What happened in the last decade in nephrology?

ESRD PATIENTS TREATED ON DIALYSIS

Eknoyan IFCC/AACC Annual meeting, 2005, Orlando, Fl.

 A high economic burden
• 5 countries (Japan, USA, Germany, Brazil, Italy ) - less than 12% of world
population - 58% of dialysis population
• next 10 countries – 29% of the world population – 21% of dialysis
population

15 countries – 41% of the world population - 79% of dialysis population

Data based on 2001 Fresenius Medical Care global survey

“ Renal replacement therapy is so costly that there is minimal

probability for the vast majority of the world’s population to take
advantage from it “

Schieppati – Bellagio Conference 2004

 A high economic burden
USA - USRDS
• 2010 – Estimated population 311mil. - US CENSUS BUREAU
• 0.22% on RRT
• Costs/year – 28.29 bil USD
INDIA – 2004 – 1.06 bilion
• No renal registry, no RRT program
• No insurance program for RRT and no state founding
• ”only 3-5% of patients needing RRT have some type of
insurance program the rest are “cash and carry”

Agarwal S.K Kidney Int Suppl. 2005 Sep;(98):S41-5

Foley AJKD
 CKD CONCEPT AND CONTINUUM

COMPLICATIONS
(CVD)

• DM
• HTN Proteinuria
GFR
• Cancers Albuminuria
• Infections
• Age
• Autoimmune diseases
• Family history of CKD Kidney Decreased
• Obstructions D
injury function Death
• Recovery from ARF Tx
• Reduction in kidney mass
• Drugs Chronic Kidney Disease
• Low birth weight
• Low income/education
• Racial factors
Proteinuria - Albuminuria

Collecting Normal Micro Albuminuria

method albuminuria Proteinuria

/ 24h < 300mg/24h - >300mg/24h

Medie 50mg/24h
Protein
Dipstick < 30mg/dl - >30mg/dl

First urine <200 mg/g - >200mg/g

P/Cr

/ 24h < 30mg/24h 30 – 300 mg/24h >300mg/24h

Medie 10mg/24h
Albumin Dipstick albumin <3 mg/dl >3mg/dl -
specific

First urine M <17mg/g M 17-250 M > 250mg/g

A/Cr F <25mg/g F 25-355 mg/g F > 355mg/g
<30 30-300 >300

K/DOQI – 2002
A.D.A. - 2001
 GFR < 60 ml/min/1,73m2
VARSTA F (Cr ser mg/dl) M (Cr ser mg/dl)
25 1,22 1,55
35 1,12 1,45
45 1,08 1,37
55 1,06 1,29
65 1 1,25
75 0,94 1,2

Cr 2 - M, 60 years – 36ml/min/1,73m² - around 25% of the function

left.
 “Microalbuminuria does
not indicate early renal
damage, it is just the
earliest indicator we
have”

López-Novoa et al. Journal of Translational Medicine 2011, 9:13

 CKD
CKD (independent of etiology):
1. Kidney damage  3 months
Damage defined by:
• Pathology (KB) or
• Damage markers (Alb., Prot., Sed. Imag.)
2. GFR <60 ml/min/1,73m²  3 months

K/DOQI - 2002
 Staging of CKD
Stage Description GFR
ml/min/1,73m2
G1 Kidney damage with normal or increased kidney >90
function
G2 Kidney damage with mild decrease of kidney 60 – 89
function
G3 A Moderate reduction of kidney function 45 – 59
B 30 – 44
G4 Severe reduction of kidney function 15 – 29
G5 Renal failure <15
 Prevalenta BCR in populatia generala

COUNTRY STUDY / AUTHOR N PREVALENCE

USA NHANES III 1988 – 1994 15625 11%
USA NHANES 1999 – 2004 12785 16,8%
AUSTRALIA Chadban SJ ( The AUSDIAB) 10949 14,1% (18,3%)
MEXICO Amato D ( Urban pop) 2005 3564 8% (GFR <60)
ITALY Cirillo 2006 4574 6.4% (GFR <60)
NORWAY Hallan SI - HUNT II - 2006 65181 10,2%
SWITZERLAND Nitsch D – SAPALDIA - 6317 8,1% (GFR<60)

ROMANIA Covic, Schiller - 2008 19509 8.8% (GFR<60)

SPAIN Otero - EPIRCE pilot 12,7%

Qiu-Li Zhang - BMC Public Health 2008, 8:117 Chadban SJ -

J Am Soc Nephrol 14: S131–S138, 2003 Otero A - Kidney Int.,
Vol. 68, Supplement 99 (2005), pp. S16–S19 Cirillo M - Kidney Int (2006) 70,
800–806. Hallan SI - J Am Soc Nephrol 17: 2275–
2284, 2006. Nitsch D - NDT (2006) 21: 935–944
Covic A, Schiller A Rev Med Chir Soc Med Nat Iasi. 2008 Oct Dec;112(4):922-31
 CKD continuum
COMPLICATIONS

3.3% 3% 4.4% 0.2% 0.2% 11% NHANES III

5,7% 5,4% 5,4% 0,2% 0,2% 16,8% NHANES 98-04
3.1% 4% 10.9% 0.3% 0.02% 18.3% AUSDIAB
5.3% 15.4% 4.2% 0.17% 0.04 25.1% UK

Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

DAMAGE
Death
persist. albuminuria / proteinuria
DECREASED FUNCTION

> 90 89 - 60 59 - 30 29 - 15 <15 eGFR

K/DOQI 2002
 2007 ESH-ESC guidelines CVD risk
BP (mmHg)
NORMAL HIGH HTN GR 1 HTN GR 2 HTN GR 3
SBP 120-129 NORMAL SBP 140 - 159 SBP 160 - 179 SBP > 180
or SBP 130-139 or or or or
DBP 80-84 DBP 85-89 DBP 90 - 99 DBP 100 - 109 DBP > 110

RF AR AR LAR MAR HAR

1-2 RF LAR LAR MAR MAR VHAR

≥ 3 RF, MS. or MAR HAR HAR HAR VHAR

ATOM

CVD VHAR VHAR VHAR VHAR VHAR

or
CKD

2007 ESH-ESC guidelines J.Hypertens.(2007) 25:1751

 CVD CONTINUUM
Myocardial Remodeling
Myocardial infarction
ischemia Ventricular
dilation
CAD

CHF
Atherosclerosis

RAAS

Endothelial Specific risk factors

dysfunction
ESHD
• anemia
• Ca/P
• Hyper H C… DEATH
RISK FACTORS

HT DM
ESKD
Albuminuria
Dyslipidemia Obesity

Proteinuria
Smoking
Low GFR

Physical inactivity
CKD CONTINUUM
ADVANCED CKD
(STAGE 4) AND
RENAL FAILURE CKD
(STAGE 5)
DEFINITON
Loss of renal functions due to progressive reduction of
nephron population
CRF = small kidneys
Exception : - renal amiloidosis
- ADPKD
- bilateral renal tumors
1. EXCRETORY FUNCTIONS
• altered maximal concentration capacity
• altered maximal dilution capacity
• altered water – electrolyte balance
• altered acid base balance – metabolic acidosis
• altered clearance capacity – intoxication

2 SYNTHESIS FUNCTIONS
• erithropoietin – renal anemia
• 1,25,(OH)2 cholecalciferol
ETIOLOGY
• ANY CHRONIC RENAL DISEASE which can induce nephron
loss

ROMANIAN NATIONAL REGISTRY

1.HT assoc CKD
2. Diabetic nephropathy
3. Chronic TIN
4. Chronic GN
5. Cystic renal diseases
Etiology of ESKD on RRT - USRDS 2014

GN

HD PD

Tx

USRDS Annual Data Report 2012 -

 ADAPTATION OF THE KIDNEY TO THE NEPHRON LOSS
ANIMAL MODELS
• 75% nephron loss – GFR and RPF increases 2,5 x
Hemodynamic phenomenon

VD RPF

Af.A Ef.eA

HP GFR
GLOMERULAR ADAPTATION
❑ Morphologic - enlarged glomeruli
- capillary dilatation
- cell proliferation and hypertrophy
❑ Functional
- Increased RPF
- Increased GFR
- Increased intra glomerular HP
TUBULAR ADAPTATION
▪ Functional
- maintenance of glomerular tubular balance
increase of GFR increase of secretion and reabsorbtion

▪ Morphologic
- PCT increases with - 15% in diameter - 35% in length
- DCT increases with -10% in diameter - 17% in length

▪ Humoral mechanism ? – present in the denerved kidney

▪ Enhanced by
- young age
- STH and Thyroid H (but thyroidectomy does not block HT)
- normo proteic diet
BRICKER’s theory of the remaining nephron function
In glomerular diseases
- glomerular destruction atrophy of the corresponding
tubule
In tubular-interstitial diseases
- tubule destruction atrophy of the corresponding
glomerulus

kidney functioning insured by the remaining nephrons

GFR < 60 ml/min/1.73m² nonreversible progression to uremia

MECHANISMS OF PROGRESSION OF CRF

- Glomerular sclerosis
- Tubular and interstitial sclerosis
- Vascular sclerosis
 Normal Mesangial
glomerulus proliferation

Segmental Global
sclerosis sclerosis
 Homodynamic adaptation
Parietal stress
(Brenner si Hostetter)
 Glomerular hypertrophy
R2 (Ichikawa si Fogo)
 Proteinuria
•Hialinosis
(Remuzzi si Bertani)
•Mesangial dysfunction  Systemic HT (El Nahas)
HP

 Lipid metabolism Af.A Ef.A N

(Moorhead)

Mesangial O Cytotoxic Af.A Ef.A D.Af.A

overload LDL effect
-Ablation
Activation
-Normal protein diet
 Immune Glomerular / vascular
Chemical Triggering agents damage
Biomechanical
AMPK Injury /
Activation of TEC

Infiltration of the TI by USF1/2 Activation of NF-ĸB and

dendritic cells, TGF- TGF- Release PAI-1, IL-1, IL-6,
lymphocytes, RI/II MCP1, RANTES, and
macrophages, mast cells CTGF TNFα

EMT /
EndMT
• Excess deposition of MioFB
•Alteration of renal collagenase activity
extra cell matrix components
• Collapse of the kidney parenchyma
collagen I, III, V, VII, XV, fibronectin;
normal components of TBM collagen IV and
laminin;
de novo synthesized proteins - tenascin, fibronectin
isoforms, laminin chains, SPARC, thrombospondin,
decorin and biglycan Declèves AE, Sharma S Nat. Rev. Nephrol. 10, 257–267 2014
Hewitson TD Am J Physiol Renal Physiol 296: F1239–F1244, 2009.
Tub

Int

Cap.

López-Novoa et al. Journal of Translational Medicine 2011, 9:13

 immune
chemical Triggering
biomechanica agents
l
Activati Glomerul
on of ar
TEC vascular
• Excess deposition of Activation of NF-ĸB
extra cell matrix components and Release PAI-1, damage
IL-
collagen I, III, V, VII, XV, fibronectin; 1, IL-6,
normal components of TBM MCP1/CCL2,RANTES/C
collagen IV and laminin; Infiltration of the and
CL5, TI TNFα
de novo synthesized comp by dendritic cells,
proteins - tenascin, fibronectin isoforms, lymphocytes,
laminin chains, SPARC, thrombospondin, decorin and
biglycan
macrophages, mast
• Alteration of renal cells
collagenase activity
• Collapse of the kidney
parenchyma
 ALTERATION OF THE EXCRETORY FUNCTION

IMPAIRMENT OF MAXIMAL CONCENTRATING ABILITY

• normal conditions – 1200 – 1300 mOsm/l
• Adv. CKD – fluid overload of the remaining glomeruli
- diuretic effect of the high urea concentrations
• Clinical signs – polyuria, nocturia, low urin density – 1010 – 1011 (isostenuria)
IMPAIRMENT OF MAXIMAL DILUTING ABILITY
• normal conditions – 40 – 50 mOsm/l
Con. Dil.
• Adv CKD - severe decline in GFR
- fluid overload

Tendency to fluid imbalance

 ALTERATION OF THE EXCRETORY FUNCTION

Na BALANCE
• Na balance is preserved even in advanced CRF – trough increase of fractional
excretion of Na
• CRF patients are salt losers – increased synthesis of Na uretic peptide
• Na retention – increased intake
• Hyponatremia – low Na diet , diuretics
K BALANCE
• K balance is preserved until late stages of CKD by increased fractional excretion of
K, hyper K emia occurs only when diuresis drops below 1000 ml/24h
• Hypo K emia – extra renal loss, Low K diet, abuse of loop diuretics
• muscle weakness, arrhythmias, ECG negative T wave, ST depression,
prolonged QT interval
• Hyper K emia - High K diet, blood transfusion, infections
•Mild (K = 5.5 – 6.5mEq/l) - ECG normal
•Moderate (K = 6.5 – 7.5mEq/l) – ECG – tall and peaked T waves
•Severe (K = >7.5 mEq/l) – ECG – absence of P wave, Wide QRS complex
ventricular arrhythmias
 ALTERATION OF THE EXCRETORY FUNCTION

METABOLIC ACIDOSIS
Normal excretion of H+ 1 – 4 mEq/kg/day
• Causes – failure in eliminating the ammonia
- impaired bicarbonate reabsorbtion
- impaired distal acidification
• Clinical signs
• pH < 7.38
• PaCO2 < 35mmHg
• Plasma bicarbonate < 20 mEq/l
•Base excess < - 3mMol/l
• Kussmaul respiration
 ALTERATION OF THE EXCRETORY FUNCTION

LOW ELIMINATION OF THE CATABOLISM AND/OR

SYNTHESIS PRODUCTS
• AZOTEMIA
• Increased serum urea levels
• Increased serum creatinine levels
• Uremic toxins - > 400 ( methyl guanidine, hippuric acid,
pyrimidines, aromatic amines, indols, phenols parathormone,
calcitonine and so on
 TRANSMEMBRANE TRANSPORT AND
METABOLIC DISORDERS
IONIC TRANSMEMBRANE TRANSPORT DISORDERS
• altered function of Na / K ATPase dependent ion pump due to uremic toxins
• increased intracellular Na concentration – swelling which leads to decreased
tubular reabsorbtion of Na, increased neuro-muscular excitability, increased
peripheral vascular resistance

CARBOHYDRATE METABOLISM DISORDERS

• Increase of insulin emia due to decreased renal clearance
• Increased peripheral resistance to insulin activity
• Increased levels of glucagon

GLUCOSE BALANCE INSTABILITY

 LIPID METABOLISM DISORDERS
• Decreased lipoprotein catabolism
• Decreased lipoprotein and hepatic lipase activity
• Increased triglyceride synthesis due to high glucose intake
• > 65% of the cases present hypertriglyceridemia, increased VLDL chol.
and decreased HDL chol. levels

PROTEIN METABOLISM DISORDERS

• Protein hypercatabolism
• Modifications in the concentration of plasma and intracellular AA
HYPOPROTEINEMIA WITH HIPOALBUMINEMIA
 RESPIRATORY DISORDERS

• UREMIC PULMONARY EDEMA

• caused by hyper hydration, LVI, increased capillary permeability
• X ray – “Fluid lung”
• UREMIC PNEUMONITIS – alveolar fibrin rich pseudo-membranes, interstitial fibrin
deposits
• PULMONARY CACIFICATIONS – due to hyper parathyroidism
• PLEURISY
 CARDIOVASCULAR DISORDERS

• HYPERTENSION
• Mild and moderate CKD 50-60%, Severe CKD - > 70% of the patients
• Fluid and sodium retention; high renin levels; other causes
• ISCHEMIC HEART DISEASE
• accelerated atherosclerosis – multiple risk factors
• Clinical features according to “Murphy’s laws “ early onset , rapid evolution ,
high frequency of bi and tri vascular lesions
• UREMIC CARDIOMYOPATHY
• Unspecific lesions – interstitial fibrosis, myocardial calcifications, myocytolysis
• Clinical features – blocks, arrhythmias, cardiac failure, cardiac arrest
• US LVH in absence of HT, decreased diastolic function
•PERICARDITIS
 GASTROINTESTINAL DISORDERS
• UREMIC STOMATITIS
• EROSIVE ESOFAGITIS
• EROSIVE GASTRITIS
• SMALL BOWEL – impaired reabsorbtion of glucose, AA, peptides
• LIVER - Hepatitis
ENDOCRINE DISORDERS

• Hormones with elevated plasma levels: PTH, glucagon, STH, prolactin, calcitonin,
FSH, aldosteron, gastrin
• Hormones with low plasma levels: Erythropoietin, adrenal steroids, T4,
1,25(OH)2D3
• Deffective receptor-hormone interaction: Insulin, glucagon, PTH
 HEMATOLOGICAL DISORDERS

• RENAL ANEMIA
• Clinical features – N N N, for a determined time period Hb values are constant in
the same patient
• Mechanisms – Mild hemolytic anemia + erythropoietin deficiency
- Iron deficiency
- folate deficiency
- infection and malnutrition
- HD
• COAGULATION DISORDERS
• Causes: alteration in PL, vascular endothelium, platelet-platelet interactions –
uremic toxins
 IMMUNE DISORDERS

• Non specific immunity

• neutrophilia with altered chemo tactic capacity, decreased phagocytic properties
and bactericidal activity
• Cell immunity
• lymphopenia with excess of Ts and depression of Th
• diminished response to tuberculin
• prolonged survival of skin allograft
• depressed L response to mitogens
• Humoral Immunity
• Decreased BL
•Altered AB synthesis
 CKD MBD

Definition of CKD–MBD
A systemic disorder of mineral and bone metabolism due to CKD manifested by
either one or a combination of the following:
• Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism.
• Abnormalities in bone turnover, mineralization, volume, linear growth, or
strength.
• Vascular or other soft-tissue calcification.

Definition of renal osteodystrophy

•Renal osteodystrophy is an alteration of bone morphology in patients with
CKD.
•It is one measure of the skeletal component of the systemic disorder of CKD–
MBD that is quantifiable by histomorphometry of bone biopsy.

(KDIGO) CKD–MBD Work Group Kidney International 2009; 76 (Suppl 113): S1–S130
 Normal endocrine regulation of phosphate
homeostasis
Intestinal phosphate
absorbtion
Pi
BONE +
FGF 23
+ -
+
KLOTHO
- KLOTHO
1-25 OH KIDNEY
PT GLAND D3
- +
Pi ELIMINATION
Modified after Kuro-o M Kidney Int (2011) 79 (Suppl 121), S20–S23
 Changes in Klotho, FGF-23, PTH,
1,25(OH)2D3, and phosphate as CKD progresses

Kuro-o M Kidney Int (2011) 79 (Suppl 121), S20–S23

 NEUROLOGICAL DISORDERS

• CENTRAL NERVOUS SYSTEM

• Uremic encephalopathy
• PERIPHERAL NERVOUS SYSTEM
• Peripheral, distal, symmetrical mixed sensorimotor polyneuropathy
• Restless leg syndrome
• Burning foot syndrome
•Stocking glove sensation
• muscle atrophy, myoclonus, paralysis
• AUTONOMIC NERVE DISFUNCTION
•Postural hypotension, Dialysis hipotension
• Impaired sweating,
•Nistagmus
 OTHER

• REUMATOLOGICAL DISORDERS : myopathy, bursitis, spontaneous ligament

ruptures, arthritis
• EYE DISORDERS : conjunctival and corneal calcifications, diminished lacrimal
secretion – “Uremic red eye”
• DERMATOLOGICAL DISORDERS
• Cutaneous hyperpigmentation
• Cutaneous calcifications
•Pruritus
 CONSERVATIVE MANAGEMENT

AIM

• Treatment of ARF / CRF episodes

• Slowing the decline of the renal function
• Prevention of uremic symptoms – acceptable costs
TREATMENT OF ARF / CRF EPISODES

• OBSTRUCTION
• INFECTIONS
• METABOLIC DISORDERS, FLUID / ELECTROLYTE,
ACID / BASE BALANCE DISORDERS
• NO NEPHROTOXIC DRUGS
• CONTROL OF BLOOD PRESSURE LEVELS
 Slowing the decline of the renal function
Low protein diet
• 1g/kg BW/day stages – G1-G3a
• 0,8g/kg BW/day stages G3b – G4
• 0,6g/kg BW/day stage G5 PD
• Pi binders

Low salt diet 4-5g/day – all CKD stages

Treat acidosis – Na HCO3

Good BP ctrl
Target < 140/90 any CKD A1 – any drugs
Target <130/80 all CKD A2-A3 – ACEI, ARB
 Slowing the decline of the renal function
Intensive G ctrl – HbA1c < 7%

Treat dyslipidemia
- Statins – Atorva, Rosuva CKD G1 –G4
-Atorva G5

Early and aggressive treatment of CVD and CVD risk factors

A.D.A.M vs. E.V.E
Treatment of co-morbidities

Treatment of renal anemia G3 and up

Iron and ESAs - folate and B12 if necessary

Treatment of CKD MBO

Treatment with P binders – normal P levels
Vitamin D
Treat HPTH
Paricalcitol stages G3 and up
Calcimimetics (cinacalcet ) G5D
Prepare for RRT access – G5 PreD
AV fistula HD
PD cat PD