Chronic Kidney Disease

Chronic Kidney Disease: A New Paradigm

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Over 26 million American adults have Chronic Kidney Disease (CKD) and millions of others are at risk.[1] Diabetes continues as the leading cause of CKD in the US (see Figure 1) and as of 2011, it has replaced hypertension as the leading cause of CKD in the world.[2-3] In 2012 there were over a million patients with Chronic Kidney Disease Stage 5 and 500,000 on dialysis, double the number in 1994, and is expected to double again by 2020.[4-5] Since diabetes and hypertension are diseases of aging, and the aging of America continues, the increase in the number of CKD patients will continue for the foreseeable future. The Government’s Healthy People 2020 goals acknowledges the burden of CKD and encourages practitioners to aggressively treat these patients to attempt to lower the morbidity and mortality caused by CKD.[6] This article highlights outcome-driven treatments that can assist the practitioner in accomplishing that goal.


Since the symptoms of CKD are very ethereal: tiredness, edema, trouble sleeping, cramps, forgetfulness, increased nighttime urination and poor appetite, the only way to make the diagnosis is by a serum creatinine blood test.[7] In order to adjust for normal age related loss of kidney function, the estimated Glomerular Filtration Rate (eGFR), calculated by the Modification of Diet in Renal Disease (MDRD) formula or a serum creatinine clearance using the Cockcroft-Gault formula is used to stage CKD.[8-9] (Figure 2)

These five (5) CKD stages, as defined by the National Kidney Foundation’s Kidney Disease Outcomes and Quality Improvement Initiative (KDOQI) first published in 2000, have been criticized for the last 10 years. The formulas have limitations at extremes of ages, weights, for some racial mixes and the very malnourished patient.[10-11] This has led to an over diagnosis of the early stages of CKD, especially in the elderly.[12] Furthermore, many believe that the earlier stages of CKD should be labeled as a ‘risk factor’ rather than a disease since the lost of function during aging is a normal phenomenon. There is a subgroup of early CKD patients who are at higher risk for adverse events. To subgroup the ‘high risk’ from the ‘low risk’ early CKD patient, multiple studies have shown that proteinuria is the single most persistent risk factor in increased progression of CKD.[13] Due to this, the stages of CKD now combine proteinuria and eGFR to identify which patient sub-groups need to be aggressively managed. (Figure 3)

Modifiable Risk Factors

Once the definition of CKD is made, management of the risk factors is paramount. Modifiable risk factors include

  • Cardiovascular (CV)
  • Hypertension (HTN)
  • Diabetic management (DM)

As early as 2000, data using a multivariable analysis showed a dramatic increase in the risk of death, CV events and hospitalization occurred with decreasing eGFR.[14] Risk of death increased sharply as the eGFR declined; from a 5 times increase of CV death at CKD 3b (eGFR 30-44mL/min/1.73m2) to a 14 times increase at CKD 5 (eGFR of <15mL/min/1.73m2). Risk of CV event showed a 17 times increase as the patient progressed from CKD 2 to CKD 5 while risk of hospitalization showed a 11 times increase during that same interval. (Figures 4-7) Since reducing CV risk should increase survival of CKD patients, it was believed that lipid lowering strategies should be effective for this population too. The large cardiovascular trials did not include CKD patients (4D, HOPE, CARE).[15] However, in 2010, the SHARP trial (Study of Heart and Renal Protection) specifically looked at decreasing CV risk by lowering lipid levels in CKD patients. The analysis sub-divided the groups by CKD stages and lipid levels.[16] Low density lipoproteins (LDLs) were decreased by 20-34mg/dL (simvastatin or simvastatin/ezetemide group) compared to placebo. Most importantly, there was a 17% overall risk reduction in cardiac endpoints for the treatment group. Secondary endpoints looked at progression of CKD and lipid lowering did not change the rate of progression of CKD (not unexpected) and the lowering of lipids did not change outcomes when the patients were already at CKD 5. It is felt that the mechanism of CV death in CKD 5 is due more to the effects of arterial calcification from renal osteodystrophy than to the cholesterol plaques seen in earlier stages of CKD.[17]

Blood pressure management of CKD patients to decrease progression to end stage renal disease has been shown to work in multiple trials.[8,18-23] Data collected by these trials has led to consensus statements identifying blood pressure goals for the CKD patient as less than 130/80 and the drug of choice as a renin-angiotensin-aldosterone (RAAS) system blocker such as an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB).[24-25] Recently published guidelines from Europe and KDIGO (Kidney Disease: Improving Global Outcomes) not only encourage the treatment of all CKD patients with RAAS blockers, they also reiterate the need for salt restriction in this cohort.[26] KDIGO went one step further and recommended treatment of all CKD patients with proteinuria, with or without hypertension, with a RAAS blocker. This radical idea (treating a disease the patient does not yet have) was suggested due to data showing inhibition of the RAAS system provides renal protection independent of blood pressure lowering.[27]

As the explosion of CKD patients occurred and the cardiac and diabetic management of these patients in the early phases of their disease has matured and progressed, survival of CKD patients improved substantially. Now, due to the identification and aggressive treatment of this population by primary care, the diabetic CKD patient is more likely to progress to End Stage Renal Disease and hemodialysis than they are to die of cardiovascular disease.[28] Thus, we will need to treat the diabetic patient as they progress through the stages of CKD. Newly published glycemic guidelines walk us through goals and treatment for our diabetic patients.[29] While the CKD patient is at higher risk for end organ damage, they are also at higher risk for hypoglycemia. The guidelines specify an A1C of about 7% as the goal for the CKD patient. The CKD 4/5 patient actually has an A1C goal greater than 7% due to the increased risk of hypoglycemia. Many CKD patients are on epogen for their CKD- induced anemia. Epogen will cause rapid red blood cell turn-over which will confound the A1C, causing it to be falsely low and not valid while the chromatography and agar gel electrophoresis used to calculate anA1C can be affected by urea and metabolic acidosis. As the kidney fails, so does the gluconeogenesis of the kidney. Thus, dosing of glycemic medications actually decreases as the kidney loses function.[7]


In 2012, what do we know about the management of the CKD patient to decrease the chance of CKD progression?

  1. Lowering the risks of cardiovascular disease by treating with a lipid lowering agent works and we need to be aggressive. While treatment decreases the death rate for the CKD patients, it does not slow CKD progression.
  2. Blood pressure control with a goal of <130/80 with our first line drug to be a RAAS blocker (ACEI or ARB). This has been shown to slow progression of CKD, especially in the proteinuric patient.
  3. Proteinuria is the most accurate predictor of patients who will progress rapidly to end stage kidney disease and dialysis. Decreasing proteinuria is effective in slowing the loss of the kidney.
  4. Diabetic control with an A1C goal of 7% and loosening the A1C goal at CKD 4/5. This has also been shown to slow the progression of CKD.

Randomized trials have shown us that with aggressive treatment, we can slow the progression of CKD allowing our patients to live longer and healthier lives than they did in the 20th century. Drugs on the horizon are showing promise in actually reversing CKD. Who knows what is in store for us in the 21st century?


Kim Zuber, PAC, MS, DFAAPA
Metropolitan Nephrology
Published on February 5, 2013

Kim Zuber, PAC practices nephrology in Alexandria, VA and Prince George’s, MD. She graduated from the St. Louis University PA program a number of years ago. She is the award winning past chair of the National Kidney Foundation’s Council of Advanced Practitioners, and speaks and writes for the NKF nationally.


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