The World Kidney Day 2011 to be held on March the 11th has the Motto: Protect Your Kidneys, Save Your Heart stressing the important link between CKD and CVD.
Editorials have appeared in all major Nephrology journals by Bill Couser and Miguel Riella stressing this link. It is now well established that CKD patients; those with albuminuria and those with reduced eGFR are at increased risk of CVD morbidity and mortality. Many argue that this is secondary to CKD with the involvement of traditional and non-traditional CVD risk factors in CKD.
An opposite veiw would argue that CKD and CVD are one and the same; Older patients affected by CKD most often have underlying CVD causing the albuminuria and the renal dysfunction. The more severe the underlying systemic CVD the more severe the renal involvement; heavier albuminuria and lower eGFR. So it is not surprising that CKD is a marker of CVD and therefore predicts poor outcome.
This is why I put forward a unifying concept, that of C-K-D: Cardio-Kidney-Damage to explain the similarities between CVD and CKD with the latter representing one of many endorgans damage caused by the former.
The 2011 Motto could read: Protect Your Heart, Save Your Kidneys
This article by Huang and colleagues from Taiwan appeared in the January 2011 issue of JASN.
It shows that patients undergoing coronary artery grafting/surgery who have pre-operative proteinuria are at a considerable higher risk to develop post-operative AKI. Odds ration from 1.66, 2.30 to 7.29 for mild, moderate and severe proteinuria respectively. This was independent of the presence of diabetes.
This article adds to the growing list of observations, including those made by the CKD Collaborative consortium and published in KI 2011, showing that proteinuria is an independent risk factor for the development of AKI.
Most of these studies overlook the following:
1. That proteinuria/albuminuria in elderly individuals is a marker of underlying vascular pathology and endothelial dysfunction. Therefore the worst the underlying CVD the higher the albuminuria. It is therefore not surprising that those with the most severe underlying atherosclerosis and CVD have the higher risk of AKI!
2. Most of these studies, including the one by Huang et al, does not take into account that elderly individuals with proteinuria are often treated with inhibitors of the RAAS. These agents, whether they are ACE inhibitors or angiotensin receptor blockers, are potentially nephrotoxic and would increase the risk of post-operative AKI.
The learning point here is:
STOP ACEinhibitors/ARBs well before any high risk surgery as these agents could increase the risk of AKI and the associated morbidity and mortality!
An article by Ix and colleagues in the January 2011 issue of CJASN describes new equations to calculate urine creatinine excretion rate.
Urine creatinine excretion is increasingly relied upon to calculate the degree of proteinuria/albuminuria through the reporting of urine protein:creatinine ratio (PCR) or albumin:creatinine ratio (ACR). Unfortunately, such formulation has a number of problems including the overestimation of proteinuria/albuminuria in patients whose urine creatinine excretion is low due to a number of factors including muscle wasting and malnutrition. In other words, a wasted individual can have a raised PCR/ACR not due to increase proteinuria/albuminuria but instead due to decreased urine creatinine excretion.
Ix and colleagues attempt to address this issue by developing equation correcting urine creatinine excretion rate to take into account the individual's age, gender, weight and race; all potential confounders of serum and urine creatinine levels. This approach is comparable to that used for estimation of creatinine-derived GFR (eGFR) and makes good sense.
Estimated urine creatinine excretion (eCER) equations:
eCER: 879.89 + 12.51 x weight (kg) - 6.19 x age + (34.51 if black) - (379.42 if female)
eCER: 1115.89 + 11.97 x weight (kg) - 5.83 x age -60.18 x phosphorus (mg/dl) - (52.82 if black) - (368.75 if female)
Correction of urine creatinine excretion rate to account for commonly available variables is an important step towards improving the estimation of PCR and ACR and enhancing the diagnostic accuracy of these ratios.
This study by Hemmelgarn and colleagues (NEJM January 27, 2011) addresses the important issue of the prevention of dialysis central venous catheters infections. the authors studied a small number of patients (n=225) randomised to have either heparin locks of the catheter's lumen three weekly after each HD session or heparin twice weekly + once a week usage of recombinant tissue plasminogen activator (rt-PA) 1mg in each lumen. Patients were followed up for 6 months and catheter malfunction was used as a surrogate marker for catheter infection. Secondary outcome was catheter-related bacteremia. The authors noted a risk of catheter malfunction almost twofold higher in patients treated with heparin alone compared to those receiving one a week a rt-PA lock. Catheter related bacteremia was also significantly reduced.
Whilst this is an interesting observation, it has a number of shortcomings including:
1) Small sample size (n=225) increasing the risk of bias and false positive results (type1 statistical error)
2) Short follow-up period (6 months)
3) The use of a surrogate endpoint for catheter infection; namely catheter malfunction instead of harder endpoints such as catheter removal, hospitalization or even death.
4) Lack of comparative analysis to other, current and cheaper, strategies such as antibiotics, citrate or taurolidine locks. Some of these have proved quite effective and much cheaper than rt-PA.
It is most important to realise that the best approach to prevent catheter related infections and their complications is the AVOIDANCE of usage of central venous catheters and use of AV fistulas or even AV grafts! Unfortunately, In the USA, a high proportion of patients starting RRT by HD depend for access on central venous catheters. It has been estimated in 2008, that 74% of those starting HD used a central venous catheter and only 16% had an AVF or functioning graft in place! This is a reflection of poor practice and inadequate planning for RRT by HD.
In order to avoid inadequate access for HD, planning of RRT is essential. For that, patients should be seen and followed-up by Nephrologists from CKD stage 4 onward. At the Sheffield Kidney Institute (UK) all CKD 5 patients are referred to a multidisciplinary outpatient clinic where a number of issues including vascular access are addressed. These include the psychological impact of ESRD on the patient and his family. The review of CVD risks and their investigation and management. The review of the patients' nutritional status. Also review of patients' suitability for renal transplantation including listing for pre-emptive transplantation. But the most important role of this pre-dialysis review clinic is to discuss with the patient his/her dialysis options and prepare access. The timing of access is key to its longterm success and to minimise complications.
Central venous catheters are poor excuses for:
Delayed referrals of ESRD patients
Poor pre-Dialysis management
Poor surgical approach and skills hampering availability of native AVF or AVgrafts.
Issue 2, 2011
Renal Disease Associated with Antiretroviral Therapy (ART) in the Treatment of HIV
(R.D. Cooper, M. Tonelli, Edmonton, Canada; Nephron Clin Pract 2011;118:262-268). In this review, the authors highlight the impact but also the potential nephrotoxicity of antiretroviral agents. They urge those treating HIV-positive individuals to discriminate between drug-related nephrotoxicity and other causes of HIV-associated kidney injury. They also stress that renal dysfunction should not be considered a contraindication to initiation of ART. However, it is important to bear in mind that kidney function at ART initiation is an independent predictor of death in HIV-infected individuals, especially in those with a history of AIDS. There is little doubt that close monitoring of renal function is essential to minimize complications and improve outcomes in HIV-infected individuals. Kidney damage related to ATR is typically reversible with early recognition and timely discontinuation of the offending agent. Nephrologists should be familiar with the potential toxicity of these agents to avoid delays in diagnosis.
The Burden of Chronic Kidney Disease (CKD) on Developing Nations: A 21st Century Challenge in Global Health
(R.A. Nugent and colleagues, USA and UK; Nephron Clin Pract 2011;118:269-277). In this review, Nugent from the Center for Global Development and her colleagues highlight issues related to the impact of CKD on health in emerging economies. Such countries are the subject of a triple hit that leads to the development of CKD and impacts on population health and survival, i.e. poverty, infectious (communicable) disease as well as westernization with the sharp rise in noncommunicable chronic disease. The latter, as highlighted in the review, includes obesity with its impact on the development of diabetes, hypertension and cardiovascular disease (CVD). Moreover, life expectancy is rising in developing countries, which is associated with increased life course exposure to risk factors that lead to CKD and CVD. Cost-effective detection and management approaches are also advocated, stressing that they have to be adjusted to meet the local needs and means and also have to take into consideration access to care and related cost. The 21st century with advances in telecommunication may open new and exciting opportunities to access healthcare in emerging countries. After all, before too long most people in those countries will have a mobile phone, but few will have access to a doctor! Perhaps, Mobile Health can be one way forward...
Clinical Characteristics of Kidney Disease in Japanese HIV-Infected Patients
(N. Yanagisawa and colleagues, Japan; Nephron Clin Pract 2011;118:285-291). The authors have studied prevalence of CKD in HIV-infected Japanese patients. They report that microalbuminuria, macroalbuminuria and proteinuria were present in 13.2, 4.55 and 9.52% of patients, respectively. The prevalence of CKD of any stage and CKD stage 3 and above was 15.4 and 9.70%, respectively. Multivariate analysis showed significant associations between the coexistence of diabetes, hypertension and hepatitis C infection with either proteinuria or albuminuria, which was significantly related to the presence of renal dysfunction. Lower CD4 cell count was associated with the presence of renal dysfunction, but higher HIV-RNA level was not. These figures bear striking similarities to those published elsewhere with a high prevalence of microalbuminuria. Care should be taken not to confound microalbuminuria due to infection, inflammation and associated with poverty in these individuals with intrinsic CKD. All too often Nephrologists do not fully appreciate that microalbuminuria is a sensitive marker of systemic infections and associated inflammation, that is reversible when the condition is treated. Caution should also be exerted when prevalence estimates are derived from single cross-sectional sampling as CKD diagnosis needs confirmatory testing to ascertain the chronic nature of the renal dysfunction. Finally, 90% of the patients reported in this study were treated with ART, which, as highlighted in the review by Cooper and Tonelli, can be associated with renal toxicity.
Proteinuria Thresholds Are Irrational: A Call for Proteinuria Indexing
(T.J. Ellam, M. El Nahas, UK; Nephron Clin Pract 2011;118:217-224). The authors draw the reader’s attention to the notion that current CKD guidelines are based on absolute thresholds of proteinuria/albuminuria, with no reference to the residual renal function. They argue that this is illogical as the severity of proteinuria is a direct reflection of the number of residual filtering nephrons as well as their pathology and the capacity of the tubules to reabsorb filtered protein/albumin. The current simplistic approach to proteinuria may also compromise its usefulness in diagnosis and prognosis of CKD. The routine measurement of the urinary protein/albumin:creatinine ratio (PCR/ACR) and estimated glomerular filtration rate (eGFR) gives rise to the opportunity to index proteinuria for renal function (i.e. a PCR:eGFR or ACR:eGFR ratio). The authors advocate consideration of the benefits of indexing PCR/ACR for eGFR to optimize treatment decisions based on proteinuria/albuminuria. Consideration should also be given to correcting urinary creatinine values (for ACR/PCR calculation) to age and gender in order to adjust for creatinine generation as already done with serum creatinine estimation and calculation of eGFR.
Africa and Nephrology: The Forgotten Continent
(I.J. Katz, T. Gerntholtz, S. Naicker, South Africa; Nephron Clin Pract 2011;117:c320-c327 ) The authors highlight the plight of healthcare and nephrology in Africa. Africa is in the grip of a double-hit by communicable (HIV/AIDS, Malaria and Tuberculosis) and non-communicable diseases impacting on healthcare and its provisions. Whilst infectious diseases remain uncontrolled, the rising tide of non-communicable diseases, such as obesity/diabetes and hypertension, is likely to increase the burden of CKD and the associated CVD. Whilst CKD in the West may predominantly mirror the underlying severity of CVD affecting an aging population, CKD in emerging economies is likely to result from a triple hit of poverty, infections and globalisation/westernisation.
The Opposite View is presented in Hemodialysis of Patients with HCV Infection: Isolation Has a Definite Role
(S.K. Agarwal, India; Nephron Clin Pract 2011;117:c328-c332 ) The author argues that whilst the Center for Disease Control (USA) has suggested that 'patients who are anti-HCV positive (or HCV-RNA positive) do not have to be isolated from other patients or dialyzed separately on dedicated machines'. This assumes that universal precautions (UP) are strictly adhered to. UP implementation involves additional costs, knowledge about UP and commitment to adhere to them. Dr. Agarwal argues that all three factors may be with variable degree responsible for not having strict UP in place in many dialysis units in developing countries. Comments are welcomed by those who share his Opposite View.
The Best Way to Detect Elevated Albuminuria
(Abbas Deeb and colleagues, France; Nephron Clin Pract 2011;117:c333-c340) Deeb and colleagues argue for the value of correcting urinary albumin excretion rate for creatininuria. Whilst this has become established practice over the last decade, attention has recently shifted to the potential of a confounding effect of the fall in urinary creatinine excretion in wasted, malnourished or ill individuals. Interestingly, a fall in urinary creatinine excretion has similar poor prognostic values in terms of morbidity and mortality than a raised ACR! So caution is called for in the interpretation of raised ACR in the general population as it could result from either an elevation of urinary albumin excretion, but also from a fall in urinary creatinine excretion; both have poor prognostic implications.
Single Estimated Glomerular Filtration Rate and Albuminuria Measurement Substantially Overestimates Prevalence of Chronic Kidney Disease
(M.J. Bottomley and colleagues, UK and Belarus; Nephron Clin Pract 2011;117:c348-c352) The authors draw attention to a point all too often neglected, i.e. the importance of multiple confirmatory testing before CKD can be diagnosed in the community. Most so-called CKD detection programs test once and assume that those found positive suffer from CKD. In the study by Bottomley et al., repeated sampling/testing revealed that 21% of those tested changed CKD stage. Proteinuria was reproducible in only 48% at 3 months. This had a major impact on estimated CKD prevalence; a point prevalence of 8.2% halved with repeat testing. This study emphasises the importance of confirming abnormal eGFR and proteinuria on at least one further sample 3 months apart before categorising the individual as having CKD. This has wide implications for screening in general populations in the West as well as in emerging countries. This may give more accurate estimates of CKD prevalence and deflate the so-called "CKD epidemic".
Patients with Chronic Kidney Disease (CKD) are at much higher risk of cardiovascular disease than the general population but the benefits of lipid reduction in this population have been far from clear. Recent data from the Study of Heart and Renal Protection (SHARP) study presented at the ASN 2010 may clarify the role of lipid-lowering therapy in this population. SHARP enrolled 9438 patients with chronic kidney disease either on dialysis or with a creatinine level of >1.7 mg/dL (150μmol/l) for men or >1.5 mg/dL (130μmol/l) for women, all with no history of MI or coronary revascularization. Patients were randomised to either ezetimibe/simvastatin (10 mg/20 mg) or placebo, with an additional 1000 patients randomised to simvastatin alone. After one year, patients in the simvastatin-alone arm were re-randomised.
After a median follow-up of nearly 5 years the simvastatin/ezetimibe group had 17% reduction in major atherosclerotic events compared with placebo (p=0.0022) and a 15.3% reduction (p=0.0012) in major vascular events. Approximately 1/3 of patients were on dialysis though the benefit in the dialysis population was not statistically significant. Further simvastatin/ezetimibe had no impact on the progression of CKD nor was there any difference in mortality between the two groups.
So where does this leave us in terms of daily clinical practice? It now seems sensible to use lipid-lowering therapy as a primary preventative measure in CKD patients at risk of vascular events but it is worth noting that even in this huge trial no effect on overall mortality was seen and the reduction in vascular events was quite modest. The simvastatin/ezetimibe combination is clearly safe (concerns about myositis and cancer were not borne out by the data) but it may be that alternative therapies such as atorvastatin could be a cheaper alternative. Whether prevalent dialysis patients should be treated in the same way isn’t so clear. Both the 4D and AURORA studies have failed to show any benefit of statins in the prevalent dialysis population. Clearly clinicians will be able to make more informed decisions once the data is finally published.
The SHARP study data can be seen at: http://www.ctsu.ox.ac.uk/~sharp/slides.htm
The ‘long and slow’ approach to haemodialysis as advocated by the group from Tassin, France has yielded impressive results in terms of blood pressure control and patient survival. This has lead to increasing interest in daily haemodialysis as more effective alternative to the standard thrice weekly prescription.
Chertow, Levin and other members of the Frequent Hemodialysis Network (FHN) report the early (12 months ) results of their study involving 245 patients comparing in center haemodialysis (HD) six times per week compared to three times per week. They conclude that frequent HD, as compared to conventional HD, was associated with a favourable outcome. Emphasis was on progression of left ventricular mass, death and quality of life based on a physical-health composite score. Whilst promising, this study is limited by the very short follow-up period that precludes any conclusion on long term outcomes in HD patients dialysed more frequently. Outcomes are also difficult to evaluate as left ventricular mass index may reflect a better fluid balance and reduced blood volume in those dialysed more frequently. Quality of life and evaluation of physical health through health surveys and questionnaires can be biased by the non-blinded nature of the study -patients dialysed six times weekly may be subject to the placebo effect of frequent medical attention.
Interestingly, the daily HD group were much more likely to experience vascular access problems. Furthermore the study was underpowered and the sample size too small to show differences in survival over such a short period of time in such patients population.
Reference: In-Center Hemodialysis Six Times per Week versus Three Times per Week. The FHN Trial Group. N Engl J Med 2010; 363:2287-2300