Kidney Failure Amplifies Cardiovascular Disease: Mechanisms and Clinical Impact

Kidney disease amplifies cardiovascular risk:

clinical impact, mechanisms and prevention

Coordinating author

Ron T. Gansevoort (Groningen, The Netherlands),

Co-authors

DETAILED MANUSCRIPT OUTLINE AND PROPOSAL FOR AUTHORS FOR SUBSECTIONS

Manuscript to include 5000 words, 150 references, max 5 figures / tables

Key messages:

In subjects with chronic kidney disease, cardiovascular disease

- is frequent

- is more severe

- has another pathophysiology (than only atherosclerosis)

- is different / difficult to prevent

- is often not recognized / diagnosed when present

- is different / difficult to treat

- is often undertreated

Introduction (RG, 300 words)

Bright’s observation that diseased kidneys are always associated with heart problems.

Since these “ancient” times there are new insights (e.g. pathophysiology, prevalence, prevention, treatment) that will be reviewed in this chapter.

Epidemiology

- Chronic kidney disease and cardiovascular risk (KM, 500 words)

eGFR vs CVD outcome, albuminuria vs CVD outcome, both independently associated with CVD (defined as atherosclerosis related, cardiac, cerebro- as well as vascular disease).

Similar association in general population, high risk and CKD populations.

Consequence: CKD defined by both eGFR and albuminuria

(RG: measurement of albuminuria allows early risk identification in contrast to measuring eGFR)

Both no interaction with diabetes / hypertension status in their association with CVD (RG: consequence: no need to discuss further in this chapter diabetic and non-diabetic CKD separately as done historically)

Describe interaction with age?!?!
(RG: some interaction with relative risk: lower risk in elderly. However, in elderly higher absolute risk. Importantly, similar as for other CVD risk factors. Message: CVD is a problem in CKD for all age groups.)

(Matsushita: Depending on the space and flow, I will think whether including subclinical CVD (CAC, LVH, etc.) would work or not in my part. This may be a good head up for mechanisms and prevention.

Respons RG: Including subclinical CVD may be interesting. Especially with the link that you suggest. Please be aware, however, that there is limited text space, and many text parts to be written. Experience is that individual co-authors like to bring more messages and to use more words (and references) than actually can be accommodated.

Response Mann: Lets concentrate on major outcomes and not on surrogates, especially not on surrogates who's intentional changes in RCT's have not been examined. Aiming at CAC has never been shown to alter outcomes, actually, as far as I know, that hypothesis has never been tested (yet billions are spend on measuring CAC). There is limited data the LVH guided therapy in hypertension changes outcomes. If there is no data on outcomes, then we may regress to surrogates.)

- Impact of cardiovascular disease in CKD patients (BH, 500 words)

Burden of CVD in CKD (prevalence, incidence)

Event rate, life expectancy etc.

CVD more important endpoint than ESRD for subjects with CKD, but essential part of CKD and not “just another organ”

Should we screen for (sub)clinical CVD in the CKD population (if there are no data to support this, then discuss).

(RG: express per CKD stage. Compare with general non-CKD population. Try to create new data for various countries in which sufficient data are available (Canada, Taiwan). Attached some figures as an example (I will contact Brenda and Chi-pang for a more detailed discussion ho to proceed with drafting figures)

Mechanisms (HM, 500 words)

Not only atherosclerotic CVD, but also for instance LVH, fibrosis, rhythm disturbances (RG: … when we will only target atherosclerotic disease we may not be effective in preventing CVC in CKD…)

(Mann: focus on human data, less on experimental data)

Explaining the association of eGFR with CVD risk

Traditional risk factors

- Blood pressure

- Lipid abnormalities

Renal risk factors

- Calcium-phosphate metabolism

- Anemia

- Acidosis

- Homocystein

- Others (e.g. oxidative stress, AGE’s, specific uremic toxins, inflammatory state)

Genes predisposing for CKD (and CVD?)

- Explaining the association of albuminuria with CVD risk

Risk marker or risk factor? Definitely risk marker. Potentially risk factor? STENO hypothesis: transcapillary leakage of molecules causing atherosclerosis? Prothrombotic state (disbalance pro- and antithrombotic proteins)? Associated lipid abnormalities? Discuss sparse evidence.

(RG: NB: mechanisms to be discussed briefly, and not in extenso)

(RG: One point to make clear is that CVD predisposes for CKD, and CKD predisposes for CVD. Vicious circle in which kidney failure amplifies risk for CVD (please refer to title of manuscript)

Prevention of CVD

(Jafar: Discussion on social determinants of CVD in CKD and what has been the global trends? Do we have any data on education, income quintiles, other sociodemographics and developmental indicators? In addition, I think it is important to highlight successful programs. However, also discuss sustainability, scalability, and thus issues around cost effectiveness and feasibility. What would be the "best buys" for CVD prevention in CKD globally? This would probably lead to BP control and diabetes control programs (esp in low and middle income countries) and therefore underscore shared risk factors in the papers. Response RG: as far as I know (I supervise a PhD student on this topic) there are 19 manuscripts on the association between SES and CKD. Sixteen of them come from the US, 3 out of Europe. None of these manuscripts (as far as I am aware) discusses the relationship between (treatment) of CVD in CKD in various SES classes, let be trends over time. That’s therefore going to be a difficult topic to discuss in our manuscript. However, I fully agree that, given the global aspect that Lancet wants to give to this series, we should mention something about local financial situations and what interventions to choose from (go for cheap interventions, with high impact, that are relatively easy to implement).

Discuss in order of intervention/relevance

Per item two topics to be discussed:

1. Effect on CVD per se

2. Given that CKD is independently and “dose-related” associated with CVD, prevention of CVD means prevention of progression of CKD (to be stressed, because in my opinion a “novelty” factor and key issue)

- Life style modification (TJ / HLH, 500 words)

A. Weight loss

B. Stop smoking

C. Sodium restriction

D. Protein restriction

(Mann: Prevention: discuss diet rather than specifics like sodium and protein, or better, discuss the latter under the heading of diet (there is data that a "healthy diet" is good for people with CKD). Discuss physical activity if there are data out. Response RG: I agree, but still would like to see discussed that

1. a low protein diet is effective insofar that it lowers proteinuria and slows down the the rate of renal function decline, especially in proteinuric patients (meta-analyses by Fouque e.a.),

2. a low salt diet potentiates the effect of ACEi on proteinuria (a.o. Heeg e.a. and Slagman BMJ 2011) and on renal function decline (Vegter e.a. JASN 2012, Lambers Heerspink e.a. in press)

Diet can be achieved, also in countries with less money to spend on health care, For Lancet we would like have such a "global" view)

- Pharmacological (HLH / TJ, 500 words)

Targeting traditional risk factors

- Blood pressure

- Lipid lowering

- Glycemic control

Targeting renal risk factors

- Phosphate binders

- Vitamin D

- EPO

Novel interventions:

- Novel agents targeting blood pressure / lipids / glycemic control

- Other agents

• Endothelin antagonists

Anti-inflammatory agents

(RG: Various preventive and therapeutic interventions to be discussed very, very briefly, and not in extenso. Summarizing data as much as possible in a table? Use meta-analyses and systematic reviews rather than individual studies. Keep in mind less developed countries: less costly life style interventions and cheaper medication (blood pressure lowering agents) can be of great help.

(Mann: Vit D receptor activation, in my view, is a sales pitch; rather talk about vitamin D and -analogues)

(Lambers: Discuss briefly that titration on renal parameters, e.g. albuminuria, can be of help, i.e. the more albuminuria is lowered, the better outcome)

Diagnosing and treating established cardiovascular disease in CKD patients (RCR, 500 words)

-Diagnosing

Complaints often aspecific

Clinical picture often aspecific

ECG abnormalities often aspecific

Cardiac damage markers often falsely (?) elevated

Stress test often not possible

Reluctance to perform CAG (fear of contrast nephropathy)

- Therapeutic intervention for CV events

Thrombolysis

PCI

CABG

Secondary prevention (beta-blocker, statin, aspirin, life style modification) prescribed less to CKD patients

(RG: Message: difficulties in diagnosing CVD and treating CV events in subjects with CKD. Effects of PCI / CABG etc often different in CKD populations, when compared to non-CKD populations. Remarkably CKD patients get less often prescribed agents for secondary prevention (Fox ea, Circulation 2010). However, presence of CKD should not lead to diagnostic and therapeutic nihilism, e.g. cardiologist not performing CAG in fear of contrast nephropathy, thoracic surgeons reluctant to perform CABG, not prescribing agents for secondary prevention.)

Future challenges / goals (RG / CPW, 500 words)

- Develop effective treatment strategies

- Limited knowledge since there are relatively few RCTs in specifically the CKD population. Discuss why (many older trials excluded the CKD population). Need for more trials/evidence

- Why is it difficult to show CV benefit with interventions in the CKD population? Excess risk is multi-multifactorial. With intervention directed at one (out of many) risk factors it may be expected that is difficult to show an overall benefit. Solutions:

1. Early prevention, prevent progression to later CKD (low eGFR) stages. Risk identification possible with assessing albuminuria. Little experience (diabetic CKD some, non-diabetic CKD PREVEND-IT)
2. Multifactorial, multidisciplinary approaches may be mandatory. For instance: STENO experience with multifactorial intervention for CVD prevention, and the Mario Negri Proteinuria Remission Clinic experience for prevention of CKD progression.

CVD prevention in CKD is not something solely for the nephrologist, but perhaps the nephrological community should take the lead to help general practitioners and specialists in vascular medicine and cardiology to develop guidelines for CVD prevention in this patient group.

Conclusions (RG / all, 400 words)

!!!! TIPS AND TRICKS !!!!

In general:

- please be concise and discuss the broad principles rather than go to into detail. The readership will be a general readership (general practitioners, health care policy makers).

- please stick approximately to your maximum word count, and your share of the maximal number of references (max 25 per specific authors subsection).

- please keep in line with the upcoming KDIGO guidelines (open for public review since last week of May, please find attached).

(Author: when we want to keep in line with the KDIGO CKD guideline, we better wait with writing our contributions until the moment that the draft of this document will be open for public review, i.e. beginning of June. Response RG: OK with me)

(Author: should we not wait starting writing until the core writing group has consensus on key messages for all papers. That will prevent double work. When there is consensus the actual writing of the 500 word text [parts should not take too much time. Response RG: OK with me)

Chronic Kidney Disease amplifies cardiovascular risk.

- Clinical impact, mechanisms and prevention -

Gansevoort RT1, Correa-Rotter R2, Hemmelgarn BR3,

Jafar TH4, Lambers Heerspink HJ5, Mann JF6, Matsushita K7, Wen CP8

1Dept. of Nephrology, University Medical Center Groningen, Groningen, The Netherlands

2Dept. Nephrology and Mineral Metabolism,
National Medical Science and Nutrition Institute Salvador Zubiran, Mexico City, Mexico

3Dept. Medicine, University of Calgary, Calgary, Canada

4Program in Health Services & Systems Research, Duke-NUS Graduate Medical School, Singapore

5Dept. of Clinical Pharmacology, University Medical Center Groningen, Groningen, The Netherlands

6Dept. of Medicine IV, University of Erlangen-Nurnberg, Erlangen, Germany

7Dept. of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA

8China Medical University Hospital, Taichung, Taiwan and Institute of Population Health Science, National Health Research Institutes, Zhunan, Taiwan

Correspondence:

R.T. Gansevoort

Dept. Nephrology

University Medical Center Groningen

P.O. Box 30.001

9700 RB Groningen

The Netherlands

Short title

Key words

Word count abstract

Word count article

Introduction

“The obvious structural changes in the heart have consisted chiefly of hypertrophy... and what is most striking, out of fifty-two cases … no valvular disease could be detected in thirty-four … This naturally leads to us to look for some less local cause.”

"It is observable, that the hypertrophy of the heart seems, in some degree, to have kept pace with the advance of disease in the kidneys; for in by far the majority of cases, when the heart was increased, the hardness and contraction of the kidney bespoke the probability of long continuance of the disease."

Bright R: “Cases and observations illustrative of renal disease accompanied with the secretion of albuminous urine" in Guy's Hospital Transactions 1:338-379,1836. Quotation retrieved with the help of dr. G. Eknoyan, Baylor College of Medicine, Houston, Texas, USA.

Epidemiology

- Chronic kidney disease and cardiovascular risk

- Impact of cardiovascular disease in CKD patients

Mechanisms

Prevention of CVD

- Life style

- Pharmacological

Diagnosing and treating established cardiovascular disease in the CKD population

Future challenges and goals

Conclusions

Contributors

RTG was responsible for the initial design of this report. All authors contributed to writing specific sections and participated in critical revision of the report.

Steering committee

This article is part of The Lancet series on chronic kidney disease, which was developed and coordinated by Guiseppi Remuzzi (Negri Bergamo Laboratories, Mario Negri Institute for Pharmacological Research, Bergamo, Italy)

Conflict of interest

Follows (authors are asked for information)

Acknowledgements

Follows (authors are asked for information)

References

For your convenience I performed a PubMed search using the key-words “chronic kidney disease” and “cardiovascular disease”, and applying a filter for “systematic reviews and meta-analyses”. Below is a selection of manuscripts that might be of interest for you. A number of key-articles not retrieved via this search has been added. This list is not intended to be complete and can / should be extended. PDF files of these manuscripts will be sent to you as ZIP file.

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