Kidney disease in hypertension and diabetes. Diagnosis, treatment.

Ludmila BrunerovaII. Dpt of Internal Medicine FNKV

and Mediscan Euromedic

Diabetic nephropathy Nephropathy in hypertension

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

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)

PathophysiologyHyperglycaemia

Glycation endproducts (AGE)

activation of signal transductionPKC, MAP kinase, NF-κB Reactive oxygen

radicals

Vasoactive systems

Hemodynamicchanges

Growth factorsCell cycle changes

Tubulointerstitial fibrosisProteinuria

GlomerulosclerosisRenal failure

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

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

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)

Phases of diabetic nephropathy

Phase 1: hyperfiltration-hypertrofic …. functional changes hyperfiltration ( GF o 20-40%) hyperperfusion renal hypertrophy asymptomatic

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

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

Phase 4: manifest diabetic nephropathy

…. proteinuria, renal insufficiency after 10-20 years of diabetes duration proteinuria > 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

Phase 5: chronic renal failure, need for RRT

> 20 years of diabetes duration > 7 years of proteinuria duration high mortality (cardiovascular

complications) complications of renal failure

Lab tests

diagnosis of DN = persistent albuminuria > 30mg/24 hours (2/3 measurements in 6 months), in presence of diabetes, after exclusion of other renal disease

urine ch+s examination of proteinuria examination of renal function Ultrasound of kidneys

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: > 300mg/24 hours (resp.

200ug/min)~0,5g/day – >3,5g/24 hours – nephrotic proteinuria

Evaluation of renal function

S-crea GFR MDRD Cystatin C

S-crea (umol/l)

100

500

900

GFR (ml/s)0,2 1,0 2,0

Principles of diagnosis – I.

Diagnosis clinical… (ADA, 2003) Progressing proteinuria in patients

with longeterm history of type 1 DM > 10 let

Microalbuminuria preceded With diabetic retinopathy Without microscopic hematuria With normal ultrasound finding

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

Principles of diagnosis- II.

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

Dif dg Typical finding in renovascular

disease Elderly, sclerotic With renal insufficiency (s-crea 130-

200umol/l) Small proteinuria (<1-2g/24 hours) Hypertension Ultrasound – asymetry, bilateral small

kidneys, reduced cortex Biopsy not indicated

Doppler, MRA, DSA

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

Dif dg

„inflammation“ sediment

With positive cultivation – urinary tract infection, asymptomatic bakteriuria

With sterile pyuria – TBC, necrosis of renal papilla

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 < 130/80mmHg Renoprotective: ACEi sartans

Urinary tract infection Early treatment

angiotenzinogen

angiotenzin I.

ACE

renin

chymase

bradykinin

NO, PG

vasodilatationvasoconctriction,atherosclerosisinflammation

AT1R AT2R

angiotenzin II.

Inacive peptides

AT1R

?

Cascade after ACEi

Cascade after sartans

Cascade after direct inhibition of renin

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

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

Case 1

What is patient´s problem? How would you treat the patients?

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

Case 2

Does the patient have diabetic nephropathy?

Why? What other examination would you

recommend? How would you treat the patient?

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

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)

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

kidney disease

GF

natrium excretion

ECF

hypertension

intrarenal ischaemia

RAAS SAS

damage of medulla

Pg, kinins

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

Epidemiology of hypertension-induced

nehropathy (HIN) 3rd after ischaemic heart disease

and stroke RR of kidney dysfunction – 12,5x

Pathology of HIN

benign nephrosclerosis stenosis of renal arteries malign nephrosclerosis

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

systemic hypertension

vasoconstriction of afferent artery

hypoperfusion

GF

impairment of renal vessel autoregulation

dilatation of afferent artery

hyperperfusion, hyperfiltration

proteins to mesangiumand Bowman´s capsula

RAS

tubulointerstitial fibrosis and dysfunction

renal failure

Clinical symptoms and lab test

asymptomatic nycturia (tubuluinsterstitial changes

in concetration) early lab findings: microalbuminuria

(5-40%), small proteinuria (<1h/day), hyperurikemia, normal renal function

late lab findings: renal dysfunction, S-crea, chronic renal failure (3%)

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

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)

Malign nephrosclerosis

rare <1% of patients with hypertension

(severe) pathogenesis – failure of renal

vessel autoregulation pathology – proliferation

endarteritis, fibrinoid necrosis of afferent arteries and capilaries – necrotic glomerulonephritis

Clinical findings and lab tests

extreme hypertension

headache, encephalopathy, coma

neuroretinopathy left heart failure

proteinuria (nephrotic)

erythrocyturia cylinder progressing renal

insufficiency

Therapy

therapy of emergent hypertension ICU i.v. antihypertensives (nitrates,

urapidil, labetalol…) hemodialysis mortality – 30%

Stenosis of renal artery/ies

Hypertension or CKD due to hemodynamicaly significant (>75%) renal arterial stenosis (RAS)… 3%

Renovascular diseases – renal arterial stenosis with/without hypertension

Ischaemic nephropathy – renal dysfunction due to renal ischaemia (bilateral RAS)

Atherosclerosis (high age, 80%) Fibromuscular dysplasia (younger

women, 25%) Embole, aneurysm, dissection,

malformation Arteritis Extramural pressure (tumors, fibrosis,

uretheral obstruction, cysts…) …. RAAS activation

Renal arterial stenosis - causes

sudden onset, worsening + retinopathy + negative family history + smoking + vascular history (IHD, PAD) + renal function impairment after

ACEi + abdominal murmur

Renovascular hypertension- clinical

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

Renal arterial stenosis - diagnosis

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

Renal arterial stenosis - therapy

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

Epidemiology

15-16% progress to ESRD (3rd after diabetic nephropathy and chronic glomerulonephritis)

mortality in dialysis (average survival 27 months)

Atherosclerotic renovascular disease

(ARD) bilateral renal arterial stenosis –

25-30% patients with renovascular disease

more frequent in diabetics after Tx – 3-10%

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

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

Forms of ARD

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

Hypertension-induced nephropathy

Ischaemic nephropathy

age 40-60 > 60

race Afroamerican Caucasian

cause

hypertension atherosclerosis

mech perfusion change in HT

hypoperfusion

goal lowering of BP stenosis correction

surviv

relatively good poor

Examination

ultrasound + doppler dynamic scintigraphy (+

enelaprilate) MRA of renal arteries CTA of renal arteries DSA of renal arteries

Therapy

revascularization - reperfusion! bypass PTA conservative treatment – in k.i. of

invasive BP control, intervention of risk

factors ASA

Prognosis and prevention

good prognosis in mild renal insufficiency (s-crea< 130 umol/l)

stabilization of renal function in s-crea 130-265 umol/l

poor outcomes in severe renal dysfunction (s-crea>265 umol/l) – 50% progress to ESRD

effect of revascularization on hypertension – mostly poor, preventive in pulmonary oedema

prevention – general prevention of atherosclerosis

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%

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)

Atheroembolic kidney disease

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

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

Atheroembolic kidney disease

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

Case III.

What nephropathy does the patient have?

What else could she have? What examination would you

recommend? How would you treat the patient?

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)

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?

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

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