CME COURSE ON ADPKD - UPDATE ON TREATMENT Vicente Torres, Rochester, USA Chair: Yves Pirson, Brussels, Belgium

Transcription

1 CME COURSE ON ADPKD - UPDATE ON TREATMENT Vicente Torres, Rochester, USA Chair: Yves Pirson, Brussels, Belgium Vicente E. Torres Division of Nephrology and Hypertension Department of Internal Medicine Mayo Clinic Rochester, MN, USA Slide 1 Thanks very much for this first introduction. Slide 2

2 I appreciate the EDTA for inviting me to give this talk. Some of the slides I will show you have already seen but maybe some repetition is not bad. So again, ADPKD is a very common disease with a prevalence between 1: live births but at a particular point in time only about 25% of them have been diagnosed. So in this sense it has been considered by the FDA as a rare disease. About 5% of the cases are due to new mutations and as you have heard, PKD1 is more severe than PKD2. Slide 3 You have already seen this slide, PKD1 with now has been split with truncating mutations and missense mutations or non-truncating mutations and that the non-truncating mutations have an intermediate phenotype. This is an observation from the group in Bretagne in France but also confirmed by the group of Peter Harris and in Canada.

3 Slide 4 Now you have already seen part of that and that ADPKD has been known for centuries but for most of this time it has been considered a congenital malformation that by the time it can be diagnosed in your life, it s an illness without a cure. Slide 5 Now, this started changing in the 1960s, 1970s and 1980s with the observation that actually they are not congenital but the cysts develop with time as focal dilatations from the renal tubules and as they grow they become disconnected and become blind sacks. But these blind sacks are not static and dead but they are a very dynamic structure Slide 6

4 with a very high turnover of fluid in the cyst which is due to an active solute transportation and that therefore, is amenable to pharmacotherapy. Slide 7 There has been an explosion of research into polycystic kidney disease since the 1980s, which has been facilitated by the foundation, by the Polycystic Kidney Disease Foundation and affiliates and also by support from the NIH, the European community and more recently Pharma.

5 Slide 8 This has been accelerated by the discovery of the PKD 1, PKD2 and PKD 1 genes between 1994 and So, this has resulted in an increased awareness of the disease and with increased awareness there have been improved outcomes and with increased research and with increased research there have been emerging therapies. Slide 9

6 Now that shows what the age of death was during the last century in the Netherlands and that showed that between the ages of 50 and 59 there was an increased mortality compared to the general population, approximately 3-4 times. This increase in mortality has been markedly becoming less and less over time and this has been confirmed by many other studies but particularly the most convincing is the one from the UK General Practice Database where the incidence rate ratio for mortality has decreased by 6% per each increasing year of entry into the study and that this reduction in mortality has been associated with more frequent recordings of blood pressures. Lower mean systolic blood pressure and lower mean diastolic blood pressure. Slide 10

7 Now one of the main duties of physicians taking care of patients with polycystic kidney disease is to inform them correctly and to let them know that the outcomes of polycystic ADKPD can be changed and that actually have been changing. This information is very important to kind of change the pessimism and the psychological burden of the disease in these patients which results in ambivalence towards diagnosis, denial, problems with reproductive decisions and eventually parental blame. All of this results in less frequent early diagnosis of the disease and more problems with compliance with medication with the patients, which is a vicious circle that results in poor outcomes. Slide 11 Now patients have also to deal with the burdens of a chronic disease and you have already seen that over the decades the number and size of the cyst and volume increases and most of the time the renal function remains normal. However, although the renal function remains normal, Slide 12

8 there are other manifestations of the disease that develop: polyuria and hypertension, proteinuria and eventually very rapid GFR decline. Slide 13 Now, the importance of hypertension on the GFR decline is great and hypertension is present in almost all patients with polycystic kidney disease prior to GFR starting to decline. The hypertension goes undiagnosed and untreated for a long time and it contributes to the GFR decline, development of ESRD and cardiovascular morbidity and mortality. Slide 14

9 The pathogenesis is multifactorial but the renin-angiotensin aldosterone system of the activation of the renin-angiotensin aldosterone system in the kidney has received special attention and because of this it has become Slide 15 almost general that the first drug of choice to treat hypertension in polycystic disease are ACE inhibitors or angiotensin 2 receptor blockers. However, this practise is not supported by clinical studies, properly performed clinical trials in part because most of the clinical

10 trials that have been conducted have been very small and of short duration. Overall, they have shown no benefit compared to betablockers although in some studies the angiotensin converting enzyme inhibitors have been better than either diuretics of calcium channel blockers in patients with CKD stages 1-3 and ADPKD. Slide 16 Now in patients with ADPKD and CKD stage 4 the clinical trials that have been performed have also been underpowered and of short duration and there was only a slight benefit in patients with a proteinuria above 2 g/ 24 h. Slide 17

11 Now, we don t have information either on what the target level of blood pressure control should be. There have been in the MDRD trials comparing vigorous blood pressure control versus standard blood pressure control and in patients who had CKD stage 4 during the first 3 years of the trial there was faster progression with rigorous blood pressure controlled with a standard control. However, in the patients that had more preserved kidney function with CKD stage 3 and had a later follow-up the GFR decline was slower after 3 years in the patients who had rigorous blood pressure control. Slide 18

12 Another study that has looked into this question is that of the University of Colorado trial and in this study it was shown that rigorous blood pressure control improved left ventricular hypertrophy but had no significant effect on GFR decline. But again, that was a short trial. Slide 19 Currently in the United States we have the HALT-PKD trial which has been going on now for a number of years and this is a two by two clinical trial design comparing ACE inhibitors versus ACE plus ARBs and rigorous versus standard blood pressure control. Unfortunately, I cannot give results on this trial because the trial will not be completed until June 2014 but I m sure the information from this trial will have an impact on our practice in regards to controlled hypertension. Slide 20

13 The best evidence that exists so far kind of supporting the use of ACE inhibitors and angiotensin 2 receptor blockers in ADPKD comes from epidemiological studies showing that the age of ESRD has increased in a number of studies over a period of time. So in the US-COLORADO registry comparing the cohort from and the age of ESRD improved from years in males, in females. Slide 21 A kind of similar observation has been made in the Danish National Registry where age of ESRD has increased with time Slide 22

14 and similarly in the US-RDS the age of ESRD has slightly but significantly improved with time. So has also been associated with an increased use of ACE inhibitors and angiotensin 2 receptor blockers and keeping blood pressures lower. So this epidemiological evidence, which is not proof but at least it s supportive Slide 23

15 that rigorous blood pressure control and use of drugs interfering with the renin angiotensin system is the right way to go. Now you have already heard that other factors have been associated in a number of studies with a more rapid decline of GFR and this includes desmopressin. So hydration is a reasonable thing to recommend to these patients. Urine sodium excretion, which reflects sodium intake. So sodium restriction should be recommended. Low HDL cholesterol, cholesterol control. More recently a study from the university of Colorado has shown an association between hyperuricemia and a faster increase in total kidney volume and increased risk of ESRD. Whether allopurinol should be considered in these patients has been raised by this study. However, it is quite possible that increase in uric acid in these patients just reflects a lower renal blood flow and higher renal vascular resistance and more severe disease. So a clinical trial here would be necessary for this. Slide 24

16 Now in terms of the hydration this is supported by the epidemiological studies of serum copeptin by the preclinical and clinical trials with vasopressin antagonists but is also supported by a preclinical study from the University of Kansas in a rat model of polycystic kidney disease where forced hydration slowed down the progression of the disease. Again, this is not supported by a clinical trial in humans but based on what we know so far a reasonable goal is to achieve a urine osmolarity of 200 mosm/kg with intake of water, which is spread out during the day and at bedtime. If you don t do it properly, in patients who have a GFR of over 30 ml/min/1.73 m2, the risk is low to minimal. The follow-up is required at least in patients that have lower GFR or who are on drugs that enhance vasopressin secretion and this is the least of conditions where vasopressin secretion may be enhanced or the effect of vasopressin may be enhanced and that one has to be more careful about the possible development of hyponatremia. Slide 25 Now, in turn when ESRD develops the treatment of choice is preemptive renal transplantation without going through dialysis. That shows the results from Mayo where about 17% of our patients have ADPKD and in 48% of the cases they have pre-emptive transplant, the majority from living donors, but this underestimates this has now been much higher in the current years because that s the overall of experience. Patients with ADPKD do very well with major cardiovascular event-free survival, which is only less than in patients with glomerulonephritis that are much younger and have the best graft survival of all groups because of the lower risk of recurrent disease. Slide 26

17 Now, that s a very nice study from Japan from Nagoya which is kind of confirming something that we thought we knew but it had never been confirmed in a proper study showing that after successful kidney transplantation, after one year there is about a 37% reduction in the size of the native kidneys, which indicates that the majority of patients with polycystic kidney disease do not need transplant and native nephrectomies prior to renal transplantation. As opposed to the kidney, the liver continues to increase in size after kidney transplantation. Slide 27 Now in addition to the hypertension and the GFR decline Slide 28

18 there are other complications of polycystic kidney disease: haemorrhage, stones, infection and pain. Slide 29 I will just mention some highlights of some recent studies. Well, the cyst haemorrhage is usually treated by rest, hydration and hold antiplatelet or anticoagulant drugs in some cases when it s severe and life threatening embolization needs to be done. A new treatment that has been suggested by some case reports and a small series is the use of tranexamic acid. Again here this has not been studied in proper clinical trials so that should be something that should be done but tranexamic acid, which is an anti-fibronolytic agent, can reduce the persistence of the cyst haemorrhage. But the dose of tranexamic acid should be reduced in the presence of reduced GFR and then some possible adverse events like glomerular thrombosis or development of clots and obstruction. Slide 30

19 In terms of cyst infection the cyst infection should be suspected with the classical triad of pain, fever and increased ESR/CRP. Slide 31 Probably the best diagnostic imaging study is 18FDG-PET/CT scanning. Unfortunately, and I don t know what it is in Europe, in the United States this is not approved for this indication. So insurance companies don t pay for that and it s very expensive. Also a limitation to this recommendation is that it has not been proven by prospective trials comparing these two other imaging modalities but in our experience we believe that it s the best imaging modality to diagnose infection. Slide 32

20 Treatment has not changed, antibiotics with good penetration into the cyst. Slide 33 In terms of nephrolithiasis, about 20% of patients with polycystic kidney disease have nephrolithiasis and uric acid stones are over represented in patients with polycystic kidney disease because of low urine ph and low citrate, which are relatively common in these patients. Dual energy CT is a technique that allows to determine the composition of this stone, which helps in the treatment of these patients. So with the dual energy technique you can easily distinguish a uric acid stone from a calcium stone, which appears blue as compared to red with uric acid stones. For patients that need intervention the 3 modalities: shock wave LT, percutaneous nephrolithotomy and FURS have been used. Indications for each one versus the other depend on the size of the stones, the location of the stones, the number of stones and the composition of the stones but

21 all of them can be used safely in polycystic kidney patients. Slide 34 In terms of chronic kidney pain, well episodic pain in polycystic kidney disease is very common but chronic kidney pain fortunately is quite rare but when it occurs, maybe in some patients, it s quite disabling and it is very frustrating to treat because there is not really a lot of successful interventions that you can do. You start with a typical progression from non-invasive non-pharmacological therapies to nonnarcotic and opioids but in pre-esrd patients it can be kind of complicated to do and important message there is that depending on how the kidneys look the intervention can be, should be different. Slide 35 Patients that have large cysts, cyst aspiration or aspiration/sclerosis or laparoscopic cyst fenestration work. The cyst aspiration can be a

22 very good diagnostic technique to determine whether this intervention would be successful or not. Slide 36 Now, in patients that have kidneys that look like this where there are no major cysts or sometimes you can have chronic pain in polycystic kidney patients that look relatively mild polycystic kidney patients. Therefore, correlation between the appearance of the kidney and the chronic pain is not very good. In these patients you can use other techniques like laparoscopic renal nerve denervation, celiac or plexus/intercostal nerve blocks. But the two that have been more recently used are thoracoscopic sympatho-splanchnicectomy. We have studied only a Mayo -- that shows relative success with this technique and there have been a couple of case reports recently using transluminal renal nerve denervation. Of course, this is just anecdotal but I think it s something that s worth exploring. Slide 37

23 Of course, in post-esrd the easy solution is nephrectomy and nowadays hand assisted laparoscopic nephrectomy can be done even in cases like this where the kidneys are huge. It has much less morbidity and mortality than the open nephrectomy. Slide 38 In addition to these renal complications of polycystic kidney disease, Slide 39

24 you have extra renal complications including liver cysts, aneurisms and others. Slide 40 In terms of liver cysts the majority of patients with liver cysts are asymptotic so they need no treatment. The patients with polycystic liver disease that develop symptoms usually due to a mass effect and this large polycystic liver can sometimes result in venous

25 compression with hepatic venous outflow obstruction and development of ascites or bile duct compression with development of jaundice. Or complications like haemorrhage, rupture or infection. Slide 41 Now the non-surgical interventions have limited value. Of course, oestrogen should be avoided and I will talk a little bit about some analogues later but usually these patients require some surgical interventions using aspiration and sclerosis, fenestration, resection fenestration and transplantation. Slide 42

26 An important message there is that one treatment does not fit all. The treatment should be directed by the appearance of the liver and when you have large liver cysts, you can use sclerosis or laparoscopic fenestration. Patients with massive polycystic liver disease but a segment of the liver and that is relatively spare it can be a liver resection combined with fenestration. Patients that have no liver spare, no liver segment is spared require liver transplant. Slide 43 Finally, this complication of subarachnoid haemorrhage from intracranial aneurisms that are the most life threatening with very high mortality and morbidity. Slide 44

27 Of course, pre-symptomatic screening would be something that would be desirable but unfortunately, it has limited value and the reason for that and from the experience that we had at Mayo is that when we screen for intracranial aneurisms in patients with ADPKD, we find them in about 9% of the patients. About 6% of those without a family history of ADPKD and about 21% of those with a family history of ADPKD but the majority of the aneurisms are very small in size. Of 38 aneurisms that we found only 2 had more than 7 ml in diameter. The majority are in the anterior circulation and small aneurisms in the anterior circulation have a very low risk of rupture. We followed these patients for a total of 316 patient years that was back in 2009, more than this now and so far we have seen no ruptures and still we have seen no ruptures. 3 patients decided, it was a personal decision, to go with pre-emptive clipping. We have had 243 patient years of imaging follow-up, more than this now. We have seen one new 2 mm aneurism developing although we cannot be sure that it was not there before or if it was missed and only two aneurisms have grown by less than 2mm in diameter. Slide 45

28 So based on this and this just shows the stability of these aneurisms over time. Slide 46 ased on this we believe that wide spread screening of aneurisms in patients with ADPKD is not justified and we recommend screening only patients that have very strong family history of intracranial aneurisms and particularly subarachnoid haemorrhage and those that have a personal history of subarachnoid haemorrhage because they might be at increased for rupture.

29 Prior to major elective surgery including renal transplantation high-risk occupation when needed for reassurance. Slide 47 If the aneurism is less than 7 cm in diameter, observation is indicated. Those that are more than 12 mm in diameter interventions and other case studies and many factors have to be taken into consideration. Slide 48

30 For those patients who have small unruptured aneurisms we recommend strict blood pressure control, use of ARBs and ACE inhibitors based on the speed of the where that seems to reduce the risk of rupture. A strict cholesterol control and smoking cessation and prompt investigation of sentinel headaches. Slide 49 Now, there are some other CNS complications of polycystic kidney disease that are worse for patients seen in ADPKD patients and are to be kept in mind. One is vasospasm in response for example, to an angiogram, dissections and retinal artery and retinal vein occlusions. Slide 50

31 Subarachnoid cysts occur in about 8% of the patients and in adults have no significance, have no symptoms except they may increase the risk for subarachnoid haemorrhage as seen in these patients. Slide 51 Then --- diverticula are common in polycystic kidney disease and when they leak and the patients can present with a spontaneous intracranial hypotension with a typical presentation of orthostatic headaches that you can diagnose because of increased uptake of contrast in the dura. Slide 52

32 You can have chest manifestations, about 26% of patients with polycystic kidney disease have pericardial effusions, which are hemodynamically non-significant and should be left alone. Slide 53 About 1/3 of the patients have bronchial ectasias if you do a CT of the chest but they are subclinical and usually have no symptoms. Slide 54

33 Other manifestations include diaphragmatic and abdominal wall hernias, Slide 55 IPMN and pancreatic cysts, Slide 56

34 diverticula that are not only colonic diverticula but also duodenal diverticula with biliary complications and malabsorption Slide 57 and seminal vesicles cysts, which together with hypomotile sperm and esospermia can be a cause of infertility in males with ADPKD.

35 Slide 58 Well, the last few minutes of the talk will be for emergency therapies. This slide just reflects what Albert was saying earlier about the importance of low calcium and increased cyclic AMP. Activation of protein kinase A which activates fluid secretion but also stimulates a number of proliferative pathways that contribute to the progression of polycystic kidney disease. Slide 59

36 Because of that, the strategies that seek to reduce the content of cyclic AMP in polycystic kidney disease by blocking vasopressin B2 receptor or activating the GI coupled receptor somatostatin receptor makes sense. Slide 60 Now there has been the TEMPO 3:4 study, which I ll present I think in more detail on Monday, which has shown positive results in the TEMPO 3: 4 study, a large prospective multicentre double-blinded study. The administration of Tolvaptan reduced by 50% the increase in total kidney volume over 2 years and reduced the reduction in renal function by 30% during the same period. Slide 61

37 It lowered the risk of episodes of 25% reduction in renal function by 61% and episodes of significant kidney pain defined as kidney pain requiring intervention or the use of narcotic medications by 36%. Slide 62 The adverse events in the patients taking Tolvaptan were dose-related mostly to the aquaretic effect. First polyuria but adverse events that are more common and that are typical of the natural history of polycystic kidney disease were more common in the placebo group than in the Tolvaptan treated group and this includes renal pain, haematuria and urinary tract infection. Adverse events like episodes or single episodes of hypernatremia or increased uric acid were more common in the Tolvaptan treated group but

38 Slide 63 the most important adverse event that was noted in the trial was an increase in liver function abnormalities and liver enzymes, which was about 4.7% of the patients treated with Tolvaptan as compared to 1.7% of the patients treated with placebo. In fact increases in transaminases were over three times the upper limit of normal. This resulted in the discontinuation of treatment in 1.8% of the patients treated with Tolvaptan because of marked elevations of liver enzymes. Slide 64 So the current status of the Tolvaptan story right now is that at the present time Tolvaptan has not been approved for the treatment of ADPKD and should not be used outside of a clinical trial. The value of Tolvaptan as long-term treatment for ADPKD will depend on the balance between benefits and risks. If the drug is eventually approved by regulatory agencies, it will require close monitoring of liver function.

39 Slide 65 In terms of the somatostatin analogues, there are three clinical trials that have been published: from Bergamo, from Nijmegen and from Mayo and they show very similar results. Slide 66

40 These results have been put together in a meta-analyses that has been recently published and that shows that during short periods of time, 6-12 months patients receiving the somatostatin analogue, either Octreotide or Lanreotide, had a reduction in liver volume both in women and men. Whereas the patients who received placebo had either no change or an increase in liver volume and the increase in liver volume was more marked in premenopausal women. So, the patients that get the most benefit from treatment with somatostatin analogues are premenopausal women with severe polycystic liver disease where you have a pretty big differential. There are now extension studies that have been published that have shown that the beneficial effect on the liver is sustained for at least two years and we have now valid results from Mayo that have not been published for 4 years and we know that this beneficial effect is sustained for at least 4 years. There are also some beneficial effects on the kidney and the best results on that are from a study from Bergamo but this one has not yet been published. Slide 67

41 There are some additional clinical trials which are being performed with polycystic disease. These two have been completed and the ELATE study compared Octreotide versus Sirolimus to Octreotide alone and showed that the addition of Sirolimus had no additional benefit and then 3 larger studies, the ALADIN 2 study which is with Octreotide, the DIPAK study in the Netherlands which with Lanreotide which is going to be the largest study with 300 patients and looking as the primary outcome at measured egfr rather than kidney volume or liver volume and then the Mayo study with Pasireotide which is another somatostatin analogue which is more potent than Octreotide or Lanreotide and maybe more effective but however, may also have more side effects. Slide 68 So I will just finish with this slide just to show you that in addition to vasopressin V2 receptor antagonists and somatostatin analogues there are many other drugs in the pipeline, some of them, a couple of them, in clinical trials. So I think there is some reason to be somewhat

42 optimistic about the treatment and the management of polycystic kidney disease and I think it is the responsibility as nephrologists to transmit this sense of optimism to the patients. I thank you for your attention. Thank you very much Vincent for this comprehensive overview of the therapeutic options available in this disease. I m afraid that we have no time for discussion because there is another session starting immediately in this room. Thank you very much once again to our three excellent speakers. Thank you very much.