Renin, angiotensin, aldosterone and you

There’s no escaping the kidneys in pharmacy.  Their significance in drug elimination, blood pressure and salt and fluid balance is undeniable.  

Renin is produced by juxtaglomerular cells in the afferent arteriole in response to decreased pressure in the kidney.  Renin is also responsible for the initial rate limiting step in the production of angiotensin.  Angiotensin-converting enzyme (ACE) facilitates the final step in the production of the active angiotensin II and is also responsible for the metabolism of certain peptides, such as bradykinin.

ACE-inhibitors (ACE-i) and angiotensin receptor blockers (ARB) reduce the effects of angiotensin II, which is responsible for vasoconstriction and aldosterone and sodium retention, to decrease the blood pressure and pressure within the kidney through different mechanisms.  ACE-i block ACE; however there are other pathways for the production of angiotensin leading to “ACE escape”.  ARBs would block angiotensin at its site of action, thereby bypassing the risk of “ACE escape”.  Both classes of medications can lead to increases in renin due to sustained lower pressures within the glomerulus.

Though increased bradykinin is the cause of the notorious ACE-i induced dry cough, it also provides added vasodilation.  A recent meta-analysis looking at mortality data from 20 trials utilizing an ACE-i or an ARB compared with a control showed that ACE-i offered a 10% mortality decrease compared with ARBs and the control drug or placebo.  The meta-analysis excluded patients who had heart disease or kidney disease, where RAAS inhibition has already been shown to have significant added benefits.  

The analysis shows that there is a clear mortality benefit to using an ACE-i in patients with hypertension without other comorbidities that would indicate RAAS inhibition.  If a patient is unable to take an ACE-i, there is no added mortality benefit to using an ARB over another antihypertensive.

Aliskiren, or Tekturna, is a direct renin inhibitor, the newest class of RAAS inhibitors.   Researchers hypothesized that using aliskiren in combination with an ACE-i or an ARB would improve outcomes by targeting RAAS through two mechanisms.  The “Aliskiren trial in type 2 diabetes using cardio-renal endpoints” studying aliskiren with an ACE-i or and ARB in diabetics was stopped early in December due to futility as well as increased risk of renal impairment, hypotension, and hypokalemia.  Prior to this in 2008, the TARGET study had also shown lack of benefit with combining an ACE-i and an ARB in patients with vascular disease or diabetes with organ damage.

The Food and Drug Administration, FDA, has recently placed a warning on aliskiren against its use in combination with an ACE-i or an ARB in patients with diabetes or moderate to severe renal impairment. 

While both an ACE-i or an ARB has clear benefit in patients with kidney disease or heart failure, ACE-i are superior to ARBs in mortality benefit in patients with hypertension alone.  Combining an ACE-i with an ARB or aliskiren should be avoided.

References:

Atlas SA.  The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition.  Journal of Managed Care Pharmacy 2007; 13(8): S9-S20.

van Vark LC, Bertrand M, Akkerhuis KM et al.  Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158 998 patients.  European Heart Journal 2012; DOI:10.1093/eurheartj/ehs075. Available at: http://eurheartj.oxfordjournals.org

Lowes R. No aliskiren with ACE inhibitors, ARBs in some patients: FDA.  theheart.org April 20, 2012.  Available at http://www.theheart.org/article/1388139.do

Understanding Love and Loss

It has been about a month since I went back to Tanzania to visit the grave of my sister.  As the pharmacy resident, I am not granted much time off during the year, I was unsure of the possibility of returning until after residency but thankfully my supervisor granted me 10 days off to go, as ~3 days were travel days, I had seven days in Tanzania.

Memu's home in 2008

In 2008 I saw Memu's unfinished house in Maji ya Chai and she told me the things she had hoped for; of having a home to herself, now becoming a reality, and how much she wanted a baby.  "Like Mama Gladness," she told me of her sister who had raised two sons by herself without accepting a man in her life.  Returning in 2010 to see all these dreams become a reality, speeding up the hill on a piki piki to see her again, I hardly even recognized the house.  It was beautiful.  It was surrounded by a fence and garden and saw her coming down the road her hair in braids followed by her boyfriend.  Not long after I left she told me

Nakupenda dada yangu nakumiss the nest time you came you see my baby

Images now came to mind of returning this third time after her death and seeing the garden overgrown as well as wondering what would happen to her baby, who is not even a year old.

The day before I came, her American boyfriend told me that he was leaving for Dar to try to get a visa for the baby.  I knew that already I was burdening Mama Gladness by staying with her and now I would not get to see Memu's baby, I had my doubts about going.

I took a cab from the airport in Kilimanjaro to Tengeru, where Mama lives.  I loved the stillness of everything, driving down the highway at night, seeing familiar sights of jungle and shambas, or farms.  Past Maji ya Chai, past Usa and we arrived at Mama's house.  I collapsed into Mama's arms and finally allowed myself to cry for the first time this trip.

I allowed Mama to spoil me.  We took tea together in the mornings and always ate supper together, talking as long as we could stay awake.  It rained most mornings until about noon which made for a good excuse to sleep in and take tea for extended hours.

The second evening I was there she asked me if I would like to see Lema's grave, her eldest son who was killed in a car accident March 20, four days before Memu.

Tengeru, Mt Meru hidden behind clouds

I couldn't without anything to offer.  I made a point of buying flowers in Arusha the next day.  Lema is buried behind Mama's house, I spent a moment over his grave.  I was not particularly close to Lema despite living with him for four months in 2008.  He was only 4 years older than I am.  I was never very sure if he liked me while I was living with him, but I remembered the last time I saw him I was walking with Memu down the highway and we saw him.

So you have come back to buy a house on the hill?

Maybe next time I told him.  It is a little too easy to fall in love with Tanzania.  I had always pictured myself someday living in a home near Memu on the hill in Maji ya Chai.

Even when he was little he liked cars, Mama Gladness told me.  She told me that when he was six years old he stole a car to drive to the field at Patandi College to go play.

I was disappointed that I could not go that same day to see Memu, but Mama and I went together the next day.  We took a bus from the market in Tengeru packed so full of people that I was halfway out of the dalla dalla, or bus, for most of the ride.  The air was sticky from the rain and hot.

We then walked past a school and down a hill that was spotted with grave sites.  Mama finally stopped at one and laid her flowers down at the base of a cross at it's head.  I cried out and dropped down, as soon as I did it felt like a lightning bolt ripped through my skull.  My tears stopped and I knelt on the ground next to my sister as my head pounded and Mama stood clutching the cross and wailing in Swahili telling Memu of her sorrows.  Her grave was covered with flowers, now blackened and dead and what now stood out more than the flowers were their cellophane wrappers.

When Mama was finished she went around the grave pulling weeds as if their presence itself was an insult aimed directly at her.  I placed my flowers at the head of the grave, pink and purple roses on a bed of blackened flowers.  We stood a moment in silence then began the walk back arm in arm in a daze.  We walked all the way back to Tengeru.  We talked the whole way back but only of good things.

My flight from Tanzania was set for Thursday evening.  That morning, I went to Maji ya Chai to see Memu's home.  I had planned to see the hospital where she had died, to try to understand the cause of death, to wonder if I could have changed anything if I had been there, but when I finally got to Tanzania, it somehow didn't seem as important.

I had pictured the house to be in decline.  I remembered this walk in better times.  Maji ya Chai seemed unaware of the great tragedy that had befallen it, healthy stocks of corn grew in shambas, trees towered over head, I remember the day as being very clear out.  Flowers grew along the drainage ditch and the creek for which Maji ya Chai, meaning "tea water" was named was flooded with the clear brown water that had become its namesake.

I was surprised to see someone working in the garden when I arrived at the house.  I explained who I was and he invited me in.  In 2010, Memu and I worked to plant beans together behind the house.  She had had a small garden with some vegetables, now her yard was now bursting with corn and a variety of other vegetables.  The house was locked and gated but exactly as I had remembered it.

Memu 2008

The day I left in 2010, I left my towel and shower shoes with Memu for the next time I came to stay with her.  My shower shoes were now neatly placed at the back door exactly where I had left them a year and a half before; I felt that maybe if I had waited long enough, Memu would walk through the gate and we would start to prepare dinner together.  A planter had been built in the behind the house, the top of the rock wall covered in cement with the words

In memory of MEMU 24MAR2012

Before leaving for this trip, all I could do was cry and feel a terrible heaviness every time that I thought of her.  I sat in the garden of her home that had represented everything she had hoped and worked for, her independence.  I thought of all the wonderful times we had together and I smiled.

My Sister

My sister died of pneumonia today.  Who knows what was really going on.  All I knew was that she was sick.  Then she was at the hospital.  Then home.  Then the hospital again.

My sister.  A 34 year old Tanzanian woman.  Calling Memu my sister usually sets off eye rolls or exasperated comments from my friends.  I am not related by blood to Memu.  I have not even spent very much time together with this woman.

Maybe because of the intensity of the experience, arriving in Tanzania the day before my 21st birthday, traveling alone by myself for the first time, then managing to make a home for myself in another culture.  Maybe because the African sense of family is much broader, any woman of similar age to myself would be greeted as "my sister" in Tanzania.  Or maybe because of the intimacy of the conversations I had with this woman my sister.  For all these reasons and more, Memu became my sister.

Her boyfriend, an American, called and told me that she was sick again this week, and back in the hospital.  He had informed me the first time, which worried me, but my sister is strong.  I was not worried.  Hearing she was back in the hospital was concerning.

I met Memu in the fall of 2008.  I came to Tanzania to volunteer.  Her nephew, son of her oldest sister (Mama Gladness), ran a volunteer house where I was staying.  She would stop by to visit.  Eager to make friends with locals, I would greet her and ask her how her day was

I cook.  I feed the animals.  I wash the clothes.

I felt I had nothing in common with this woman.

A month into my stay, all the other volunteers left which was the best thing that ever happened to me.  I started spending more time at Memu's home which she shared with her mother.  I would watch her do chores, helping where I could, though I probably slowed her down more so than anything else.  Some of my best memories are in her kitchen, a shed attached to the cow pen.  With a pot propped above a small fire, the room would fill with smoke till I could barely see and my eyes watered as we chopped vegetables and talked about anything and everything.

English was difficult for my sister, but this did not deter her from asking me the most complex questions about America and the philosophy of life.  I was like a child.  She taught me how to carry water, to pick coffee, to cook like an African, and helped me learn to speak kiSwahili and kiMeru, the language of her tribe.

Every day I would finish volunteering and I could not wait to see my sister, tell her about my day and discuss differences between life in Tanzania and life in America.

My sister helps me with my suitcase

I learned that she was building a house in Maji ya Chai, water like tea.  In the month before I left, she took me to see the house.  Maji ya Chai is a small town between Arusha and Moshi.  While wazungu, or white people, have flooded into Arusha and surrounding suburbs for safari and volunteer work, Maji ya Chai was untouched by tourism.

We walked past shops and stands selling vegetables and began a long trek uphill.  We walked past empty fields of mahindi, corn and migomba, banana trees.  We walked across a small brown creek, for which Maji ya Chai received its name.  We walked through fields and past goats and past the water tower and finally as we seemed to near the end of civilization and I felt I could walk no further, there her house was at the top of the hill like a little oasis.

At the time Memu was living in the home of her mother; she had painstakingly saved money from selling the milk of her cow and piece by piece, bought land and built a house.  She had just finished the roof and had yet to add furniture and a few other finishing touches.

The only thing present in the house was a rug, so we laid out the rug on the floor, Memu bought sodas for us and we laid down on the mat drinking soda pop talking about boys and giggling like school girls.  It was one of the best days of my life, I can still remember pieces of that day so vividly, and fondly.

I came back in 2010, although my trip was cut dramatically shorter.  I stayed in her, now finished home, in Maji ya Chai for 3 weeks.  I almost didn't recognize it.  Fully furnished with a beautiful garden and even electricity, most prized of all was a water spigot in the back yard.  Even in Memu's mother's house, Memu would have to walk a half mile to the stream or to her friend's home that had a pump and carry water back every day in order to take care of animals, wash clothes, cook.  This home was a little piece of paradise that she had dreamed up and built up herself.

When I dream of Africa I dream of lying in her garden facing the sky and watching lizards and people pass by.  I dream of having a house on the hill in Maji ya Chai next to hers where I could visit often and laugh talk and learn.

I made the choice to stay and live in America and help people of my own country that do not have good access to health care.  I thought about coming back after classes were over, but I was busy with studying for the pharmacy boards and made the decision to wait until after my residency year.  I've been talking to my boss and making plans to come back in November.

Although I don't think that Memu would see these decisions as a failure on my part to be a true friend, let alone a true sister to her it has been difficult not to look back with regret if I had known! if I had known.  But I didn't know.  The Memu I know is a healthy woman, and stubborn to the point that even if she had hired help with her work, would probably do it herself anyway.  I felt so distanced from what was going on and so confident that she would get better.

I think of her fierce independence, her thought provoking questions in broken English, and her smile.  I think of her incredible patience with me and my complete lack of knowledge of Meru language and culture then her impatience watching her fiercely argue in Swahili to get the best deal on vegetables or bus fare.

It seems just too ironic that I decided to work with an underserved population in America then to hear that my sister died of pneumonia today.  No matter what the cause I know I would feel her loss but aside from that I cannot help but feel anger that her death today seemed to be so preventable.

In the end it didn't matter that she was well off by African standards.  That she had worked hard her entire life.  That despite not having a high school education I consider her one of the most intelligent persons I have ever met.  She died today because she was a woman living in Tanzania, without access to the same kinds of facilities medications and equipment that would be available in other countries.

People die preventable deaths in Africa everyday but Memu's strength had always made her seem untouchable to me.  I feel cliche writing this, I really don't know how to express what I feel.  If I just close my eyes everything will be alright.

She will be buried in her garden in Maji ya Chai on Tuesday.

Nakupenda dada yangu, I love you my sister.



http://www.youtube.com/watch?v=SyJzaPUbmEg