DIDACTIC LECTURE FOR CLINICAL 3

Document Sample
DIDACTIC LECTURE FOR CLINICAL 3 Powered By Docstoc
					 DIDACTIC LECTURE FOR CLINICAL 3


CHRONIC RENAL FAILURE AND
RENAL REPLACEMENT THERAPY



                                   1
PRE TEST FOR CKD

 1. How will you investigate and treat a
 young Nigerian male with a 24-hour
 proteinuria in excess of 3.5g?

2. Define Nephrotic Syndrome
Discuss aetiopathogenesis and histological
  classification of Glomerulonephritis?

                                             2
KIDNEY STRUCTURE (L/S)




                         3
WHAT DOES KIDNEY DO




                      4
PREAMBLE

• Chronic Renal Failure defines a clinical
  state or illness or toxicity in which the
  hallmark of symptomatology is referred to
  as uraemic syndrome (US). Uraemic
  syndrome as a term itself has confounded
  the nephrology world and Teschan
  highlighted the dilemma of defining
  uraemia in his review of uraemia.1
Teschan PE. Uremia: an overview. Seminars in Nephrology
  14,199-204 (1994)                                     5
PREAMBLE CON’D

• It is obvious in our Clinical practice that the
  term CRF is believed to define foremost
  deteriorating excretory function of the
  kidneys measures by (Glomerular
  Filtration Rate) GFR whereas the kidneys
  functions are much more than
  EXCRETORY FUNCTION.


                                                6
WHAT IS DEFINITION OF CRF (CKD) ?
• Chronic Renal Failure (Chronic Kidney Disease)
  is characterized by progressive destruction of
  renal mass with irreversible sclerosis and loss of
  nephron over a period of months or years
  resulting in the progressive loss of the ability of
  the kidneys to excrete wastes, concentrate
  urine, conserve electrolytes, maintain body fluid,
  and also there is initiation of pathological
  changes in several important membranes
  employing array of different pathophysiological
  mechanisms.
                                                        7
CRF DEFINITION CONT’D

• The end result of these interferences in
   the normal mechanisms of an individual is
   systematic and progressive death of cells
   and tissues of the body from
   overwhelming mounting uraemic toxins.

Rutherford WE, Blondin J Miller JP, Greenwalt AS, Vavra JD. Chronic
   progressive renal disease: rate of change of serum creatinine
   concentration. Kidney Int 11, 62-70 (1977)

El Nahas AM, Coles GA. Dietary treatment of chronic renal failure: ten
   unanswered questions. Lancet I,597-600 (1986)

                                                                         8
CRF DEFINITION CONT’D

• Currently a new definition of CRF is being
 used world wide because of its simplicity
 and because it addresses precise
 classification of stages of the CRF. In this
 classification the word Renal is replaced
 with Kidney and Failure is replaced with
 Disease. Thus Renal Failure forms a
 distinct STAGE, the last of spectrum.

                                                9
CRF DEFINITION CONT’D

1.Kidney damage for ≥3months as defined by
  structural or functional abnormalities of the
  kidney with or without decreased GFR, manifest
  by either:
a. Pathological abnormalities; or
b. Markers of kidney damage, including
  abnormalities of the composition of the blood or
  urine, or abnormalities in imaging tests.
2. GFR < 60 ml/min per 1.73m2 for ≥ 3 months
  with or without kidney damage.
National Kidney foundation: K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease:
    Evaluation, Classification and Stratification; Am J Kidney dis 39[Suppl]: S1-S266, (2002)
                                                                                                10
CRF DEFINITION CONT’D

• These definitions have incorporated those
  kidney diseases “cases” that are just silent
  and may not be obvious to the patient and
  are just detected by laboratory or imaging
  methods. These definitions also facilitate
  easy classification.
• But note that CRF is replaced with the
  word Chronic Kidney Disease (CKD).
                                              11
CKD CLASSIFICATION
Stage          Description                    GFR(ml/min
                                              per 1.73m2)
1       Kidney damage with normal or          ≥ 90
        increased GFR
2       Kidney damage with mild decrease in   60-89
        GFR
3                                             30-59
        Moderate decrease in GFR
4                                             15-29
        Severe decrease in GFR
5                                             < 15
        Kidney failure
                                                       12
Stages of Chronic kidney Disease
Stage   Description                  GFR (mL per minute     Metabolic Consequences
                                     per 1.73 m2)




-       At increased risk            Higher than 60 (with   -
                                     risk factors for
                                     chronic kidney
                                     disease
1       Kidney damage (early)        90 or Higher           -
        with normal or elevated
        GFR
2       Kidney damage with mildly    60 – 89*               Parathyroid hormone level begins to rise
        decreased GFR (early renal                          (GFR of 60 to 80).
        insufficiency)
3       Moderately decreased GFR     30 – 59                Calcium absorption decreases (GFR < 50)
        (moderate kidney failure)                           Lipoprotein activity declines & malnutrition
                                                            develops
                                                            Onset of LVH and Anemia (EPO deficiency)
4       Severely decreased GFR       15 - 29                Triglyceride concentration begins to rise
        (pre-end-stage kidney                               Hyperphosphatemia or Metabolic acidosis
        disease)                                            develop
                                                            There is a tendency toward hyperkalemia.
5       Kidney failure (end-stage    < 15                   Uraemia develops
        kidney disease [uremia])                                                                   13
WHEN KIDNEYS FAILED




                      14
PATHOPHYSIOLGY OF CRF

 Between 1 – 1.2 million nephrons are
 available to each kidney and each
 contributing as SNGFR (single nephron
 glomerular filtration rate) to the total GFR.
 Regardless of the aetiology of renal injury
 the end result is progressive nephron loss
 or destruction through glomerulosclerosis.


                                             15
PATHOPHYSIOLOGY CONT’D

 Adaptive mechanisms are possible
 because of a number of mediators –
 Primary, Secondary and Tertiary
 Mediators. They are chemical messengers
 and they interact with a number of
 tissues, cells and with one another to
 cause glomeruli sclerosis, hemodynamic
 changes such as intraglomerular
 hypertension and deposition of varied
 macromolecules.
                                       16
PATHOPHSIOLOGY CONT’D

 Each nephron loss, there is compensatory
 adaptive mechanism of hyperfiltration and
 hypertrophy of surviving nephrons .This
 initial adaptive glomerular response is
 believed to lead to endothelial injury,
 increased glomerular capillary
 permeability, and increased filtration of
 macromolecules.

                                         17
PATHOPHSIOLOGY CONT’D

The end results of these changes are:

• Marked haemodynamic changes as
  evidenced by intraglomerular hypertension

• Activation of mesangial cells to proliferate.

• Increased deposition of mesangial matrix.
                                              18
Mechanisms of Glomerular Injury

• The mechanisms involved emphasise the
  interplay of Mediators, Leucocytes and
  Microvasculature.
• The immediate resultant of these forces is
  Acute Inflammation.
• The concept of Glomerular inflammation is
  that of dynamic process, controlled by
  positive and negative feedback
  mechanisms.                               19
ENDOGENOUS MEDIATORS OF
INFLAMMATION (EM)

• Inflammatory response occurs because of
  local release of ENDOGENOUS
  MEDIATORS (EM).
• These EM include:
  1. Complement
  2. Coagulation Factors
  3. Kinin Cascades
  4. Cytokines
                                            20
ENDOGENOUS MEDIATORS CONT’D

5. Lipid mediators
6. Adhesion Molecules
7. LEUCOCYTES, Macrophages/ Monocytes




                                        21
CYTOKINES

 We can somewhat recall our knowledge
 from pathology and haematology on:
 Complement, Coagulation factors, Kinin
 cascades and Leucocytes, Macrophages/
 Monocytes BUT not so with CYTOKINES,
 ADHESION MOLECULES and LIPID
 MEDIATORS. Let’s talk briefly on
 CYTOKINES as important mediator in
 Glomerular Injury.
                                          22
CYTOKINES

Definition: Cytokines are referred to as
 CHEMICAL COMMUNICAOTRS between
 cells (Arai et al 1990)

The term cytokines is applied to most
 proteins (and glycoproteins) that act as
 chemical communicators.

                                            23
CYTOKINES CONT’D

Cytokines are
(a)MOSTLY SECRETED by various cells but
   some are
(b) (b) EXPRESSED on the cell surface (e.g.
   IL-1α and TNF).
(c)Others are bound to Glycoproteins such
   as DECORIN in the extracellular matrix
   and heparan sulphate proteoglycan on
   the cell surface.
                                          24
CYTOKINES CONT’D

Cytokines can be produced by various cells
 when damaged or exposed to appropriate
 stimuli. However, (a) Leucocytes (b)
 Macrophages (c) Lymphocytes are
 programmed to synthesize them
 abundantly.
Cytokines are Pleiotropic and often have
 activities in common.
                                         25
CYTOKINES FUNCTIONS

Cytokines are LOCAL MEDIATORS but some
 act at distant sites (e.g. IL-6 in pyrexia
 induction and generation Acute Phase
 Response).
Cytokines bind to specific receptors which
 have been arranged into SUPERFAMILIES
 WHICH IN TURN ACTIVATE COMPLEX
 INTRACELLULAR SIGNALLING PATHWAYS.
                                         26
CYTOKINES CONT’D
Cytokines are classified into three main
   groups:
1. Chemokines( CINC, MCP-1, RANTES, MIP-1α, and MIP-1 β)
2. Pro-inflammatory (IL-1, TNF- α, IFN- ‫)צּ‬
3. Anti-inflammatory Cytokines (IL-6, IL-4, IL-13)
This suggests that there are some that
   promote severe inflammatory reaction
   and some that prevent inflammatory
   reaction, thus the balance of the two will
   prevail in any situation.                             27
Example of Cytokines

CINC (Cytokine Induced Neutrophil
  Chemoattractant);
MCP-1(Monocyte Chemoattractant Protein);
RANTES (Regulated upon Activation Normal
  T-cell Expressed and Secreted);
MIP-1α and MIP-1β (Microphage
  Inflammatory Protein)

                                       28
COMPLEMENT SYSTEM

Complement System consists of 20 protein
components that participate in a sequence
of reactions leading to the activation of
humoral (antibody) agents. These proteins
are thought to be produced by glomerular
  cells
as against Liver source. They have
nomenclature of C1-20, however only
C1-9 take part in inflammatory reactions.   29
COMPLEMENT SYSTEM CONTD

Activation of complement occurs by two
Mechanisms:
1. Classical pathway
2. Alternative pathway
In classical pathway activation,
antigen (ag’)-antibody (ab) combination
triggers reactions involving early
Components of complement protein C1(q,r,s) C4
and C2, the product then reacting with C3
                                                30
COMPLEMENT SYSTEM CONTD

 These reactions lead to activation of C3 to
 C3b which then catalyses C5 to C5b and
 C5b in a series of reactions that lead to
 combination of C5b+C6+C7+C8+C9, and
 this is what is referred to Membrane
 Attack Complex.



                                           31
COMPLEMENT SYSTEM CONTD

 Alternative Pathway depends on Factors B,
 D, Properdin (P) and others whose activity
 is enhanced by surfaces that incorporate
 polysaccharides, bacterial
 lipopolysaccaharides or aggregated
 macromolecules.
 The Factors B, D and P activate C3 to C3b
 and then C3b behaves like Classical
 pathway to form Membrane Attack
 Complex.
                                          32
ADHESION MOLECULES

These are necessary to anchor the
Leucocytes and other cells to the
Endothelium for effective inflammatory
response.
These Adhesion Molecules include:
1. Selectins (L-Selectin; P-Selectin; E-
   Selectin)
2. Integrins
3. Mucin-Like Molecules                    33
ADHESION MOLECULES CONT’D

4. Immunoglobulin superfamily molecules
  (ICAM-1,-2,-3) Intercellular Adhesion
  Molecules
VCAM-1 (Vascular Cell Adhesion Molecule)
PECAM (Platelet-Endothelial Cells Adhesion
  Molecule)



                                             34
CONSEQUENCES OF GLOMERULAR
INFLAMMATION
The usual pathophysiological consequences
of acute glomerular inflammation is
proteinuria and reduced GFR (Clinical)
To Histopathologists the viewpoint is triad of
1. Leucocytes infiltration (cell infiltration)
2. Increased Number of Glomerular cells
    (Cell Proliferation)
3. Accumulation of Extracellular Matrix &
    Mesangial Expansion.
                                                 35
CONSEQUENCES OF GLOMERULAR
INFLAMMATION

There are two outcomes:
1. Glomerular cell death through APOTOSIS
2. Disruption of cell matrix
These, however, are in addition to
haemodynamic responses to inflammatory
   injury


                                        36
CONSEQUENCES OF GLOMERULAR
INFLAMMATION

Glomerular Cell death occur because of
elaboration of:
1. Reactive Oxygen Species
2. Release of Neutrophil/Leucocyte
   Proteases
3. Activity of TNF-α
4. Activation of CD8+ Lymphocytes
5. Activity of antibody/complement
                                         37
CONSEQUENCES OF GLOMERULAR
INFLAMMATION

Glomerular Cell and Mesangial Proliferation:
These are consequences of elaboration of
1. Platelet Derived Growth Factor (PDGF)
2. Basic Fibroblast Growth Factor (bFGF)
3. Angiotensin II, Endothelin, IL-1, IL-
   6,TGF-β, Extracellular Matrix Proteins.


                                           38
CONSEQUENCES OF GLOMERULAR
INFLAMMATION

Extracellular Matrix Expansion
This is brought about by the activity of the
following:
1. TGF-β
2. PDGF
3. Macrophages activities

                                               39
Immune Glomerulonephritis: Summary




                                     40
Immune Glomerulonephritis: Summary




                                     41
SUMMARY:CLINICAL
 Initially the nephron adaptability allows for
 continued normal clearance of plasma
 solutes such that substances such as urea
 and creatinine start to show significant
 increases in plasma levels only after total
 GFR has drifted to 50% of normal, this is
 about the time when renal reserve has
 been exhausted. At this point the plasma
 creatinine value will double from its basal
 level of (50µmol/L – 133µmol/L).
                                            42
SUMMARY: CLINICAL

 The clinical implication of this is that the
 basal plasma creatinine value needs be
 known because doubling the value at
 anytime in the course of CRF suggests
 exhaustion of renal reserve and reduction
 of GFR from normal GFR by 50% even
 though the new value may still be within
 normal range.

                                                43
EPIDEMIOLOGY/PREVALENCE OF CRF

 CRF is common but community based
studies are lacking.
Hospital based studies reveal the
incidence of CRF to be between 2-8.4% of
hospital medical admission.
Recent data reveals increasing incidence
>15% of hospital medical admission.

                                       44
EPIDEMIOLOGY/PREVALENCE

 World wide, there is surge of ESRD in the
 last 11/2 decades and this has reached
 epidemic levels.
 The incidence of new ESRD patients in the
 U.S.A. (in 1998) was 308 cases per million
 populations and this has nearly doubled
 by the year 2004 and it is projected that
 prevalence will increase from 340,000
 patients in 1999 to 651,000 patients in
 2010.
                                           45
EPIDEMIOLOGY/PREVALENCE

 15-year data of 540 CRF patients was
 reviewed at Ife, there was male
 preponderance accounting for 69.6%. This
 finding corroborates the finding in another
 Centre (Lagos) in Nigeria. Also United
 States Renal Data System (USRDS) and
 earlier works showed males to be more
 prone to progressive CRF than female.

                                           46
EPIDEMIOLOGY/PREVALENCE

 CRF can be found in people of any age,
 from infants to the very old. In advanced
 economic countries, U.S.A., Europe,
 Japan, the highest incidence of ESRD
 occurs in those older than 65years.This is
 not so in Nigeria, our recent data at Ife
 show the ESRD to be highest among
 productive, economically viable population
 (age 40 – 60years).
                                          47
MORBIDITY/MORTALITY IN CRF

 CRF is a major cause of morbidity and
 mortality all over the world. The 5-year
 survival rate for a patient undergoing
 chronic dialysis in the United States is
 approximately 35%.
 The mortality from ESRD in Nigeria is
 absurdly high. The quality of life adjusted
 years survive (QALYS) cannot be
 calculated implying very high mortality
 rate within the first year of diagnosis of
 ESRD.                                       48
CAUSES OF CRF

• Systemic Hypertension
• (CGN) Primary Glomerular disease MN,
    FSGS, MCD, MPG, RPG
•   DM
•   Secondary glomerular disease SLE, RA,
    MCT, Scleroderma, Wegener Disease,
    Goodpasture syndrome, mixed
    cryoglobunemia, Hepatitis B,C; HIV,
    Syphilis, TTP, HUS,
    Henoch-Scholein P.                      49
CAUSES OF CRF CONT’D

•   Drugs: Heroin, Gold, Penicillamine, other
    Heavy Metals
•   Heredofamilial – Polycystic Kidney disease,
    ADPKD, ARPKD, Alport’s Syndrome, Cystinosis,
    Dent disease, Fabry Disease, Neil-Patella
    Syndrome
•   Vascular disease – Hypertensive
    Nephrosclerosis, PAN, C-ANCA positive and P-
    ANCA positive vasculitides, ANCA -ve
    vasculitides, RVT, RAS.
                                               50
CAUSES OF CRF CONT’D

• Tubulointerstitial disease – chronic
    hypercalcemia, chronic hypokalemia,
    Sarcoidosis, multiple myeloma, cast
    nephrpathies.
•   Obstructive uropathy – BPH, Ca
    Prostate, retroperitoneal fibrosis,
    urolithiasis, urethral stricture,
    neurogenic bladder.
•   The list is endless, and there is degree
    of overlapping.                            51
CLINICAL FEATURES

 Patients whose renal adaptation maintains
 a GFR of 70 – 90ml/min are generally
 asymptomatic and do not experience
 clinically evident of fluid and electrolytes
 imbalance or overt endocrine and
 metabolic disturbances. The clue to renal
 injury at this stage can be historical and
 then back up with laboratory and imaging
 evidences.
                                            52
CLINICAL FEATURES CONT’D

The patients may complain of:-
• Facial puffiness ± leg swelling
• Smoky urine/Frothy urine, Lassitude, Nocturia
• CVS Symptoms
The Laboratory evidences include:
• Proteinuria, Micro / macrohematuria,
    Leucocyturia, Casts,
• Falling Specific Gravity (Isosthenuria)
    culminating into nocturia
• Such other Laboratory findings such as rising
    serum creatinine (>176µmol/L) and abnormal
    results of kidney imaging.

                                                  53
CLINICAL FEATURES CONT’D

The disturbances become clinically manifest
  through the stages of CKD and particularly when
  GFR ≤ 30ml/min (Stage 3 CKD).
• Uraemic symptoms, endocrine and metabolic
  disturbances become evident
• Fluid and electrolytes imbalance are overt.
• Cardiovascular abnormalities are obvious and
  these include hypertension, CHF, uraemic
  cardiomyopathy, cardiac arrhythmia, pericarditis,
  arteriosclerosis etc.
                                                 54
CLINICAL FEATURES CONT’D

 – Encephalopathy, peripheral neuropathy,
   psychotic symptoms, restless leg syndrome,
   sleep disorder.
 – Gastrointestinal (GI) symptoms – anorexia,
   nausea, vomiting, hiccough, diarrhoea,
   dyspepsia, gastric bleeding.
 – Skin manifestation – dry skin, pruritus,
   ecchymosis, and platelet dysfunction.
 – Fatigue, malnutrition, erectile dysfunction,
   lassitude, decreased libido, amenorrhoea.
                                                  55
CLINICAL FEATURES CONT’D

• Hyperphosphatemia suppresses the renal
 hydroxylation of 25 hydroxyvitamin D to
 active 1,25-dihydrocholecalciferol
 (calcitriol). Thus calcitriol (1,25–
 dihydroxyvitamin D) is low when the GFR
 is < 30ml/min and this initiates the
 complex renal bone disease (RBD) called
 CKD-MBD Chronic Kidney Disease-Mineral
 and Bone Disease).
                                           56
CLINICAL FEATURES: Physical

  The physical examination often helpful to reveal
  the findings characteristics of the condition
  underlying CKD(e.g. hypertension, diabetes,
  lupus, arteriosclerosis, Wegener, heredofamilial
  disease – (Alport, Nail-patella syndrome, Dent,
  Polycystic Kidney Disease).
Or complications of CKD (e.g. pallor, bleeding
  diathesis, Pericarditis both haemorrhagic and
  non-haemorrhagic presenting with chest pain
  and pericardial rub, pulmonary oedema, shallow
  skin, fluffy hair, peripheral oedema, ascites,
  bone tenderness, bone fracture, neurological 57
INVESTIGATIONS: Laboratory

Electrolytes, serum urea (BUN) and serum
  creatinine, protein, albumin:
• Hyperkalemia, low serum bicarbonate,
  hypocalcemia, hyperphosphatemia,
  hyponatremia (in ESRD with free-water excess)
• Hypoalbuminemia in patients who are nephrotic
  and/or malnourished
Haematological:
• Normochromic normocytic or Hypochromic
  anaemia - Other underlying causes of anaemia
  should be ruled out e.g. worm infestation.
  Infection and Iron status etc.
                                              58
INVESTIGATIONS: Laboratory

Urine
• Urinalysis - Dipstick proteinuria may
  suggest glomerular or a tubulointerstitial
  problem.
• Urine sediment finding of RBCs, RBC
  casts, suggests proliferative
  glomerulonephritis. Pyuria and/or WBC
  casts are suggestive of interstitial nephritis
  (particularly if eosinophiluria is present) or
                                               59
INVESTIGATION:Laboratory

24-Hour Urine profile for:
• Total protein and estimation of GFR using
  endogenous creatinine clearance ( CrCl )
  and urea clearance and averaging the two
  values (i.e. {CrCl + UrCl}/2 ) reduces the
  error usually associated with the use of
  measurement of GFR using endogenous
  creatinine clearance, CrCl.
                                           60
INVESTIGATION:Laboratory

Serum and urine protein electrophoresis to
  screen for a monoclonal protein possibly
  representing multiple myeloma.




                                             61
INVESTIGATION:Laboratory

Serology:
• Antinuclear antibodies (ANA), double-
  stranded DNA (dsDNA) antibody levels to
  screen for systemic lupus erythematosus
• Serum complement levels - May be
  depressed with some
  glomerulonephritides, these include C1,C3,
  C5, C1q etc
                                          62
INVESTIGATION:Laboratory

Serology:
• C-ANCA and P-ANCA levels - Helpful if
  positive in diagnosis of Wegener
  granulomatosis and polyarteritis nodosa
  (PAN) or microscopic polyangiitis,
  respectively
• Anti-glomerular basement membrane
  (anti-GBM) antibodies - highly suggestive
  of underlying Goodpasture syndrome        63
INVESTIGATION:Laboratory

Serology:
• Hepatitis B and C, HIV, Venereal Disease
  Research Laboratory (VDRL) serology -
  conditions associated with some
  glomerulonephritides




                                             64
INVESTIGATION:Imaging

• Plain abdominal x-ray - Particularly useful to look
    for radio-opaque stones or nephrocalcinosis
•   Intravenous pyelogram (IVU) - Not commonly
    used because of potential for radio contrast
    nephropathy; however, often used to diagnose
    renal stones.
•   Retrograde pyelogram may be indicated if a high
    index of clinical suspicion for obstruction exists
    despite a negative study finding
•   Voiding cystourethrogram (VCUG) - Criterion
    standard for diagnosis of vesico-ureteral reflux.
                                                    65
INVESTIGATION:Imaging

Renal ultrasound:
• Small echogenic kidneys are observed in
  advanced renal failure. The hallmark of CRF is
  loss of corticomedullary differentiation.
• Structural abnormalities, such a polycystic
  kidneys is also diagnosed.
• This is a useful test to screen for
  hydronephrosis, which may not be observed in
  early obstruction, or involvement of the
  retroperitoneum with fibrosis, tumour, or diffuse
  adenopathy.
                                                  66
INVESTIGATION:Imaging

Renal radionuclide scan:
• Useful to screen for renal artery stenosis
• Reliable estimation of GFR is to use
  [Mag3, DMSA, DPTA, Iothalamate, EDTA
  (these are short forms of radionuclide
  dyes used)] that assess the kidney
  dynamically or adynamically also
  quantitates differential renal contribution
  from each kidney to total GFR.                67
INVESTIGATION:Imaging

Computed Tomography (CT) Scan:
• CT scan is useful to define better renal
  masses and cysts usually noted on
  ultrasound. Also, it is the most sensitive
  test for identifying renal stones. IV
  contrast-enhanced CT scans should be
  avoided in patients with renal impairment
  to avoid acute renal failure
                                               68
INVESTIGATION:Imaging

MRI:
• Very useful in patients who require a CT scan
  but who cannot receive intravenous contrast. It
  is reliable in the diagnosis of renal vein
  thrombosis just as CT scan and renal
  venography.
• Magnetic resonance angiography also is
  becoming more useful for diagnosis of renal
  artery stenosis, although renal arteriography
  remains the criterion standard.
• MRI is also used to determine Kidney Volume.    69
INVESTIGATIONS: Other Tests

• The Cockcroft-Gault formula for estimating
 CrCl should be used routinely as a simple
 means to provide a reliable approximation
 of residual renal function in all patients
 with CKD. The formulae are as follows:
CrCl (male) = ([140-age] X weight in
 kg)/(serum creatinine X 72)
CrCl (female) = CrCl (male) X 0.85
                                           70
INVESTIGATIONS: Other Tests

Renal Biopsy
• Renal histology in CKD reveals findings
  compatible with the underlying primary
  renal diagnosis.
• The renal tissue obtained is processed
  through three phases, Light microscopy
  (LM), Immunoflorescence (IF) and
  Electron Microscopy (EM) after appropriate
  staining.                                71
TREATMENT OF CRF

Medical Care:
Medical care of the patients with CKD should focus
  on the following:
• Delaying or halting progression of CKD.
• Treatment of the underlying comorbid conditions
  ( DM, Vasculitis etc) if possible.
• Aggressive blood pressure control to target
  value.
• Maintaining adequate nutrition or preventing
  malnutrition associated with CRF.              72
TREATMENT OF CRF

Medical Care:
• Use of ACE inhibitors and/or ARB (avoid in
    bilateral renal artery stenosis [RAS], RAS in a
    solitary kidney).
•   Aggressive glycemic control in patients with
    diabetes
•   Protein restriction - Controversial
•   Treatment of hyperlipidemia
•   Avoidance of nephrotoxins - IV radiocontrast,
    nonsteroidal anti-inflammatory agents (NSAID),
    aminoglycosides and wide range of drugs and
    herbal preparations.
                                                      73
TREATMENT OF CRF: Medical care
Treating pathologic manifestations of
  CKD:
• Anemia with erythropoietin
• Hyperphosphatemia with dietary
  phosphate binders and dietary phosphate
  restriction
• Hypocalcemia with calcium supplements
  +/- calcitriol (active Vitamin D3)
• Hyperparathyroidism with calcitriol or
  vitamin D analogs or non-calcium based
  drugs like Sevelamer or Lanthonium      74
TREATMENT OF CRF: Medical care

Treating pathologic manifestations of
  CKD:
• Volume overload with loop diuretics or
  ultrafiltration during dialysis
• Metabolic acidosis with oral alkali
  supplementation (best treated with dialytic
  therapy)

                                            75
TREATMENT OF ADVANCED CKD

Renal Replacement Therapy (RRT):
• Eventually when the GFR of the CKD
  patient falls to 20ml/min there is need for
  RRT and becomes particularly mandated
  when the GFR is at 10-15ml/min. At this
  point ESRD is diagnosed & QALYS is
  compromised and thus the patient
  requires kidney-assisted device; some
  form of RRT.
                                                76
RENAL REPLACEMENT THERAPY (RRT)

Definition:
 This is method by which some or all the
   functions of the kidneys are substituted
   by mechanical or biological device or
   when the native kidney of the patient is
   replaced by an allograft.
RRT is of two varieties:
(1)DIALYSIS and
(2)TRANSPLANTATION                          77
RENAL REPLACEMENT THERAPY (RRT)

Dialysis:
• Dialysis is either
(i) Haemodialysis (HD)
(ii) Peritoneal Dialysis (PD)- CAPD or its APD
   forms (Automated Peritoneal Dialysis).
However, the commonest type of dialysis
   used worldwide is haemodialysis.

                                             78
HAEMODIALYSIS

• Hemodialysis is a life saving device
  that saves many lives across the
  globe on daily basis.
• HD is an approximate of Natural
  kidney
• HD does not replace Endocrine and
  metabolic functions of natural
  kidney                                 79
How does HD machine work?

HD consists of 2 major components:
• (a) the machine that process blood
  for purification
• (b) the Water Reverse Osmosis
  (WRO)




                                       80
DIALYSIS MACHINE (BLOOD
PURIFICATION)




                          81
PRINCIPLES OF HEMODIALYSIS




                             82
PRINCIPLES OF HEMODIALYSIS




                             83
Physiology of Purification of Blood


There are two principal pathways
1.Diffusion across semipermeable
 membrane called Diffusion Transport
2.Convective Transport mechanism



                                       84
Diffusion Transport Mechanism

This is governed by the following properties:
a.Solute concentration across the
  semipermeable membrane creating
  concentration gradient
b.Membrane Surface Area available for
  transport (the larger the surface area
  available the greater the amount of
  solutes transferred)
                                            85
B. Convective Transport (CT)

As against Diffusion Transport as major
 mechanism underlying the removal of
 toxin in HD the CT operates as a
 result of fluids flow (blood and
 dialysate) across the membrane
 dragging the solutes along as they
 cross the membrane and this is called
 Solvent Drag.
                                      86
C. The Mass Transfer Coefficient (MTC)

The MTC depends on
(i) Porosity and thickness of the
    membrane
(ii)The molecular size of the solutes
(iii)The conditions of flow of blood and
    dialysate.

                                       87
MTC contd

• Therefore the Mass Transfer
 Coefficient (MTC) increases with
 thinner and more porous membranes,
 with decreasing molecular size, and
 with increasing flow rates of both
 blood and dialysate.


                                   88
Recall of Convective Transport (CT)

• B. Convective Transport (CT): As
 against Diffusion Transport as major
 mechanism underlying the removal of
 toxin in HD the CT operates as a
 result of fluids flow (blood and
 dialysate) across the membrane
 dragging the solutes along as they
 cross the membrane and this is called
 Solvent Drag.                        89
CONVECTIVE TRANSPORT (CT)

The CT is governed by the following
  properties which defines Sieving
  Coefficient:
• Molecular size of the solutes
• The membrane pore structure
• And the flow rate

                                      90
FLUID REMOVAL IN HD

Fluid Removal:
• Another major function of the HD is
 Fluid haemostasis. This is achieved by
 fluid removal because in renal failure
 there is problem of fluid
 accumulation. When the kidneys as a
 major source of fluid haemostasis fail
 there is fluid accumulation.           91
FLUID REMOVAL IN HD

Fluid removal is achieved by:
• Pressure gradient across the membrane
  by application of Hydrostatic Pressure
• Under the influence of pressure gradient
  across the membrane fluid moves from
  High hydrostatic pressure to Low
  hydrostatic pressure. This process of
  filtering cell-free fluid from blood is called
  “Ultrafiltration”                              92
FLUID REMOVAL IN HD

The pressure gradient is created by:
• pressurising the blood compartment of
  the Dialyser (this is called positive or
  above atmospheric, pressure)
• or by application of suction to the
  dialysate compartment of the Dialyser
  (this is called negative or subatmospheric,
  pressure)
• or by combination of positive and negative
  pressures.                                 93
CONCEPT OF TRANSMEMBRANE
PRESSURE (TMP)

TMP:
• The pressure gradient created by
  manipulation of the hydrostatic
  pressure across the Dialyser
  membrane is called
  Transmembrane Pressure (TMP).
                                     94
Concept of Oncotic Pressure (OP)

• When the UFR is regressed
  mathematically against the TMP a linear
  regression line is obtained and the
  intercept of this line on TMP axis is the
  Oncotic Pressure (OP) of plasma
  proteins.
• Naturally Oncotic Pressure always
  opposes the Hydrostatic Pressure
  Gradient. UFR occurs only when HPG is
  greater than OP.
                                              95
Concept of Ultrafiltration Coefficient (UC)

• The slope UFR vs TMP regression line is
  called “Ultrafiltration Coefficient
  (UC)” of the Dialyser and is measured
  in millilitres per hour per millimetre of
  mercury (ml/hr/mmHg)

• The intrinsic efficiency of dialyser in
  respect of fluid removal resides in its
  Ultrafiltration Coefficient. The high flux   96
Concentration Polarisation Concept

• The term “Concentration Polarisation” comes
  from the solvent drag force of solutes (plasma
  protein) i.e. convective transport, which drags
  the plasma proteins to the dialyser membrane
  surface at a rate greater than diffusion force
  back into the blood. After sometime these
  proteins become huge and create high Oncotic
  Pressure that opposes the HPG. Once the
  Oncotic Pressure is greater than HPG the UFR is
  impeded inspite of increased TMP. This is the
  period of Concentration Polarisation            97
Clinical Practice
• In clinical practice, the best estimate of the TMP
    required for a given rate of fluid removal is
    based on manufacturer’s specifications and the
    patient is weighed frequently to ensure that the
    rate of fluid removal achieved is equal to that
    desired.
•   However, several manufacturers have
    introduced hardware modules that can control
    the rate of UFR directly. The advantage of these
    hardware modules is elimination of inaccuracy of
    TMP estimation and variability of the dialyser
    Ultrafiltration Coefficients.                    98
Concept of Na Modelling

• Ultrafiltration draws fluid from vascular
  compartment and as fluid is rapidly removed
  from vascular compartment it leads to increase
  concentration of protein with resultant increase
  in Oncotic Pressure. Vascular refilling comes
  from cellular and interstitial fluids but the rate of
  refilling is slow to the rate of removal. This leads
  to hypotensive crisis during dialysis particularly
  when the UFR exceeds 2-3kg. There are some
  patients that have hypotension persistently
  during dialysis. One of the reasons is low
  predialysis plasma Na.                              99
Dialysate Na2+ Manipulation

• Increase Dialysate Na Concentration
 has been found to correct hypotension
 during dialysis but also increases plasma
 potassium (K) concentration by the same
 %age of Na concentration that corrected
 the hypotension. In an individual with
 renal disease and tendency to
 accumulation of potassium concentration
 an increase of potassium will lead to
 undesirable consequence.                  100
Concept of Na2+ Remodelling

• Na remodelling is a concept of altering Na
 concentration during dialysis from Sodium
 Programmable Hardware. Newer HD
 machines have this technology, it senses
 the plasma Na concentration




                                           101
Acid-Base Balance

The metabolic acidosis created by the
  uraemic syndrome is corrected during
  dialysis by system of alkalisation. Thus the
  alkalisation is achieved during HD by
  either of these two alkaline solution:
• Sodium acetate
• Sodium Bicarbonate

                                            102
Sodium Acetate

The draw back for acetate buffering system
 is dependency on conversion in the Kreb’s
 cycle of the liver to bicarbonate (1:1) ratio
 and profound cardiovascular instability by
 its direct vasodilatory effect and/or its
 metabolites. It leads persistently to
 hypotensive crisis during dialysis


                                            103
Sodium Bicarbonate

Bicarb buffering system has two ports:
• (a) “Acid Concentrate” – this consists of
  dialysate without Na bicarbonate to which
  3-5 mmol of acetic acid has been added.
  This acetic acid gives it the name “acid
  concentrate” and it functions by
  preventing calcium and magnesium
  carbonates from precipitating
• (b) “Bicarbonate Concentrate”- (this
  contains Na bicarbonate and Na chloride)104
Drawback of Sodium Bicarbonate
Dialysis
•   technical complexity
•   requiring two concentrates
•   requiring two proportioning systems
•   and two monitoring systems
•   Machines are harder to calibrate and maintain
•   the machines are prone to malfunction because
    of local build up of carbonate precipitates
•   the cost of bicarb-dialysis is higher than acetate
    based dialysis.
                                                     105
Dialysis Prescription and Adequacy

The goals of Dialysis are:
• relief of uremic symptoms
• restoration of an acceptable quality of life
• minimization of major organ system
  dysfunction.




                                             106
Measuring Effectiveness

There are two ways of measuring the
  prescribed dose of HD to gauge its
  effectiveness:
• (i) Qualitative measurement
• (ii) Quantitative measurement



                                       107
Measurement of Dialysis Adequacy

• Qualitative measurement tends to be
 subjective, vague and difficult to use in a
 standardized format and influence by
 factors other than the dialytic process
 itself.

• Therefore Quantitative measurement
 focuses on easy to measure, standardized
 parameters that are influenced by dialysis
                                          108
Urea as a Marker

• Urea as a surrogate marker of small
 uremic toxins has come to play major role
 in assessing the prescription and adequacy
 of dialysis. Urea concentration in the blood
 and subsequent clearance with therapy
 correlates well with the changes observed
 clinically, and as such a correlation implies
 that urea mirrors the important toxins
 handled by dialyser membrane.
                                            109
Urea Kinetic Modelling
UKM to determine effectiveness of dialysis is
  measured by:
• (1) Kt/V
• (2) Percent Reduction of Urea (PRU) =
                 100*(PreUrea-Post
  Urea)/PreUrea

• (3) Urea Reduction Ratio (URR) =
                        100 * {1- Post
  urea/PreUrea}

• (4) Protein Catabolic Rate (PCR) or (nPCR) =
  {Urine Urea (mmol) * 4.2} / ID interval (hr)*
  Weight (kg)                                     110
Urea Kinetic Modelling Kt/V

• The standard Urea Kinetic Modelling is
 Kt/V but its application in clinical practice
 is beset with difficulty in the mathematical
 complexity. This shortcoming is gradually
 fading out because of incorporation of
 software in the newer machines that
 calculate this. The target value for good
 quality of life is between 1.2-1.6

                                             111
Calculating Kt/V Urea Modelling

Using linear regression modelling
• Kt/V = {0.4 * PRU} -1.2
         =       {0.026 * PRU}-0.460
         = {0.024 * PRU}-0.276
         = [-ln (R-0.03) + (4-3.5R) ×
  (UF/W)]
PRU is Percent Reduction of Urea, W
  represents post dialysis weight or patient’s
  dry weight in Kg and UF, volume of        112
Clinical Practical point

• The easiest to measure in clinical setting is
  PRU and /or URR but it is also beset with
  number of problems such as:
• the clinical importance of Urea as
  surrogate marker of uremic toxin or a
  marker of malnutrition in dialysis patient
• the timing of taking blood to determine
  urea postdialysis
• the recirculation, Cardiopulmonary
  recirculation and A-V fistula                113
Dialysis Prescription

• The doctor must prescribe what dose of
 dialysis his patient needs. In coming to
 this conclusion the prescribing doctor
 must have basic knowledge of what Kt/V
 is and various factors that are associated
 with it. And also determine what Kt/V level
 is desired.


                                           114
Dialysis Prescription

• Kt/V value of 1.2 has been associated with
  good quality of life and this corresponds to
  URR or PRU of 65%
• and increases of 0.2 Kt/V for every 5% of
  PRU up to Kt/V of 1.6 is also found to be
  asociated with good outcome. Increase of
  Kt/V above 1.6 does not confer additional
  benefit.
                                            115
What is Kt/V?

• K= is Urea clearance of dialyser and this is
    supplied by the manufacturer (note that at best
    the given value is at best about 80% of actual
    value under clinical conditions.
•   T= is the time spent or intended to be spent on
    dialysis
•   V= is the volume of distribution of Urea in the
    body which is approx 60% of total body volume
    in Male and approx 55% in Female


                                                  116
How to Calculate Time

• Example: In a 50 kg man, using a dialyser
 with a urea clearance declared to be 300
 ml/min to achieve a Kt/V = 1.2. What time
 should the patient spend?




                                          117
Answer

• K = 300ml/min but at best it is 80% =
  300 * 0.8 = 240 ml/min = 0.240L/min
• V = 60% * Weight (kg) = 0.6 * 50 = 30
  L
• Kt / V = 1.2
• Kt = 1.2 * V =1.2 * 30L = 36L
• t = 36 L / 0.240L/min = 150 min = 2
  hours 30 min (2.5 hours)
                                          118
Indications for Initiation of Dialysis

Clinical
  Absolute
    Persistent Nausea/Vomiting
    Pulmonary oedema
    Encephalopathy
    Refractory oedema
    Pericarditis
    Bleeding diathesis
    Malnutrition
    Uncontrolled HT
                                         119
Indication for Initiation of Dialysis

Clinical
  Relative
    Sleep disturbances
    Early peripheral neuropathy
    Peripheral oedema
    Persistent pruritus
    Poorly controlled Ca & Po4
    Anaemia
    Depression
                                        120
Indications for Initiation of Dialysis

Biochemical
   Creatinine level >600umol/L
   GFR <15mls/min
   BUN > 25mmol/L
   K >6.0mmol/L
   HCO3 <12 mmol/L
   Hypercatabolism
     Daily rise in creatinine > 100umol/L
     Daily rise in urea > 10 mmol/L
     Daily rise in K > 1.0mmol/L
                                             121
VASCULAR ACCESS IN HD

Vascular access is a major requirement in
 HD system and indeed limiting factor for
 its procedure. In any patient with vascular
 access failure the procedure cannot be
 done. In such individual the alternative is
 to switch the patient to PD.



                                          122
VASCULAR ACCESS

TEMPORARY/ACUTE         PERMANENT

• Subclavian            • AVF Arterial/Venous
                             fistulas
• Internal Jugular      •    AVG Arterial /Venous
                             grafts
• Femoral/ hard vs. soft •   Tunneled Permacaths



                                                123
VASCULAR ACCESS IN HD

Vascular Access can either be:
• Temporary
• Permanent
Temporary is usually applied for Acute
  dialysis, thus the access is discontinued
  within few days or weeks.
Examples are: Femoral Vein, Internal
  Jugular Vein and Subclavian Vein Access.
                                              124
125
126
VASCULAR ACCESS IN HD

Temporary Vascular Access:
Internal Jugular Vein and Subclavian Vein
  Access can serve as permanent access
  when the catheter is tunneled or at least
  can last for several months or years. But it
  is not so with Femoral Vein access.



                                            127
VASCULAR ACCESS IN HD

Temporary vascular Access:
Complications of Temporary Vascular Access
• Bleeding/Haemorrhage
• Infection (Exit site, Tunnel, Systemic)
• Stenosis
• DVT, Cellulitis
• Thrombo-embolism
                                        128
VASCULAR ACCESS IN HD

Permanent Vascular Access:
• Arterio-Venous Fistula (A-V Fistula)
• Graft
A-V Fistula is arterialisation of the vein by
  surgical procedure.
Graft is method by which two vessels (vein-
  vein or vein-artery) are connected
  together through graft.
                                            129
VASCULAR ACCESS IN HD

Permanent Vascular Access:
These accesses last several months and
  years.
Complications:
• Infection (local and systemic)
• Stenosis with steal syndrome
• Distal structure iscaehmia and gangrene.
• Thrombosis and loss of access.
                                             130
PEIRTONEAL DIALYSIS

• PD is a process by which blood is purified
  using the peritoneal membrane as filter.
• Types
   Acute
   Intermittent
   CAPD
   APD

                                             131
PERITONEAL MEMBRANE

• Peritoneal Membrane consists of at least
  three layers:
1.The Mesothelium
2.The Peritoneal capillaries
3.The Interstitial Tissue.
Mesothelium: Last structure encountered
before peritoneal cavity and derived from
embroyonic mesodermal layer.
                                             132
MESOTHELIAL CELLS
CHARACTERISTICS

• Mesothelium consists of flat layer of
  polygonal cells forming mosaic structure.
• They are active secretory cells with a lot
  of extensive rough endoplasmic
  reticulum, golgi apparatus and numerous
  lamellar bodies.
• Divided into two layers Parietal and
  Visceral with approx. ratio of 20%:80%
                                           133
MESOTHELIAL CELLS
CHARACTERISTICS
• Mesothelial function: prevention of
  friction.
• Mesothelial Cells: divided into two
  populations by immunocytochemistry.
1.CA 125 Positive cells approx. 90%
2.CA 125 negative cells approx. 10%
The importance of this is the monitoring of
peritoneal membrane changes that occur
during chronic PD use.
                                              134
THE PERITONEAL CAVITY

• This is the space formed between the
  Visceral and Parietal peritoneal membrane
• The cavity contains <100ml of surfactant-
  like-fluid containing phosphatidylinecholine
• Anatomically the surface area is between
  1m2 - 2m2.
• However, the effective functional surface
  area is < 1m2.
                                            135
INTERSTITIAL AND VASCULAR
STRUCTURES

• The vascular layer is the part that actually
  involved in PD.
• Changes that occur in the Interstitial and
  Vascular structures can be studied by the
  presence of the following in effluent:
IL-6, IL-8, glycated albumin, glycated IgG,
  Pentosidine, vonWF

                                             136
MECHANISM OF PERITONEAL
TRANSPORT

• Diffusion
• Ultrafiltration
• Fluid Absorption




                          137
                                            Intravascular space
Peritoneal cavity




                    Capillary Endothelium                         138
139
140
141
DIALYSATE OSMOTIC AGENT

1. Glucose Based
2. Glucose polymers eg Icodextrin
3. Glycerol Based
4. Amino acid based
5. Electrolytes
•   Na
•   Ca
•   Mg
•   Cl
•   Lactate now Bicarbonate based fluids are produced

                                                        142
PD CATHETERS

Acute
Chronic
  Straight or Coiled
  Single or double cuff
    Tenckhoff
    TWH
    Ash
    Pail handle (Cruz)
    Moncrief-Popovich
                           143
PERITONEAL EQUILIBRATION TEST
(PET)

PET is a test done to characterise the
  peritoneum at the very beginning of
  chronic PD to guide the doctor.
On the basis of the various studies the
  peritoneum has been divided into 4
  groups.



                                          144
PERIONEUM EQUILIBRATION TEST
(PET)

• High Transporters
• High Average Transporters
• Low Transporters
• Low Average Transporters




                               145
PET Status and Survival


PET Status                2 Year Survival
• High                       71%
• High Average               72%
• Low Average                80%
• Low                        91%


                                        146
TYPICAL CAPD PROCEDURE




                         147
148
KIDNEY TRANSPLANTATION

Renal transplantation is the gold standard
 for the treatment of ESRD as it replaces all
 the functions of the fibrotic kidneys, and
 this is unlike dialysis, which replaces only
 the excretory function of the kidneys at
 exclusion of other functions. The quality of
 life is superior with transplant but this is at
 a cost of immunosuppressive therapy the
 allograft recipient will have to take for life
 or for the life of allograft.
                                              149
KIDNEY TRANSPLANTATION

Sources of Allograft:
There are mainly two sources of allograft
  namely (i) Cadaveric (ii) Living related or
  unrelated allograft. The third and fourth
  sources are still at experimental stage and
  will take awhile before they are widely
  accepted, and these are Xenograft
  (sourcing kidney across specie e.g. from
  pig, ape, gorilla) and Cloning.
                                           150
KIDNEY TRANSPLANTATION

For a successful transplant to take place
  rigorous screening of both donor and
  recipient is mandatory.
• Blood Group must be compatible
• Both must be free infection: Bacterial,
  Fungal, Viral
• Both must be free of cancer
• The donor is screened to ensure he/she is
  safe to donate.
                                          151
KIDNEY TRANSPLANTATION

Allograft Rejection:
1. Hyperacute Rejection
2. Accelrated Acute Rejection
3. Acute Rejection
4. Chronic Rejection


                                152

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:1
posted:9/15/2012
language:English
pages:152