MANAGEMENT STRATEGY IN

ADPKD

ADPKD Introduction
Autosomal dominant polycystic kidney disease (ADPKD) - one of the most common inherited disorders in humans Most frequent genetic cause of renal failure in adults Accounts for ~4% of end-stage renal disease (ESRD).

Inheritance : Autosomal Dominant

Incidence 1 : 700 to 1 : 1000 In India : 10,00,000 cases

ADPKD - multisystemic and progressive disorder

Characterized by formation and enlargement of cysts in the kidney and other organs (eg, liver, pancreas, spleen) Clinical features usually begin in the third to fourth decade of life, but cysts may be detectable in childhood and in-utero

Pathophysiology
The main feature of ADPKD is bilateral progressive cystic dilation of the renal tubules, which may lead to end-stage renal disease (ESRD) Hepatic cysts, cerebral aneurysms, and cardiac valvular abnormalities also may occur

 Modern ADPKD research started when epithelial cell lining the cysts in kidneys of ADPKD patients was successfully isolated and maintained in ex vivo cultures.

 It is observed that cyst cells continue to proliferate, secrete fluid and destroy the surrounding normal tissue by expansion.

Cyst fluid contains many hormonal activities including ADH & EGF (Epidermal Growth Factor)

The abnormality
Approximately 85-90% of patients with ADPKD have an abnormality on the short arm of chromosome 16 (ie, ADPKD type 1 [ADPKD1]) A second defect, termed ADPKD type 2 (ADPKD2), is responsible for 5-15% of ADPKD cases and is found on the long arm of chromosome 4 A third genotype may exist, but no genomic locus is assigned.

PKD1 and PKD2 expressed in most organs and tissues

Proteins encoded by PKD1 and PKD2 polycystin 1 and polycystin 2 - function together to regulate the morphologic configuration of epithelial cells The polycystins - expressed as early as the blastocyst stage and expressed in a broad array of terminally differentiated tissues The functions of the polycystins have been scrutinized to the greatest extent in epithelial tissues of the kidneys and liver and in vascular smooth muscle.

Mortality/Morbidity
The major cause of morbidity is progressive renal dysfunctionIn - half of patients with ADPKD undergo renal replacement therapy by age 60 years Cardiovascular pathology and infections account for approximately 90% of deaths of those patients treated by hemodialysis or peritoneal dialysis and after renal transplantation Another cause of mortality is subarachnoidal hemorrhage from intracranial aneurysms (ICAs). This complication is rare and severe.

 Sex - ADPKD is slightly more severe in males than in females, but it is not statistically significant
Age - Symptoms generally increase with age. Children very rarely present with renal failure from ADPKD

The mean age of onset of ESRD in patients with ADPKD1 is 53 years; in patients with ADPKD2, it is 74 years.

Clinical manifestations
Renal - A decrease in urine-concentrating ability is an early manifestation of the disease Microalbuminuria occurs in 35% of patients with ADPKD Patients may develop renal failure, usually in the fourth to sixth decade of life

Clinical manifestations contd.

Hypertension is one of the most common early manifestations of ADPKD Pain - located in the abdomen, the flank, or the back, is the most common initial complaint Hematuria - frequently is the presenting manifestation and usually is self-limited Stroke - aneurysm screening with magnetic resonance angiography

Physical examination
Palpable, bilateral flank masses occur in patients with advanced ADPKD Nodular hepatomegaly occurs in those with severe polycystic liver disease Symptoms related to renal failure (eg, pallor, uremic fetor, dry skin, edema) are rare upon presentation.

Diagnosis
Renal USG - sensitivity 100% for subjects 30 years or older with a positive family history Diagnostic criteria - two or more cysts in one kidney and at least one cyst in the contralateral kidney in young subjects, but four or more in subjects older than 60 years Most often, the diagnosis is made from a positive family history and imaging studies showing large kidneys with multiple bilateral cysts and possibly liver cysts

Diagnosis contd.
Before the age of 30 years - CT scan or T2-weighted MRI is more sensitive for detecting presymptomatic disease because the sensitivity of ultrasound falls to 95% for ADPKD type 1 and <70% for ADPKD type 2

Screening for ADPKD

Imaging Genetic testing

Benefits of Testing for ADPKD

Identification of possible kidney donors Family planning Early detection of complication Early treatment of complication

Detriments of screening
Psychological Educational and career implication Insurability

Diagnosis in absence of family history

Bilateral renal cyst and 2 or more of: 1.bilateral renal enlargement 2. 3 or more hepatic cyst 3.cerebral artery aneurysm 4. arachnoid cyst 5. pineal gland cyst 6. pancreatic cyst 7. splenic cyst

Genetic testing:Linkage
PKD1and PKD2 genes Linkage analysis

Treatment
No specific medication is available for ADPKD However, clinical trials with vasopressin 2 receptor antagonists (Tolvaptan), somatostatin, rapamycin (sirolimus) and some more agents are ongoing At present, treatment is largely supportive, as there is no single therapy that has been shown to prevent the decline in kidney function.

ADPKD:Renal manifestation
Hypertension Pain ESRD Infected cyst Stones Hematuria

ADPKD:HTN
5-40% OF CHILDREN WITH ADPKD 50% OF 20-35 AND N RF 100% WITH ESRD Principle form of presentation

HTN:Etiology
Association with renal size Streching of vessels Distal ischaemia Activation of RAS PKD1 N PKD2 found in vessel walls Impaired NO mediated vasodilation Insulin resistance

HTN:Associations
Reduced renal bld flow Abnormal sodium handling Remodeling of renal vasculature

HTN:Complications
LVH Diastolic dysfunction Worsening of MVP Worsening of aneurysm Hematuria Major risk factor for IHD/MI Worsening of Proteinuria/CKD Increased risk of pre-eclampsia/fetal loss

HTN:Treatment
Early detection imp Ambulatory BP monitoring ACEI>CCB/HCTZ for proteinuria but no effect on Cr Optimal BP unclear, likely <130/80

ADPKD:Renal manifestation
Hypertension Pain ESRD Infected cyst Stones Hematuria

Pain
Most common symptom Etiology Inf Stones Bleeding Clot colic Pressure on capsules/adjacent organs Diverticulitis

Pain:treatment
1. Treat identifiable causes 2. Analgesics 3. Percutaneous cyst aspiration and sclerosant 4. Transcatheter arterial embolization 5. Open cyst unroofing 6. MAS Denervation 7. MAS or open nephrectomy

ADPKD:Renal manifestation
Hypertension Pain ESRD Infected cyst Stones Hematuria

ESRD
On average occurs between 4th-6th decade Later in PKD2 than PKD1 Once begins,avg decline 5 ml/min/yr 50% develop ESRD by age 60

ESRD:Etiology
Not completely understood Only about 1% of nephrons develop cysts Pressure atrophy? HTN? Increased apoptosis in nephrons Vascular remodeling Analgesic nephropathy

ESRD:Risk factors
1. PKD1 2. Male 3. African american 4. Hematuria <30yrs 5. HTN<35 yrs 6. Hyperlipidemia 7. Low HDL 8. Sickle cell trait 9. Smoking 10.Rate of cyst growth/size of kidneys

ESRD:Prevention
ACEI slows rate of proteinuria but no effect on Cr compared to CCB, HCTZ Cyst unroofing has no effect

ADPKD:Renal manifestation
Hypertension Pain ESRD Infected cyst Stones Hematuria

Infected cysts
90% occur in women Ascending infection E. coli,Klebsiella,Proteus and Pseudomonas Instrumentation a major risk factor Poor antibiotic penetration r/o obstruction

Infected cysts:T/t
Lipophillic antibiotics (flouroquinolones, septran,chloramphenicol) Percutaneous cyst aspiration Nephectomy

ADPKD:Renal manifestation
Hypertension Pain ESRD Infected cyst Stones Hematuria

ADPKD:Stones
5-10 times the incidence of general population 30% of pts are symptomatic Contemporary endourological management

ADPKD:Renal manifestation
Hypertension Pain ESRD Infected cyst Stones Hematuria

hematuria
50% of ADPKD pts Presenting symptom in 25% Hematuria a/w worsening Cr

 Transexamic acid is plasminogen inhibitor-antifibrinolytic agent consider using in cases of severe hematuria in ADPKD

ADPKD:Transplant issues
When to consider transplantation When to consider native nephrectomy Timing of native nephectomy Issues unique to ADPKD after RT

When to consider transplant

GFR < 10cc/min Symptomatic uremia

Indication for native nephectomy

Chr. Pain HTN Cyst infection Renal mass GI(Early satiety,constipation) No room for renal allograft Respiratory compromise Recurrent calculi

Native nephrectomy
Rate of native nephrectomy for ADPKD decreased over last 3 decades 85% in 1970s 47% in 1980s 20% contemporary series

Issues unique to ADPKD post RT

ADPKD have graft survival outcomes similar to RT population as a whole But the following is more prevalent 1.diverticulitis+/- perforation 2.arachnoid hemorrhage(no CVAs overall) 3.erythrocytosis with need for phlebotomy 4.no increased risk of cardiovascular ds.

 NEWER PHARMACOLOGICAL AGENTS

TOLVAPTAN
Otsuka Pharmaceutical (basic manufacturer of Tolvaptan) is proceeding with multinational, multicentre, phase III clinical trial to examine the efficacy & safety of Tolvaptan in ADPKD Trials of tolvaptan in humans with ADPKD are ongoing (Ref: Clin Ther. 2010 Jun;32(6):1015-32 ) Approximately 1500 patients will be randomised to either Tolvaptan or Placebo and will be observed for the duration of 5 years

Mechanism of action (V2RA)

Tolvaptan has been shown to decrease cyst and kidney volume.

 Shillingford also observed in a small group of renal transplantation that size of cyst in native ADPKD kidney significally reduced when treated with sirolimus in comparison to CNI. Cincinnati Rapamycin Trial as well as ongoing multicentre trial in UK & US has shown favourable results in cysts of PKD in tuberous sclerosis.

Sirolimus therapy in polycystic kidney disease A pilot study, Nov. 2009 Transplant proceedings A.R. Soliman, E. Ismail, S. Zamil, Cairo university, Egypt.

Diagram : dysregulation & accumulation of mTOR in epithelial lining of cyst, which may be final common pathway in cystogenesis.

Safety and tolerability of Sirolimus treatment in patients with polycystic kidney Andreas L. Serra, Andreas D. Kistler, Daine Poster et al. Nephrol Dia. Trans (2009) 3334-3342

Sirolimus reduces polycystic liver volume in ADPKD patients JASN 19, 631-638, 2008 Qian, Hui Du, Bernal F. King et al.

SOMATOSTATIN Somatostatin has been shown to reduce chloride and fluid secretion in cyst by inhibition of adenylatecyclase & CAMP in epithelial cells of cysts. Mario Negri Institute of Pharmacological research in Italy will enroll 66 ADPKD patients to test the efficacy of long acting somatostatin octreotide LAR. This study will treat patients with an estimated GFR > 40 ml/min./1.73 m2 and follow the response of therapy by serial MRI over 3 years.

Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease
ADPKD(n-34) and ADPLD(n=8). Liver volume decreased by 4.95%+/-6.77% in the octreotide group but remained practically unchanged (+0.92%+/-8.33%) in the placebo group (P=0.048). Among patients with ADPKD, total kidney volume remained practically unchanged (+0.25%+/-7.53%) in the octreotide group but increased by 8.61%+/-10.07% in the placebo group (P=0.045). Changes in GFR were similar in both groups. In summary, octreotide slowed the progressive increase in liver volume and total kidney volume, improved health perception among patients with PLD, and had an acceptable side effect profile
Ref: J Am Soc Nephrol. 2010 Jun;21(6):1052-61. Epub 2010 Apr 29

(R) - Roscovitine

(R) roscovitine is a (R) sterioisomer of roscovitine.

-- Roscovitine is a low molecular weight compound of 2, 6, 9 tri-substituted purine family. -- 3 week course has long lasting beneficial effect. -- In clinical trials it is well tolerated.

 (R) roscovitine is a protein kinase inhibitor with preferenitial selectivity for cyclin dependent kinase (CDKs)
Prevents phosphorylation of Rb (retinoblastoma) protein

Normalize the level of several cyclins

Prevent cell proliferation, transcription and apoptosis Prevents cyst progression.

Mechanism of action (Roscovitine)

Roscovitine on renal tubular epithelial cell implications for autosomal dominant polycystic kidney disease
The cyclin kinase inhibitor roscovitine has shown efficacy in treatment of murine PKD Renal tubular epithelial cells exposed to 'low' concentrations of roscovitine showed minimal apoptosis in association with markedly increased levels of the antiapoptotic protein p21 Data in this study provide a mechanistic explanation of how roscovitine is effective in PKD
Ref: Am J Nephrol. 2009;29(6):509-15. Epub 2008 Dec 10

TRIPTOLIDE
Natural Chinese herbal compound. Restores intracellular Ca2+ regulation in cyst lining cells Thus inhibits c-AMP dependent cell proliferation and water secretion.

Triptolide reduces cyst formation in a neonatal to adult transition Pkd1 model of ADPKD
Daily injections with triptolide significantly reduced the total number of cysts per kidney, with a pronounced effect on the number of microcysts and the overall cystic burden Additionally, renal function as assessed by blood urea nitrogen levels was also improved in triptolide-treated mice These results suggest that the model of ADPKD is amenable to short-term kidney cyst formation drug studies
Ref: Nephrol Dial Transplant. 2010 Jul;25(7):2187-94. Epub 2010 Feb 4

colchicine
A very old drug that has been hypothesized to have a preventative role in ADPKD is colchicine. It is better known for its role in the management of gout. It is a potent anti inflammatory agent and has effects which may be useful in delaying cyst growth.

CFTR Inhibitors
Cyst growth in ADPKD is based on the accumulation of fluids within the cyst by the action of a complex pump known as CFTR which is the same protein which is abnormal in cystic fibrosis. Inhibtors of CFTR have been available. Recently they have been shown to be of efficacy in reducing cyst growth in mouse models of APKD.

 How to monitor the therapeutic efficacy in ADPKD. - Very slowly progressive disease. - Initially GFR remains stable. - Once when Serum Creatinine exceeds normal value GFR declines 5 ml/min/yr, leading to ESRD within 10 years.

However individual variability is substantial.

 Consortium for Radiologic Imaging studies of PKD (CRISP) followed 241 ADPKD patients by sequential MRI measurement of cyst & renal volumes. According to them, Volumetric kidney measurements by MRI is the gold standard to determine disease progression. They also observed that Renal & cyst volumes correlated inversely with GFR and directly to hypertension and urinary albumin excretion. Average annual increase in renal volume was 5.3%. Cyst growth was more aggressive in young or who had large renal volume at the time of diagnosis.

Comparison of potential treatments for PKD Compund Mechanism Molecular target PKD Models Han:SPRD rat orpk mice bpk mice Human Potential side Effect on effects liver cysts Oral mucositosis, tremor, hypertension

Rapamycin

Antiproliferative mTOR

Unknown

Vasopressin V2R antagonist

Inhibit fluid secretion and cAMP cell proliferation Inhibit fluid secretion and cAMP cell proliferation Ca2+ signalling Antiproliferative (PC2dependent)

pcy mice PCK Hypernatremia, No rat Pkd2 thirst Diarrhoea, anorexia, gallstones

Somatostatin

PCK rat Human

Yes

Triptolide

Pkd1 mice (from E10.5)

Male infertility Nausea, transient elevation of creatinine, hypokalemia

Unknown

Roscovitine

Cyclincpk mice jck Antiproliferative dependent mice kinases (Cdk)

Unknown

Tyrosine bpk mice Diarrdoea, Antiproliferative EGF receptor kinase inhibitor Han:SPRD rat rashes Batimastat Caspase inhibitor Inhibit matrix degradation Antiaptosis Metalloprotein Han:SPRD rat Arthralgia ases Caspases Han:SPRD rat Diarrhoea

No Unknown Unknown

Pioglitazone

PeroxisomeproliferatorAntiproliferative activated receptor(PPAR- )

Pkd1 mice (from E7.5)

Hypoglycemia, weight gain, Unknown fluid retntion

 Is it time to start clinical trials in ADPKD ? Of course Yes.. ADPKD patients have waited enough & suffered enough to find a cure of their disease so any measure to halt the progression of disease is highly warranted.

Phase I/II study is initiated by the cleveland clinic which will enroll a total of 45 patients and monitor the changes in iothalamate, GFR and total kidney volume measured by CT over the period of 12 months. The patients will be divided into 3 groups. Control (15), low dose of sirolimus (15) (trough blood level 2-5 ng/ml) and high dose of sirolimus (15) (trough blood level 5-8 ng/ml.).

 Other trial will treat 300 ADPKD patients with everolimus. It has been started in Germany and Austria and will follow ADPKD patients with estimated GFR between 30 to 89 ml/min/1.73m2 (CKD stage II & III) for 2 years by repeated MRI. Dose is the same as given in organ transplantation.

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