of urinary DHA excretion, as a tool for therapeutic drug monitoring. Although we believe the UPLC-MS/MS assay will greatly enhance treatment monitoring, additional studies are needed MFMER slide-32

33 Results Clinical Drug Trial The median (range) 24 hr urinary DHA excretion was: 256 ( ) mg off drug therapy. 85 (7 236) mg on allopurinol treatment. 0.2 ( ) mg on febuxostat treatment MFMER slide-33

34 Case 2 55 yr old female, native of India Multiple stones onset in mid 20s; 3 SWL+ 1 ureteroscopy; passed 3-4 others; most recent in 2013 Brother died at age 10 with kidney stones and kidney failure Parents both had one kidney stone each but no other kidney failure in family 2017 MFMER slide-34

35 Case 2 cont d Creatinine was 0.8 and 0.7 in 2014 and 2015 Bump in May 2017 to 1.6 and in June to It was 2.5 in the middle of October and more recently 2.6. She had a kidney biopsy in early October 2017 which showed evidence of oxalate crystal deposition. She has had some issues with dehydration and an episode of SVT that required a hospitalization recently. BTW use of herbal remedies 2017 MFMER slide-35

36 Case MFMER slide-36

37 Case MFMER slide-37

38 Case MFMER slide-38

39 Case 2 cont d Genetic testing for AGXT performed in the RKSC research lab. Homozygous c.568g>a change Type 1 Primary Hyperoxaluria 2017 MFMER slide-39

40 Primary Hyperoxaluria 2017 MFMER slide-40

41 Primary Hyperoxaluria: Hepatic pathways PH1 (74%): AGT PH2 (8%): GRHPR PH3 (8%): HOGA LDH OXALATE LDH OXALATE PH 1 and PH2: Cytosolic LDH: Glyoxalate Oxalate (-) PH3:?? Ancillary tests PH1: Glycolate PH2: Glycerate PH3: 4-hydroxyglutamate 2017 MFMER slide-41

42 Urine oxalate is a key risk factor for ESRD in PH Zhao et al Clin J Am Soc Nephrol 11: , MFMER slide-42

43 Renal failure is common especially in PH1 Zhao et al Clin J Am Soc Nephrol 11: , MFMER slide-43

44 Proximal tubule CaOx RSS PT Ox = (UOx*V)/(GFR*(1-r)) PTCaOx RSS = (UFCa * PT Ox)/ 40 Worcester et al: A test of the hypothesis that oxalate secretion produces proximal tubule crystallization in PH1. AJP 305: MFMER slide-44

45 Urine Proximal Tubular CaOx RSS by patient type 2017 MFMER slide-45

46 Relationship between plasma oxalate and egfr in PH, EH and USD patients Perinpam M, et al. Clin Biochem. 50(18): , MFMER slide-46

47 Glycolate Oxidase (GO) Knockdown with sirna to Starve Substrate for Oxalate Synthesis in PH1 Liebow et al: JASN 28: MFMER slide-47

48 2017 MFMER slide-48

49 Case 3 56 yr old gentleman Status post bilateral percutaneous nephrolithotomy age 36 Chronic kidney disease and hypertension with a baseline creatinine of 1.6 mg/dl Acute rise of creatinine to 2.6 mg/dl CT scan revealed very large stone burden in both kidneys. DMSA scan revealed 10% function in the right kidney and 90% in the left. The patient was however asymptomatic MFMER slide-49

50 Case 3 cont d Left PCNL with a secondary left PCNL on March 21, and a tertiary ureteroscopy over 10 d period. Removed stones were 100% cystine. The patient tolerated these procedures well. The left collecting system was completely devoid of stone at the end of these procedures. Postop CT still reveals stone material within most papillae on the left. The right atrophic kidney remains filled with a staghorn MFMER slide-50

51 Case 3- pre op 2017 MFMER slide-51

52 Case 3 post op 2017 MFMER slide-52

53 Case 3 5 mos later a procedure on the right to save function ; largely not successful Cr fluctuates mg/dl BP as high as 200 systolic; worsening LE swelling improved when Cardia, lisinopril, furosemide titrated up Albumin creat ratio (ACR) 2523 mg/g Before the initial procedure predicted 24 hr protein mg/day 2017 MFMER slide-53

54 Case 3 Kidney biopsy: Focal global sclerosis and mild arteriosclerosis Medical management continued Most recent visit 6 mos later BP 132/81 ACR 426 mg/g Cr 2.3 (but CysC 1.44 mg/l, egfr 49 ml/min/1.73m 2 ) 2017 MFMER slide-54

55 Cystinuria 2017 MFMER slide-55

56 Glomerular Capillary Cystine Apical Membrane + - Cystinuria Basolateral Membrane Cystine (and dibasic amino acids) SLC7A9 (b 0,+ AT) SLC3A1 (rbat) Cystine 2 Cysteine Blood URINE: should contain 0.4% of filtered cystine Cystinuria: contains 100% or more of filtered cystine 2017 MFMER slide-56

57 Cystinuria: The Problem Cystine is poorly soluble in urine Precipitates into crystals Crystals grow into stones One year 2017 MFMER slide-57

58 ICF Facebook Page: Highlights in Patient Viewpoint The doctors here are just so mis-informed and keep pushing me to do things that I know and are proven to NOT work but they never want to listen. HEY A- HOLE, LITHOTRIPSY DOES NOT WORK!!!!! In desperate need of some help. Anyone else suffer a mental break down due to this disease? Kaitlin tried to OD on Narco two weeks ago. Had to have her stomach pumped and was in ICU for three days. There's a 5mm stone heading south and taking prisoners on the way down. Dr. doubled my Delaudid prescription 2017 MFMER slide-58

59 Cystinuria causes worse health-related quality of life (HRQoL) than non-cystine stones Frank Modersitzki, MPH, Laura T Pizzi, PharmD, MPH, David S Goldfarb, MD Urolithiasis. 42:53-60, 2014 Improving HRQoL Domains with Time Since Last Stone 2017 MFMER slide-59

60 The only consequence is cystine stones, because cystine is poorly soluble Treatment of cystine stones Quantitate 24-hour cystine excretion Maintain water diuresis Maintain water diuresis low salt diet Low protein (methionine) diet Alkalinize urine d-penicillamine; thiola 2017 MFMER slide-60

61 Cystine excretion: Direct relationship to Na Goldfarb et al: KI 69: , MFMER slide-61

62 Case 3 Cystine MW 240 g/m 24 excretion = 533 mg Theoretic solubility 250 mg/l 2017 MFMER slide-62

63 Drug treatments for Cystinuria 2017 MFMER slide-63

64 Tiopronin Pak et al: J Urol 136: , MFMER slide-64

65 Cystine Solid Phase Assay: Cystine Supersaturation and Capacity Undersaturated Urine Add Cystine A measured amount of cystine crystals are incubated in stirred urine samples for 48 hours. Courtesy, John Asplin, Litholink Corp, Chicago IL Supersaturated 2017 MFMER slide-65

66 Study to determine tiopronin (CBTD) dose effect 1- People with cystinuria treated with tiopronin 2- Each subject takes part in 4 study periods (randomized): (1) CBTD at 0 g/d x 7 days (2) CBTD at 1 g/d (3) CBTD at 2 g/d (4) CBTD at 3 g/d (all BID dosing) 3-24-hour urine collection performed on Day 7 of each period 4- Mean cystine capacity of urine at each dose of CBTD is compared 2017 MFMER slide-66

67 Effect of CBTD Dose on CysCap N=8 P values MFMER slide-67

68 Importance of Treatment Adherence Without adherence to medical management, stone recurrence rates post-surgery are 45% at 3 months With adherence medical management, stone recurrence rates drop to 25% at 36 months Adherent patients (11/20) underwent significantly fewer surgical procedures per year vs. noncompliant patients (9/20) [1.0/patient vs. 4.0/patient, respectively (p<0.05)] 73% of the adherent patients were stone-free vs. 33% of the non-adherent group Byiani, CS, et al. Journal of Urology (2005): MFMER slide-68

69 Loss of GFR in cystinuria: still above that expected 2017 MFMER slide-69

70 JASN 2014

71 The future? RKSC 90+ gene panel Known and candidate monogenic causes

72 Call for questions MFMER slide-72

73 Acknowledgements 2017 MFMER slide-73

74 Questions?

75 2017 MFMER slide-75

76 Genetic hypercalciuria: pharmacologic treatments Thiazide diuretics Indapamide or chlorthalidone have longer half-lives and can be given once daily Be careful with dosing and close follow-up Potassium Citrate Citrate is a crystallization inhibitor Also can reduce urine calcium (? Effects on bone via neutralizing acid load)? Orthophosphate (K Phos neutral) Indirect effects on vitamin D and urine calcium Also a crystal growth inhibitor Large doses/ GI side effects/ no randomized trial 2017 MFMER slide-76

77 What disease is most likely? A. Primary Hyperoxaluria B. Enteric Hyperoxaluria C. Dent disease D. APRT deficiency E. Cystinuria 100% A MFMER slide-77

78 What diagnostic test would be most helpful? A. Urinalysis B. 24 hr urine oxalate C. Plasma oxalate D. Urine cystine E. Dual energy CT of the kidneys F. Urine retinol binding protein 100% A MFMER slide-78

79 Urine microscopy 2017 MFMER slide-79

80 What disease is most likely? A. Primary Hyperoxaluria B. Enteric Hyperoxaluria C. Dent disease D. APRT deficiency E. Cystinuria 100% A MFMER slide-80

81 What treatment would be most helpful? A. Potassium citrate B. Febuxostat C. Allopurinol D. Indapamide E. Very low protein diet F. Low sodium diet 100% A MFMER slide-81

82 APRT Deficiency 2017 MFMER slide-82

83 How would you interpret the elevated plasma oxalate? A. It is consistent with primary hyperoxaluria B. It is consistent with enteric hyperoxaluria C. It is consistent with excess dietary oxalate D. It is consistent with her reduced egfr (no oxalate issues) 100% A MFMER slide-83

84 What diagnostic test would now be helpful? A. Liver biopsy for enzyme analysis B. Genetic testing for alanine glyoxylate transferase (AGXT) mutations C. 72 hour fecal fat D. Spot urine for glycolate, glyoxylate, hydroxyoxoglutarate (HOG) 100% A MFMER slide-84

85 What diet measure would you stress? A. Low Salt B. High fluid intake C. Low protein D. These all help 100% A MFMER slide-85

86 What drug would you add on? A. Tiopronin B. D-penicillamine C. Potassium citrate D. Hydrochlorothaizide E. Febuxostat 100% A MFMER slide-86

87 Cystinuria: Current Solutions Increase solubility of cystine in urine Increase the ph of urine: CITRATE Decrease the concentration of cystine Increase the urine volume Decrease the amount of cystine excreted: REDUCE SALT, PROTEIN Change the cystine into cysteine Use cystine-binding thiols 2017 MFMER slide-87

88 Three forms of PH PH1 PH2 PH3 Enzyme AGT GR/HPR HOGA 1 Urine Glycolate Glycerate HOG % 74% 8% 8% Robijn S, KI 80:1146, MFMER slide-88

89 Cystine capacity (CysCap) and prediction of kidney stone events in cystinuria Modersitzki F, Harvey L, Assimos DG, Goldfarb DS ASN 2016 Cyscap+ patients had: higher UpH, higher V, lower Cys24, lower CysSS CysCap+ patients had significantly fewer stone events 2017 MFMER slide-89

90 Epidemiology Expected prevalence of the homozygous state is at least 1:50, , ,000 cases world wide cases in the US, cases in the UK cases in the Nordic Countires. Lack of awareness is likely, contributing to the low number of reported cases MFMER slide-90