Screening for, Monitoring, and Treatment of Chronic Kidney Disease Stages 1 to 3: A Systematic Review for the U.S. Preventive Services Task Force and for an American College of Physicians Clinical Practice Guideline
Howard A. Fink, MD, MPH; Areef Ishani, MD, MS; Brent C. Taylor, PhD, MPH; Nancy L. Greer, PhD; Roderick MacDonald, MS; Dominic Rossini, MD; Sameea Sadiq, MD; Srilakshmi Lankireddy, MD; Robert L. Kane, MD; and Timothy J. Wilt, MD, MPH
This is a balanced systematic review of the literature relating to the impact of treatment including ACE inhibitors and ARBs on outcomes in CKD; ESRD and Mortality. The authors conclude that the evidence is in general fair but seldom strong and therefore current recommendations for screening and early treatment to prevent hard endpoints such as death or ESRD are weak.
They also reported that the evidence for strict BP control is weak.
They conclude that the role of screening or monitoring in improving outcomes is uncertain as hardly any study reviewed addressed that point. And that the evidence for benefit is strongest for ACE inhibitors and ARBs, and more specifically in patients with albuminuria combined with diabetes and cardiovascular disease.
This manuscript should be read by all those interested in the management of CKD as it shows the limitations of available data and highlights the value of careful and systematic analysis.
Read the full article on OLA:
For a number of years some nephrologists have advocated online hemodiafiltration (HDF) as the therapy of choice in chronic dialysis patients. The theory being that enhanced convective removal of middle molecules allows the removal of uraemic toxins that contribute to the inflammatory state in haemodialysis and promote cardiovascular disease. A number of observational studies have shown a survival benefit of HDF.
The recently published KDIGO guidelines provide a welcome and timely synthesis of the evidence base to support the management of AKI.The guidelines focused on 4 key domains: i) AKI Definition, ii) Prevention and Treatment of AKI, iii) Contrast-induced AKI and iv) Dialysis Interventions for the treatment of AKI.
The full summary of clinical practice statements is available at www.kdigo.org but a key recommendation is that clinicians effectively adopt the previously published AKI Network definition and staging of AKI as follows:
- An increase in serum creatinine by ³0.3mg/dl (³26.5mmol/l) within 48 hours or an
- Increase in serum creatinine to ³1.5 times baseline within the previous seven days or
- Urine volume £0.5ml/kg/hours for 6 hours.
1.5-1.9 times baseline
³0.3mg/dl (³26.5mmol/l) increase
<0.5ml/kg/hour for 6-12 hours
2.0-2.9 times baseline
<0.5ml/kg/hour for ³12 hours
3 times baseline
³4.0 mg/dl (³353.6mmol/l) increase
OR initiation of renal replacement therapy
OR in patients less than 18 years a decrease in eGFR <35mls/minute/1.73m2
<0.3ml/kg/hour for ³24 hours OR
Anuria ³12 hours
The rationale for the staging system comes from a plethora of studies showing that the risk of death and renal replacement therapy (RRT) increases with each stage. Furthermore evidence suggesting patients in whom AKI resolves are at increased risk of death, CKD and cardiovascular disease has prompted KDIGO to make an ungraded suggestion that all those with resolved AKI should be considered to be at increased risk of CKD and be managed as per the KDOQI guidelines for individuals at risk of CKD. However whilst there is no doubt that standardising the definition and staging of AKI provides a clear framework for studying outcomes in both epidemiological and clinical research the bedside utility of the proposed classification and staging maybe be questioned by many 'real-world' practicing clinicians. In particular it is not clear how staging will alter immediate management and outcomes. As with the CKD classification sustem the danger is that an epidemiological tool gets imposed onto clinical practice without any evidence that the classification system per se can improve outcomes or can lead to specific interventions. Furthermore the evidence that monitoring people with resolved AKI as being at risk of CKD can i) prevent the onset of CKD or ii) is cost-effective is not presented.
Many other recommendations are made most of which are eminently sensible/obvious (e.g. use vasopressors for those with shock) but a few caught my eye:
- recommended use of oral NAC in contrast nephropathy – despite v weak evidence, plus the fact that NAC has poor oral bioavailability and increases tubular secretion of creatinine
- that regional citrate be the anticoagulant of choice in CRRT unless the patient is shocked/has liver disease – of course these are the very patients that are most likely to be on CRRT and given the complexities of citrate use it’s a shame no practical protocol was provided…
- that dialysis dose be measured in AKI either by using Kt/V ( almost certainly meaningless in a catabolic patient with AKI) or the effluent flow rate in CRRT – again no evidence from the Veterans and Australasian studies that dose of RRT in AKI has any impact on survival.
- support the use of CRRT in haemodynamically unstable patients whilst this is routine practice in many places the meta-analyses indicate this again has no impact on patient outcomes… and as well all know CRRT is rarely continuous.
- The use of insulin to maintain glycaemic control despite the risks of hypoglycaemia.
As with previous KDIGO reviews, the clear message is that there is a lack of evidence (particularly, well-designed interventional outcome studies) to underpin much of our everyday clinical practice. Indeed only 14.8% of the recommendations were graded '1A' whilst 63.9% of the recommendations were level 2. Thus these are not prescriptive guidelines but provided nuanced guidance for the clinician. The KDIGO co-chairs bullishly argue that recommendations should be made even when the evidence is weak as clinicians often ask "what do the experts do?" – this may be true but as history tells us the track record of expert opinion in the absence of evidence can often be deeply flawed.
The recommendation that an empirical definition and staging system be used in the management of AKI will arouse controversy and debate. As yet no data has been presented to show that these tools in themselves can improve outcomes in AKI and many clinicians will be wary about implementing what is essentially a research-based diagnostic and staging system into the clinical arena in the absence of such data – as was the case in CKD........
- Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW: Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365-3370.
- Clinical practice Guidelines for Acute Kidney Injury 2012. http://www.kdigo.org/clinical_practice_guidelines/AKI.php
- Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A: Acute kidney injury network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.
- Rabindranath K, Adams J, Macleod AM, Muirhead N: Intermittent versus continuous renal replacement therapy for acute renal failure in adults. Cochrane Database Syst Rev 2007:CD003773.
- Palevsky PM, Zhang JH, O'Connor TZ, Chertow GM, Crowley ST, Choudhury D, Finkel K, Kellum JA, Paganini E, Schein RM, Smith MW, Swanson KM, Thompson BT, Vijayan A, Watnick S, Star RA, Peduzzi P: Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 2008;359:7-20.
- lomo R, Cass A, Cole L, Finfer S, Gallagher M, Lo S, McArthur C, McGuinness S, Myburgh J, Norton R, Scheinkestel C, Su S: Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med 2009;361:1627-1638.
This meeting organised by Professor Neveen Soliman, Cairo University is proving a great success.The meeting is well attended and intends to introduce young nephrologists and older ones...to the complexity of inherited diseases and challenges of genetics, diagnostics and management in these patients.
A number of excellent talks by Profs Soliman, Sayers and Levtchencko.
Also comprehensive review on hyperoxaluira by Dr Hafez Bazaara followed by discussion of management by Prof Khaled Eweda and Alaa Fayez on the complexities of dual liver and kidney transplantation for patients with type1 hyperoxaluria. Surigcal challenges were highlighted by Dr Fayez who explained difficulties of intraoperative fluid balance between keeping the renal allograft overhydrated and the liver underhydrated...fantastic achievements for Egypt pediatric nephrology and surgery.
I gave a talk on the genetics of kidney disease which highlighted the relevance of genetics of albuminuria, hematuria as well as decreased GFR and its decline in CKD. Key genes appear to be the complex MYH9/APOL1 on chromosome 22 and the increasingly recognised role of the UMOD gene, coding for uromodulin (Tamm-Horsfall protein), in hypertension, hyperuricemia as well as the progression of chronic interstitial disease. Elevated uromodulin urine levels have been associated with increased risk of CKD progression over a 10 year period in a proof of concept study (1).
The latter may explain the uric acid and its "nephrotoxocity" story; those with UMOD mutations may have progressive CKD with elevated uric acid and even gout as main features. Those with raised uric acid in the absence of UMOD mutations may be harmless?
Genotyping of UMOD may highlight those at risk of progression and raise issues related to allopurinol therapy of hyperuricemia to prevent CKD progression. Pilot studies in children with juvenile hyperuricemic nephropathy have proved of limited impact so far (2). Also, of not eallopurinol is capable of reducing BP.
The observations related to UMOD gene mutations illustrate an interesting and emerging concept that common variants in gene regions known to be associated with monogenic diseases may be associated with milder disease-related phenotypes in the general population (3).
1. Kottgen et al.JASN 2010; 21;337-344.
2. Bleyer et al. QJM 2003;96:867-8.
3.O'Seaghadha and Fox. Nephron 2011;118:c55-63
Follow the IKDW meeting on Facebook Global Kidney Community
Lectures will be posted on the new Pediatric Nephrology section of OLA
READ BLOG AFTER ABSTRACT:
Article by Peraza et al published in the April 2012 issue of AJKD.
BACKGROUNd; An epidemic of chronic kidney disease of unknown cause has emerged along the Pacific coast of Central America, particularly in relatively young male sugarcane workers. In El Salvador, we examined residence and occupations at different altitudes as surrogate risk factors for heat stress.
STUDY DESIGN: Cross-sectional population-based survey.
SETTING & PARTICIPANTS:
Populations aged 20-60 years of 5 communities in El Salvador, 256 men and 408 women (participation, 73%): 2 coastal communities with current sugarcane and past cotton production and 3 communities above 500 m with sugarcane, coffee, and service-oriented economies.
Participant sex, age, residence, occupation, agricultural history by crop and altitude, and traditional risk factors for CKD.
Serum creatinine (SCr) level greater than the normal laboratory range for sex, estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2), and proteinuria categorized as low (protein excretion ≥30-<300 mg/dL) and high grade (≥300 mg/dL).
Of the men in the coastal communities, 30% had elevated SCr levels and 18% had eGFR <60 mL/min/1.73 m(2) compared with 4% and 1%, respectively, in the communities above 500 m. For agricultural workers, prevalences of elevated SCr levels and eGFR <60 mL/min/1.73 m(2) were highest for coastal sugarcane and cotton plantation workers, but were not increased in sugarcane workers at 500 m or subsistence farmers. Women followed a weaker but similar pattern. Proteinuria was infrequent, of low grade, and not different among communities, occupations, or sexes. The adjusted ORs of decreased kidney function for 10-year increments of coastal sugarcane or cotton plantation work were 3.1 (95% CI, 2.0-5.0) in men and 2.3 (95% CI, 1.4-3.7) in women.
The cross-sectional nature of the study limits etiologic interpretations.
Agricultural work on lowland sugarcane and cotton plantations was associated with decreased kidney function in men and women, possibly related to strenuous work in hot environments with repeated volume depletion.
ANOTHER INTERPRETATION OF THIS STUDY COULD BE:
Dehydration in Agricultural workers working in extreme heat. Whilst the naive cover of the April issue of AJKD falls for it and suggests and "EPIDEMIC"of kidney disease in Central America...the critical reader would notice:
1. Cross sectional analysis with a SINGLE serum creatinine measurement does NOT identify an "EPIDEMIC" of kidney disease!!!!
2. CKD takes more than a single measurement of serum creatinine.
3. Raised serum creatinine in heat exposed manual workers is more likely to reflect dehydration under extremely strenuous conditions.
4. The control group working in the same agricultural fields, sugarcane and cotton plantation, but in the cooler altitude areas of El salvador dont seem to suffer as much...Heat and dehydration being less prevalent in cooler higher altitude!
5. Women in hot coastal areas dont seem to share the men heat induced raised creatinine risk because they have a smaller muscle mass and their serum creatinine is lower; MDRD calcuklated GFR does not fully correct for difference in body mass. I also suspect that women are assigned less strenuous agricultural role with less exposure to heat.
Once more nephrologists have forgotten:
1. That serum creatinine can be raised for many reasons including:
High meat diet, high muscle mass and dehydration; all potential confounders in hard working male agricultural workers.
2. That raised serum creatinine in a cross sectional study doesnt make for CKD!
3. That raised serum creatinine measured once does not make for an EPIDEMIC...!!!
WHEN WILL NEPHROLOGISTS LEARN???
More than 15 years ago Wieslander and co-workers working in Lund, Sweden, identified a number of components of peritoneal dialysis solutions that are potentially damaging both in mesothelial cells in culture as well as in vivo. Among these are the glucose degradation products (GDP) that occur when glucose containing solutions are sterilised at high temperature. In order to reduce the formation of these agents a new generation of peritoneal dialysis solutions based on 2 separate compartments were developed where the glucose component was sterilised at a very low pH (2-3) in order to reduce GDP formation and then combined with a buffer to neutralise the pH just prior to infusion into the patient. There have been several clinical studies that have explored the clinical benefit of these new solutions but the benefits have not been clearly demonstrated. Against this background the eagerly awaited BalANZ study has just been published in JASN and is important since it is the largest randomised controlled trial of biocompatible peritoneal dialysate vs standard dialysate to date. The investigators are to be congratulated for persisting despite recruitment difficulties, and successfully recruiting 185 incident peritoneal dialysis patients to this 2 year study. Patients were randomized 1:1 to receive either a neutral pH, lactate buffered, low GDP Balance solution (Fresenius Medical Care, Bad Homburg, Germany) or a conventional, standard, lactate-buffered PD solution (stay.safe).
The primary outcome measure was the difference in the slope of the decline in residual renal function and this was not met. However there was a significant difference between the groups both in time to anuria (p=0.009) and time to first peritonitis episode (p=0.01) in favour of the more biocompatible solution. Indeed the peritonitis rate in the biocompatible group was 0.30 vs 0.49 (p=0.01) episodes per year. In addition there was a significant reduction in over all infection in the biocompatible group (4 non PD infections out of 91 patients vs 20 out of 91 in the control group). Thus the biocompatible group demonstrated meaningful benefits in terms of infection and time to anuria compared with the control solution.
As usual with studies of this kind there are several caveats – for example few patients were on automated peritoneal dialysis and the use of icodextrin was relatively low. There was also a difference in ultrafiltration between the groups with lower 24 hour ultrafiltration in the Balance group at 3 and 6 months, although there was no significant difference in dialysate glucose concentrations used. Unfortunately, this study did not report information on membrane function. Furthermore it is not clear that the results would be apply to other types of more biocompatible solutions since the concentrations of glucose degradation products vary between the types – for example Physioneal (Baxter) is reported to contain higher concentrations of 3-deoxyglucosone than the Balance solution. Clearly this study has to be considered in light of those that have gone before where the value for biocompatible solutions has not been clearly demonstrated. However it gives an important signal of a significant benefit for the more biocompatible solution for two important outcome measures in patients on peritoneal dialysis – time to anuria and peritonitis rates. Progress in medicine is incremental, and although this study has not answered all the outstanding questions on the impact of solution design on patient outcomes in PD, it has provided important information relevant to patients and their clinical teams.
In the UK all citizens are entitled to free care at time of need as part of the country's National Health Service (NHS). Introduced in 1945 after the war by a Labour government the NHS ensures that all people receive free healthcare irrespective of their financial status and it has been incredibly popular amongst patients and clinical staff. A cornerstone of the NHS has been the investment in General Practioners (GPs) in primary care. GPs are family doctors responsible for the overall health of their patients and have been in recent years incentivised to take on management of non-communicable chronic diseases such as CKD, Diabetes and hypertension.
Last week I came across an interesting, if somewhat depressing analysis of healthcare resources in my own city of Sheffield from Dr Parvez Hossain and colleagues. Whilst the number of GPs per head of the population was the same across the city when social deprivation was factored in there were some startling differences - those with non-communicable diseases from socially deprived areas had far fewer GPs. Or to put it another way the number of GPs per head of the population was the same for the most affluent and the most deprived -BUT the poorer you were the more likely you were to have an NCD and so you effectively had access to less healthcare. Reading the paper reminded me of the graph I saw at medical school on the impact of vaccination and antibiotics on the decline of infectious diseases such as TB, cholera and typhoid - the effect of all these interventions was minimal when set against improvements in housing and sanitation. Similarly the battle against NCDs such as diabetes and CKD will require societal and governmental action to have the biggest impact.
The paper highlights what has long been recognised as the inverse care law of healthcare - ie those that that need healthcare the most often have the least access to it - even in systems such as the UK which have a relatively sophisticated and equitable form of healthcare. As individual clinicians we need this kind of data to understand the population we work in so we can try to impact on healthcare at a societal level.
A decade has now passed since the epoch-making introduction of the concept of a generic “chronic kidney disease”(CKD) based on estimates of glomerular filtration rate (eGFR) and the presence of “kidney damage” persisting for 3 months or more (NKF-KDOQI-2002). An immense amount of epidemiological data, accumulated in millions of subjects, has supported the notion that CKD so defined is described as “common, harmful and treatable.” Much smaller amounts of information, from randomized controlled trials and well-designed observational studies have suggested that treatment, directed at lowering blood pressure or reducing proteinuria, can have a salutary effect on survival and complications, at least in certain conditions (most notably in advanced diabetic nephropathy and in nephrotic syndrome due to primary and other secondary glomerular diseases).
These revelations have generated much enthusiasm for widespread attempts to identify CKD early in its course in the general population, using the vehicle of screening for albuminuria and/or reduced eGFR. While little doubt exists that such programs would enhance the visibility of CKD in society as a whole, questions still linger as to whether such early identification among subjects, not currently under medical care for specific diseases causing progressive CKD, would yield benefits to society in a cost-effective manner.
To my knowledge, no prospective trial of screening vs no screening for generic CKD (i.e. not cause specific), with patient-centered outcomes of prolongation of life expectancy or avoidance of serious (and possibly fatal) complications (such as acute kidney injury or ischemic heart disease), has yet shown such benefits.
Translating statistically valid associations derived from large cross- sectional epidemiological (observational) studies to real-life clinical situations can be hazardous, as many unrecognized biases and confounding variables can creep into the data, however diligent the investigators are in avoiding these shortcomings.
Thus, it seems to me, that the time is ripe to ask some hard questions and to advocate efforts to secure answers to them--- rather than to assume that society needs mass screening for CKD and needs it now.
The Questions are:
1) Are the current estimates of prevalence of CKD (at each Stage and according to age and gender) in the general ambulatory population( i.e. asymptomatic candidates for screening) correct?- here I would choose to define CKD as a generic entity having some meaningful impact on survival or meaningful patient-centered morbidity
2) Is the incidence of newly diagnosed CKD (at each Stage and according to age and gender) increasing in the general population and at what rate? Here, data from developing and developed nations would be desirable.
3) Are the current criteria used to diagnose CKD appropriate and equally applicable to subjects of all ages, genders, ancestral groups and geographic locations? What are the most appropriate thresholds of eGFR and albuminuria for defining CKD as a target for specific interventions to reduce progression or to avoid complications?
4) Will periodic screening of subjects in the general population, without known risk factors such as diabetes or hypertension, using eGFR and/or albuminuria lead to improved outcomes compared to no screening and accomplish this in a cost-effective manner.
5) Will screening of subjects in the general population for high blood pressure or diabetes yield superior long- term outcomes compared to screening for generic CKD using absolute threshold for eGFR and/or albuminuria as CKD defining criteria?.
I submit that until these Questions are answered widespread screening of the general population should not be advised. The risks of an uncertain number of false positives, leading to unnecessary investigations and promoting unwanted anxiety among screenees is too great. Un-validated re-assurance for the false negative screenees is another potential risk. An eGFR of >60ml/min without proteinuria, currently regarded as indicating the absence of CKD in many epidemiological studies, does not exclude renal disease, especially in the young (e.g. Autosomal- dominant Polycystic Kidney Disease).
Simple tools (such as the Framingham Risk Score) are already widely available to identify and quantify, in absolute terms, the time-related risk of cardio-vascular disease. Adding eGFR or albuminuria to these tools contributes only marginally to improving their accuracy in classifying risk in the general population but these same simple tools may underestimate risk in patients treated by dialysis.
CKD, as currently defined, is largely a ”condition” of older and elderly adults, predominantly identified in these groups by a slight reduction in eGFR (using creatinine-based methods) and no proteinuria which might be normal for the subjects age and gender. One could also challenge the appropriateness of including “isolated microalbuminuria” (i.e., normal eGFR and urinary:albumin to creatinine ratio of 30-300mg/gm) as defining a “kidney disease” especially as these values can fluctuate widely and are influenced greatly by air pollution, diet, exercise, inter-current illness, obesity, high blood pressure, underlying atherosclerosis, remote infection and others. No one has yet shown that interventions directed to correcting “isolated microalbuminuria” per se have a beneficial effect on patient-centered outcomes (such as ESRD or cardiovascular disease), indeed some studies have suggested the potential for harm. Amelioration of “Isolated microalbuminuria” is not yet an acceptable surrogate end-point for studies evaluating therapeutic interventions.
Therefore, I urge caution in jumping to conclusions that early identification of many forms of generic CKD, using current diagnostic criteria, will have a net beneficial impact on the overall health of society, at a reasonable cost. We need some clear answers to some hard Questions first. Assuming that universal screening for CKD is without material risk for harm may not be correct. Advocates of such screening do so at their own risk.
Richard J. Glassock, MD
Geffen School of Medicine at UCLA
March 17, 2012
An interesting pilot study is published in this months cJASN adds more data to the never ending debate about the benefits of calcium binders versus non calcium based binders. A multicentre RCT based in Napoli, Italy assigned 212 CKD3/4 patients to sevelamer or calcium carbonate. The primary endpoint was all cause mortality and 22/105 patients died in the calcium carbonate arm compared to 12/107 in the sevelamer arm (p<0.05) over 3 years follow up. The time to dialysis inception was longer in the sevelamer arm though the criteria for starting dialysis were not standardised. One of the criticisms of the DCOR study ( a huge RCT which failed to show any difference in outcomes between sevelamer and caclcium binders in a prevalent dialysis population) was that by the time dialysis starts all the vascular calcification has taken place - therefore the authors are to be commended for doing an RCT in the predialysis population. Furthermore the de novo onset of coronary artery calcification was 81.8% in the calcium group versus 12.8% in the sevelamer group.
However there are a numbers of issues to bear in mind:
i) the study wasnt blinded - not clear why not
ii) there was not target phosphate to achieve - clinicians just had to maintain phosphate concentration between 2.7-4.6mg/dl
iii) the problem with this approach is that the final and time-average phosphate concentration was significantly lower in the sevelamer group than the calcium group! Thus its impossible to know whether the improvement in mortality is due to better phosphate control or use of a non-phosphate binder..... in fact in adjusted models for baseline and time-varying covariates the protective effect of sevelamer was lost!
iv) to my mind the most interesting part of the study is the that its the first RCT to suggest that lowering phosphate in the predialysis population may improve outcomes.
v) this study reinforces the need for an RCT in the predialysis population to address 2 specific issues - what the optimal phosphate level is (if any) and whether using a calcium vs non-calcium binder makes a difference. To be fair to the authors they acknowledge that this is a pilot study and recognise the need for a large RCT
vi) Whilst in my opinion the cost of sevelamer doesn't justify its widespread use in the predialysis population once the drug becomes generic and prices fall it would be reasonable to use sevelamer as an alternative to calcium based binders.