Kidney disease in hypertension and diabetes. Diagnosis, treatment.

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Kidney disease in hypertension and diabetes.
Diagnosis, treatment.

• Ludmila Brunerova
• II. Dpt of Internal Medicine FNKV
• and Mediscan Euromedic

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• Diabetic nephropathy
• Nephropathy in hypertension

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Diabetic nephropathy - definition

• nephropathy caused by diabetes (Kimmelstiel
  Wilson glomerulosclerosis as a microangiopathy
  disease)
• nephropathy as a macroangiopathy disease in
  diabetes
• urinary tract infection in diabetic patients

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Kidney disease in diabetes

• ? Diabetic nephropathy (DN)
• ? Non-diabetic nephropathy
• ? glomerular
• ? primary glomerulonephritis
• ? secondary glomerulopahies
• ? non-glomerular
• ? renovascular disease
• ? chronic TIN (tubulointerstitial nephritis)
• ? necrosis of papilla
• ? polycystic renal disease
• ? reflux nephropathy
• ? Iatrogenic renal impairment (drugs,
  radiocontrast)

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Pathophysiology
Hyperglycaemia
Glycation endproducts (AGE)
Vasoactive systems
Hemodynamic changes
activation of signal transduction PKC, MAP
kinase, NF-?B
Reactive oxygen radicals
Growth factors
Cell cycle changes
Tubulointerstitial fibrosis
Proteinuria
Glomerulosclerosis
Renal failure
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Epidemiology

• 4-8 diabetic patients
• type 1 diabetes mellitus
• proteinuria 25-45 type 1 diabetic patients
• microalbuminuria 20-30 type 1 diabetic patients
• maximal prevalence after 15 years of diabetes
  duration
• small risk of development of diabetic nephropathy
  after 25 years of diabetes duration

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• type 2 diabetes mellitus
• prevalence 25 after 15 years of diabetes
  duration ( Pima Indians 50)
• year incremental in incidence of microalbuminuria
  15-25 in bad control of risk factors

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Epidemiology of chronic renal failure in diabetic
patients

• good evidence
• since 1990 diabetic nephropathy has been one of
  the three most common causes of renal failure
• prevalence of diabetics in dialysis therapy 35,
  mortality 29 (versus 20 in nondiabetic patients)

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Phases of diabetic nephropathy

• Phase 1 hyperfiltration-hypertrofic
• . functional changes
• hyperfiltration (? GF o 20-40)
• hyperperfusion
• renal hypertrophy
• asymptomatic

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• Phase 2 latent
• . normalization of functional changes, onset of
  morphologic changes
• after 2-4 years of diabetes duration
• GF ? or normal, albuminuria not present
• thickening of basal membrane
• mesangial thickening
• asymptomatic

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• Phase 3 incipient diabetic nephropathy
• . progression of morphologic
  changes, microalbuminuria, normal function
• after 6-15 years of diabetes duration
• GF normal, typical morphologic changes
• microalbuminuria (30-300mg/24 hours)
• in 20 DM1, 80 progress to phase 4, marker of
  nephropathy progression
• in 40 DM2, only 20-40 progress to phase 4,
  marker of endothelium dysfunction (cardiovascular
  morbidity and mortality)
• ? asymptomatic, or hypertension in DM2

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• Phase 4 manifest diabetic nephropathy
• . proteinuria, renal insufficiency
• after 10-20 years of diabetes duration
• proteinuria gt 300mg/24 hours, 15-40 incremental
  per year
• GF ? in 0,17 ml/s/year renal insufficiency
• hypertension, nephrotic syndrome, progression of
  other diabetic complications, complications of
  renal insufficiency

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• Phase 5 chronic renal failure, need for RRT
• gt 20 years of diabetes duration
• gt 7 years of proteinuria duration
• high mortality (cardiovascular complications)
• complications of renal failure

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Lab tests

• diagnosis of DN persistent albuminuria gt
  30mg/24 hours (2/3 measurements in 6 months), in
  presence of diabetes, after exclusion of other
  renal disease
• urine chs
• examination of proteinuria
• examination of renal function
• Ultrasound of kidneys

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Proteinuria

• physiological 15-25mg/24 hours
• mikroalbuminuria 30-300mg/24 hours
  (20-200ug/min),
• Transient 30-100mg/24 hours resp. 20-70ug/min
• persistent 100-300mg/24 hours resp 70-200ug/min
• albuminuria gt 300mg/24 hours (resp.
  200ug/min)0,5g/day
• gt3,5g/24 hours nephrotic proteinuria

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Evaluation of renal function

• S-crea
• GFR
• MDRD
• Cystatin C

S-crea (umol/l)
900
500
100
0,2
1,0
2,0
GFR (ml/s)
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Principles of diagnosis I.

• Diagnosis clinical (ADA, 2003)
• Progressing proteinuria in patients with
  longeterm history of type 1 DM gt 10 let
• Microalbuminuria preceded
• With diabetic retinopathy
• Without microscopic hematuria
• With normal ultrasound finding

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Principles of diagnosis- II.

• Diagnostic problems in type 2 DM
• Proteinuria can be present in time of diagnosis
• Coincidence with retinopathy is less frequent in
  type 2 DM
• Microscopic hematuria in progressed stages of
  diabetic nephropathy
• Relatively frequent concomittance with non
  diabetic nephropathy

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Dif dg

• Typical clinical-laboratory finding for DN
• Long history of diabetes
• Diabetic retinopathy present
• Mikroalbuminuria (longterm)? proteinuria ?
  nephrotic proteinuria ? renal insufficiency
• Renal biopsy not indicated

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Dif dg

• Typical finding in renovascular disease
• Elderly, sclerotic
• With renal insufficiency (s-crea 130-200umol/l)
• Small proteinuria (lt1-2g/24 hours)
• Hypertension
• Ultrasound asymetry, bilateral small kidneys,
  reduced cortex
• Biopsy not indicated
• Doppler, MRA, DSA

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Dif dg

• Atypic finding in patient with DM
• Rapid progression of proteinuria and renal
  insufficiency
• Short history of diabetes, no retiopathy
• Glomerular erythrocyturia
• Discrepancy ultrasonography vs clinical
• Chronic renal insufficiency without proteinuria
  and/or retinopathy
• Renal biopsy indicated to exclude
  glomerulonephritis

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Dif dg

• inflammation sediment
• With positive cultivation urinary tract
  infection, asymptomatic bakteriuria
• With sterile pyuria TBC, necrosis of renal
  papilla

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Metabolic control diabetes, Lipids, obesity Glycaemic control (IIT, event. gliquidon, low protein diet), weight reduction
smoking stop smoking
hypertension albuminuria Optimal BP control with target BP lt 130/80mmHg Renoprotective ACEi sartans
Urinary tract infection Early treatment
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angiotenzinogen
Cascade after ACEi
renin
angiotenzin I.
AT1R
Cascade after sartans
ACE
chymase
Cascade after direct inhibition of renin
angiotenzin II.
Inacive peptides
bradykinin
NO, PG
AT1R
AT2R
vasoconctriction, atherosclerosis inflammation
vasodilatation
?
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Case 1

• Man, 42 years
• Type 1 diabetes for 23 years, CSII
• Diabetic retinopathy
• Microalbuminuria first evidenced 8 years ago
• Smoking, no other treatment
• Now coming for hypertension and oedema of legs

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Case 1

• Lab urea 18mmol/l, s-crea 198umol/l
• Na 145, K 5,9 Ca 2,1 P 1,9
• albumin 22g/l, glycaemia 13mmol/l
• Cholesterol 6,4 mmol/l, LDL 4,4 HDL 0,9 Tg 1,7
• Urine protein 2, glucose 2
• GF 0,75ml/s, proteinuria 8,6g/day

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Case 1

• What is patients problem?
• How would you treat the patients?

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Case 2

• Type 2 diabetic woman 44 years, obese
• Diabetes for 2 years, good control on diet, no
  other diseases, no medication
• In preventive check found hypertension 190/100,
  urea 14mmol/l, s-crea 239umol/l
• Urine protein 1, erythrocyte 85, glomerular
  origin, proteinuria 1,8g/day
• Ultrasound bilateral kidney 87mm, cortex 9mm

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Case 2

• Does the patient have diabetic nephropathy?
• Why?
• What other examination would you recommend?
• How would you treat the patient?

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Conclusion I.

• Diabetic nephropathy microvascular complication
  connected to poor glycaemic control
• leading cause for need of dialysis
• Prevention and therapy nephroprotective
  strategies BP control (ACEi, sartans), glycaemic
  control, lipid control

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Kidney disease in hypertension

• kidney and regulation of blood pressure
• exretion of salt and water (volume of
  extracelullar fluid)
• endocrine function secretion of
  vasoconstrictors (RAS) and vasodilatators (Pg,
  calicrein, kinins)
• perception of osmolarity and volume (pressure)

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Kidneys?? hypertension

• role of kidneys in primary hypertension
  (unability to excrete salt load)
• kidney disease as cause of secondary hypertension
  (renoparenchymal, renovascular)
• hypertension causes renal damage
• hypertension is the leading factor of progression
  of kidney disease

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kidney disease
damage of medulla
intrarenal ischaemia
? GF
RAAS
? SAS
? Pg, kinins
? natrium excretion
? ECF
hypertension
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Hypertension-induced renal dysfunction

• hypertension nephropathy longterm hypertension
  causes kidney damage
• ischaemic nephropathy - atherosclerotic changes
  in macrovessels (altogether with diabetes,
  hyperlipidaemia).. renovascular hypertension
• vascular nephropathy (nephrosclerosis)
  affection of smaller renal vessel causes kidney
  dysfunction
• renovascular kidney disease vascular
  nephrosclerosis ischemic nephropathy

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Epidemiology of hypertension-induced nehropathy
(HIN)

• 3rd after ischaemic heart disease and stroke
• RR of kidney dysfunction 12,5x ?

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Pathology of HIN

• benign nephrosclerosis
• stenosis of renal arteries
• malign nephrosclerosis

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Benign nephrosclerosis

• in autopsy 16-18 men and 15-27 women
• clinical follow up 15 of patients with
  hypertension
• pathology thickening of arterial wall,
  hyalinosis, infiltration of interstitium,
  interstitial atrophy and fibrosis
• smaller kidneys

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systemic hypertension
vasoconstriction of afferent artery
hypoperfusion
impairment of renal vessel autoregulation
RAS
dilatation of afferent artery
tubulointerstitial fibrosis and dysfunction
hyperperfusion, hyperfiltration
? GF
proteins to mesangium and Bowmans capsula
renal failure
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Clinical symptoms and lab test

• asymptomatic
• nycturia (tubuluinsterstitial changes in
  concetration)
• early lab findings microalbuminuria (5-40),
  small proteinuria (lt1h/day), hyperurikemia,
  normal renal function
• late lab findings renal dysfunction,
• ? S-crea, chronic renal failure (3)

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Diagnosis and dif dg

• longterm history of hypertension
• exclusion of other renal diasease
• hypertonic eye changes
• small proteinuria
• dif dg ischaemic nephropathy (bilateral renal
  arterial stenosis), cholesterol microembolization

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Treatment

• blood pressure control 130/80 (125/75)
• diet, salt intake
• ACE inhibitors, sartans, verapamil other
  antihypertensive drugs
• intensive treatment of other risk factors
  (lipids, glycemia)

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Malign nephrosclerosis

• rare
• lt1 of patients with hypertension (severe)
• pathogenesis failure of renal vessel
  autoregulation
• pathology proliferation endarteritis, fibrinoid
  necrosis of afferent arteries and capilaries
  necrotic glomerulonephritis

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Clinical findings and lab tests

• extreme hypertension
• headache, encephalopathy, coma
• neuroretinopathy
• left heart failure

• proteinuria (nephrotic)
• erythrocyturia
• cylinder
• progressing renal insufficiency

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Therapy

• therapy of emergent hypertension
• ICU
• i.v. antihypertensives (nitrates, urapidil,
  labetalol)
• hemodialysis
• mortality 30

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Stenosis of renal artery/ies

• Hypertension or CKD due to hemodynamicaly
  significant (gt75) renal arterial stenosis (RAS)
  3
• Renovascular diseases renal arterial stenosis
  with/without hypertension
• Ischaemic nephropathy renal dysfunction due to
  renal ischaemia (bilateral RAS)

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Renal arterial stenosis - causes

• Atherosclerosis (high age, 80)
• Fibromuscular dysplasia (younger women, 25)
• Embole, aneurysm, dissection, malformation
• Arteritis
• Extramural pressure (tumors, fibrosis, uretheral
  obstruction, cysts)
• . RAAS activation

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Renovascular hypertension- clinical

• sudden onset, worsening
• retinopathy
• negative family history
• smoking
• vascular history (IHD, PAD)
• renal function impairment after ACEi
• abdominal murmur

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Renal arterial stenosis - diagnosis

• Lab hypokalemia, ? PRA, ? aldosterone (secondary
  hyperaldosteronism), proteinuria, ? S-crea
• Ultrasound renal asymetry (10-15mm), cave
  bilateral stenosis, IR
• Dynamic renal scintigraphy with enalaprilate
• MRA
• DSA

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Renal arterial stenosis - therapy

• Aims
• hypertension control
• preservation of renal function
• PTA fibromuscular dysplasia and
  hypertension/renal dysfunction, others?
• Surgery (aortorenal bypass) aneurysm, restenosis
• Pharmacological slow titration of ACEi/AT1 (Cave
  k.i. bilateral stenosis), diuretics, other
  antihypertensives

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Ischaemic nephropathy

• ? GF due to hemodynamic significant obstruction
  of blood flow in both renal arteries or in renal
  artery of solitary kidney or renal failure due to
  total kidney aperfusion
• atherosclerotic renovascular disease
• atheroembolic kidney disease

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Epidemiology

• 15-16 progress to ESRD (3rd after diabetic
  nephropathy and chronic glomerulonephritis)
• ? mortality in dialysis (average survival 27
  months)

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Atherosclerotic renovascular disease (ARD)

• bilateral renal arterial stenosis 25-30
  patients with renovascular disease
• more frequent in diabetics
• after Tx 3-10

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Forms of ARD

• Acute renal failure or Rapidly progressing renal
  insufficiency
• sudden occlusion of stenotic renal arteries with
  thrombosis, or embolization
• trias nephralgia hypertension hematuria (
  leucocytosis, subfebrile)
• ? poststenotic perfusion after ACEi or sartans
• in 2 weeks after treatment, ARF in 6-10 patients
  with significant stenosis

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Forms of ARD

• chronic renal insufficiency and failure
• chronic kidney ischaemia due to hypoperfusion in
  significant renal arterial atherosclerotic
  stenosis
• asymptomatic. left heart failure (RAS)
• loss of renal function - ? GF 4ml/min/year
• collateral circulation

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Diagnosis and dif dg

• progression of renal insufficiency of unknown
  origin in elderly hypertonic patiens with
  atherosclerotic history (stroke, MI)
• rapid and significant impairment of renal
  function after antihypertensives (not only ACEi,
  sartans)
• dif dg acute tubular necrosis, other
  nehropathies connected with hypertension

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Hypertension-induced nephropathy Ischaemic nephropathy
age 40-60 gt 60
race Afroamerican Caucasian
cause hypertension atherosclerosis
mech perfusion change in HT hypoperfusion
goal lowering of BP stenosis correction
surviv relatively good poor
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Examination

• ultrasound doppler
• dynamic scintigraphy ( enelaprilate)
• MRA of renal arteries
• CTA of renal arteries
• DSA of renal arteries

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Therapy

• revascularization - reperfusion!
• bypass
• PTA
• conservative treatment in k.i. of invasive
• BP control, intervention of risk factors
• ASA

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Prognosis and prevention

• good prognosis in mild renal insufficiency
  (s-crealt 130 umol/l)
• stabilization of renal function in s-crea 130-265
  umol/l
• poor outcomes in severe renal dysfunction
  (s-creagt265 umol/l) 50 progress to ESRD
• effect of revascularization on hypertension
  mostly poor, preventive in pulmonary oedema
• prevention general prevention of
  atherosclerosis

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Atheroembolic kidney disease

• embolization of parts (cholesterol) of
  atheromatic plaque to peripheral circulation
  (arteries 150-250 um) induction of inflammation
• spontaneous (aneurysm of aorta, anticoagulation
  therapy)
• after intervention (DSA, PTA)
• 0,6-6

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Atheroembolic kidney disease

• Acute cholesterol microembolization
• suddan lumbal pain, subfebrile
• hypertension, oliguria
• proteinuria, hematuria
• abdominal (vomitus, ileus, GIT bleeding,
  spleen infarction)
• nervous (paresthesia, paresis, amaurosis, TIA)
• skin (cyanosis, livedo, ulceration of
  peripheral parts of limbs)

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Acute cholesterol microembolization

• diagnosis difficult
• coincidence with intervention
• impairment of renal function
• eosinophilic leucocyturia
• biopsy (microembolization)
• dif dg other causes of ARI
• therapy nephroprotection (hydration, blood
  pressure control), poor outcome

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Atheroembolic kidney disease

• Chronic cholesterol microembolization
• successive embolization from exulcerated
  atherosclerotic plaques in elderly sclerotic
  patients
• successive development and progression of renal
  dysfunction
• lab nonsignificant (proteinuria in FSGS)
• ultrasound aneurysm of abdominal aorta

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Case III.

• 76 year-old woman
• History of hypertension (for 40years), type 2
  diabetes on diet, MI (2x), stroke 1x
• Multicombination antihypertensive therapy,
  statins
• BP 150/95mm Hg
• S-crea 140umol/l, urea 17mmol/l
• Urine protein 1, no erythrocytes, proteinuria
  0,9g/day
• Ultrasound bilateral kidney 80mm, cortex 7mm

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Case III.

• What nephropathy does the patient have?
• What else could she have?
• What examination would you recommend?
• How would you treat the patient?

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Case IV.

• Woman 40 years
• Sudden unset of severe hypertension 190/100,
  normal urea and creatinin, normal urine
• Therapy with perindopril in dose 10mg started, Ca
  blocker (amlodipin 10mg) and BB (metoprolol
  100mg) added
• After 2 months BP 110/60, urea 16mmol/l,
  creatinin 349umol/l
• Ultrasonography asymetry of kidneys (R 85mm, L
  108mm)

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Case IV.

• What type of hypertension did the patient
  obviously had?
• What was wrong in the diagnostic process?
• What was wrong in the therapy?
• What examination would you recommend?
• What treatment?

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Conclusion II.

• Relation between hypertension and renal function
  reciprocal
• Untreated hypertension leads to renal damage
• Kidney diseases lead to hypertension
• Prevention and therapy blood pressure control
  to target
• Inhibitors of RAS, revascularization if possible

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Conclusion

• Diabetes is the leading cause for dialysis
  treatment in developed countries
• Reciprocal relationship between hypertension and
  renal disease
• Untreated hypertension causes renal damage and
  failure