Giving patients good news

I was rounding at one of the rehab/sub-acute hospitals today. One of the patients was a 70 y.o. African American man who had undergone a kidney transplant 12 days ago. He had delayed graft function and so he had continued right along with his normal dialysis schedule. He had been on dialysis for 3 years.

Over the week-end, his kidney opened up (recovered renal function in his transplant kidney) and so we held his dialysis on Sunday (patients on the TTS schedule received the Saturday dialysis on Sunday due to a Thanksgiving schedule shift). Today his creatinine fell further and I told him he was done with dialysis.

He immediately began to cry and convulse. I wasn’t sure if these were tears of joy or a seizure. After a few minutes he was able to speak again and told me how happy and grateful he was to be off dialysis.

It was one of those moments the makes being a doctor special.

The fall of cholesterol

The cholesterol theory of heart disease has been getting knocked around a bit these days.

Just writing that sentence feels rebelous. To call cholesterol’s causative link with heart disease a theory seems blasphemous. I started thinking about this when I looked over some summaries of the Jupiter data.

The results of the JUPITER trial indicate that rosuvastatin is associated with a significant reduction in major cardiovascular events, including death, in apparently healthy persons with LDL cholesterol less than 130. The reduction in risk was roughly twice as high as one would predict from the reduction in the LDL:

Moreover, the results were quite different from those of trials that recruited on the basis of elevated LDL.

Those trials “generally reported a 20% reduction in vascular risk for each 1 mmol/L (38.7 mg/dL) absolute reduction in the LDL cholesterol level, an effect that would have predicted a proportional reduction in the number of events in our study of approximately 25%,” the investigators wrote.

“However, the reduction in the hazard seen in our trial, in which enrollment was based on elevated high-sensitivity C-reactive protein levels rather than on elevated LDL cholesterol levels, was almost twice this magnitude and revealed a greater relative benefit than that found in most previous statin trials,” they added.

This mismatch with reduction in LDL and reduction is risk is similar to the findings of with ezetimibe which showed no reduciton in the progression of atherosclerosis despite dramatic reductions in cholesterol.

Add to that the increase rather than reduction in first major cardiovascular events associated with torcetrapib which successfully increased HDL and reduced LDL. Another nail in the coffin also comes with torcetrapib which despite increasing HDL and reducing LDL failed to reduce atheroma volume.

It seems that large swaths of the cholesterol theory need to be revised and updated to account for this new data. While we wait for this new hypothesis it is important to reevaluate all of the conclusions and health recommendations we make based on intermediate end-points rather than on clinical outcomes. The primary health recommendations that I have in my sites are dietary. Low fat diets have repeatedly failed studies on endpoints and are propagated on their ability to improve the lipid profiles. Well, both ezetimibe and torcetrapib improve the lipid profiles and do little else of benefit to patients.

From a 2002 JAMA review:

In the Minnesota Coronary Survey,51 cardiovascular events were not significantly reduced by a high-polyunsaturated-fat diet despite a decrease in serum cholesterol, but the mean duration of dietary intervention was only about 1 year. Two secondary prevention trials testing the approach of total fat reduction did not find a significant reduction in serum cholesterol or CHD events.5253

A more recent reveiw from Circulation comes to a similar conclusion. It reminds me of a NYT magazine article about the Atkins diet. This wonderful article has a section that looks at the lack of correlation between Heart Healthy diets and actually reducing cardiac events.

It began in January 1977, when a Senate committee led by George McGovern published its ”Dietary Goals for the United States,” advising that Americans significantly curb their fat intake to abate an epidemic of ”killer diseases” supposedly sweeping the country. It peaked in late 1984, when the National Institutes of Health officially recommended that all Americans over the age of 2 eat less fat. By that time, fat had become ”this greasy killer” in the memorable words of the Center for Science in the Public Interest, and the model American breakfast of eggs and bacon was well on its way to becoming a bowl of Special K with low-fat milk, a glass of orange juice and toast, hold the butter — a dubious feast of refined carbohydrates.

In the intervening years, the N.I.H. spent several hundred million dollars trying to demonstrate a connection between eating fat and getting heart disease and, despite what we might think, it failed. Five major studies revealed no such link. A sixth, however, costing well over $100 million alone, concluded that reducing cholesterol by drug therapy could prevent heart disease. The N.I.H. administrators then made a leap of faith. Basil Rifkind, who oversaw the relevant trials for the N.I.H., described their logic this way: they had failed to demonstrate at great expense that eating less fat had any health benefits. But if a cholesterol-lowering drug could prevent heart attacks, then a low-fat, cholesterol-lowering diet should do the same. ”It’s an imperfect world,” Rifkind told me. ”The data that would be definitive is ungettable, so you do your best with what is available.”

ACTH for membranous nephropathy

Once you go beyond the modified Ponticelli, the treatment of idiopathic membranous feels like hunting in the woods. I have a woman in her late thirties who I have been treating for almost three years. She has between 6 and 10 grams of proteinuria, no renal failure (Cr or 0.8 and stable) no hypertension, and a middling albumin with terrible lipids. She doesn’t get much edema and is able to limit her use of loop diuretics to very occasionally.

We started with conservative therapy for 6 months to see where the proteinuria is going. After that we decided to give treatment a try because of the heavy proteinuria. She also had high levels of urinary IgG and urine beta-microglobulin.

She was reluctant to use cyclophosphamide because of concerns about future fertility. And I’m reluctant to use it in a young patient especially for a disease which is causing her minimal problems right now.

We started with MMF. Little effect.

We then gave a trial of CSA. Little effect.

We gave a trial of Pentoxifylline (Trental). little effect

What now? Tacro? Rituximab?

Anyone have any experience with ACTH?

I must say I have been seduced by the preliminary data (case series, rct) on ACTH. To me it looks more compelling than the alternatives (rituximab and tacro). The fact you have to go to a specialty pharmacy to get the stuff is a little intimidating.

Link to a description of membranous nephropathy from a lecture I give on Hep B, C and HIV associated renal pathology.

Renal Vitamins

Just saw this post on the Renal Fellow’s Network. I appreciate his flippant attitude toward renal vitamins as they are so routine as to invite disregard but they may have an effect on mortality.

This 2004 article based on the DOPPS database shows a significant reduction in mortality (RR 0.84) associated with use of water soluble vitamins.

I always have a healthy skepticism for DOPPS data as they have been on the wrong side of the anemia, Kt/V and statin debate. Each time being refuted by the RCT. But I’ll take the position that since no one will ever do a randomized controlled trial we should go forward with the renal vitamins.

I first heard about this data on renal vitamins during the at the Easterling Lecture given by Eric Young for the Michigan NKF in 2003. At the time this was explained by the reduction of homocysteine induced by the folate in the vitamin. Since that has also fallen to the blade of the RCT, I wonder what componant of the renal vitamin explains the benefit.

CKD in the NYT

Kidney Disease a Takes a Growing Toll

Nice article on the increasing prevelance of chronic kidney disease. They even mention the controversy of geriatric CKD, one of my newest interests.

The article mentions the NKF of Michigan’s project to raise awareness of CKD by using hair dressers. I am the newest member of the NKF of Michigan’s Scientific Advisory Board.

Also the article has a quote by Steven Fadem, a nephrologist I shared a limo with last week at the EVOLVE Primary Investigator’s Meeting. Crazy small world.

MBD and Clinical Practice

Glen Chertow on MBD and clinical practice.

Starts with the high mortality of CVD in ESRD slide shown at every gatheriong of nephrologists.

MBD as a non-traditional risk factor for CVD

HEMO, 4D, Wrone on homocysteine, D-COR all RCT, All negative. [should add correction of anemia study]

45% drop out in D-COR lead to a loss of power and contributed to negative trial.

Cinacalcet approved based on its ability to get the PTH down and get patient to guidelines but we are missing the information on whether this helps patients.

Power is the probablity of detecting the treatment affect if it really exists. 90% power means that 9 out of 10 times you will detect a treatment effect if it exists.

With 3883 patients EVOLVE had 88% power to detect 20% reduction in cardiovascular disease. If the benefit is 15%, which would phenomenally important to our patients, we may not be able to detect it.


bill goodman talking on KDIGO. Goodman wrote the article that interested me in the topic of vascular calcification and binder choice.

What is KDIGO
Kidney Disease Improving Global Outcomes
established in 2003

Independent non-profit, established by the NKF
The concept was to take K/DOQI and generalize the guidelines for a global audience.

The KDIGO mission is to provide:

  • Clinical Practice Guidelines
  • Guideline database
  • Work groups
  • Controversy conferences
  • Mineral and bone inititative (in draft)
  • Hepatitis C in kidney disease (coming)
  • Care of transplant patient (coming)
  • Acute kidney disease (coming)

CKD Mineral and Bone Disease
A rose from the perception that international perspective needed to define renal osteodystrophy

use the phrase ROD exclusively to define: alterations in bone morphology in patients with CKD
classification based on bone histology, bone turnover, mineralization and volume.

CKD-MBD is a systemic disorder of mineral and bone metabolism due to ckd manifested by either one or a combination of the following:

  • abnormalities of Ca, Phos, PTH, Vitamin D
  • abnormal bone turnover, mineralization, volume, linear growth or strength
  • vascular or soft tissue calcification

KDIGO revisited the concept of guidelines
They graded evidence and created their guidelines by limitting the data to:

  • RCT of at least six months in duration
  • N>50 excepts for pediatrics and bone biopsy
  • Intermediate endpoints including: BMD, bone biopsy, vascular calcification and biochemical endpoints are not considered unless they have been validated prospectively [unclear if any surrogates have been validated]
  • Observational studies acceptable if a clinical outcome examined conducted with a high methodological quality and had a relative risk of >2.0 or <0.5

treatment of CKD-MBD

  • lowering high phos
  • abnormal PTH levels in CKD-MBD
  • treatment of bone and bisphosphonates, other osteoporosis medication and growth hormone
  • evaluation and treatment of kidney transplant bone disease

there is little evidence to provide guidance for a specific therapeutic target range for any biochemical parameter

  • extreme values are associated with greater mortality risk
  • little evidence to support preferred treatments

KDIGO concluded that PTH guidelines are mainly opinion based and not informed by randomized clinical trials

150-300 is based on evidence just not rct and outdated

phos and calcium guidelines are loose

repeated emphasis through out document on the lack of evidence from RCT with hard outcomes

Data Gaps

Evolve is really important, largest prospective clinical trial on dialysis population