Polycystic Kidney Disease Flashcards
What is the common protein in ADPKD proteins?
Polycystin
Polycystin 1 = PKD 1
Polycystin 2 = PKD 2
Other genes that involved?
GANAB
DNAJB 11
ALG 9
Pathophysiology of PKD
Loss of functional Polycystin (mutation) of genes
2nd hit hypothesis: + acquired somatic loss of haplotype
Increased cAMP - decreasing intracellular Ca2+ — (leads to increase fluid secretion+cyst formation)
Angiogenesis
Abnormal cilia function
What is the function of these gene?
PKD-1: regulate tubular epithelial cells adhesions and differentiation (cyst formation)
PKD-2: act as ion channel (if lack - increase fluid secretion into cyst)
PKD-1 vs PKD-2 (diff)
Gene involvement: PKD-1 (chr 16), PKD-2 (chr 4)
Severity: PKD-1 > PKD-2
Cyst formation: earlier in PKD-1 (young age) , lesser in PKD-2
Progression: PKD-1 > PKD-2
ESRF: earlier in PKD-1 (50+) > PKD-2 (70+)
What is the common cause of death in pt with ADPKD?
- Cardiac death
- Infection
- Neurological cx - ruptured aneurysm / ICB
Causes of hypertension in ADPKD
- Activation of RAAS
- Impaired endothelium-dependent vasorelaxation (sama gene in vascular smooth ms)
- Increased sympathetic nerve activity, plasma endothelin rec and insulin resistance
What is ‘total kidney volume’ (TKV)
Total volume of cyst that can potentially affect the kidney function
*prognostic marker
** higher TKV, high BP
USG criteria for diagnosis
Age: 15 / 30 / 40 / 60
What are the differential diagnosis for atypical presentation ?
ARPKD
Von Hippel Lindau dz
Tuberous sclerosis dz
DM with HNF1B mutations
Medullary sponge disease
Oro-facial digital syndrome type 1
What are the kidney manifestation of ADPKD?
- Mass effect - renomegaly
- HPT and TOD (mainly cardiac cx)
- Hematuria - cyst ruptured / haemorrhage / infection / renal Stone / RCC
- CKD - leading to ESRF
Risk factor leading to ESRF
- rate of eGFR deterioration: 4.5-6.0 ml/min per year
- Male
- Diagnosis before age of 30 yo
- Hematuria episode before age of 30
- Onset of hpt before 35 yo
- HPL: low HDL
- PKD-1
- Sickle cell trait
Extrarenal manifestation
- Polycystic kidney disease
- Intracranial aneurysm
- Other vascular abN: Arterial dissection, coronary art aneurysm, retina vessels occlusion
- Valvular heart dz: MVP
- Cyst elsewhere: pancreas, seminar vesicles, prostate - defective motility
Role of neurological screening?
When is indicated?
Not indicated for all
UNLESS
1. FH of intracranial aneurysm / ICB
2. Prev aneurysm ruptured
3. Prep for elective Surgery - with potensial hemodynamic instability
4. High risk occupations - pilot
5. Anxiety pt despite explaination
Principal of ADPKD mx
CKD retardation
Non pharm mx
1. Low salt diet (<2g/day)
2. Increase water intake (aim urine Osm 250)
3. Monitor cyst growth & cx (renal / extrarenal)
4. Family counselling / screening
Pharm mx
1. Control BP
- aim BP: 120/80mmhg / 110/75mmHg (young, eGFR > 60)
- ACE / ARB
2. Disease modifying agent: tolvaptan
Important clinical trial in ADPKD
BP
ACE / ARB
BP: HALT PKD (study A)
NJEM 2014
Standard BP vs intensive BP
(120-130/70-80) vs (95-110/60-75)
- intensive BP - slower TKV increament, reduced albuminuria, lower LV mass index
- NO diff in eGFR
ACE / ARB: HALT PKD (study B)
NJEM 2014
(Lisinopril) vs (lisinopril+placebo) vs (telmisartan)
NO diff in eGFR declined / TKV / ESKD / albuminuria / death
Important clinical trial in ADPKD
Tolvaptan
(Vasopressin antagonists)
TEMPO 3:4
TEMPO 4:4
REPRISE
TEMPO 3:4 trial
Tolvaptan vs placebo
Up to 3 yrs f/up
Primary end point: slower TKV growth
(2.8% vs 5.5% per year ~ p<0.001)
Sec end point: slower renal function decline
Discont due to SE (up to 23%)
TEMPO 4:4 trial
Additional 2 years f/up of TEMPO 3:4
Support the sustained dz modifying effect of tolvaptan seen in TEMPO 3:4
Safety profile was similar
REPRISE trial
Tolvaptan vs placebo
Important clinical trial in ADPKD
Other agent:
TAME PKD: metformin
MTori (everolimus)
ALADIN 1 & 2: Octreotide