Multidisciplinary Approach to Preventive Medicine

RMMJ Rambam Maimonides Medical Journal Rambam Health Care Campus 2015 July; 6(3): e0029. ISSN: 2076-9172
Published online 2015 July 30. doi: 10.5041/RMMJ.10214
Special Fifth Anniversary Issue

The Envy of Scholars: Applying the Lessons of the Framingham Heart Study to the Prevention of Chronic Kidney Disease

Walter G. Wasser, M.D,1,2* Amnon Gil, M.D,3 and Karl L. Skorecki, M.D., F.R.C.P.(C), F.A.S.N.2,4,5

1Division of Nephrology, Mayanei HaYeshua Medical Center, Bnei Brak, Israel
2Division of Nephrology, Rambam Health Care Campus, Haifa, Israel
3Division of Nephrology, Carmel Medical Center, Haifa, Israel
4Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
5Director of Medical and Research Development, Rambam Health Care Campus, Haifa, Israel.

*To whom correspondence should be addressed. E-mail:


During the past 50 years, a dramatic reduction in the mortality rate associated with cardiovascular disease has occurred in the US and other countries. Statistical modeling has revealed that approximately half of this reduction is the result of risk factor mitigation. The successful identification of such risk factors was pioneered and has continued with the Framingham Heart Study, which began in 1949 as a project of the US National Heart Institute (now part of the National Heart, Lung, and Blood Institute). Decreases in total cholesterol, blood pressure, smoking, and physical inactivity account for 24%, 20%, 12%, and 5% reductions in the mortality rate, respectively. Nephrology was designated as a recognized medical professional specialty a few years later. Hemodialysis was first performed in 1943. The US Medicare End-Stage Renal Disease (ESRD) Program was established in 1972. The number of patients in the program increased from 5,000 in the first year to more than 500,000 in recent years. Only recently have efforts for risk factor identification, early diagnosis, and prevention of chronic kidney disease (CKD) been undertaken. By applying the approach of the Framingham Heart Study to address CKD risk factors, we hope to mirror the success of cardiology; we aim to prevent progression to ESRD and to avoid the cardiovascular complications associated with CKD. In this paper, we present conceptual examples of risk factor modification for CKD, in the setting of this historical framework.

Keywords: ACE inhibitor, chronic kidney disease, FGF23, proteinuria, risk-factors


Rav Dimi from the Babylonian Talmudic Academy of Nehardea said: “Jealousy between scholars increases wisdom.”

Babylonian Talmud, Tractate Bava Batra 21a


Over the last half century, we have witnessed a global reduction in the coronary heart disease mortality rate by approximately 60% (Figure 1).1 Cardiovascular disease mortality rates in the US dramatically decreased from 805 deaths per 100,000 people in 1963 to 236 per 100,000 people in 2010.2 Before that time, the incidence of cardiovascular disease-related death was on the rise. Myocardial infarction and sudden death would occur without warning, striking down individuals in mid-life, during the peak of their productivity.3 In addition, the pathophysiology of these disorders was not understood.

Figure 1Figure 1
Global Age-standardized Coronary Heart Disease (CHD) Mortality Rates in Men and Women 45 to 74 Years of Age, Based on World Health Organization Statistics

It was in this context that the US National Heart Institute launched and co-ordinated the Framingham Heart Study in 1949. This study would become a cornerstone in cardiac epidemiology, heralding numerous follow-up studies in different constituencies and formats. The study, which began with 5,209 patients who were followed longitudinally, is still ongoing and has enrolled three generations of participants. The analysis gave rise to the concept of risk factors for coronary disease, including hypertension, high cholesterol, and smoking. This recognition led to vigorous risk-reduction campaigns.46

Models of the decrease in cardiac mortality from 1980 to 2000 found that risk factor reduction explained 44% of the reduction in cardiac death; treatment was responsible for an additional 47% reduction in mortality. Furthermore, reductions in total cholesterol, blood pressure, smoking, and physical inactivity accounted for 24%, 20%, 12%, and 5% reductions in the mortality rate, respectively.7

Cardiovascular risk prediction formulae, which are important for gauging individual cardiovascular risk, are also useful for understanding population-wide coronary disease risk.1,8 The Framingham risk estimation system, the most commonly used tool for this purpose, has been adjusted for use in various countries and was developed via cardiac epidemiological studies. Research is presently underway to incorporate sets of single-nucleotide polymorphisms (SNPs) obtained from genome-wide association studies (GWAS) to increase the accuracy of coronary heart disease risk determination.9

Paralleling these developments, clinicians who received scientific fellowship training in the laboratories of renal physiologists returned to their academic internal medicine departments to create divisions of nephrology.10 These departments supported active research on renal physiology while also providing clinical care to nephrology patients.11 The first kidney biopsies were performed in the 1950s. Although hemodialysis was first performed in 1943, it was typically performed outside of these departments because the procedure was viewed in many centers as academically unworthy.10 Kidney transplantation was first developed in 1963.12 The provision of dialysis therapy to people with kidney disease challenged the young specialty. Hemodialysis initially lacked specific funding, and committees such as the Admissions and Policies Committee of the Seattle Artificial Kidney Center at Swedish Hospital determined which patients would receive treatment.13 Such groups, consisting of seven citizens selected by The Kings County Medical Society, were formed to prevent doctors from needing to make these decisions regarding their own patients. Although the deliberations of the “God committee” were secret, a prominent article in Life Magazine detailing the thinking involved did emerge.13

The idea of federal funding for end-stage renal disease (ESRD) was debated among clinicians, and a vocal minority backed Boston nephrologist Dr Norman Levinsky who wrote in the influential New England Journal of Medicine in August 1964 that “both chronic dialysis and transplantation … are properly considered clinical experiments rather than established modes of treatment at this time.”14 Dramatically, in October, 1971, Shep Glazer, then Vice President of the National Association of Patients on Hemodialysis testified before the House Ways and Means Committee while being dialyzed. In 1972, congressional approval was attained to expand funding for the Medicare dialysis program; soon afterward, nearly every nephrology division embraced dialysis. The creation of the ESRD Program as part of the Medicare program for patients of any age who required dialysis tasked nephrologists with the substantial job of providing dialysis treatments, an endeavor that overwhelmed, hindered, and did not provide incentives for the performance of epidemiologic research for the identification and mitigation of risk factors in order to reduce the onset and progression of chronic kidney disease (CKD). Physiological research regarding the pathogenesis of chronic kidney disease led to new treatments for patients and a vital taxonomy of kidney diseases; however, it did not significantly influence the treatment of the majority of individuals with CKD. Over the next 60 years, the progressive advances in hemodialysis technologies did not affect the dialysis patient 5-year mortality that remained at ~50% (a mortality rate just slightly lower than that of lung cancer).15

Although the initial estimates of individuals who would require dialysis were low, the number of patients receiving dialysis treatment increased exponentially. From an initial 5,000 patients in 1972, the US ESRD program expanded more than 100-fold to 636,905 patients by 2012.16 Today, although 17,330 kidney transplants are performed annually, 81,981 patients remain on the active transplant waiting list, and numerous kidney transplantation candidates die while still on dialysis.16

Numerous pathophysiological studies, particularly those conducted by Drs Neal Bricker and Barry Brenner, have led directly to a paradigm shift in the treatment of CKD. Bricker proposed the “trade-off hypothesis,” in which he provided evidence that the production of hormonal factors in the setting of chronic renal failure was a homeostatic adaptation and not a consequence of a reduced glomerular filtration rate.17,18 As examples, he listed parathyroid hormone (PTH) and natriuretic factor. Bricker postulated that a circulating inhibitor of sodium transport alters the net movement of sodium from tubular fluid to the blood; recently this factor was purported to have been isolated.19

Brenner and colleagues showed that intraglomerular hypertension increases in residual nephrons following nephron loss. Systemic hypertension also increases intraglomerular pressure, which is modulated by the vascular tone of the pre- and post-glomerular arterioles, intraglomerular architecture, and hemodynamics. Elevated glomerular capillary pressure leads to an increased number of large non-selective pores on the glomerular capillary wall, which promotes proteinuria.2022 Growth-promoting factors are released in the remnant glomeruli, and these factors produce excessive extracellular matrix in the mesangial area, obliterating the capillary lumen and creating typical sclerotic lesions. Nephron loss is increased, and this effect augments these processes in other glomeruli.22 Glomerular hypertrophy in remnant nephrons, compensatory to nephron loss, also contributes to glomerular sclerosis. The latter effect was reduced in a rat model of nephron loss without hypertrophy, compared with five-sixths of nephrectomized rats with a higher glomerular area, despite similar elevations in intraglomerular pressure.23 Brenner and colleagues showed that the inhibition of the vasoconstricting effect of angiotensin II via angiotensin-converting enzyme (ACE) inhibitors, which is most pronounced at the level of the post-glomerular arterioles, reduces intraglomerular hydraulic pressure. The effect of these agents on kidney injury progression supports the association between high glomerular pressure and sclerosis. In addition, angiotensin II inhibition reduces the synthesis of reactive oxygen species, inflammatory cytokines, cell adhesion molecules, and profibrotic molecules such as TGFβ.24


As the number of patients receiving dialysis care escalated, the potential associated costs began to alarm health care planners. In the words of the Kidney Disease: Improving Global Outcomes (KDIGO) 2009 Conference Report, the “rising prevalence, poor outcomes, and high costs of chronic kidney disease has led to its recognition as a public health threat.”25 Fundamentally, this recognition represented a paradigm shift for nephrologists and transformed kidney failure from a life-threatening condition that affected a few people (although these few required dialysis and transplantation) to a common condition that is the target of prevention, early detection, and management by non-nephrologist physicians and public health agencies.26 As a result, a quiet but significant revolution took place, beginning with the description of the model currently in use for CKD (Figure 2). This model spearheaded a redefinition of the diagnosis and treatment of CKD that relied on functional measures and the classification of kidney dysfunction via the degrees of albuminuria and nephron function loss (measured by estimated glomerular filtration rate, eGFR). The overwhelming numbers of patients with CKD has led nephrologists to follow cardiologists in using a Framingham-like model to identify the risk factors for CKD.

Figure 2Figure 2
Composite Ranking for Relative Risks by Glomerular Filtration Rate (GFR) and Albuminuria


The association between ESRD and accelerated cardiovascular mortality has long been recognized.27 Mogensen first described microalbuminuria as a cardiovascular risk factor in people with diabetes.28 Bigazzi et al. showed the importance of microalbuminuria in predicting cardiovascular risk among people with hypertension.29 Recent meta-analyses have demonstrated the continuous associations among macroalbuminuria, microalbuminuria, coronary risk,30 and stroke.31 Other studies have shown that the use of renin–angiotensin–aldosterone system (RAAS) agents to decrease protein excretion can effectively reduce coronary risk.3236

In line with these findings, screening 60% of the patients at highest risk has prevented virtually all forms of cardiovascular disease.37,38 However, elderly patients present “reverse metabolic syndrome”39,40 in which lipid levels and blood pressure are reduced, thereby making screening for coronary disease challenging. Detection techniques such as ultrasound measurement of the carotid intima-media thickness and CT scanning of the coronary arteries to show calcifications might accurately reveal subclinical atherosclerosis; however, these techniques are costly and therefore often unavailable. Estimated GFR and urinary albumin excretion might provide a cost-effective method to identify precisely the patients with cardiovascular disease.

Small increases in serum creatinine are associated with cardiovascular events and mortality.41,42 Go and colleagues studied the health records of ~1.1 million adults in the Kaiser Permanente Renal Registry between 1996 and 2000 for >2 years and found an impressively graded association between estimated GFR and the risks for death, cardiovascular events, and hospitalization (Figure 3).43 Proteinuria was an independent risk factor for death. Chronic kidney disease, as determined via the combination of decreased renal function (estimated GFR) and markers of kidney damage (proteinuria), accurately predicted cardiac events and death more effectively than each individual risk factor alone.4447 Foley and associates recently showed that the use of a “near-normal” estimated GFR cut-off of 94 mL/min and an albumin-creatinine ratio (ACR) of 9 mg/g, rather than the standard CKD thresholds, is highly sensitive and specific for selecting participants at risk of dying over the ensuing 9 years.48 Similarly high thresholds for estimated GFR without albuminuria successfully predicted cardiac death in two additional studies.49,50

Figure 3Figure 3
Death from Any Cause According to the Estimated GFR among 1,120,295 Ambulatory Adults

Cardiovascular disease in the setting of CKD requires recognition and active treatment. Most patients with CKD succumb to cardiovascular disease rather than kidney disease. Recent meta-analyses51,52 and KDIGO guidelines53 recommend the use of statin therapy for patients with CKD but not those receiving dialysis.


The effort to reduce CKD began with therapy for proteinuria and hypertension, which are recognized risk factors for CKD.54,55 The rate of progressive renal deterioration has a linear relationship with blood pressure treated by anti-hypertensive agents.56 Large controlled trials have documented the protein reduction properties of effective anti-hypertensive therapy.5759 The success in implementing these therapies led to the identification of other CKD risk factors.

The relationship between reduced proteinuria and progressive renal disease was first demonstrated in the Modification of Diet in Renal Disease (MDRD) Study in 1995,55 which also showed that patients with high urinary protein excretion benefit more from ACE inhibitor-based therapies.55 The inhibition of the RAAS either via ACE inhibitors or angiotensin receptor blockers (ARBs) reduces proteinuria and progressive renal deterioration in excess of what would be expected based on the reduction of blood pressure alone with other non-RAAS agents.60 The ACE Inhibition in Progressive Renal Disease (AIPRD) study, a cumulative meta-analysis of 11 clinical trials including the Ramipril Efficacy in Nephropathy (REIN) study, found a strong correlation between proteinuria and the decline rate of glomerular filtration rate (GFR) in patients with CKD.61 Together, the MDRD and AIPRD studies revealed an impressive 40% reduction in the risk of doubling serum creatinine concentrations with ACE inhibitor treatment compared with other antihypertensive drugs in patients with CKD with protein levels >0.5 g per day.62 A similar effect was shown in patients with type 1 diabetes undergoing captopril treatment.63

The Reduction of End Points in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study found that baseline albuminuria was the strongest predictor of the primary composite end-point of doubling of serum creatinine, end-stage renal disease (ESRD), or death in patients with type 2 diabetes mellitus (T2DM) with a serum creatinine level of 1.5–3.0 mg/dL.34 Overt proteinuria or microalbuminuria predicted kidney deterioration in a population with a high prevalence of CKD,64 individuals with hypertension and diabetes, and the general population.29,65,66 Significantly lower persistent microalbuminuria (6% in 3 years) was observed in patients with hypertension and T2DM with normal albuminuria treated by trandolapril compared to those receiving placebo (10%) or verapamil (11.9%).67 The anti-proteinuric and renal protection provided by ACE inhibitors was also observed in patients with diabetes and normal blood pressure but without microalbuminuria. The increase of albuminuria, even within the normal range, and the decrease of creatinine clearance were significantly lower in patients receiving enalapril compared with those receiving a placebo.68

The theoretical added therapeutic benefit of ARBs emanates from the blockage of angiotensin II to the angiotensin type 1 (ATI) receptor interactions as well as through enhanced angiotensin II binding to the vasodilatory angiotensin type 2 (ATII) receptors.69 Albuminuria decreased by 28% among losartan-treated patients over the first 6 months of the RENAAL study compared with a 4% increase among the placebo group. The decrease in albuminuria in the losartan group was associated with improved kidney function, going beyond the drug’s blood pressure-lowering effect.34 Changes in albuminuria showed an approximately linear relationship with the degree of long-term kidney protection. In particular, every 50% reduction in albuminuria was associated with a corresponding ~36% reduction in the risks of doubling of serum creatinine level, stage 5 CKD, or death. A similar effect was observed regarding other ARBs32,70 such as irbisartan. Treatment with ARBs has also been successful in patients with incipient diabetic nephropathy.71,72 The anti-albuminuric and renal protective effects of ARBs are similar, although slightly weaker, than the corresponding effects of the ACE inhibitors in early diabetic nephropathy.73

Despite the enormous progress that has been made in the treatment of progressive kidney disease via RAAS inhibition, the residual kidney risk after treatment with an ACE inhibitor or an ARB remains high and is associated with residual albuminuria.74,75 For example, in the RENAAL trial, losartan reduced the 3-year risk of doubling serum creatinine levels from 47% to 44%.33 In light of these high residual risk rates, recent reviews have examined various new strategies to enhance the effects of RAAS blockade.69,76 The RAAS is an endocrine cascade system that can be inhibited at many levels, but it can be compensated for at other levels with a clinical response known as “escape.”69,76

Clinical trials have examined the use of the combination of an ACE inhibitor and an ARB to prevent target organ damage.77 The Renal Outcomes with Telmisartan, Ramipril, or Both in People at High Vascular Risk (ONTARGET) trial compared the ACE inhibitor ramipril with the ARB telmisartan, alone and in combination, among patients at high risk for vascular disease.78,79 Although the achieved mean blood pressure was lower in patients who received telmisartan or both agents than in those who received ramipril alone, no difference was observed with regard to the primary outcomes among any of the groups, and more adverse outcomes were noted in the combination group. Importantly, this trial did not evaluate ARB and ACE inhibitor therapy in patients with advanced proteinuric renal disease. The VA Nephron-D Diabetes in Nephropathy Study (VA NEPHRON-D), a trial using a combination therapy (i.e. ACE inhibitor and ARB therapy versus ARB monotherapy) in patients with proteinuric diabetic nephropathy, was stopped because of the increased adverse events of hyperkalemia and acute kidney injury (AKI).80 The Aliskiren Trial in Type II Diabetes Using Cardiorenal Endpoints (ALTITUDE) randomly assigned 8,561 patients to aliskiren (300 mg daily) or a placebo as an adjunct to ACE/ARB monotherapy as an angiotensin receptor blocker. The trial was stopped prematurely because of adverse events (hyperkalemia and hypotension).81 Therefore, ACE inhibitors should not be used concomitantly with ARBs and renin inhibitors because of the increased risks for hypotension, hyperkalemia, and renal dysfunction.82

Many studies have attempted to achieve additional benefit from ACE inhibitors and other renin–angiotensin–aldosterone-blocking agents by increasing their dosages. This reasoning is based on the original observation that the optimal anti-proteinuric dose is not necessarily equal to the optimal antihypertensive dose. Many of these results have shown additional proteinuria reduction,8387 whereas others have not.8890 However, similar to the initial studies regarding combination therapy with renin–angiotensin–aldosterone-blocking agents, many of these high-dosage studies are also short-term examinations using blood pressure and albuminuria as outcome variables. These studies have not had sufficient power, and lack the duration needed to detect the safety signals and side effects rates that might emerge from end-point trials.82 Therefore, before ultrahigh RAAS-blocking agent dosing can be recommended as a renoprotective therapy, further study of these drugs with kidney and cardiovascular event data is needed.82

Optimization strategies for RAAS blockade have been suggested. First, a combination of sodium restriction and diuretic therapy is required to reach optimal RAAS inhibition in proteinuric patients.9196 Second, hyperkalemia, which limits the use of RAAS agents, has recently received effective treatment with patiromer and sodium zirconium cyclosilicate among outpatients.97,98 These two novel drugs add to the pharmacopoeia that until recently was limited to sodium and calcium polystyrene sulfonate, which have adverse gastrointestinal effects.

Importantly, a few clinical caveats exist when treating proteinuria with RAAS inhibitors. First, greater initial decreases of renal function predict longer preservation of renal function.99 An initial loss of estimated GFR is not a concern unless it exceeds 30%, at which point diuretic-induced hypo-volemia and renal artery stenosis should be considered.100 In addition, the importance of monitoring urinary albumin decreases following RAAS blockade.101 If the urinary albumin–creatinine ratio is not lowered by ≥30% or to <300 mg/g despite a blood pressure lower than 130/80 combined with a low-sodium diet, then switching to another RAAS blocker or diltiazem should be considered.79,102 Greater reductions in proteinuria are seen with treatment using non-dihydropyridine calcium channel blockers (CCBs) than with dihydropyridine CCBs.102

RAAS Inhibitors for Cardiovascular Protection
The ACE inhibitors reduce the rates of death, myocardial infarction, stroke, and heart failure among patients with heart failure,103 left ventricular dysfunction,104 previous vascular disease,105 and/or high-risk diabetes.106 The ARBs are an alternative for patients who cannot tolerate ACE inhibitors Although ACE inhibitors and ARBs have an additive effect, the more effective indication is to combine ACE inhibitor therapy with an aldosterone antagonist.

The MDRD study and other clinical interventions demonstrated strong interactions among proteinuria, hypoalbuminemia, blood pressure, CKD progression, and an increase in the inflammatory state.55,107 Furthermore, microalbuminuria is an independent risk factor for cardiovascular disease. In patients with T2DM, an albuminuria level of 20.1–30 mg/d was associated with a relative risk for cardiovascular disease of 9.8, and the relative risk for microalbuminuria was 12.4 compared with patients with albuminuria levels below 10 mg/d.108 The beneficial effect of albuminuria reduction for cardiovascular outcomes is likely associated with improvements in endothelial function in addition to the indirect effect mediated through the mitigation of renal dysfunction.

The ONTARGET trial assessed cardiovascular morbidity in patients with cardiovascular disease or high-risk diabetes but without significant albuminuria. Similar beneficial effects were observed regarding ARBs as ACE inhibitors for cardioprotection. However, the combination of these agents with ACE inhibitors was not associated with an increase in cardiac benefit, whereas adverse events were more common.79

Hypertension is an uncontrolled and global public health challenge that is equally prevalent in developed and developing nations.109 In 2000, 25% of the world’s population had hypertension; however, approximately 29% (1.56 billion people) are expected to have hypertension by 2025. This increase has been ascribed to the massive “epidemiologic transition” of the developing world, with increasing proportions of elderly populations.110,111 Hypertension is the leading cause of cardiovascular morbidity and mortality and a major cause of CKD.

Perry et al. were one of the earliest groups to document carefully the association between increasing levels of systolic blood pressure, cardiovascular disease, and CKD risk.112 They described the direct association between increments in blood pressure elevation and the development of renal failure in 11,912 male veterans, 48% of whom were African-Americans, followed for 15 years at Veterans Administration Hypertension clinics during the mid-1970s. The risk ratios for a systolic blood pressure of 165–180 mmHg and of >180 mmHg were 2.8 and 7.6, respectively. Hospitalization for myocardial infarction doubled the risk for this disease; congestive heart failure increased the risk 5-fold and increased the rate of subsequent ESRD. The ESRD rate decreased by two-thirds among individuals whose systolic blood pressure fell by 20 mmHg.112 In addition, an increased risk of ESRD was associated with African ancestry (risk ratio=2.2).

The Multiple Risk Factor Intervention Trial (MRFIT) examined the development of cardiovascular complications in 12,000 men over 16 years and found that elevations in baseline systolic blood pressure were correlated with the development of ESRD, even within the high-normal and mild hypertensive ranges.113 This study also showed that effective blood pressure control stabilized or improved kidney function in Caucasians but not in African-Americans.114 In a 25-year observational study of 177,570 men and women, Hsu et al. demonstrated that small increases in systolic blood pressure within the pre-hypertensive and mild hypertensive ranges were correlated with increased CKD risk over time and an increase in the number of patients with ESRD.115 One risk factor for ESRD was high blood pressure (hazard ratio (HR) 2.94, 95% CI 2.21–3.92 for stage 2 hypertension; HR 2.33, 95% CI 1.78–3.05 for stage 1 hypertension; and HR 1.72, 95% CI 1.32–2.24 for pre-hypertension versus normal).

Forman and Brenner reviewed the evidence regarding a response to aggressive blood pressure reduction in “normotensive” individuals at high risk (diabetes, coronary artery disease, and cerebrovascular disease) and suggested maintaining a blood pressure below 120/80 in these patients.116 However, the clinical trials such as the ACCORD study,117 the Irbesartan Diabetic Nephropathy Trial (IDNT),118 and the International Verapamil SR-Trandolaptil Study (INVEST)119 found no benefit in bringing the blood below 130/80. Tight control of systolic blood pressure in the latter two studies did not yield improved cardiovascular outcomes and was in fact associated with an increase in all-cause mortality. These results have been summarized in other papers.120,121

Whether kidney and cardiovascular risks are lower in non-diabetic patients with CKD and blood pressures <130/80 compared with <140/90 remains unclear. This issue was examined by four randomized trials,56,59,122,123 two of which failed to show a significant benefit.59,122 However, the MDRD study showed that a reduction in blood pressure from <140/90 to <125/75 reduced the risk of kidney disease progression (HR 0.68) after 10 years of reduced blood pressure.56 Similarly, strict mean arterial blood pressure control in children below the 50th percentile for age versus a conventional therapy that corresponded to the 50th to 90th percentile for age led to decreased proteinuria and progression to ESRD (HR 0.65).124 The Cardio-Sis trial also demonstrated a benefit of blood pressure control in non-diabetic patients. Patients in the tight control group (<130 mmHg) developed less left ventricular hypertrophy (11% of 483 patients; odds ratio 0.63) and less frequently (4.8%) reached a composite cardiovascular end-point (HR 0.50) compared with patients under standard control (<140 mmHg; 17% and 9.4%, respectively).123

No evidence supports a preference for RAAS agents over other anti-hypertensive drugs among patients with CKD who present with hypertensive nephrosclerosis without proteinuria. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) did not find differences in the risk of exacerbated GFR or ESRD between patients given lisinopril, amlodipine, or chlorthalidone,125 even for the subgroup of patients with estimated GFRs <60 mL/min. Although proteinuria was not directly measured in these patients, it was not expected to be elevated.126

Multidrug Remission CKD Clinic Protocols
Small annual differences in the rates of GFR decline can result in large differences regarding ESRD onset time.127 The goal of the RAAS-based individually tailored multidrug anti-proteinuric and antihypertensive treatments used over the last 15 years is to reduce proteinuria and the annual decline in eGFR.128 These protocols129 employ a combination therapy of ACE inhibitors and ARBs shown to reduce protein, kidney, and cardiovascular events more effectively than ACE inhibitors or ARB monotherapy.127,129,130 When proteinuria is minimal, a dual RAAS inhibitor is no more effective than a monotherapy (e.g. the ONTARGET Trial).79 The recent closure of the ALTITUDE and VA NEPHRON-D trials has placed the use of combination RAAS therapies on hold.80,81 A modified therapeutic strategy featuring a combination of lower-than-recommended doses of ACE inhibitors and ARB might block the RAAS system without excessive blood pressure reduction; moreover, the side effects of hyperkalemia and reduced kidney function are presently being investigated.130 The ongoing VALID trial, Preventing ESRD in Overt Nephropathy of Type 2 Diabetes Trial, is testing whether halved dosages of ACE inhibitor and ARB administered together compared with full doses of each agent alone result in a larger reduction in proteinuria and a delay in ESRD among approximately 100 individuals with type 2 diabetes over 3 years ( The trial will be completed in February 2016.

Updating the “Trade-off” Hypothesis

Hyperparathyroidism. The progression of CKD and cardiovascular mortality have been directly correlated with changes in the levels of phosphate, calcium, PTH, vitamin D, and fibroblast growth factor 23 (FGF23).131 Laboratory studies in rats have demonstrated that PTH decreases glomerular filtration by decreasing the Kf on the renal podocyte.132 The suppression of PTH via parathyroidectomy, calcimimetics (calcium-sensing receptor agonists), or dietary phosphate restriction attenuated the increase in serum creatinine in a rat remnant kidney model.133 Patients with CKD and secondary hyperparathyroidism have an increased mortality risk134 and a significantly shorter renal survival than those with CKD alone.135 Parathyroidectomy effectively reduces cardiovascular events and mortality in patients receiving hemodialysis with secondary hyperparathyroidism.136

Phosphate. The effect of phosphate on CKD progression might be directly mediated by changes in renal perfusion, calcifications, and intracellular calcium-phosphate concentrations, or through its indirect effects on PTH or calcium levels.137,138 The Irbesartan Diabetic Nephropathy Trial found that the risk of doubling serum creatinine levels, ESRD, or death139 was higher by a factor of 1.8 in hyperphosphatemic diabetics.139 The AASK analysis of African-American patients with hypertensive nephrosclerosis noted that phosphorus was directly associated with a renal composite consisting of 50%, 25 mL/min GFR decline, or ESRD.140 Additional studies have shown that increasing serum phosphate concentrations are correlated with progressive renal failure141144 and that phosphate restriction145,146 and phosphate binders stabilize renal function.147,148 An analysis of the medical files of 40,538 outpatients receiving hemodialysis registered in the Patient Profile System of Fresenius Medical Care found that high phosphorus was correlated with increased relative risks of death (1.07, 1.25, 1.43, 1.67, and 2.02 for serum phosphorus levels of 5–6, 6–7, 7–8, 8–9, and >9 mg/dL, respectively). Higher adjusted calcium levels as well as moderate and severe hyperparathyroidism (PTH levels ≥600 pg/mL) were also associated with increased rates of death.149 High phosphate is also associated with increased mortality in patients with CKD.141,149,150 Serum phosphate levels within the normal range are associated with coronary artery calcification as determined by CT scanning in patients with stage 3 and 4 CKD with or without diabetes mellitus.151 The graded152,153 associations between serum phosphate levels of >3.5 mg/dL and coronary artery calcifications,156 cardiovascular disease, and mortality have also been extended to the general population.155159

In studying the population disparities in mineral metabolism,41,160 African-American patients with CKD demonstrate marked deficiencies in serum 25-hydroxyvitamin D (25-OH vitamin D) and higher PTH levels than Caucasians.161163 As these patients progress toward the need for dialysis, they show even more severe secondary hyperparathyroidism and 25-OH vitamin D deficiencies.164166 This result was also shown by the multicenter Study to Evaluate Early Kidney Disease (SEEK) in 1,860 patients with early CKD, of whom 12% were African-American. African-Americans had significantly higher PTH, calcium, phosphorus, and bone-specific alkaline phosphatase levels. In addition, they had a 1.8-fold greater risk of elevated phosphate, a 2.7-fold greater risk of a 25-OH vitamin D deficiency <30 mg/mL, and a 4.7-fold greater risk of a severe 25-OH vitamin D deficiency. They also developed secondary hyperparathyroidism earlier in their CKD course at a GFR of 45–60 mL/min, whereas Caucasians generally developed hyperparathyroidism after their GFRs decreased to <30 mL/min.167 Gutierrez et al. showed that both healthy African-Americans and those with CKD had a fractional excretion of inorganic phosphate that was approximately 30% lower than that for Caucasians (P<0.001), and the fractional excretion of calcium in African-Americans was approximately 35% lower than in Caucasians. Both African-American and Caucasian patients with CKD had eGFRs between 15 and 60 mL/min, and they had similar PTH and FGF23 levels.168

Kestenbaum and colleagues described the results of a genome-wide association study (GWAS) that investigated common genetic variations associated with serum phosphorus concentrations in the general population.169 Seven loci were described, and one locus was found directly adjacent to SLC34A1, which encodes the kidney-specific type IIa sodium-phosphate cotransporter (NaPi2a). Another was located adjacent to the calcium-sensing receptor, and one was located close to the FGF23 receptor. The SLC34A1 was also one of the 13 loci identified by the CKDGen consortium, which performed a meta-analysis of the GWAS data in 67,093 individuals of European ancestry from 20 predominate population studies to identify new genetic susceptibility loci for reduced renal function.170 Although studied extensively in murine models where NaPi2a has been shown to serve as the central mediator of renal phosphate reabsorption,171,172 the role that this transporter plays in humans had been controversial until recently. Magen and associates recently described two siblings with autosomal recessive Fanconi’s syndrome and hypophosphatemic rickets who featured a 21-base-pair in-frame duplication on SLC34A1. Functional studies have shown a complete loss of function of the mutant cotransporter, its failure to reach the plasma membrane, and an impairment of renal phosphate reabsorption. This study provided the first evidence in humans of the critical role that NaPi2a plays in human renal phosphate handling.173 Subsequently, novel loss-of-function mutations in SLC34A1 were identified in members of families with idiopathic infantile hypercalcemia (IIH) not attributed to abnormalities in inactivation of vitamin D processsing, many with nephrocalcinosis.174,175

A gain-of-function mechanism might explain the hyperphosphatemia in patients with CKD, especially in light of its recent identification as a prominent CKD locus.176 People who tend toward lower fractional excretions of phosphate might exhibit increased levels of NaPi2a.167 The high and inducible levels of expression suggest that variant versions differ in folding and may trigger an “endoplasmic reticulum associated stress response (ERAD).”177

Vitamin D. The diminished production of 1,25-OH vitamin D in renal disease likely facilitates interstitial fibrosis by allowing fibroblasts to proliferate.139 Vitamin D has been shown to prevent glomerular disease in animal models,178,179 and its derivatives decrease urine albumin excretion as well as reducing serum creatinine and glomerulosclerosis in subtotally nephrectomized rats.180,181 In a retrospective analysis, patients with CKD who were treated with calcitriol showed a decreased rate of CKD progression.182 Increasing evidence has shown that the vitamin D analogue, paricalcitol, an inhibitor of the renin–angiotensin system,183 reduces urinary albumin. Three recent studies showed that paricalcitol reduces proteinuria in patients with CKD, including those presenting with diabetes.184186 Paricalcitol reduced albuminuria and slowed the progression of kidney injury in laboratory animals.187,188 A recent double-blind, placebo-controlled study resulted in a 20% reduction in the urinary albumin-to-creatinine ratios (P=0.053) and a 28% reduction in the 24-hour urine albumin (P=0.009) of patients receiving 2 μg of paricalcitol for 24 weeks compared with those receiving a placebo.189

Decreased levels of 25-OH and 1,25-OH vitamin D are commonly observed in patients with CKD190 as well as associated with increased cardiovascular mortality.164,191 The treatment of CKD and ESRD populations using vitamin D compounds is associated with decreased mortality rates.192,193 However, a meta-analysis of 76 trials including 3,667 participants found that these compounds failed to reduce PTH levels or mortality rates consistently.194 Newer vitamin D compounds did decrease PTH levels (by 11 pmol/L); intravenous therapy was more effective than oral therapy, but mortality rates were not affected. Additional observational studies by the same group confirmed the reduction of serum PTH and the increase in calcium and phosphorus following treatment with vitamin D compounds but failed to show increased survival rates.195,196 These studies sparked a call for randomized controlled trials to establish a causal association between vitamin D supplementation and decreased CKD mortality.197

Although the decreased production of 1,25-OH vitamin D has traditionally been ascribed to decreased renal mass (which subsequently leads to elevated serum phosphate and the inhibition of reduced 25-OH D-1alpha-hydroxylase), these mechanisms fail to explain the decline in 1,25-OH vitamin D in patients with early CKD who still have sufficient kidney mass and normal serum phosphate levels.198

FGF23. Fibroblast growth factor 23 (FGF23), which was initially characterized in a study of rare inherited disorders associated with phosphate metabolism,199 regulates phosphate homeostasis and explains the decreases in 1,25-OH vitamin D in patients with early kidney disease. Its phosphaturic effect in the proximal tubules is accomplished through the down-regulation of sodium-phosphate co-transporters, and it decreases 1,25-OH vitamin D levels via the inhibition of 25-OHD-1-alphahydroxylase and the upregulation of the 25-OHD-24 hydroxylase pathway (Figure 4).198203 Levels of FGF23 predict CKD progression from mild to moderate in patients of European ancestry,142 and they are among the strongest markers of CKD progression, with areas under the receiver-operating characteristic (ROC) curves of 0.84 for the C-terminal FGF23 and 0.81 for intact FGF23.131 Elevated FGF23 levels in patients with early CKD also predict early cardio-vascular events such as myocardial infarction and stroke as well as the need for coronary artery or carotid artery intervention, peripheral arterial amputation or intervention, and death.204 Elevated FGF23 levels are associated with increased mortality,205,206 vascular calcifications,207 left ventricular hypertrophy and mass index,208 and bone metabolism abnormalities in patients with ESRD.209 Strategies to reduce FGF23 in early-stage CKD patients include dietary phosphate restriction,210 the use of phosphate binders,211 the administration of niacin,212 and the restriction of administration of vitamin D-type drugs and favoring therapy with calcimimetics.213,214

Figure 4Figure 4
The Pathogenesis of Secondary Hyperparathyroidism (SHPT) in Chronic Kidney Disease (CKD)

The phosphate-regulating properties of FGF23 are mediated via FGFR1c, which requires alpha Klotho as a co-receptor. Its sites of action in the kidney are the subject of an active investigation and include the decreased expression of NaPi2a and NaPi2c.215 The recent demonstration of FGF23-mediated signaling in the distal convoluted tubule at the site of the alpha Klotho co-receptor adjacent to the NaPi2a-expressing proximal tubular cells likely represents FGF23 bioactivity through nephron-specific events that have yet to be elucidated.216 Saito et al. hypothesized that the initial aberration in this signaling pathway is the inappropriate upregulation of NaPi2a receptors;217 this theory is consistent with the association between the SLC34A1 locus and CKD described above.

An intriguing study recently found associations between FGF23 and body mass index (BMI), waist circumference, waist-to-hip ratio, serum lipids, and fat mass. In two cohorts of elderly European Caucasian participants, FGF23 was negatively associated with HDL and apolipoprotein A1 as well as positively associated with triglycerides. An increase of one standard deviation in the log-FGF23 levels was associated with a 7%–20% increase in BMI, waist circumference, and waist-to-hip ratio as well as a 7%–18% increase in trunk and total body fat mass as determined using whole-body dual X-ray absorptiometry. Levels of FGF23 were higher in participants with metabolic syndrome or at an increased risk of metabolic syndrome,218 indicating that FGF23 underlies cardiovascular risk via either phosphate or adverse lipid metabolism. The authors of that study cautioned against extending this association to African-American and Latino populations receiving dialysis; however, they emphasized that these populations have lower FGF23 levels205 and a dialysis survival advantage.164,219,220

Consistent experimental and human epidemiologic findings have suggested a need to test therapeutic approaches to lower phosphate levels in patients with CKD.221 Pilot studies of patients with stage 3 or 4 CKD suggest that phosphate binders, low phosphate diets, and vitamin B3 derivatives such as niacin and nicotinamide reduce phosphate absorption, serum phosphate, and FGF23. This novel therapeutic approach will be tested in the CKD Optimal Management with Binders and Nicotinamide (COMBINE) Study, with intermediate cardiovascular disease endpoints to include left ventricular hypertrophy (LVH), vascular calcification, and CKD progression.

Obesity and Metabolic Syndrome
Obesity and associated metabolic syndrome, the results of Western dietary habits and sedentary lifestyles, exist at epidemic proportions in the US and are spreading worldwide.222 The continuous increase in obesity decreases life expectancy and general health.223 Obese participants are at greater risks for hypertension, insulin resistance and diabetes, hyperlipidemia, various cancers, and coronary vascular disease.224 Obesity and metabolic syndrome are also associated with pathologic renal changes and decreased renal function.224,225

Recently, the likely causes of the obesity epidemic were reviewed.226 Attempts to battle the problem have concentrated on decreasing fast food and trans fats intakes by providing nutritional information in stores and restaurants as well as reducing the consumption of soft drinks and high-fructose corn syrup.222 Numerous studies have associated increased trans fats intake with an increased risk of coronary disease.227229 The intake of high-fructose corn syrup causes lipid abnormalities and hepatic insulin resistance.230 Epidemiologic studies show that the consumption of beverages containing a combination of sugars (including fructose) are associated with increases in body weight, metabolic syndrome, and cardiovascular disease.231 Similarly, the heightened use of artificial sweeteners is associated with obesity.232 Increasing evidence suggests that artificial sweeteners do not activate food reward pathways in the same manner as natural sweeteners,233 as demonstrated by the lack of the prolonged signal depression in the hypothalamus observed following glucose ingestion. Finally, sucrose ingestion, compared with saccharin ingestion, results in the greater activation of the higher gustatory areas such as the insula, orbitofrontal cortex, and the amygdala; this information might be useful for limiting energy intake.233235

Obesity. The incidence of obesity, defined as a BMI of ≥30 kg/m2, has doubled since 1960. This condition affects one-third of the adult population in the US. The rise in overweight children from 6% to 19% over the past 25 years is even more alarming.236 Obesity is rapidly exceeding smoking as the leading cause of preventable death in the US.224 Eight studies have related excess body weight to the development of CKD and ESRD.237 An analysis of 320,252 members of the Kaiser Permanente Health System demonstrated that obesity is a risk factor for ESRD, with adjusted relative risks of 1.87, 3.57, 6.12, and 7.07 for those with BMIs of 25–29.9, 30–34.9, 35–39.9, and >40 kg/m2, respectively.238 Although the World Health Organization continues to use BMI to define obesity, the waist-to-hip ratio has been shown to predict more accurately the myocardial infarct risk worldwide.239 The link between obesity (defined by waist-to-hip ratio) and CKD has been reported.240 Even lean individuals with a high waist-to-hip ratio were at risk for developing microalbuminuria and a reduced estimated GFR.241 Obesity-related focal segmental glomerulosclerosis has also been described.242 The pathogenesis of this disorder is likely related to hyperfiltration, with increases in kidney mass and a glomerular hypertrophy effect. Hyperfiltration and increased filtration fraction are surrogate markers for elevated glomerular capillary pressures, which eventually result in obesity-associated glomerulosclerosis.243 Obesity-associated focal segmental glomerulosclerosis is associated with a lower rate of nephrotic syndrome and a more indolent course than idiopathic focal segmental glomerulosclerosis.242

Paradoxically, a strong association between increased body mass index (BMI) and lower mortality has been described in numerous studies of patients with stage 5 CKD undergoing maintenance hemodialysis with the benefits of a larger size extending into morbid obesity (BMI>35 kg/m2).244 This has been extended by two studies of patients with CKD where low BMI predicted greater mortality, whereas increased BMI was associated with greater survival even after adjustment for known confounding variables.245,246 The reasons for this association have not been determined.

Metabolic Syndrome. Associations between metabolic syndrome and both CKD and microalbuminuria have also been found in numerous studies, and Peralta et al. recently reviewed these relationships.247 After examining the data of 6,217 adults in the National Health and Nutrition Examination Survey III (NHANES), 24.7% of whom had metabolic syndrome, Chen et al. demonstrated graded relationships between the components of metabolic syndrome and the risks for CKD and microalbuminuria.248 Due to the cross-sectional nature of the study, determination of the temporal relationship between metabolic syndrome and CKD was not possible.247 The Atherosclerosis Risk in Communities Study (ARIC) examined more than 15,000 individuals and found that 21% (n=2,110) and 7% (n=691) developed metabolic syndrome and CKD, respectively, over a 9-year period; moreover, a similar graded relationship was found between the components of the syndrome and the risk for CKD. The odds ratio for the rate of CKD among participants with metabolic syndrome was 1.24 (95% CI 1.01–1.51).

Similarly, experimental hyperlipidemia models have demonstrated associations among progressive kidney damage, atherosclerosis, focal segmental glomerulosclerosis, and tubule-interstitial disease.249 Interestingly, a recent investigation of 19,246 participants in the southern US documented an association between a high saturated fat intake and albuminuria; however, no relationship was found with regard to decreased GFR.250 Moreover, an increased fructose intake (≥74 g/day) was implicated in obesity, metabolic syndrome, uric acid elevations, and hypertension; furthermore, it was a risk factor for kidney disease.251 High-fructose diets in animals led to renal hypertrophy, tubular cell proliferation, and injury. In a remnant kidney model, rats fed diets high in fructose developed metabolic syndrome and kidney disease progression.252 In humans, 6-week diets containing 25% fructose caused insulin resistance, visceral obesity, and abnormalities in serum lipids consistent with metabolic syndrome.253 The NHANES revealed an association between the ingestion of sugar-sweetened drinks and elevated uric acid levels; hypertension was also observed.253 Similarly, the Nurses’ Health Study found that ≥2 daily servings of artificially sweetened soda was independently associated with a ≥30% decline in estimated GFR over 11 years.254

A recent histopathologic study compared samples from 12 patients with metabolic syndrome undergoing nephrectomy for renal cancer with those from 12 controls.255 Samples from the patients with metabolic syndrome showed greater tubular atrophy, interstitial fibrosis, and arteriosclerosis as well as global and segmental glomerulosclerosis. These prominent interstitial changes led Saito et al. to postulate that the proximal tubular cell and, specifically, the multiligand megalin and cubilin receptors play a prominent role in the pathogenesis of this disorder.217

Welsh et al. recently engineered two mouse models lacking glomerular podocyte insulin receptors.256 Within 5 weeks, the animals began to show albuminuria and a shortening of the foot processes under electron microscopy. At 8 weeks, albuminuria, increased creatinine levels, the foci of segmental sclerosis, a thickening of the basement membranes, histologic evidence of apoptosis, and histopathologic features of diabetic nephropathy were observed, demonstrating the importance of podocyte insulin sensitivity in kidney function.257

According to the KDIGO guidelines, many patients with CKD should be treated with statins to prevent cardiovascular disease.53

Diabetes Mellitus. The importance of tight glycemic control to prevent kidney disease-related outcomes was recently demonstrated by the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/ EDIC).258 The DCCT examined 1,441 participants with type 1 diabetes mellitus (1982–1993) assigned to intensive (median HgA1C 7.2%) versus conventional (9.1%) treatment for 6.5 years. Subsequently, participants were followed for >18 years in the observational EDIC. The intensive treatment used three or more daily insulin injections or insulin pump therapy guided by self-monitored glucose. During the DCCT, the intensive treatment reduced the rate of microalbuminuria (albumin excretion rate (AER) >40 mg/24 h) by 39% and that of macroalbuminuria (AER >300 mg/24 h) by 54% (24%–74%). During EDIC years 1–8, participants previously assigned to the DCCT intensive treatment experienced lower rates of microalbuminuria and macroalbuminuria, with risk reductions of 59% (30%–73%) and 84% (67%–92%), respectively. The beneficial effects of intensive therapy became evident at the end of the follow-up assessment, with reduced risks of impaired GFR (<60 mL/min) and hypertension of 50% (18%–69%) and 20% (6%–21%), respectively. The risk for retinopathy and neuropathy was also reduced, but not the risk for cardiovascular events.

With regard to type 2 diabetes, the kidney disease outcomes of the United Kingdom Prospective Diabetes Study (UKPDS),259 Kumamoto,260 Action in Diabetes and Vascular Disease Trial (ADVANCE),261 and Action to Control Cardiovascular Risk in Diabetes (ACCORD)262 trials are consistent with those of the DCCT for patients with type 1 diabetes.258 These analyses account for the relative differences in hemoglobin A1C achieved between treatment groups and the differences in study duration. A meta-analysis of type 2 diabetics263 featured 28 trials that included 34,912 participants with type 2 diabetes who were randomly assigned to an intensive glycemic control group (n=18,717) or a conventional glycemic control group (n=16,195). Targeting intensive glycemic control reduced the risk of microvascular complications (i.e. nephropathy and retinopathy) but increased the risks for hypoglycemia and serious adverse events. Tight glucose control confers long-term benefits regarding the prevention of progressive diabetic kidney disease.

Many individuals are not candidates for intensive glucose control in view of frequent episodes of hypoglycemia, impaired cognitive status, multiple comorbidities, and shortened life expectancies. Clinical guidelines have therefore recommended hemoglobin A1C targets as follows: specifically “individualized” care with A1C ~6.5% for healthy, young patients; <7% in older individuals or those with comorbid conditions, and <8% in older individuals with just a few years of life expectancy.264,265

Other Risk Factors
Studies recently have identified uric acid,266268 acidosis,269272 and acute kidney injury273,274 as potentially modifiable risk factors for CKD.


By nature, nephrologists are intelligent, creative, and competitive. As such, we are envious of the extraordinary success of our cardiology colleagues in the treatment of cardiovascular disease, and we wish to mirror their success. The aforementioned discussion of CKD risk factors makes the conceptual historical point of the importance of risk factor modification. Using this approach, in collaboration with our fellow clinicians, we can prolong the lives of individuals with kidney disease, target cardiovascular prevention, and decrease the number of patients referred for renal replacement therapy and kidney transplantation. Research presently under-way will target multiple novel pathways and identify multidrug approaches to accomplish these goals.97,98,275

The plateauing incidence of ESRD in the US over recent years indicates that these efforts have already shown success. The latest United States Renal Data System (USRDS) Annual Data Report from 2014 showed that the rate of ESRD has fallen from 368 cases per 1 million people in 2009 to 359 cases per 1 million people in 2012. The actual incidence has also fallen from 115,114 in 2009 to 114,813 in 2012.16 This marks the first time that the USRDS has reported a decrease in the number of new patients with ESRD since it began reporting in 1980. A decrease in incidence counts has also been reported for a number of other countries including Israel,16 perhaps reflecting attention to risk factor treatment.


The authors are indebted to Dr Barry M. Brenner whose many lectures and discussions find themselves reflected in the content of this article. The authors are also grateful to Margie Serling Cohn, Head Librarian of the Alfred Goldschmidt Medical Sciences Library of the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, for her continuous support to us over many years in locating many of the articles and reference materials required in the pursuit of scholarly activity. We wish her best of luck on her forthcoming retirement.


ACCORD Action to Control Cardiovascular Risk in Diabetes
ACR albumin-creatinine ratio
ADVANCE Action in Diabetes and Vascular Disease Trial
AKI acute kidney injury
AIPRD ACE Inhibition in Progressive Renal Disease
ALLHAT Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial
ALTITUDE Aliskiren Trial in Type II Diabetes Using Cardiorenal Endpoints
ARB angiotensin receptor blocker
ATI angiotensin II type 1
ATII angiotensin II type 2
CKD chronic kidney disease
COMBINE CKD Optimal Management with Binders and Nicotinamide
DCCT/EDIC Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications
ESRD end-stage renal disease
FGF23 fibroblast growth factor 23
GFR glomerular filtration rate
IIH idiopathic infantile hypercalcemia
KDIGO Kidney Disease: Improving Global Outcomes
LVH left ventricular hypertrophy
MDRD Modification of Diet in Renal Disease
MRFIT Multiple Risk Factor Intervention Trial
ONTARGET Renal Outcomes with Telmisartan, Ramipril, or Both in People at High Vascular Risk Study
RAAS renin–angiotensin–aldosterone system
NHANES National Health and Nutrition Examination Survey III
REIN Ramipril Efficacy in Nephropathy
RENAAL Reduction of End Points in NIDDM with the Angiotensin II Receptor Antagonist Losartan
SEEK Study to Evaluate Early Kidney Disease
T2DM type 2 diabetes mellitus
UKPDS The United Kingdom Prospective Diabetes Study
VALID Preventing ESRD in Overt Nephropathy of Type 2 Diabetes
VA NEPHRON-D Diabetes in Nephropathy Study, Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy.


Conflict of interest: No potential conflict of interest relevant to this article was reported.

Cooney MT, Dudina A, D’Agostino R, Graham IM. Cardiovascular risk-estimation systems in primary prevention: do they differ? Do they make a difference? Can we see the future? Circulation. 2010;122:300–10.
National Institutes of Health, National Heart, Lung, and Blood Institute. Disease Statistics. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute; 2013 [Accessed June 23, 2015]. Fact Book Fiscal Year 2012. pp. 33–52. Available at:
Braunwald E. Shattuck lecture--cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med. 1997;337:1360–9.
Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J 3rd. Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study. Ann Intern Med. 1961;55:33–50.
Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837–47.
Wilson PW, Castelli WP, Kannel WB. Coronary risk prediction in adults (the Framingham Heart Study). Am J Cardiol. 1987;59:91G–4G.
Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000. N EnglJ Med. 2007;356:2388–98.
Batsis JA, Lopez-Jimenez F. Cardiovascular risk assessment--from individual risk prediction to estimation of global risk and change in risk in the population. BMC Med. 2010;8:29.
Humphries SE, Drenos F, Ken-Dror G, Talmud PJ. Coronary heart disease risk prediction in the era of genome-wide association studies: current status and what the future holds. Circulation. 2010;121:2235–48.
Peitzman SJ. Chronic dialysis and dialysis doctors in the United States: a nephrologist-historian’s perspective. Semin Dial. 2001;14:200–8.
Peitzman SJ. Nephrology in the United States from Osler to the artificial kidney. Ann Intern Med. 1986;105:937–46.
Murray JE, Merrill JP, Harrison JH, Wilson RE, Dammin GJ. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N Engl J Med. 1963;268:1315–23.
Alexander S. Medical miracle and a moral burden of a small committee: they decide who lives, who dies. Life. 1962:102–25.
Levinsky NG. Management of chronic renal failure. N Engl J Med. 1964;271:460–3.
Ympa YP, Sakr Y, Reinhart K, Vincent JL. Has mortality from acute renal failure decreased? A systematic review of the literature. Am J Med. 2005;118:827–32.
United States Renal Data System, 2014 Annual Data Report: Epidemiology of Kidney Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2014 [Accessed May 19, 2015]. Available at:
Bricker NS. On the pathogenesis of the uremic state. An exposition of the “trade-off hypothesis”. N Engl J Med. 1972;286:1093–9.
Bricker NS, Morrin PA, Kime SW Jr. The pathologic physiology of chronic Bright’s disease. An exposition of the “intact nephron hypothesis”. Am J Med. 1960;28:77–98.
Cain CD, Schroeder FC, Shankel SW, Mitchnick M, Schmertzler M, Bricker NS. Identification of xanthurenic acid 8-O-beta-D-glucoside and xanthurenic acid 8-O-sulfate as human natriuretic hormones. Proc Natl Acad Sci U S A. 2007;104:17873–8.
Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol. 1981;241:F85–93.
Matsusaka T, Hymes J, Ichikawa I. Angiotensin in progressive renal diseases: theory and practice. J Am Soc Nephrol. 1996;7:2025–43.
Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest. 1986;77:1925–30.
Fogo A, Ichikawa I. Evidence for a pathogenic linkage between glomerular hypertrophy and sclerosis. Am J Kidney Dis. 1991;17:666–9.
Yoshida Y, Fogo A, Ichikawa I. Glomerular hemodynamic changes vs. hypertrophy in experimental glomerular sclerosis. Kidney Int. 1989;35:654–60.
Levey AS, de Jong PE, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011;80:17–28.
Levey AS, Astor BC, Stevens LA, Coresh J. Chronic kidney disease, diabetes, and hypertension: what’s in a name? Kidney Int. 2010;78:19–22.
Lindner A, Charra B, Sherrard DJ, Scribner BH. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med. 1974;290:697–701.
Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med. 1984;310:356–60.
Bigazzi R, Bianchi S, Baldari D, Campese VM. Microalbuminuria predicts cardiovascular events and renal insufficiency in patients with essential hypertension. J Hypertens. 1998;16:1325–33.
Perkovic V, Verdon C, Ninomiya T, et al. The relationship between proteinuria and coronary risk: a systematic review and meta-analysis. PLoS Med. 2008;5:e207.
Ninomiya T, Perkovic V, Verdon C, et al. Proteinuria and stroke: a meta-analysis of cohort studies. Am J Kidney Dis. 2009;53:417–25.
Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.
Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.
de Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;65:2309–20.
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145–53.
Ibsen H, Olsen MH, Wachtell K, et al. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study. Hypertension. 2005;45:198–202.
Chamnan P, Simmons RK, Khaw KT, Wareham NJ, Griffin SJ. Estimating the population impact of screening strategies for identifying and treating people at high risk of cardiovascular disease: modelling study. BMJ. 2010;340:c1693.
Marshall T. Targeted case finding for cardiovascular prevention. BMJ. 2010;340:c1376.
Vischer UM, Safar ME, Safar H, et al. Cardio-metabolic determinants of mortality in a geriatric population: is there a “reverse metabolic syndrome”? Diabetes Metab. 2009;35:108–14.
Hallan SI. Kidney function for the non-nephrologist: an emerging tool for predicting mortality risk. Kidney Int. 2010;79:8–10.
Weiner DE, Tighiouart H, Amin MG, et al. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol. 2004;15:1307–15.
Henry RM, Kostense PJ, Bos G, et al. Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study. Kidney Int. 2002;62:1402–7.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–305.
Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375:2073–81.
Hemmelgarn BR, Manns BJ, Lloyd A, et al. Relation between kidney function, proteinuria, and adverse outcomes. JAMA. 2010;303:423–9.
DeFilippis AP, Kramer HJ, Katz R, et al. Association between coronary artery calcification progression and microalbuminuria: the MESA study. JACC Cardiovasc Imaging. 2010;3:595–604.
Hallan S, Astor B, Romundstad S, Aasarod K, Kvenild K, Coresh J. Association of kidney function and albuminuria with cardiovascular mortality in older vs younger individuals: The HUNT II Study. Arch Intern Med. 2007;167:2490–6.
Foley RN, Wang C, Snyder JJ, Rule AD, Collins AJ. Kidney function and risk triage in adults: threshold values and hierarchical importance. Kidney Int. 2010;79:99–111.
Soveri I, Arnlov J, Berglund L, Lind L, Fellstrom B, Sundstrom J. Kidney function and discrimination of cardiovascular risk in middle-aged men. J Intern Med. 2009;266:406–13.
Van Biesen W, De Bacquer D, Verbeke F, Delanghe J, Lameire N, Vanholder R. The glomerular filtration rate in an apparently healthy population and its relation with cardiovascular mortality during 10 years. Eur Heart J. 2007;28:478–83.
Upadhyay A, Earley A, Lamont JL, Haynes S, Wanner C, Balk EM. Lipid-lowering therapy in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012;157:251–62.
Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012;157:263–75.
Wanner C, Tonelli M. Kidney Disease: Improving Global Outcomes Lipid Guideline Development Work Group Members. KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kidney Int. 2014;85:1303–9.
Klahr S, Schreiner G, Ichikawa I. The progression of renal disease. N Engl J Med. 1988;318:1657–66.
Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med. 1995;123:754–62.
Sarnak MJ, Greene T, Wang X, et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Ann Intern Med. 2005;142:342–51.
Ruggenenti P, Perna A, Gherardi G, Benini R, Remuzzi G. Chronic proteinuric nephropathies: outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury. Am J Kidney Dis. 2000;35:1155–65.
Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int. 2002;61:1086–97.
Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288:2421–31.
Remuzzi G, Ruggenenti P, Perico N. Chronic renal diseases: renoprotective benefits of renin-angiotensin system inhibition. Ann Intern Med. 2002;136:604–15.
Jafar TH, Stark PC, Schmid CH, et al. Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis. Ann Intern Med. 2003;139:244–52.
Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med. 2001;135:73–87.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456–62.
Hoy WE, Wang Z, VanBuynder P, Baker PR, Mathews JD. The natural history of renal disease in Australian Aborigines. Part 1. Changes in albuminuria and glomerular filtration rate over time. Kidney Int. 2001;60:243–8.
Ruilope LM, Campo C, Rodriguez-Artalejo F, Lahera V, Garcia-Robles R, Rodicio JL. Blood pressure and renal function: therapeutic implications. J Hypertens. 1996;14:1259–63.
Iseki K, Ikemiya Y, Iseki C, Takishita S. Proteinuria and the risk of developing end-stage renal disease. Kidney Int. 2003;63:1468–74.
Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med. 2004;351:1941–51.
Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med. 1998;128:982–8.
Slagman MC, Navis G, Laverman GD. Dual blockade of the renin-angiotensin-aldosterone system in cardiac and renal disease. Curr Opin Nephrol Hypertens. 2010;19:140–52.
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet. 2003;361:117–24.
Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation. 2002;106:672–8.
Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870–8.
Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med. 2004;351:1952–61.
Ruggenenti P, Perna A, Remuzzi G. Retarding progression of chronic renal disease: the neglected issue of residual proteinuria. Kidney Int. 2003;63:2254–61.
Eijkelkamp WB, Zhang Z, Remuzzi G, et al. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. J Am Soc Nephrol. 2007;18:1540–6.
Ruggenenti P, Cravedi P, Remuzzi G. The RAAS in the pathogenesis and treatment of diabetic nephropathy. Nat Rev Nephrol. 2010;6:319–30.
Teo K, Yusuf S, Sleight P, et al. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J. 2004;148:52–61.
Weber MA. Hypertension treatment and implications of recent cardiovascular outcome trials. J Hypertens Suppl. 2006;24:S37–44.
Ontarget Investigators. Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547–59.
Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369:1892–903.
Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367:2204–13.
Persson F, Rossing P. Sequential RAAS blockade: is it worth the risk? Adv Chronic Kidney Dis. 2014;21:159–65.
Hou FF, Xie D, Zhang X, et al. Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losar tan in chronic renal insufficiency. J Am Soc Nephrol. 2007;18:1889–98.
Rossing K, Schjoedt KJ, Jensen BR, Boomsma F, Parving HH. Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria. Kidney Int. 2005;68:1190–8.
Weir MR, Hollenberg NK, Zappe DH, et al. Antihypertensive effects of double the maximum dose of valsartan in African-American patients with type 2 diabetes mellitus and albuminuria. J Hypertens. 2010;28:186–93.
Schmieder RE, Klingbeil AU, Fleischmann EH, Veelken R, Delles C. Additional antiproteinuric effect of ultrahigh dose candesartan: a double-blind, randomized, prospective study. J Am Soc Nephrol. 2005;16:3038–45.
Burgess E, Muirhead N, Rene de Cotret P, et al. Supramaximal dose of candesartan in proteinuric renal disease. J Am Soc Nephrol. 2009;20:893–900.
Persson F, Rossing P, Reinhard H, et al. Optimal antiproteinuric dose of aliskiren in type 2 diabetes mellitus: a randomised crossover trial. Diabetologia. 2010;53:1576–80.
Schjoedt KJ, Astrup AS, Persson F, et al. Optimal dose of lisinopril for renoprotection in type 1 diabetic patients with diabetic nephropathy: a randomised crossover trial. Diabetologia. 2009;52:46–9.
Andersen S, Rossing P, Juhl TR, Deinum J, Parving HH. Optimal dose of losartan for renoprotection in diabetic nephropathy. Nephrol Dial Transplant. 2002;17:1413–18.
Krikken JA, Laverman GD, Navis G. Benefits of dietary sodium restriction in the management of chronic kidney disease. Curr Opin Nephrol Hypertens. 2009;18:531–8.
Buter H, Hemmelder MH, Navis G, de Jong PE, de Zeeuw D. The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. Nephrol Dial Transplant. 1998;13:1682–5.
Esnault VL, Ekhlas A, Delcroix C, Moutel MG, Nguyen JM. Diuretic and enhanced sodium restriction results in improved antiproteinuric response to RAS blocking agents. J Am Soc Nephrol. 2005;16:474–81.
Navis G, de Jong PE, Donker AJ, van der Hem GK, de Zeeuw D. Moderate sodium restriction in hypertensive subjects: renal effects of ACE-inhibition. Kidney Int. 1987;31:815–19.
Houlihan CA, Allen TJ, Baxter AL, et al. A low-sodium diet potentiates the effects of losartan in type 2 diabetes. Diabetes Care. 2002;25:663–71.
Vogt L, Waanders F, Boomsma F, de Zeeuw D, Navis G. Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan. J Am Soc Nephrol. 2008;19:999–1007.
Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372:211–21.
Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015;372:222–31.
Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36:646–61.
Mangrum AJ, Bakris GL. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in chronic renal disease: safety issues. Semin Nephrol. 2004;24:168–75.
Xie D, Hou FF, Fu BL, Zhang X, Liang M. High level of proteinuria during treatment with renin-angiotensin inhibitors is a strong predictor of renal out-come in nondiabetic kidney disease. J Clin Pharmacol. 2011;51:1025–34.
Bakris GL, Weir MR, Secic M, Campbell B, Weis-McNulty A. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int. 2004;65:1991–2002.
Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med. 1991;325:293–302.
Jong P, Yusuf S, Rousseau MF, Ahn SA, Bangdiwala SI. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study. Lancet. 2003;361:1843–8.
Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet. 2006;368:581–8.
Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE sub-study. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000;355:253–9.
Keane WF, Brenner BM, de Zeeuw D, et al. The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the RENAAL study. Kidney Int. 2003;63:1499–507.
Rachmani R, Levi Z, Lidar M, Slavachevski I, Half-Onn E, Ravid M. Considerations about the threshold value of microalbuminuria in patients with diabetes mellitus: lessons from an 8-year follow-up study of 599 patients. Diabetes Res Clin Pract. 2000;49:187–94.
Pereira M, Lunet N, Azevedo A, Barros H. Differences in prevalence, awareness, treatment and control of hypertension between developing and developed countries. J Hypertens. 2009;27:963–75.
Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217–23.
Abegunde DO, Mathers CD, Adam T, Ortegon M, Strong K. The burden and costs of chronic diseases in low-income and middle-income countries. Lancet. 2007;370:1929–38.
Perry HM Jr, Miller JP, Fornoff JR, et al. Early predictors of 15-year end-stage renal disease in hypertensive patients. Hypertension. 1995;25:587–94.
Klag MJ, Whelton PK, Randall BL, et al. Blood pressure and end-stage renal disease in men. N Engl J Med. 1996;334:13–18.
Walker WG, Neaton JD, Cutler JA, Neuwirth R, Cohen JD. Renal function change in hypertensive members of the Multiple Risk Factor Intervention Trial. Racial and treatment effects. The MRFIT Research Group. JAMA. 1992;268:3085–91.
Hsu CY, Iribarren C, McCulloch CE, Darbinian J, Go AS. Risk factors for end-stage renal disease: 25-year follow-up. Arch Intern Med. 2009;169:342–50.
Forman JP, Brenner BM. ‘Hypertension’ and ‘microalbuminuria’: the bell tolls for thee. Kidney Int. 2006;69:22–8.
Accord Study Group. Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–85.
Berl T, Hunsicker LG, Lewis JB, et al. Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial. J Am Soc Nephrol. 2005;16:2170–9.
Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010;304:61–8.
Mancia G. Effects of intensive blood pressure control in the management of patients with type 2 diabetes mellitus in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Circulation. 2010;122:847–9.
Zanchetti A, Grassi G, Mancia G. When should anti-hypertensive drug treatment be initiated and to what levels should systolic blood pressure be lowered? A critical reappraisal. J Hypertens. 2009;27:923–34.
Ruggenenti P, Perna A, Loriga G, et al. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet. 2005;365:939–46.
Verdecchia P, Staessen JA, Angeli F, et al. Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial. Lancet. 2009;374:525–33.
Wuhl E, Trivelli A, Picca S, et al. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009;361:1639–50.
Rahman M, Pressel S, Davis BR, et al. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005;165:936–46.
James MT, Hemmelgarn BR, Tonelli M. Early recognition and prevention of chronic kidney disease. Lancet. 2010;375:1296–309.
Wilmer WA, Rovin BH, Hebert CJ, Rao SV, Kumor K, Hebert LA. Management of glomerular proteinuria: a commentary. J Am Soc Nephrol. 2003;14:3217–32.
Hebert LA, Wilmer WA, Falkenhain ME, Ladson-Wofford SE, Nahman NS Jr, Rovin BH. Renoprotection: one or many therapies? Kidney Int. 2001;59:1211–26.
Ruggenenti P, Schieppati A, Remuzzi G. Progression, remission, regression of chronic renal diseases. Lancet. 2001;357:1601–8.
Gentile G, Remuzzi G, Ruggenenti P. Dual renin-angiotensin system blockade for nephroprotection: still under scrutiny. Nephron. 2015;129:39–41.
Kronenberg F. Emerging risk factors and markers of chronic kidney disease progression. Nat Rev Nephrol. 2009;5:677–89.
Marchand GR. Effect of parathyroid hormone on the determinants of glomerular filtration in dogs. Am J Physiol. 1985;248:F482–6.
Ogata H, Ritz E, Odoni G, Amann K, Orth SR. Beneficial effects of calcimimetics on progression of renal failure and cardiovascular risk factors. J Am Soc Nephrol. 2003;14:959–67.
Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K. Secondary hyperparathyroidism is associated with higher mortality in men with moderate to severe chronic kidney disease. Kidney Int. 2008;73:1296–302.
Schumock GT, Andress DL, Marx SE, Sterz R, Joyce AT, Kalantar-Zadeh K. Association of secondary hyperparathyroidism with CKD progression, health care costs and survival in diabetic predialysis CKD patients. Nephron Clin Pract. 2009;113:c54–61.
Costa-Hong V, Jorgetti V, Gowdak LH, Moyses RM, Krieger EM, De Lima JJ. Parathyroidectomy reduces cardiovascular events and mortality in renal hyperparathyroidism. Surgery. 2007;142:699–703.
Alfrey AC. The role of abnormal phosphorus metabolism in the progression of chronic kidney disease and metastatic calcification. Kidney Int Suppl. 2004:S13–17.
Loghman-Adham M. Role of phosphate retention in the progression of renal failure. J Lab Clin Med. 1993;122:16–26.
Ritz E, Gross ML, Dikow R. Role of calcium-phosphorous disorders in the progression of renal failure. Kidney Int Suppl. 2005:S66–70.
Norris KC, Greene T, Kopple J, et al. Baseline predictors of renal disease progression in the African American Study of Hypertension and Kidney Disease. J Am Soc Nephrol. 2006;17:2928–36.
Schwarz S, Trivedi BK, Kalantar-Zadeh K, Kovesdy CP. Association of disorders in mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol. 2006;1:825–31.
Fliser D, Kollerits B, Neyer U, et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol. 2007;18:2600–8.
Voormolen N, Noordzij M, Grootendorst DC, et al. High plasma phosphate as a risk factor for decline in renal function and mortality in predialysis patients. Nephrol Dial Transplant. 2007;22:2909–16.
Levin A, Djurdjev O, Beaulieu M, Er L. Variability and risk factors for kidney disease progression and death following attainment of stage 4 CKD in a referred cohort. Am J Kidney Dis. 2008;52:661–71.
Noori N, Sims JJ, Kopple JD, et al. Organic and inorganic dietary phosphorus and its management in chronic kidney disease. Iran J Kidney Dis. 2010;4:89–100.
Ibels LS, Alfrey AC, Haut L, Huffer WE. Preservation of function in experimental renal disease by dietary restriction of phosphate. N Engl J Med. 1978;298:122–6.
Cozzolino M, Staniforth ME, Liapis H, et al. Sevelamer hydrochloride attenuates kidney and cardiovascular calcifications in long-term experimental uremia. Kidney Int. 2003;64:1653–61.
Nagano N, Miyata S, Obana S, et al. Sevelamer hydrochloride, a phosphate binder, protects against deterioration of renal function in rats with progressive chronic renal insufficiency. Nephrol Dial Transplant. 2003;18:2014–23.
Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15:2208–18.
Kestenbaum B, Sampson JN, Rudser KD, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005;16:520–8.
Stavroulopoulos A, Porter CJ, Pointon K, Monaghan JM, Roe SD, Cassidy MJ. Evolution of coronary artery calcification in patients with chronic kidney disease Stages 3 and 4, with and without diabetes. Nephrol Dial Transplant. 2011;26:2582–9.
Ix JH, De Boer IH, Peralta CA, et al. Serum phosphorus concentrations and arterial stiffness among individuals with normal kidney function to moderate kidney disease in MESA. Clin J Am Soc Nephrol. 2009;4:609–15.
Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation. 2005;112:2627–33.
de Boer IH, Rue TC, Kestenbaum B. Serum phosphorus concentrations in the third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis. 2009;53:399–407.
Dhingra R, Sullivan LM, Fox CS, et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med. 2007;167:879–85.
Foley RN, Collins AJ, Ishani A, Kalra PA. Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J. 2008;156:556–63.
Foley RN, Collins AJ, Herzog CA, Ishani A, Kalra PA. Serum phosphorus levels associate with coronary atherosclerosis in young adults. J Am Soc Nephrol. 2009;20:397–404.
Foley RN, Collins AJ, Herzog CA, Ishani A, Kalra PA. Serum phosphate and left ventricular hypertrophy in young adults: the coronary artery risk development in young adults study. Kidney Blood Press Res. 2009;32:37–44.
Chonchol M, Dale R, Schrier RW, Estacio R. Serum phosphorus and cardiovascular mortality in type 2 diabetes. Am J Med. 2009;122:380–6.
Mehrotra R, Kermah D, Fried L, Adler S, Norris K. Racial differences in mortality among those with CKD. J Am Soc Nephrol. 2008;19:1403–10.
Dawson-Hughes B. Racial/ethnic considerations in making recommendations for vitamin D for adult and elderly men and women. Am J Clin Nutr. 2004;80:1763S–6S.
Nesby-O’Dell S, Scanlon KS, Cogswell ME, et al. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988–1994. Am J Clin Nutr. 2002;76:187–92.
Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ, Shaw S. Evidence for alteration of the vitamin D-endocrine system in obese subjects. J Clin Invest. 1985;76:370–3.
Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72:1004–13.
Gupta A, Kallenbach LR, Zasuwa G, Divine GW. Race is a major determinant of secondary hyperparathyroidism in uremic patients. J Am Soc Nephrol. 2000;11:330–4.
Sawaya BP, Butros R, Naqvi S, et al. Differences in bone turnover and intact PTH levels between African American and Caucasian patients with end-stage renal disease. Kidney Int. 2003;64:737–42.
Gutierrez OM, Isakova T, Andress DL, Levin A, Wolf M. Prevalence and severity of disordered mineral metabolism in Blacks with chronic kidney disease. Kidney Int. 2008;73:956–62.
Gutierrez OM, Isakova T, Smith K, Epstein M, Patel N, Wolf M. Racial differences in postprandial mineral ion handling in health and in chronic kidney disease. Nephrol Dial Transplant. 2010;25:3970–7.
Kestenbaum B, Glazer NL, Kottgen A, et al. Common genetic variants associate with serum phosphorus concentration. J Am Soc Nephrol. 2010;21:1223–32.
A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA. 1982;247:1707–14.
Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hyper-calciuria, and skeletal abnormalities. Proc Natl Acad Sci U S A. 1998;95:5372–7.
Segawa H, Onitsuka A, Kuwahata M, et al. Type IIc sodium-dependent phosphate transporter regulates calcium metabolism. J Am Soc Nephrol. 2009;20:104–13.
Magen D, Berger L, Coady MJ, et al. A loss-of-function mutation in NaPi-IIa and renal Fanconi’s syndrome. N Engl J Med. 2010;362:1102–9.
Schlingmann KP, Ruminska J, Kaufmann M, et al. Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile hypercalcemia. J Am Soc Nephrol. 2015 Jun 5; [Epub ahead of print]
Rajagopal A, Braslavsky D, Lu JT, et al. Exome sequencing identifies a novel homozygous mutation in the phosphate transporter SLC34A1 in hypophosphatemia and nephrocalcinosis. J Clin Endocrinol Metab. 2014;99:E2451–6.
Kottgen A, Pattaro C, Boger CA, et al. New loci associated with kidney function and chronic kidney disease. Nat Genet. 2010;42:376–84.
Oakes SA, Papa FR. The role of the endoplasmic reticulum stress in human pathology. Annu Rev Path. 2015;10:173–94.
Kuhlmann A, Haas CS, Gross ML, et al. 1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat. Am J Physiol Renal Physiol. 2004;286:F526–33.
Branisteanu DD, Leenaerts P, van Damme B, Bouillon R. Partial prevention of active Heymann nephritis by 1 alpha, 25 dihydroxyvitamin D3. Clin Exp Immunol. 1993;94:412–17.
Hirata M, Makibayashi K, Katsumata K, et al. 22-Oxacalcitriol prevents progressive glomerulosclerosis without adversely affecting calcium and phosphorus metabolism in subtotally nephrectomized rats. Nephrol Dial Transplant. 2002;17:2132–7.
Piecha G, Kokeny G, Nakagawa K, et al. Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats. Am J Physiol Renal Physiol. 2008;294:F748–57.
Coen G, Mazzaferro S, Manni M, et al. No acceleration and possibly slower progression of renal failure during calcitriol treatment in predialysis chronic renal failure. Nephrol Dial Transplant. 1994;9:1520.
Thomas MC, Cooper ME. Into the light? Diabetic nephropathy and vitamin D. Lancet. 2010;376:1521–2.
Alborzi P, Patel NA, Peterson C, et al. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension. 2008;52:249–55.
Agarwal R, Acharya M, Tian J, et al. Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int. 2005;68:2823–8.
Fishbane S, Chittineni H, Packman M, Dutka P, Ali N, Durie N. Oral paricalcitol in the treatment of patients with CKD and proteinuria: a randomized trial. Am J Kidney Dis. 2009;54:647–52.
Tan X, Wen X, Liu Y. Paricalcitol inhibits renal inflammation by promoting vitamin D receptor-mediated sequestration of NF-kappaB signaling. J Am Soc Nephrol. 2008;19:1741–52.
Mizobuchi M, Morrissey J, Finch JL, et al. Combination therapy with an angiotensin-converting enzyme inhibitor and a vitamin D analog suppresses the progression of renal insufficiency in uremic rats. J Am Soc Nephrol. 2007;18:1796–806.
de Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010;376:1543–51.
Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 2007;71:31–8.
Ravani P, Malberti F, Tripepi G, et al. Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int. 2009;75:88–95.
Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K. Association of activated vitamin D treatment and mortality in chronic kidney disease. Arch Intern Med. 2008;168:397–403.
Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003;349:446–56.
Palmer SC, McGregor DO, Macaskill P, Craig JC, Elder GJ, Strippoli GF. Meta-analysis: vitamin D compounds in chronic kidney disease. Ann Intern Med. 2007;147:840–53.
Palmer SC, McGregor DO, Craig JC, Elder G, Macaskill P, Strippoli GF. Vitamin D compounds for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev. 2009;(4):CD008175.
Palmer SC, McGregor DO, Craig JC, Elder G, Macaskill P, Strippoli GF. Vitamin D compounds for people with chronic kidney disease requiring dialysis. Cochrane Database Syst Rev. 2009;(4):CD005633.
Al-Aly Z. Vitamin D as a novel nontraditional risk factor for mortality in hemodialysis patients: the need for randomized trials. Kidney Int. 2007;72:909–11.
Gutierrez OM. Fibroblast growth factor 23 and disordered vitamin D metabolism in chronic kidney disease: updating the “trade-off” hypothesis. Clin J Am Soc Nephrol. 2010;5:1710–16.
Juppner H, Wolf M, Salusky IB. FGF-23: more than a regulator of renal phosphate handling? J Bone Miner Res. 2010;25:2091–7.
Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol. 2007;18:1637–47.
Wahl P, Wolf M. FGF23 in chronic kidney disease. Adv Exp Med Biol. 2012;728:107–25.
Gutierrez O, Isakova T, Rhee E, et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol. 2005;16:2205–15.
Shigematsu T, Kazama JJ, Yamashita T, et al. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis. 2004;44:250–6.
Seiler S, Reichart B, Roth D, Seibert E, Fliser D, Heine GH. FGF-23 and future cardiovascular events in patients with chronic kidney disease before initiation of dialysis treatment. Nephrol Dial Transplant. 2010;25:3983–9.
Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359:584–92.
Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant. 2009;24:2792–6.
Nasrallah MM, El-Shehaby AR, Salem MM, Osman NA, El Sheikh E, Sharaf El, Din UA. Fibroblast growth factor-23 (FGF-23) is independently correlated to aortic calcification in haemodialysis patients. Nephrol Dial Transplant. 2010;25:2679–85.
Gutierrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009;119:2545–52.
Wesseling-Perry K, Pereira RC, Wang H, et al. Relationship between plasma fibroblast growth factor-23 concentration and bone mineralization in children with renal failure on peritoneal dialysis. J Clin Endocrinol Metab. 2009;94:511–17.
Gutierrez OM, Wolf M. Dietary phosphorus restriction in advanced chronic kidney disease: merits, challenges, and emerging strategies. Semin Dial. 2010;23:401–6.
Oliveira RB, Cancela AL, Graciolli FG, et al. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol. 2010;5:286–91.
Muller D, Mehling H, Otto B, et al. Niacin lowers serum phosphate and increases HDL cholesterol in dialysis patients. Clin J Am Soc Nephrol. 2007;2:1249–54.
Wetmore JB, Liu S, Krebill R, Menard R, Quarles LD. Effects of cinacalcet and concurrent low-dose vitamin D on FGF23 levels in ESRD. Clin J Am Soc Nephrol. 2010;5:110–16.
Nishi H, Nii-Kono T, Nakanishi S, et al. Intravenous calcitriol therapy increases serum concentrations of fibroblast growth factor-23 in dialysis patients with secondary hyperparathyroidism. Nephron Clin Pract. 2005;101:c94–9.
Tomoe Y, Segawa H, Shiozawa K, et al. Phosphaturic action of fibroblast growth factor 23 in Npt2 null mice. Am J Physiol Renal Physiol. 2010;298:F1341–50.
Farrow EG, Davis SI, Summers LJ, White KE. Initial FGF23-mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol. 2009;20:955–60.
Saito A, Kaseda R, Hosojima M, Sato H. Proximal tubule cell hypothesis for cardiorenal syndrome in diabetes. Int J Nephrol. 2011;2011:957164.
Mirza MA, Alsio J, Hammarstedt A, et al. Circulating fibroblast growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly individuals. Arterioscler Thromb Vasc Biol. 2011;31:219–27.
Frankenfield DL, Rocco MV, Roman SH, McClellan WM. Survival advantage for adult Hispanic hemodialysis patients? Findings from the end-stage renal disease clinical performance measures project. J Am Soc Nephrol. 2003;14:180–6.
Wolf M, Betancourt J, Chang Y, et al. Impact of activated vitamin D and race on survival among hemodialysis patients. J Am Soc Nephrol. 2008;19:1379–88.
Isakova T, Ix JH, Sprague SM, et al. Rationale and approaches to phosphate and fibroblast growth factor 23 reduction in CKD. J Am Soc Nephrol. 2015 May 12; pii: ASN2015020117. [Epub ahead of print].
Hurt RT, Kulisek C, Buchanan LA, McClave SA. The obesity epidemic: challenges, health initiatives, and implications for gastroenterologists. Gastroenterol Hepatol (N Y). 2010;6:780–92.
Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med. 2005;352:1138–45.
Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of comorbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009;9:88.
Pi-Sunyer X. The medical risks of obesity. Postgrad Med. 2009;121:21–33.
McAllister EJ, Dhurandhar NV, Keith SW, et al. Ten putative contributors to the obesity epidemic. Crit Rev Food Sci Nutr. 2009;49:868–913.
Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Trans fatty acids and cardiovascular disease. N Engl J Med. 2006;354:1601–13.
Mente A, de Koning L, Shannon HS, Anand SS. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med. 2009;169:659–69.
Mozaffarian D, Aro A, Willett WC. Health effects of trans-fatty acids: experimental and observational evidence. Eur J Clin Nutr. 2009;63(Suppl 2):S5–21.
Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009;119:1322–34.
Tappy L, Le KA. Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev. 2010;90:23–46.
Yang Q. Gain weight by “going diet?” Artificial sweeteners and the neurobiology of sugar cravings: neuroscience 2010. Yale J Biol Med. 2010;83:101–8.
Smeets PA, de Graaf C, Stafleu A, van Osch MJ, van der Grond J. Functional magnetic resonance imaging of human hypothalamic responses to sweet taste and calories. Am J Clin Nutr. 2005;82:1011–16.
de Araujo IE, Oliveira-Maia AJ, Sotnikova TD, et al. Food reward in the absence of taste receptor signaling. Neuron. 2008;57:930–41.
Cui M, Jiang P, Maillet E, Max M, Margolskee RF, Osman R. The heterodimeric sweet taste receptor has multiple potential ligand binding sites. Curr Pharm Des. 2006;12:4591–600.
Ogden CL, Yanovski SZ, Carroll MD, Flegal KM. The epidemiology of obesity. Gastroenterology. 2007;132:2087–102.
Nguyen S, Hsu CY. Excess weight as a risk factor for kidney failure. Curr Opin Nephrol Hypertens. 2007;16:71–6.
Hsu CY, McCulloch CE, Iribarren C, Darbinian J, Go AS. Body mass index and risk for end-stage renal disease. Ann Intern Med. 2006;144:21–8.
Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet. 2005;366:1640–9.
Ejerblad E, Fored CM, Lindblad P, Fryzek J, McLaughlin JK, Nyren O. Obesity and risk for chronic renal failure. J Am Soc Nephrol. 2006;17:1695–702.
Pinto-Sietsma SJ, Navis G, Janssen WM, de Zeeuw D, Gans RO, de Jong PE. A central body fat distribution is related to renal function impairment, even in lean subjects. Am J Kidney Dis. 2003;41:733–41.
Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int. 2001;59:1498–509.
Griffin KA, Kramer H, Bidani AK. Adverse renal consequences of obesity. Am J Physiol Renal Physiol. 2008;294:F685–96.
Kovesdy CP, Anderson JE. Reverse epidemiology in patients with chronic kidney disease who are not yet on dialysis. Semin Dial. 2007;20:566–9.
Evans M, Fryzek JP, Elinder CG, et al. The natural history of chronic renal failure: results from an unselected, population-based, inception cohort in Sweden. Am J Kidney Dis. 2005;46:863–70.
Kovesdy CP, Anderson JE, Kalantar-Zadeh K. Paradoxical association between body mass index and mortality in men with CKD not yet on dialysis. Am J Kidney Dis. 2007;49:581–91.
Peralta CA, Kurella M, Lo JC, Chertow GM. The metabolic syndrome and chronic kidney disease. Curr Opin Nephrol Hypertens. 2006;15:361–5.
Chen J, Muntner P, Hamm LL, et al. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med. 2004;140:167–74.
Joles JA, Kunter U, Janssen U, et al. Early mechanisms of renal injury in hypercholesterolemic or hypertriglyceridemic rats. J Am Soc Nephrol. 2000;11:669–83.
Lin J, Judd S, Le A, et al. Associations of dietary fat with albuminuria and kidney dysfunction. Am J Clin Nutr. 2010;92:897–904.
Johnson RJ, Sanchez-Lozada LG, Nakagawa T. The effect of fructose on renal biology and disease. J Am Soc Nephrol. 2010;21:2036–9.
Gersch MS, Mu W, Cirillo P, et al. Fructose, but not dextrose, accelerates the progression of chronic kidney disease. Am J Physiol Renal Physiol. 2007;293:F1256–61.
Nguyen S, Choi HK, Lustig RH, Hsu CY. Sugar-sweetened beverages, serum uric acid, and blood pressure in adolescents. J Pediatr. 2009;154:807–13.
Lin J, Curhan GC. Associations of sugar and artificially sweetened soda with albuminuria and kidney function decline in women. Clin J Am Soc Nephrol. 2011;6:160–6.
Alexander MP, Patel TV, Farag YM, Florez A, Rennke HG, Singh AK. Kidney pathological changes in metabolic syndrome: a cross-sectional study. Am J Kidney Dis. 2009;53:751–9.
Welsh GI, Hale LJ, Eremina V, et al. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab. 2010;12:329–40.
Fornoni A. Proteinuria, the podocyte, and insulin resistance. N Engl J Med. 2010;363:2068–9.
de Boer IH. DCCT EDIC Research Group. Kidney disease and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37:24–30.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837–53.
Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103–17.
Zoungas S, Chalmers J, Neal B, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371:1392–406.
Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376:419–30.
Hemmingsen B, Lund SS, Gluud C, et al. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013;11:CD008143.
Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364–79.
American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014;37(Suppl 1):S14–80.
Feig DI. Uric acid: a novel mediator and marker of risk in chronic kidney disease? Curr Opin Nephrol Hypertens. 2009;18:526–30.
Ben-Dov IZ, Kark JD. Serum uric acid is a GFR-independent long-term predictor of acute and chronic renal insufficiency: the Jerusalem Lipid Research Clinic cohort study. Nephrol Dial Transplant. 2011;26:2558–66.
Kanji T, Gandhi M, Clase CM, Yang R. Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis. BMC Nephrol. 2015;16:58.
Kovesdy CP, Kalantar-Zadeh K. Oral bicarbonate: renoprotective in CKD? Nat Rev Nephrol. 2010;6:15–7.
Kraut JA, Madias NE. Consequences and therapy of the metabolic acidosis of chronic kidney disease. Pediatr Nephrol. 2011;26:19–28.
Driver TH, Shlipak MG, Katz R, et al. Low serum bicarbonate and kidney function decline: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis. 2014;64:534–41.
Goldenstein L, Driver TH, Fried LF, et al. Serum bicarbonate concentrations and kidney disease progression in community-living elders: the Health, Aging, and Body Composition (Health ABC) Study. Am J Kidney Dis. 2014;64:542–9.
Lo LJ, Go AS, Chertow GM, et al. Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease. Kidney Int. 2009;76:893–9.
Liu KD. Acute kidney injury: is acute kidney injury a risk factor for long-term mortality? Nat Rev Nephrol. 2010;6:389–91.
Oparil S, Schmieder RE. New approaches in the treatment of hypertension. Circ Res. 2015;116:1074–95.