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Diabetes and the Kidney

Diabetes and the Kidney. Forgetting, or trying to forget, “Diabetic Nephropathy” Dr Peter Drew, Wrexham. TOTAL ECLIPSE. SIDE, ANTALYA, SOUTHERN TURKEY 29 th MARCH 2006 13.55 hrs LOCAL TIME 11.55 hrs BST. Is there anything else to consider?. Infection, simple and complicated

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Diabetes and the Kidney

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  1. Diabetes and the Kidney Forgetting, or trying to forget, “Diabetic Nephropathy” Dr Peter Drew, Wrexham

  2. TOTAL ECLIPSE SIDE, ANTALYA, SOUTHERN TURKEY 29th MARCH 2006 13.55 hrs LOCAL TIME 11.55 hrs BST

  3. Is there anything else to consider? • Infection, simple and complicated Asymptomatic bacteriuria Ascending infection, interstitial nephritis Emphysematous pyelonephritis Xanthogranulomatous pyelonephritis • Renovascular disease • The neuropathic bladder • “Acute-on-chronic” renal failure

  4. Asymptomatic Bacteriuria FACT: Asymptomatic bacteriuria is three times more common in diabetic women than non-diabetics FACT: Diabetic women have more severe urinary infections than non-diabetics, with greater incidence of pyelonephritis and hospitalisation FACT: Serious but uncommon infections occur primarily in diabetics

  5. Why should this be so? Diabetes affects the host defences: Impaired migration of leucocytes Impaired phagocytosis and intracellular killing in leucocytes Impaired recruitment of other cells through chemotaxis Possibly impaired bladder emptying Improved culture medium with higher glucose levels

  6. If the blood sugar is above 10 mmol/l Your leucocytes don’t work

  7. So should we treat asymptomatic bacteriuria in Diabetics?

  8. No effect of antimicrobial treatment • Frequency of symptomatic UTI • Time to symptomatic UTI • Hospitalisation with UTI • But treated group had nearly 5 times as many days on antibiotics • “Diabetes itself should not be an indication for screening for or treatment of asymptomatic bacteriuria”

  9. Study Design • Included adult women, (aged >16 years) but with a mean age of about 55 years. Only about 15% sexually active • Excluded patients with significant renal impairment • Excluded pregnant women (LE Nicolle, Screening for asymptomatic UTI in pregnancy. Health Canada (1994) 100-105) • Excluded patients with a renal transplant (DR Snydman, Posttransplant microbiological surveillance. Clin Infectious Diseases (2001)33: suppl 1: S22-S25)

  10. Are Diabetics more likely to have symptomatic UTI?

  11. Surely, this is a given? • Large case-control prospective study on Washington State • Postmenopausal, with over 1092 case and 1271 controls • Showed risk of symptomatic UTI was greater if on pharmaceutical medication, (OR=2.9)but not according to glycaemic control (HbA1), post-void residual volume or sexual activity

  12. More specific for Diabetes… • Evidence of subacute renal failure, maybe over weeks and months • Trivial proteinuria • Turbid urine • Thick white deposit on centrifugation with white cell casts and bacteria (best seen in polarised light) Acute bacterial interstitial nephritis

  13. N.R. aged 56 yrs • Referred by GP with history of declining renal function over at least a two month period. • History of macro and micro haematuria • An ultrasound had shown an irregular bladder (later cystoscopy showed no sinister pathology) and no obstruction

  14. N.R. aged 56 yrs

  15. N.R. aged 56 yrs • Heavy pyuria and growth of Staph aureus from urine. Organisms & wbc casts. • Prolonged (> 6 months) treatment with flucloxacillin led to progressive improvement in function and disappearance of the pyuria • Remains “well” eight years on with a creatinine of around 200 umol/l

  16. Neurogenic Bladder • Common if there is evidence of neuropathy elsewhere • Incomplete bladder emptying predisposes to infection and functional obstruction increases the severity of infection • In the extreme, the high pressure bladder with chronic retention is a kidney killer

  17. Emhysematous Pyelonephritis • Rare and extremely dangerous • Immune suppressed, mainly diabetic • Acute presentation • Chills, flank pain, confusion and shock • Commoner in women • Mortality rate is very high • Associated with mixed infections, especially with gas-forming enterobacter spp.

  18. Xanthogranulomatous Pyelonephritis An unusual suppurative granulomatous reaction to chronic infection, often in presence of a calculus or obstruction and usually some immune suppression The histological hallmark is presence of foamy lipid-laden macrophages (Xanthoma cells) with diffuse infiltration of plasme cells and histiocytes It presents as mass disease

  19. The Propensity to “Acute Renal Failure” • Diabetes, particularly when associated with microvascular complications, is a potent risk factor for “ATN” • The risk appears to multiply other risks rather than just add to them • How can this be explained (in 10 minutes)?

  20. Number of chronic risk factors (Preexisting renal disease, hypertension, CCF, Diabetes, Age>70,Cirrhosis) in 143 patients with ARF Rasmussen & Ibels, Am.J.Med. 1982

  21. Acute and Chronic risk factors(approximate odds ratios for chance of ARF) • Septic shock (x100) • Dabetes & Volume depletion (x100) • Volume depletion (x10) • Congestive heart failure (x9) • Aminoglycoside use (x6) worse in elderly • Radiocontrast exposure (x5) • NSAID exposure Brezis et al. In Brenner & Rector “The Kidney” 4th ed. 1991)

  22. The enigma of “ATN” • There are many puzzles associated with the common cause of renal failure we associate with sepsis, shock, diabetes , contrast agents and non-steroidal drugs • Can we identify common ground that explains how each of these risks works, and how the risks might amplify each other?

  23. Puzzle 1 The function of the kidney and the urine flow rate are often dissociated in acute tubular necrosis

  24. Functional Changes in ATN • Earliest feature is loss of ability of the kidney to concentrate the urine • Increased fractional excretion of sodium • Tends toward isosthenuria • Reduced excretion of urea • Increased renal excretion of Na/H exchanger isoform 3 (sensitive & specific) (deCheyron Am J Kid Diseases (2003))

  25. The microscopic appearances are considered by many to be diagnostic

  26. Puzzle 2 Despite all the functional mayhem, the renal biopsy seldom shows major changes in ischaemic ATN

  27. Puzzle 3There is no perfect animal model The rabbit and rat are relatively resistant to hypotensive damage. Models often require total occlusion for 90 minutes or more resulting in extensive damage not usually seen in human cases. Same true for toxic models

  28. Puzzle 4 • The kidney has a generous blood supply, with approximately 25% of the resting cardiac output. Where measured in ATN, it is still 30-50% of normal even though GFR may be reduced close to zero. • Furthermore the resting gradient between arterial and venous O2 saturation in the kidney is low, suggesting that there is plenty of capacity to cope with reduced blood flow

  29. O2 Pressure (kPa) 10 5 2 1 DEPTH (mm) 10 20 30 The hypoxic medulla produces lactic acid

  30. SUSCEPTIBLE TO HYPOXIC DAMAGE PARS RECTA OF PROXIMAL TUBULE THICK ASCENDING LIMB OF HENLE

  31. In the normal kidney, at the best of times, the medullary thick limb and the pars recta are working flat out. Anything that reduces the supply of oxygen and energy to these parts will interfere, first with their functional capacity, and then with their structure. In the ascending thick limb, this means inability to generate the concentrating process

  32. Major Risk Factors Affect the Microcirculation and increase Medullary Hypoxia In volume depletion the afferent arterioles are vasoconstricted and worse if NSAIDs in use. Contrast, myoglobin and haemoglobin all cause vasoconstriction With age, and diabetic microangiopathy the circulation is in a precarious state anyway

  33. In Kimmelstiel-Wilson diabetic Nephropathy,both the afferent and efferent renal arterioles are affected whereas in Hypertension it tends to be just afferents. Extensive disease

  34. The Thurau-Boylan Hypothesis of Tubuloglomerular Feedback • Increased chloride ion transport at the macula densa leads to afferent arteriolar vasoconstriction • reduced reabsorption in pars recta or thick limb of Henle provides that increase After Thurau & Boylan, Am J Med 1976

  35. Mechanism Of TGF reflex is obscure High levels of renin and angiotensin in acute tubular necrosis but blockade does not abolish Nitric oxide modulates (and reduces) the effect, as seen with volume expansion

  36. Puzzle 6 How can this explain the situation in anuria when there should be no filtration and no flow past the macula densa?

  37. Elegant studies with Inulin and Dextrans In Established ATN • Demonstrate differential backleak depending on the size of the dextran with approximately 50% of GFR leaking out • Doesn’t explain the very low/zero clearances seen in severe ATN Moran & Myers, JCI 1985

  38. Puzzle 7 Similarly, the presence of tubular leak only explains about 50% of the loss of filtration in anuric ATN. There must be other processes going on.

  39. Best Guess: Multiple factors • Jean Oliver, in microdissection studies over 50 years ago, suggested obstruction at the level of the medullary collecting duct, draining thousands of nephrons • There is evidence of backleak and increased interstitial pressure causing medullary oedema • There is functional impairment with TGF

  40. And nobody else has either “No coherent and consistent pathogenetic hypothesis of ischaemic ATN in humans can be suggested” Olsen & Solez 1994, Puzzle No 8

  41. A long-winded way of saying • The abnormal microcirculation pre-disposes diabetics to ATN • It is probably the reduced flow in the vasa recta, which come off the efferent arterioles • If the flow is reduced, a little bit of hyperosmolar contrast will sludge it up completely • Throw in some NSAIDs for good measure

  42. Renovascular Disease • Accelerated atheroma of diabetes makes renal artery atheroma more likely • Widespread use of ACE-I in diabetics makes it more likely to reveal this renal artery stenosis • Coexistence of diabetic nephropathy,and renovascular disease might be expected

  43. How common is ARVD in DM? • Italian study of diabetics with hypertension found that 99 out of 596 had >50% stenosis of at least one renal artery Zuccala et al (1998) NDT 13:26-29 • Similar results, 16-17% prevalence, in two more recent studies Valabhji et al. (2000) Diabetes Care 23:539-543; Courreges et al.2000) Diabetes Metab 26:90-96 • 30-40% of those undergoing angios for PVD have ARVD, as do 10-15% of those with coronary angios. Missouris et al. (1994) Am J Med 96:10-14; Jean et al. (1994) Cathet Cardiovasc Diagn 32:8-10

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