The organs of the human body were created to perform ten functions among which is the function of the kidney to furnish the human being with thought.

Size: px

Start display at page:

Download "The organs of the human body were created to perform ten functions among which is the function of the kidney to furnish the human being with thought."

Gregory Benson
5 years ago
Views:

1 The organs of the human body were created to perform ten functions among which is the function of the kidney to furnish the human being with thought. Leviticus Rabba 3 Talmud Berochoth 6 1 b

2 Objectives Why is chronic kidney disease important? How do you interpret the tests of kidney function? What is the importance of egfr? Assessment of Chronic Kidney Disease. Lithium and Kidney function. Pathophysiological changes linked to clinical importance.

3 Chronic Kidney Disease (CKD) Australia or NZ Healthy Adult Community Data from AusDiab Increased risk 1:3 CKD 1:7 Dialysis or Transplant 1:1400

4 How much CKD in Australia and New Zealand? 16% ofadults >25yrs have protein orblood in urine or moderately severe reduction in kidney function* GFR <60mL/min 6.6% Albumin in urine 7.5% 2.5% Blood in Urine *MDRD based egfr

5 CKD predicts rate of all cause death (age standardized/100 person years) HMO population N=1,120,295 adults 1,120,295 adults Rate of death > <15 Estimated GFR (ml/min/1.73m 2 ) Median Follow-up = 2.8 yrs Go et al., N Engl J Med, 2004

6 Kidneys working! How do we measure changes in kidney function?

7 Stages of CKD a clinical continuum Kidney damage or mild reduction GFR RRT = Dialysis or transplant Proteinuria GFR >90 ml/min GFR ml/min GFR ml/min GFR <30 ml/min GFR S CR Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

8 Estimated Glomerular Filtration Rate egfr Plasma creatinine inaccurate marker of kidney function 50% loss of kidney mass before changes in plasma creatinine egfr is a derived formula estimating kidney function. Limitations: Initially derived from MDRD study. Accuracy around stage 3a CKD egfr40-59 ml/min/1.73m 2 Inaccurate above 60 ml/min/1.73m 2 Improved with the CKD-EPI formula addition of proteinuria sub groups Underestimates GFR compared to Cockcroft & Gault (tends to over estimate GFR).

9 egfr A Major determinant is AGE Lab variation in plasma creatinine +/- 15umol/l No estimation related to weight No estimation related to weight (standardisedto BSA 1.73m 2 ) (muscle bulk) source of creatinine correction factor for African-Americans but not for Māori / Pacific People.

10 Renal Function: Age-related changes.

11 Impact of Age Male with a plasma creatinine of 100 umol/l Age 65 egfr = 68 ml/min/1.73m 2 Age 75 egfr = 63 ml/min/1.73m 2 Less variation with greater degree of renal impairment. What is senesence versus CKD?

12 Similar risk for Cardiovascular disease. Importance of staging kidney disease

13 Referral Information Renal function for past 5 years (where possible) Urine analysis - albumin / creatinine ratio* protein/ creatinine ratio (>23g/mol) -presence of white or red blood cells. Blood pressure control & medications * differences to what is measured.

14 65 year old male: Please review deteriorating kidney function.

15 No change in egfr over 3 years. Variation around a mean. Calculated creatinine clearances ml/min.

16 Interpreting egfr Extra creatinine values last few years very useful. Important to add other variables proteinuria and blood pressure control. Medications Proportion muscle mass Intercurrent illness or excess activity. Why do we get these fluctuations in egfr?

17 Progressive Nephropathy Overall in CKD Lose the protective vasodilation or vasoconstriction Kidney senses these highs and lows in perfusion pressure Creatinine does rise and fall as you correct this (a linear relationship almost) Pre-glomerular pressure response lost and post-glomerular compensation lost

19 Renal blood flow not protected vascular bed. Hypertension 160/96 egfr 46 ml/in 110/70 Hypotension for patient egfr 30ml/min

20 Hypertension - Arteries stiffen Long standing arterial pulsation: Medial degeneration Direct effects on matrix proteins, collagen and elastin Elastin fibres break reduplication Detachment smooth muscle fibres Increased VSMC Calcification Oxidative stress AGE add to stiffness

21 Arteriosclerosis and Pulse Wave Velocity Systole Diastole

22 Pulse Wave Forms Shape force felt by artery. Older stiff vessel reflected wave early SBP DBP Increased pressure Heart brain kidney SE Greenwald J Pathol 2007

23 Impact of vascular stiffness Heart - impaired diastolic perfusion -diastolic dysfunction -additional impact of coronary calcification Brain - increased risk stroke Kidneys - arteriolosclerosis, glomerulosclerosis

24 Arteriolosclerosis Interstitial fibrosis glomerulosclerosisand tubular atrophy Compensatory glomerular hypertrophy

25 Kidneys reflect vascular injury In patients with CKD Stage 3 Hypertensive nephrosclerosis is a major aetiology. Impact of proteinuria marker of endothelial injury Blood pressure control main focus of therapy.

26 Prevalence of LVH in kidney failure Renal Insufficiency General Population Mild Moderate Severe Start Dialysis CCr ml/min <25 Prevalence LVH 17% 27% 31% 45% 75% Levin et al, AJKD 1999;34:

27 LV disease predicts survival on dialysis Months

28 Intramyocardial fibrosis and calcification

29 Middleton & Pun Kidney Int 2010

30 CKD predicts rate of all cause death (age standardized/100 person years) HMO population N=1,120,295 adults 1,120,295 adults Rate of death > <15 Estimated GFR (ml/min/1.73m 2 ) Median Follow-up = 2.8 yrs Go et al., N Engl J Med, 2004

31 Proteinuria bubbles appearing on the surface of the urine indicate renal disease with a prolonged course

32 Assessment of Proteinuria Proteinuria influenced by Exercise Obesity Hypertension Early morning urine before physical activity Orthostatic benign proteinuria.

34 Take Home Points egfris an estimate, not an absolute value. Hypertension is a major component of Kidney disease Contributes to progression of CKD. Most patients with CKD die of CVD strongest risk factor Any referral for CKD must have egfr, Blood Pressure and urinalysis. Proteinuria and hypertension are major prognostic factors require more aggressive treatment. Proteinuria conveys a greater risk for CVD. Frequently require 3 drug therapy drug type.

35 Look deep into nature and you will understand everything better Albert Einstein

36 HOT NEW TOPIC Renal glucose reabsorption in healthy individuals Glucose ~180 g of glucose per day filtered SGLT-2 ~90% SGLT-1 ~10% Gerich JE. Diabetic Medicine. 2010;27:136

37 Canagliflozin Lowers RT G 125 Urinary Glucose Excretion (g/day y) T2DM+CANA RT G* ~ mmol/l (~70 90 mg/dl) CANA Plasma glucose (mg/dl) T2DM mean RT RT G ~13.3 G ~240 mmol/l mg/dl *Renal threshold for glucose (~240 mg/dl)

GLUT-2 transfers glc to interstitium & plasma Basal Na/K pump

38 Sodium Glucose Transport Actions of SGLT2 inhibitors. SGLT2 transfers glc & Na from lumen into cytoplasm of tubule cells GLUT-2 transfers glc to interstitium & plasma Basal Na/K pump creates a Na gradient Proximal tubule cell 1Wright EM Physiology 2004; 19:

40 Zinman B et al. N Engl J Med 2015;373: Cardiovascular Outcomes and Death from Any Cause.

41 Figure 8 Potential mechanisms for the beneficial effect of empagliflozin on cardiovascular outcomes Remember impact of SSRI s and insulin resistance. DeFronzo, R. A. et al. (2016) Renal, metabolic and cardiovascular considerations of SGLT2 inhibition Nat. Rev. Nephrol. doi: /nrneph

43 CKD in the setting of Lithium Therapy. 65 year male 20 yrhistory of a bipolar disorder Lithium therapy for 15 years (drug monitoring mmol/l) Polydipsia and polyuria 3.5l/day Plasma creatinine 230 umol/l: egfr28ml/min/1.72m 2 Overnight fluid deprivation urine osmolality 468 mosom/kg ddavp max urine osmolality 528 mosom/kg Do you stop his lithium?

44 Lithium and the Kidney Effective drug in management of bipolar unipolar disorders. Major side effect renal manifestations 60% have evidence of impaired renal concentrating ability 20 30% significant polyuria & polydipsia. Short term reversible Long term irreversible functional lesion associated with an interstitial fibrosis

45 Lithium Transport Lithium is excreted by the kidneys Lithium can substitute for sodium on several transport proteins providing entry into cells. Several pathways: Na/H exchange (NHE3) and sodium co-transport (Proximal tubule) ENaC cortical collecting tubule Pathways for lithium out of cells are more limited: Na/H exchange 1?

46 Lithium enters CCD via ENaC Lithium and NDI Inhibition AVP stimulated phosphorylation of AQP2 Limited trafficking AQP2 to apical membrane Impaired water reabsorption Clinically polyuria. AQP2 in human kidney Nielsen et al

47 Urinary concentrating ability in individuals with mood disorders. Is it truly a drug effect of lithium? Role of psychogenic polydipsia? Role of washout medullary gradient by polyuria alone? Drug-induced polydipsia? (serotonergic vs non-serotonergic drugs)

48 Demographics: cross-sectional study of ddavp-stimulated urinary concentrating ability. Impact of psychotropic agents Lithium Lithium naive Female: male 36: 19 31: 6 Age - mean (range) 48 (20 68) 33 (16 66) Duration - lithium therapy 22 (11-28 years) Alternative + supplementary Drugs Serotonergic agents SSRI s 5 8 Tricyclics 6 7 No serotonergic effects MAOIs 3 2 Benzodiazipines 4 0 Anti-epileptics Anti-psychotics

49 Baseline data after overnight water deprivation in the lithium naïve and lithium treated group Lithium naive Lithium Uosm > 750mosm/kg Lithium Uosm mosom/kg Lithium Uosm < 300 mosm/kg Age 33 (15-66) 43 (20-68) 51 (30 68) 43, 54 Duration lithium 13.5 ± ± 2.7 years 25, 28 years therapy years Baseline plasma Osm. Baseline plasma [Li] Baseline plasma [Cr] Baseline plasma [AVP] 290 ± ± ± 2 298, ± 3 umol/l 4.3 ± 0.6 pmol/l 0.73 ± 0.06 mmol/l 0.83 ± , ± 3 95 ± 5 135, ± ± , 18.2

impaired urinary concentrating ability, and decreased urinary AQP2 excretion

50 Urinary osmolality, and AQP2 excretion grouped according to the length of exposure to lithium, compared to Lithium-naïve individuals, The reduction of impaired urinary concentrating ability, and decreased urinary AQP2 excretion correlated with the duration of lithium therapy (r = 0.63 for AQP2) Bedford et al. CJASN 2008

51 Actions of amiloride on urinary concentrating ability and urinary aquaporin 2 (AQP2) excretion in human volunteers on lithium therapy Early treatments to ameliorate lithium-induced polyuria utilized the ENaC channel blocker, amiloride (Battle et al. NEJM 1985) What impact does this have on urinary AQP2? No RCTs of amilorideon lithium-induced NDI.

52 Amiloride and Lithium therapy A randomised placebo controlled trial Double blind placebo controlled trial. Cross-over design. 6 week run-in period on their normal lithium medication, Amiloride or placebo (5mg 1 st week and increased to 10mg 2 nd week) 6 weeks of a placebo or amiloride treatment, 6 weeks washout and then a final 6 weeks of placebo or amiloride. Measurements as for previous clincal studies standard overnight ddavp stimulation test at start and end of each treatment arm. Female : Male Age (years) Duration of lithium therapy 9 : 2 58 (37 71) 20 (8 34)

53 180 placebo amiloride pre placebo amiloride post Amiloride caused a significant increase in maximal urinary osmotic pressure and a significant but lesser increase in AQP2 excretion Bedford et al. CJASN pre post

54 Osmolytes in the renal medulla of rat with lithium-induced NDI given drinking water containing 0.2 mmol-1 amiloride. Control 60 mmol Lithium lithium+ amiloride Inositol (mmol kg-1 protein) 221 ± ± 10** 179 ± 8 Sorbitol (mmol kg-1 protein) 35 ± 9 3 ± 1** 7 ± 2 GPC (mmol kg-1 protein) 352 ± ± 20** 231 ± 38 Betaine (mmol kg-1 protein) 69 ± ± 10 Urea (mmol kg-1 protein) 2868 ± ± 117** 2132 ± 184 Osmol (mosm/kg) 1211 ± ± 19** 1132 ± 154 mean ± SEM, **p<0.01, *<p<0.05 compared to control values; p<0.01, p<0.05 compared to lithium only values.

55 AQP2 Expression Renal Inner Medulla Control Lithium 7weeks Lithium 7 weeks + Amiloride 3 weeks 37kDa 29kDa AQP2 western blot Control Lithium Lithium + amiloride Bedford et al. AJP Renal 2008

56 Mechanisms of chronic lithium injury

57 Lithium nephrotoxicity 65 male 20 yrhistory of a bipolar disorder Lithium therapy for 15 years (drug monitoring mmol/l) Polydipsia and polyuria 4.5l/day Plasma creatinine 233 umol/l Renal biopsy diffuse interstitial fibrosis.

58 Lithium-induced microcysts in renal cortex

59 Lithium-induced interstitial fibrosis after 15 years therapy

60 Lithium nephrotoxicity Presne and colleagues (kidney Int 2003) 74 patients with lithium-induced nephropathy, 12 of whom reached ESRD. The degree of interstitial fibrosis on renal biopsy was related to duration of therapy and cumulative dose of lithium. if estimated creatinine clearance was 40 ml/min, stopping lithium did not alter the progression to ESRD Is there a point of no return where fibrosis continues to progress despite suppression of the triggering toxic event?

61 Lithium nephrotoxicity Presne and colleagues (kidney Int 2003) 74 patients with lithium-induced nephropathy, 12 of whom reached ESRD. The degree of interstitial fibrosis on renal biopsy was related to duration of therapy and cumulative dose of lithium. if estimated creatinine clearance was 40 ml/min, stopping lithium did not alter the progression to ESRD Is there a point of no return where fibrosis continues to progress despite suppression of the triggering toxic event? Do you stop his Lithium therapy? NO.

62 Does Amiloride modify chronic lithium-induced fibrosis Rats Lithium-induced NDI after 4 weeks Amiloride 0.2mmol in drinking water + lithium for a further 5 months compared to control & lithium alone. Tissue for immunohistochemistry, western blotting and RT-PCR

63 Results- Staining for fibrosis- Masson s trichrome Scale bar- 100 µm 5 *** *** % cortical area stained Control Lithium Lithium + amiloride

64 C D CTGF expression

65 Summary Amiloride down-regulates fibrosis but not morphological changes. Lithium induces progressive morphological changes along with interstitial fibrosis. Not a classical macrophage mediated fibrosis Speculative mechanisms Alterations adenylyl cyclase intracellular phosphorylation Inhibition of GSK3 β and upregulation of β catenin and the Wnt canonical pathway

66 Acknowledgements: Funding HRC (NZ) NKF(NZ) Otago Medical Research Foundation, University of Otago Research Grant, Collaborators - A/Prof John Leader & Dr Jenny Bedford PhD students: Rena Jeng, Priya Kalita, Leunie van der Tholen

67 What is man, when you come to think upon him, but a minutely set, ingenious machine for turning, with infinite artfulness, the red wine of pinot noir into urine? Apologies to Karen Blixen C19 th writer.

The organs of the human body were created to perform ten functions among which is the function of the kidney to furnish the human being with thought.

The organs of the human body were created to perform ten functions among which is the function of the kidney to furnish the human being with thought. Leviticus Rabba 3 Talmud Berochoth 6 1 b Outline &