Clinical Evaluation and Management of Chronic Kidney Disease in the Elderly

Rong-zheng Yue; Ping Fu

doi:10.4103/2225-1243.168527

REVIEW ARTICLE

Year : 2015 | Volume : 2 | Issue : 4 | Page : 117-122

Clinical Evaluation and Management of Chronic Kidney Disease in the Elderly

Rong-zheng Yue, Ping Fu
Department of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China

Date of Web Publication

28-Oct-2015

Correspondence Address:
Ping Fu
Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/2225-1243.168527

Abstract

A suitable evaluation and management structure is important for slowing and delaying the progression of chronic kidney disease (CKD) and improving the quality of life in the elderly patients. Due to the special features of the elderly CKD patients, there also exist some problems to be solved or researched currently. According to the latest guideline for clinical practice, we discuss some aspects in diagnosis and prognosis of the elderly CKD patients as well as the management of common complications, so as to reduce over-diagnosis, and better predict the risks of progression to end stage renal failure and take necessary measures for clinical intervention as soon as possible.

Keywords: Aged patient, chronic kidney disease, diabetic kidney disease

How to cite this article:
Yue Rz, Fu P. Clinical Evaluation and Management of Chronic Kidney Disease in the Elderly. J Integr Nephrol Androl 2015;2:117-22

How to cite this URL:
Yue Rz, Fu P. Clinical Evaluation and Management of Chronic Kidney Disease in the Elderly. J Integr Nephrol Androl [serial online] 2015 [cited 2023 Jun 5];2:117-22. Available from: http://www.journal-ina.com/text.asp?2015/2/4/117/168527

Introduction

Chronic kidney disease (CKD) has become a serious public health problem in our country. ^[1] The increasing age is a generally accepted risk of the occurrence and progress of CKD. ^[2] At present, although there are no statistical data about the morbidity of elderly CKD, some researches in the regional areas show elderly CKD patients take higher morbidity than young patients. ^{[3],[4],[5],[6]} Hence, patients entering end stage renal disease (ESRD) are increasing gradually. Due to the special relation between renal function and aging, elderly patients will suffer from double kidney injury risk through renal structure and function changes and drug and operation interventional therapies. China is about to enter an aging era. There is no doubt that doctors will face more and more elderly CKD patients in clinical practice. Combined with the susceptible renal pathological basis of elderly patients, this paper will elaborate CKD diagnosis of elderly patients, prognosis evaluation and management of common complications from the latest guidelines of clinical practice.

Elderly Patients' Pathological Basis to Susceptible Kidney Disease

With the increase of age, elderly patients' renal structure will change, mainly including renal artery atherosclerosis, thickened intima and tunica elastic, lumen stenosis, cortical glomerular ischemia, kidney sclerosis, renal tubular atrophy, and renal tubular atrophy. Based on glomerular sclerosis, the incidence is <5% of people more than 40-year-old, but for people more than 80-year-old, it will reach to 30% and accompanied by micro albumin urine. ^[7] The incidence of renal tubular interstitial fibrosis in the elderly is also higher than the young. Function changes mainly include increased renal vascular resistance, gradual decreased renal blood flow, glomerular filtration rate (GFR) and ultrafiltrate coefficient, increased glomerular capillary pressure, increased sensitivity to vaso-active substance, decreased automatic adjustment ability, affected proximal and distal renal tubular function, urine concentration and dilution dysfunction, and decreased renal function to drug excretion.

The elderly not only suffer from the changes of renal structure and function, but also have some basic diseases, such as mellitus, hypertension, congestive heart-failure, and urinary obstruction. Moreover, they have more chances accepting drug and surgical treatments (such as heart and vascular surgeries). This will increase kidney injury chance. Under the same stress factors, the elderly have more severe reactions than the young to ischemia - hypoxia, inflammation, and renal toxicity drugs.

With kidney aging decreased renal reserve function and the decline of self-adjustment ability, the regeneration and repair ability of aged kidney will decrease obviously. In elderly acute kidney injury (AKI), only 30% of the renal function can be repaired completely. The accumulated acute injury will evolve into CKD. ^[8]

Not only does aging accelerate the progress of kidney disease, but also geromorphism often takes on in the process of CKD. They interact with each other and come into a vicious spiral. CKD is the generally accepted geromorphism. Young 5 ^th stage CKD dialysis patients have similar vascular complication incidence with the elderly, which will lead to premature death. ^[9] Besides the discovery in epidemiology, the obviously increased cell senescence makers can also be found in the renal tissue pathology of IgA kidney disease and diabetic nephropathy. And it has no relation with age. CKD-induced cell senescence and progeria mainly derive from gradual accumulated toxicant and function damage, which will increase disease progression and the risk of death. The biological mechanism causes cell senescence and progeria includes DNA, mitochondrial damage, telomere loss, increased reactive oxygen species, sustained inflammatory response, and stem cell depletion. ^[10]

Many factors in the progress of renal senescence seem unable to change or interfere, like anatomy, molecular and functional changes. At the same time, the genetic background plays an important role in aging-caused kidney injury. However, life style and environmental factors also have a considerable function. Currently, it has been confirmed that food limit renal senescence relieved measure is good to ease kidney disease. ^[11],[12] Sirt excitomotor can provide new idea and method to protect elderly renal function through regulating renal senescence signal channel. ^[13]

View Chronic Kidney Disease Diagnosis, Stage, and Progress Assessment through Kidney Disease: Improving Global Outcomes Guideline

0How to assess elderly renal function accurately

In 2002, kidney disease outcomes quality initiative (K/DOQI) team made a CKD assessment, stage and level clinical practice guideline (K/DOQI guideline) as the conceptual frame to access and manage CKD. According to K/DOQI guideline, the diagnosis of CKD mainly relies on serum creatinine (Scr)-based GFR evaluation formula to assess the accuracy estimated GFR (eGFR). However, whether these formulas suit the elderly, many clinical doctors and scholars put forward their queries.

In 2012, based on K/DOQI guidelines, kidney disease: Improving global outcomes (KDIGO) published CKD assessment and clinical practice guideline (hereinafter referred to as KDIGO guideline). ^[14] It still defined CKD as more than 3 months abnormal renal structure or function but gave a more detailed definition of kidney injury. If the time of kidney injury was <3 months, further follow-up should be conducted. Based on GFR assessment, KDIGO guideline still emphasized the important value of Scr, but it also pointed out the significance of C (CysC): First, GFR estimation formula could be used to finish preliminary assessment, namely, eGFRcreat (1A). If this method couldn't get an accurate result, other indicators (like CysC or clearance determination [2B]) were useful to do the verification. The eGFRcreat of an adult was 45-59 mL/(min 1.73 m ² ). However, if the patient lacked kidney injury sign, CysC should be used. According to CysC (eGFRcys) and Cys C (eGFRcreat cys) formulas, GFR could be calculated. If eGFRcys and eGFRcreat cys were all less than 60 mL/(min 1.73m ² ), CKD (2C) could be confirmed.

Stage Standard of Chronic Kidney Disease

According to the previous standard, no matter what age the patients are, GFR <60 mL/(min·1.73 m ² ) is the critical value between 2 and 3 stage. This will miss parts of the CKD patients and result in many over diagnosis cases, especially for elderly female patients. Therefore, KDIGO guideline adds two new indexes based on K/DOQI guideline: Cause and albuminuria, namely, cause - G. F. R. - albuminuria (AGA) three-dimensional stage method (1B). ^[15] Besides emphasizing the significance of cause and albuminuria, CGA method also changes G3 stage in K/DOQI Guideline into G3a stage and G3b stage. Through hierarchical analysis, it can be found G3 stage patients have obvious individual renal function deterioration tendency and all-cause death risk in the low eGFR group. Moreover, in all-cause death cases, cardiovascular events take up 44%. Whereas, the elderly take up high proportion in cardiovascular diseases and decreased renal function is the independent risk of cardiovascular events.

Assessment of Chronic Kidney Disease Progress

KDIGO Guideline indicates CKD progress can refer to the following two points:

GFR stage deterioration: GFR stage changes, eGFR decline d25% relative to the baseline value.
Quick CKD progress: Each year, eGFR fall rate > 5mL/(min 1.73 m ² ) continuously.

For the accuracy of CKD progress assessment and positive correlation between Scr test frequency and follow-up time, KDIGO guideline suggests patients assessing GFR and albuminuria at least 1-time every year. Patients have high progress of risk, especially elderly CKD patients, more active GFR and albuminuria assessments are needed when the test result will influence treatment decision. In addition, a comprehensive assessment should be conducted according to the cause, age, gender, race, hypertension, hyperglycemia, hyperlipidemia, smoking time, obesity, cardiovascular disease, persistent renal toxicity exposure, etc.

The above CKD stage and progress assessment improvements aim to decrease over diagnosis of elderly CKD patients to some extent and better predict ESRD progress of every sub-groups (especially elderly CKD patients), or the risk of combined diseases, which will provide necessary clinical intervention to high risk group.

Prevention and Treatment of Elderly Chronic Kidney Disease Progress and Management of the Common Complications

The prevention and treatment of CKD progress need combine its cause, complication, and other risk factors. K/DOQI Guideline points out:

The confirmed effective measures include: Strict blood pressure and blood glucose control use angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEI or ARB);
Unclear measures: Limit protein intake, lipid lowering therapy, regulate anemia;
Prevent and correct GFR acute decline, such as off-capacity, urinary obstruction, various infections, phlebography, some antibiotics (such as aminoglycoside and amphotericin B), ACEI or ARB, ciclosporin, tacrolimus, etc.

In addition, the guideline also refers to the importance of life style to CKD progress. K/DOQI guideline gives refinement, emphasis and revision to some of the problems, and the concrete prevention, treatment, and management methods of blood pressure, blood glucose, and acute renal injury are as follows:

Elderly chronic kidney disease combined with hypertension

At present, the target control value of hypertension in elderly CKD patients is still a big controversy. In 2012, although K/DOQI added elderly CKD nondialysis blood pressure management suggestions, the clear blood pressure target value and reducing plan hadn't been put forward. The guideline only suggested referring to adult CKD blood pressure reduce target goal and gradually increasing treatment intensity by age, complications, and received therapies and closely concerning side effects of blood pressure reducing therapy. In addition, the guideline held CKD incidence and blood pressure took on J type curve on patients more than 60-year-old no matter he or she conducted blood pressure reducing therapy or not. ^[16] Hence, pay attention to over anti-hypertension therapy.

In 2014, American Joint National Committee 8 guideline recommended patients more than or equal to 60-year-old to decrease blood pressure to systolic blood pressure (SBP) <150/90 mmHg (1 mmHg = 0.133 kPa). For patients SBP ≥150 mmHg or diastolic blood pressure ≥90 mmHg, drug treatment needed to start to reduce blood pressure (SBP <140/90 mmHg [target value]). Among patients ≤18-year-old, the initial blood pressure reduces therapy should include ACEI or ARB, to improve renal prognosis. This recommendation suits all the CKD patients accompanied by hypertension, regardless of races and combined mellitus (B). ^[17] The evidence of this guideline comes from randomized control studies which keep a high level. All the evidence levels and recommendations are assessed in the light of their influence degree to people's health.

In addition, the author thinks even if the guideline provides the time, drugs, and treatment target of initial hypertension therapy, it cannot become the succedaneum of a clinical decision. In clinical practice, doctors need to take the individual difference and physiological and pathological condition into consideration to make individual blood pressure reduce plan and reasonably assess blood pressure reduce goal and treatment risk. In view of the specificity of pathogenesis, clinical manifestation, treatment, and prognosis in elderly CKD patients combined with hypertension, α and β receptor combined block benefits cannot be ignored in drug combination plan. ^[18] In addition, some guides, such as changing life style, quitting smoking, losing weight, increasing exercise, and reducing excessive sodium intake, can help the elderly to reduce antihypertensive drug usage. Through intensive and comprehensive managements, elderly CKD patients' hypertension control will be greatly improved.

Elderly diabetic kidney disease

Due to complex pathogenesis, diabetic kidney disease (DKD) is always accompanied by cardio cerebral vascular disease, metabolic disturbance, hemodynamic instability, systemic inflammatory reaction and oxidative stress. So it is very hard to manage and has a poor prognosis. According to our research, among the first visit DKD patients, 77.2% patients are already in DKD clinical proteinuria stage and renal inadequacy stage and 24.8% of them combined with cardiovascular complication. ^[18] From this data, we find DKD patients often have late first visit, and most of them just pay more attention to blood glucose itself but have no clear consciousness and concept about the time of kidney injury consciousness and how to check kidney injury. In order to find and diagnose DKD early, American Diabetes Association proposes to do screening every year to new-diagnosed 2 type diabetics. For 1 type diabetics, after 5 years, conduct screening every year. Microalbuminuria is the main index ^[19] for it is not restricted by random urine or total volume urine.

The clinical progress of elderly DKD doesn't follow normal development progress. It is common that diabetics are often combined with various non-DKD clinical symptoms. Some scholars conduct renal needle biopsy to 216 cases 2 type diabetic patients with renal injury. Only 6.5% patients are DKD patients. The common non-DKD combined types are IgA kidney disease and membranous nephropathy. ^[20] Although renal biopsy remains controversial to diabetic patients with a renal injury, ^[21] the author still holds that renal biopsy is helpful to remove nondiabetic nephropathy to untypical clinical patients. Meanwhile, it is also beneficial to make suitable treatment specification according to every clinical and pathological type.

The course of elderly DKD always continues for years to a decade. Moreover, the case rate of related macroangiopathy and microvascular chronic complications is higher than the general population. Patients with the mild state will suffer from decreased vision, limb pain, numbness, abnormal sensation, and intermittent limping. Severe patients often have symptoms such as lower extremity ischemic gangrene lesion and have the risk of amputation. Besides, the uncontrollable complications, such as hypertension will aggravate intractable edema and different degrees of cardiovascular involvement, will influence life quality seriously and threat patients' life at any time. There are some factors will influence the occurrence and development of diabetic vascular disease, such as glucose metabolism disorder, lipid metabolism disorder, hemodynamic and hemorheological abnormality, genetic susceptibility background, inflammation, oxidative stress, etc. ^[22]

Once elderly DKD enter clinical proteinuria period, it will develop into final-stage renal failure irreversibly. Moreover, the high case rate and incidence of cardiovascular events and other events will bring poor prognosis. The main therapeutic tools are blood glucose control, blood pressure control, lipid metabolism regulation, sufficient and reason use of ACEI and/or ARB, VEC and sertoli cell protection, hemodynamics and hemorheology improvement, antifibrosis, low grade anti-inflammatory therapy, etc. However, they haven't final conclusion and guideline currently. For hypoglycemic strategy, many guidelines propose individual treatment and the continuous life style intervention. ^[23] Moreover, other methods include blood pressure control and risk control of cardiovascular disease. When it comes to clinical indication, ACEI or ARB, statins, and antiplatelet therapy are proposed.

Therefore, besides early screening and accurate diagnosis, the author stresses active and early prevention of vascular lesion. Delaying kidney development and decreasing cardio cerebral vascular events are the long-term goal of elderly DKD treatment. For different patients, to get the appropriate treatment specification, multi-discipline collaboration, and detailed integrated management are needed in clinical exploration and conclusion.

Elderly chronic kidney disease accompanied by acute kidney injury

When eGFR gradually decreases, the incidence of elderly AKI will increase accordingly. Especially for patients accompanied by albuminuria, diabetes or hypertension, even if eGFR takes on slight reduction, the incidence of AKI will increase obviously. The so called AKI on CKD refers to a group of clinical syndromes on quick GFR decrease which take place in the short-term on the basis of original CKD. Elderly CKD patients are always accompanied by hypertension, diabetes and cardiovascular disease, which makes them exposed to some high AKI risk factors, such as renal toxicity drugs, surgical operation, vascular interventional therapy, etc. So, AKI on CKD is very common in clinical practice. Generally speaking, if the patient has suffered from CKD before, 50% decrease of eGFR can be diagnosed as AKI on CKD. If the CKD patient keeps renal failure, in the short term, 15-30% obvious decrease of eGFR can be diagnosed as AKI on CKD. The main causes and risks are:

Various accompanied infections, especially severe infection, such as hematosepsis, etc.;
Insufficient renal perfusion, such as dehydration, hypopiesia, or excessive diuresis;
The use of renal toxicity drugs
Large operation. ^[24]

The clinical manifestations of elderly AKI on CKD are not obvious and often ignored. In many cases, it is found by clinical doctors' careful observation and timely check.

KDIGO Guideline recommends patients who have high AKI risk caused by some transient disease or receive renal toxicity drug therapy stop using potential renal toxicity drugs and kidney excreted drugs. These drugs include but not limited to renin-angiotensin-aldosterone system blocker (ACEI and/or ARB, aldosterone inhibitor, direct renin inhibitor), diuretic, nonsteroidal anti-inflammatory drugs, melbine, Li, and digoxin. In addition, strict GFR monitoring, electrolyte and drug concentration and early active diagnosis are important guarantees to improve renal function, reduce mortality, and extend patients' life.

Integrated 'Three Dimensions' Management Mode for Chronic Kidney Disease Patients

CKD is a kind of life management chronic disease and needs multi-discipline participation and cooperation, including paramedic, doctors, dietitian, etc. Since August 2011, our department first set up CKD nondialysis patient's follow-up management center and follow-up team, we had professional personnel to manage and guide patients taking regular follow-up and managing the corresponding procedures. The contents of follow-up include doctor's diagnosis and treatment, nurse's follow-up and dietitian's guide. The targeted follow-up is conducted according to each patient's specific condition. The clear task and close cooperation between every discipline guarantee the specialty, comprehensiveness, and effectiveness of this work. In addition, our follow-up center has built personal file and follow-up database for the patients. On the one hand, it can help doctor, nurse, and dietitian recognize and check patients' disease progression and follow-up condition timely. On the other hand, it can prevent follow-up lost effectively. Moreover, through filling up follow-up record, patents' involvement initiative will be mobilized, and doctor's dynamic monitoring of disease progression and compliance can be realized. The ultimate goal is to delay kidney disease's progress, improve patients' life quality and prognosis by early detection, treatment, and intervention. At the end of July 2014, our center totally had 1060 file-built CKD cases. Among them, 192 patients were more than 65-year-old, taking up 18.1% of the total population. Moreover the return rate was above 95%.

Besides, for the quick development of elderly CKD and severe cardiovascular complications, the tendency to ESRD cannot be inhibited even by various treatment methods. Besides the integrated management of CKD nondialysis, our center also conducts comprehensive assessment to patients' renal replacement therapy. According to reliable prediction, progressive elderly CKD patients' renal failure risk is 10-20% or higher within 1-year. Combing with patients' state of illness, economic situation, willingness, and cultural degree, the timely help about renal replacement therapy time and mode, especially establishment and maintenance of long-term vascular access, can help patients transit to renal replacement therapy stage steadily. Normative effective follow-up and multi-dimension education can provide timely and effective guide to patients. It is also the effective way to improve the ability of self-management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Aparicio M, Bellizzi V, Chauveau P, Cupisti A, Ecder T, Fouque D, et al. Protein-restricted diets plus keto/amino acids - A valid therapeutic approach for chronic kidney disease patients. J Ren Nutr 2012;22(2 Suppl):S1-21.
2.	Aronow WS, Fleg JL, Pepine CJ, Artinian NT, Bakris G, Brown AS, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. J Am Coll Cardiol 2011;57:2037-114.
3.	Task Force for the Management of Arterial Hypertension of the European Society of Hypertension; Task Force for the management of arterial hypertension of the European Society of Cardiology 2013 ESH/ESC Guidelines for the Management of Arterial Hypertension. Blood Press 2013;22:193-278.
4.	Caudrillier A, Mentaverri R, Brazier M, Kamel S, Massy ZA. Calcium-sensing receptor as a potential modulator of vascular calcification in chronic kidney disease. J Nephrol 2010;23:17-22.
5.	Chong YB, Keng TC, Tan LP, Ng KP, Kong WY, Wong CM, et al. Clinical predictors of non-diabetic renal disease and role of renal biopsy in diabetic patients with renal involvement: A single centre review. Ren Fail 2012;34:323-8.
6.	Coca SG, Cho KC, Hsu CY. Acute kidney injury in the elderly: Predisposition to chronic kidney disease and vice versa. Nephron Clin Pract 2011;119(Suppl 1):c19-24.
7.	De Santo NG, Perna A, Cirillo M. Low protein diets are mainstay for management of chronic kidney disease. Front Biosci (Schol Ed) 2011;3:1432-42.
8.	Dorresteijn JA, van der Graaf Y, Spiering W, Grobbee DE, Bots ML, Visseren FL; Secondary Manifestations of Arterial Disease Study Group. Relation between blood pressure and vascular events and mortality in patients with manifest vascular disease: J-curve revisited. Hypertension 2012;59:14-21.
9.	Gansevoort RT, de Jong PE. Challenges for the present CKD classification system. Curr Opin Nephrol Hypertens 2010;19:308-14.
10.	Gesing A, Masternak MM, Lewinski A, Karbownik-Lewinska M, Kopchick JJ, Bartke A. Decreased levels of proapoptotic factors and increased key regulators of mitochondrial biogenesis constitute new potential beneficial features of long-lived growth hormone receptor gene-disrupted mice. J Gerontol A Biol Sci Med Sci 2013;68:639-51.
11.	Hallan SI, Dahl K, Oien CM, Grootendorst DC, Aasberg A, Holmen J, et al. Screening strategies for chronic kidney disease in the general population: Follow-up of cross sectional health survey. BMJ 2006;333:1047.
12.	Hsu CY, Ordoñez JD, Chertow GM, Fan D, McCulloch CE, Go AS. The risk of acute renal failure in patients with chronic kidney disease. Kidney Int 2008;74:101-7.
13.	Gesing A, Masternak MM, Lewinski A, Karbownik-Lewinska M, Kopchick JJ, Bartke A. Decreased levels of proapoptotic factors and increased key regulators of mitochondrial biogenesis constitute new potential beneficial features of long-lived growth hormone receptor gene-disrupted mice. J Gerontol A Biol Sci Med Sci 2013;68:639-51.
14.	Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1-150.
15.	Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1-150.
16.	Scheen AJ, Mathieu C. Management of hyperglycaemia in type 2 diabetes: A patient-centered approach. Rev Med Liege 2012;67:623-31.
17.	Speeckaert MM, Vanfraechem C, Speeckaert R, Delanghe JR. Peroxisome proliferator-activated receptor agonists in a battle against the aging kidney. Ageing Res Rev 2014;14:1-18.
18.	2013 ESH/ESC Guidelines for the Management of Arterial Hypertension. Blood Press 2013;22:193-278.
19.	Sun YM, Su Y, Li J, Wang LF. Recent advances in understanding the biochemical and molecular mechanism of diabetic nephropathy. Biochem Biophys Res Commun 2013;433:359-61.
20.	Yang W, Lu J, Weng J, Jia W, Ji L, Xiao J, et al. Prevalence of diabetes among men and women in China. N Engl J Med 2010;362:1090-101.
21.	Jing Y, Yan S, Yan Z. Elderly chronic kidney disease survey in Guiyang. Chin J Gerontol 2011;8:1408-10.
22.	Zhang L, Zhang P, Wang F, Zuo L, Zhou Y, Shi Y, et al. Prevalence and factors associated with CKD: A population study from Beijing. Am J Kidney Dis 2008;51:373-84.
23.	Zhuo L, Ren W, Li W, Zou G, Lu J. Evaluation of renal biopsies in type 2 diabetic patients with kidney disease: A clinicopathological study of 216 cases. Int Urol Nephrol 2013;45:173-9.
24.	Zhang L, Wang F, Wang L, Wang W, Liu B, Liu J, et al. Prevalence of chronic kidney disease in China: A cross-sectional survey. Lancet 2012;379:815-22.