The paper in the Lancet (2011;377, 721) by Navarra et al. reports the outcome of a large, phase 3, clinical trial on the use of Belimumab (a human monoclonal antibody that blocks BLyS (B-lymphocyte stimulator) activity. Increased activity of B lymphocytes and their products including BLyS are known to be increased in active SLE. This trial shows that blocking BLyS activity through infusion of Belimumab (1m/kg or 10 mg/kg) for up to 48 weeks, along with standard care, leads to decreased SLE activity indices. Belimumab at 10mg/kg proved significantly more effective than standard care alone. Clearly Belimumab, which has recently been approved by the FDA for the treatment of SLE, will add a new therapeutic option to those currently available including Rituximab (anti-CD20) that also acts on B lymphocytes and their depletion (Rituximab treatment for vasculitis. Jayne D. Clin J Am Soc Nephrol. 2010 Aug;5(8):1359-62).
In this paper by Seliger and colleagues from Baltimore USA, the authors report an increased risk of stroke in CKD (mainly 3) who are using ESAs. This observational study of 12,426 patients individuals confirmed the previous observation made in diabetic CKD patients treated with Darbopoietin alpha (the TREAT study). The current report highlights the fact that high dose of ESAs are associated with significantly increased risk of stroke in patients with a history of cancer (under active treatment) and those with a previous history of stroke. A posthoc analysis of the TREAT study showed increased risk in those who failed to respond to Darbopoietin raising the suspicion that it may be the high dose of ESA rather than the acheived Hb level that is associated with increased complications; strokes and cancer. The observation by Seliger and colleagues reinforces the FDA recommendations that Darbepoietin alpha and epoietin alpha should be prescribed at the lowest possible dose to achieve the lowest Hb level. Whether these agents should be used at all in patients with a history of cancer or stroke is very much questionable.
Albumin:Creatinine Ratio - A Flawed Measure. The Merits of Estimated Albuminuria Reporting (Tim Ellam, Sheffield; Nephron Clin Pract 2011;118:c324-c330) Ellam presents the Opposite View to the fact that urine Albumin:Creatinine Ratio (ACR) is a reliable indicator of urinary albumin excretion. He reminds the reader of the limitations of this calculation and the fact that confounders of urine creatinine excretion are seldom considered. For instance, a low urinary excretion of creatinine may reflect muscle wasting and ill health, thus raising ACR in the absence of changes in urine albumin excretion. Low urinary creatinine excretion, like that of albumin, is known to be associated with CVD and increased mortality, thus confoundingthe prognostic significance of a raised ACR. The author argues that urinary creatinine excretion needs to be adjusted for key confounders such as age, gender, race and muscle mass. This, in fact, has been recently suggested by Ix and colleagues (Clin J Am Soc Nephrol 2011;6:184-191) who have put forward urine creatinine excretion formulas that adjust for gender and age. So beware Nephrologists when you use ACR/PCR to bear in mind such important confounders; after all, they are the same that justified formulations that include age, gender and race for adjustments in serum creatinine measurements and eGFR calculations.
Proteinuria in Type 2 Diabetic Patients with Renal Impairment: The Changing Face of Diabetic Nephropathy (Packham and colleagues on behalf of the collaborative study group, Melbourne, Chicago, Ill., Nashville, Tenn., and Groningen; Nephron Clin Pract 2011;118:c331-c338) The authors note that over one fifth of patients with type 2 diabetic nephropathy and established renal impairment have proteinuria levels below those traditionally associated with overt nephropathy. They attribute this to the likelihood that these patients are receiving ACEis, ARBs, or a combination of both. Another important consideration is that the type of patients with so-called diabetic nephropathy has been changing since the early days of description of the natural history of diabetic nephropathy by Mogensen et al. (Scand J Clin Lab Invest 1976;36:383-388) in the seventies!? Those were predominantly younger patients with progressive nephropathy and heavy proteinuria, which was the rationale behind ACEis. Nowadays, the patients we see are older, with type2 diabetes mellitus and often suffer from longstanding hypertension preceding the diagnosis of diabetes mellitus by years. They often have diffuse and severe atherosclerosis with consequent renovascular disease and ischemic nephropathy. Proteinuria in these patients is mild to moderate and progression slow. ACEi, ARB or a combination of both is likely to be harmful (see results of the ONTARGET study, Lancet 2008;372:547-553). It is high time Nephrologists reconsider the use of ACEis/ARBs in such patients. Some have even stopped them in advanced nephropathy in patients with diabetes to good effects (Ahmed et al., Nephrol Dial Transplant 2010;25:3977-3982).
Treatment of HIV-Associated Nephropathies (Elewa and colleagues, Cairo, Porto Alegre and Rochester, Minn.; Nephron Clin Pract 2011;118:c346-c354) This review highlights a number of new and important issues including the perceived increased prevalence of CKD in HIV-infected individuals and the association with known predisposing factors such as the black race, low CD4 count, high HIV RNA copies level, but also new and interesting risk factors such as a family history of CKD and the presence of diabetes mellitus, hypertension or hepatitis C co-infection. In emerging countries/regions where HIV prevalence is high, CKD is likely to result from the triple hit of poverty, infections and westernization with increased incidence of hypertension and diabetes. Also, additional environmental or inherited factors may be necessary to initiate human HIVAN. Elewa and his colleagues remind us that the evidence upon which HAART treatment recommendations is based is weak. A recent search involving the Cochrane Central Register of Controlled Trials (CENTRAL) found no RCT-based evidence upon which to base guidelines for the treatment of HIVAN. Clearly, more research is needed to understand HIVAN, its epidemiology, classification and treatment.
Metformin: The Safest Hypoglycaemic Agent in Chronic Kidney Disease (Nye and Herrington, Oxford; Nephron Clin Pract 2011;118:c380-c383). The authors remind the reader that lactic acidosis following treatment of patients with diabetic nephropathy with metformin is rare and unpredictable. It is usually precipitated by an additional acute condition predisposing to tissue hypoxia. Metformin is an effective oral agent in the treatment of type 2 diabetes and in the prevention of its complications, particularly in overweight patients. Although a number of reports have been published suggesting that metformin is a cause of lactic acidosis, a systematic review of all the available trials and cohort studies does not support this. In fact, the evidence suggests that type 2 diabetes mellitus itself may be associated with reduced lactate clearance and may be a more important risk factor for lactic acidosis than metformin.
We should be cautious not to deprive our diabetic patients from an excellent drug on the basis of a poor understanding of the published literature. This is one more proof that we seldom read the evidence upon which we base our practices; withdrawal of metformin in patients with a serum creatinine>150 micromol/l!? One would hope that those who draft guidelines do...?!
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".