Kidney transplant patients need even better aftercare!

Patients with chronic kidney disease (CKD), and dialysis patients especially, have a significantly higher cardiovascular morbidity and mortality than healthy people. Kidney transplantation is the best renal replacement therapy available. Compared to dialysis patients, transplant recipients have significantly better long-term survival and quality of life [2]. Although their cardiovascular risk decreases, cardiovascular complications are still the main cause of shortened patient and organ survival [3, 4]. One recently published review [5] shows current data and derives important conclusions for further long-term improvements in outcomes after kidney transplantation – a highly topical issue, especially for cost reasons and organ or donor scarcity. The manuscript is a work product of the American Society of Transplantation’s Kidney-Pancreas Community of Practice (AST-KPCOP) Cardiovascular Disease Workgroup and appeared in the reputable journal Nephrology Dialysis Transplantation.

Most of the ‘traditional’ cardiovascular risk factors (such as smoking, high blood pressure, diabetes mellitus, overweight, lipid metabolic disorders/dyslipidaemia) are reinforced by chronic kidney disease. Severe disorders of mineral and bone metabolism may also be included in the multiple consequences and forms of damage resulting from poor clearance of toxins in the body; the imbalance in the calcium and phosphate metabolism leads to bone decalcification and, parallel to that, to an increase in calcium/phosphate deposits in the cardiovascular system. ‘The most dangerous cardiovascular diseases (CVD)

include coronary artery and cerebrovascular calcification, cardiac insufficiency, heart valve disease, arrhythmias and pulmonary hypertension’, explains Prof. Denis Fouque, Centre Hospitalier Lyon Sud, France, Vice-Chairman of the European Renal Best Practice group of ERA-EDTA and a member of the KDIGO Advisory Board.

After successful kidney transplantation, the detoxification function and also the calcium/phosphate metabolism can return almost completely to normal, but the cardiovascular risk does not decrease to the level of people with healthy kidneys [6, 7]. This is due not only to existing damage, but also to cardiovascular risk factors specific to transplantation. The immunosuppressive drugs that transplant patients need on a daily basis for the rest of their life may cause metabolic disorders such as post-transplantation diabetes (up to 42% of patients), dyslipidaemia (50%), and hypertension (up to 90%) (‘de novo traditional CVD risk factors’ [8, 9, 10]). Unfortunately, almost one transplant patient out of four continues to smoke [11].

Non-traditional risk factors include metabolic effects of immunosuppressive therapies, chronic inflammatory responses, infectious complications, chronic anaemia, proteinuria, and compromised function of the transplanted kidney resulting in CKD stage 3 or greater [12]).

‘Transplantation aftercare is now focused primarily on preventing organ rejection and the side-effects of immunosuppressive therapies’, explains Professor Darshana Dadhania, transplantation nephrologist and Associate Professor of Medicine at Weill Cornell Medical Center / New York Presbyterian Hospital, New York – and senior author of the review by AST-KPCOP. ‘Early diagnosis and management of cardiovascular disease is a secondary focus at best and due to complex interactions between traditional risk factors, immunosuppressive medications and chronic kidney disease, a traditional approach to cardiovascular disease management is inadequate. ´

This may be attributable to a number of causes: whereas a highly specialized nephrological team handles the entire medical management of patients with advanced CKD or on dialysis in the pre-transplantation phase, the transition to the post-transplantation phase is not a continuum, but first of all a ‘cut’, because perioperative treatment and care is performed by the transplantation surgeons, assisted where relevant by consultants from multiple disciplines. Although patients generally remain in transplantation aftercare after leaving hospital, cardiovascular screening protocols are variable and do not have a clearly defined, standardized agenda. Aftercare may be provided by surgeons, general practitioners, cardiologists, diabetologists and nephrologists. Professor Janani Rangaswami, nephrologist and Associate Professor of Medicine at Einstein Medical Center/Jefferson University, Philadelphia and the leading author of the review by AST-KPCOP, summarizes by saying that, ‘Instead of end-to-end seamless patient care throughout the treatment chain, from CKD to dialysis to transplantation, different medical teams usually assume responsibility for the patient, with a less than optimal approach towards jointly targeting heart disease risk reduction after kidney transplantation.’ This fragmentation, of post-transplantation care especially, results in ‘snapshots’ of care and management processes, and in long-term undertreatment of modifiable cardiovascular risk factors.

There are several things that must change in future. One is that all practitioners, general internists, cardiologists, diabetologists and nephrologists, must recognize that event-free outcome surrounding the time of the transplant surgery is not the only goal and the long-term survival of kidney transplant is dependent on successful management of the patients’ cardiovascular disease. ‘The multi-disciplinary team of physicians need to work collaboratively to manage cardiovascular disease pre and post-transplant to ensure long-term event-free survival of the patient,’ emphasizes Professor Dadhania. In addition, the knowledge gap between the optimal management of cardiovascular disease in a patient with and without CKD must be closed with reliable data and evidence on modification of cardiovascular risk factors; a critical issue that is a consequence of kidney patients generally being under-represented in cardiovascular outcome studies. Ultimately, this is the only way to reach a medical consensus on optimal procedures.

‘Instead of the fragmentation hitherto, what we need in order to provide optimized transplantation aftercare is a cardio-nephrological team that acts as a cohesive unit, i.e. a combination of the multi-disciplinary clinical care model and the team approach. In addition to purely nephrological aspects, transplantation aftercare must focus more on cardiovascular risk screening and the respective forms of intervention’, emphasizes Professor Rangaswami. ‘Only in this way can we continue to improve the survival of patients and the transplanted organs.’ Our kidneys filter out toxic waste from the blood and regulate the fluid balance in the body as well as the balance of electrolytes and acid/base amongst others. Kidneys are important organs whose functions most of us take for granted, but when kidneys silently stop working this can create a life threatening situation. Renal replacement therapy, RRT, (dialysis or kidney transplantation) may save

the lives of many patients for years and even decades, as kidney function can be replaced by machines for a long period of time – but patients on dialysis (and transplanted patients to a lesser extent) have shorter life expectancies. This is why kidney failure (end-stage renal disease) should be prevented wherever possible.

A new analysis of data in the ERA-EDTA Registry shows that men are affected by kidney failure much more often than women [13]. In 2016, 26,446 men and 14,820 women started renal replacement therapy. Amongst older patients (>75 years of age), the difference was even more striking: the incidence in men was 2.7 times higher than that in women. ‘One can only speculate about the reasons’, explains Professor Ziad Massy (Paris), Clinical Nephrology Governance Chair/Chair of the Registry. The protective effects of oestrogens in women and/or the damaging effects of testosterone might cause kidney function to decline faster in men than in women [3]. Moreover, elderly women seem to be more inclined to choose conservative care instead of RRT [3].

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[1] Rangaswami J, Mathew RO, Parasuraman R et al. Cardiovascular disease in the kidney transplant recipient: epidemiology, diagnosis and management strategies. Nephrol Dial Transplant. 2019 Apr 15. [Epub ahead of print] DOI: 10.1093/ndt/gfz053

[2] Wolfe RA, Ashby VB, Milford EL et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. NEJM 1999; 341(23): 1725-30

[3] Ojo AO, Hanson JA, Wolfe RA et al. Long-term survival in renal transplant recipients with graft function. Kidney int 2000; 57(1): 307-13

[4] Report URDSUad. 2008. National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Bethesda, MD.

[5] Janani R, Sidney Kimmel S, Roy M et al., Dadhania D. Cardiovascular Disease in the Kidney Transplant Recipient: Epidemiology, Diagnosis and Management Strategies. NDT-00120-2019.R1_14-Feb-2019

[6] Anavekar NS, McMurray JJ, Velazquez EJ et al. Relation between renal dysfunction and
cardiovascular outcomes after myocardial infarction. NEJM 2004; 351(13): 1285-95

[7] Arend SM, Mallat MJ, Westendorp RJ et al. Patient survival after renal transplantation; more than 25 years follow-up. NDT 1997; 12(8): 1672-79

[8] Kasiske BL, Snyder JJ, Gilbertson D et al. Diabetes mellitus after kidney transplantation in
the United States. Am J Transplant 2003; 3(2): 178-85

[9] Kasiske BL, Anjum S, Shah R et al. Hypertension after kidney transplantation. Am J Kidney Dis 2004; 43(6): 1071-81

[10] Premasathian NC, Muehrer R, Brazy PC et al. Blood pressure control in kidney transplantation: therapeutic implications. J Hum Hypertens 2004;18(12):871-877

[11] Kasiske BL, Klinger D. Cigarette smoking in renal transplant recipients. JASN 2000; 11(4): 753-59

[12] Kidney Disease: Improving global outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009: S1 -S155

[13] Pippias M, Kramer A, Noordzij M et al. The European Renal Association – European Dialysis and Transplant Association Registry Annual Report 2014: a summary. Clin Kidney J. 2017 Apr;10(2):154-169