Chronic Kidney Disease and its Main Comorbidities

Chronic kidney disease is also called chronic renal failure and chronic renal insufficiency. If the disease is severe enough to require renal therapy, it is termed end stage renal disease. According to the US Renal Data System (2016), Medicare spent over $50 billion in 2013 for patients ages 64 and older with Chronic Kidney Disease (CKD). They estimated that about 20% of the money spent on all patients 65 years or older was spent on CKD. In reality, the real cost of CKD is much higher since Medicare only covers about 80% of the people with End-Stage Renal Disease (ESRD).

The definition of chronic kidney disease was initially proposed in 2002 by the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) and was later adopted by the international community, specifically, the Kidney Disease Improving Global Outcomes (KDIGO) (Levey et al., 2003). Chronic kidney disease is defined as kidney damage or glomerular filtration rate < 60 ml/min/1.73 m2 for 3 months or more regardless of the original cause (KDIGO, 2012). Based on this definition, it is possible for a patient to have chronic kidney disease with a normal GFR. Kidney damage in the above definition refers to renal pathology whether established by imaging studies, renal biopsy or deduced from urine sediment abnormalities including increased rates of albumin excretion. Increased rate of albumin excretion is termed albuminuria and, it is an indirect measure of glomerular permeability. It is defined as an albumin-to-creatinine ratio > 30mg/g in two out of three urine specimens. In effect, albuminuria reflects increased glomerular permeability to macromolecules.

The GFR is equivalent to the sum of the individual filtration rates of the remaining functioning nephrons. The glomeruli filter about 180 liters of plasma per day which is about 125 ml/min for a normal adult that is 130 ml/min/1.73 m2 in young men and 120 ml/min/1.73 m2 in young women (Stevens, Coresh, Greene, & Levey, 2006).

Currently, the glomerular filtration rate (GFR) is the best indicator of renal function for both patients with no disease and patients with kidney dysfunction. However, it is just an estimate based on age, sex, race and the serum creatinine level. The assumption made when calculating the GFR is that the serum creatinine has been stable for several days.

Creatinine is an amino acid derivative that is freely filtered by the glomerulus. However, its secretion is inhibited by drugs including Trimethoprim and cimetidine thereby reducing its clearance and falsely altering the GFR. Also, the level of creatinine is affected by muscle mass and dietary intake. Given the tendency of creatinine to vary, it is important to get an idea of how the creatinine is fairing by getting a trend rather than a single measurement.

The difference between chronic kidney disease and acute kidney injury is the duration of the kidney damage. If the damage persists for three months or less, it is termed acute kidney injury.

In 2012, KDIGO published a clinical practice guideline for the evaluation and management of Chronic Kidney disease which sought to provide guidance in the evaluation, management and treatment of patients with chronic kidney disease. They recommended a new method of staging CKD which is based on its cause, the GFR category and albuminuria category (KDIGO, 2012).

The causes of CKD are myriad including immune diseases (such as lupus nephritis, membranous nephropathy and minimal change disease), glomerular diseases leading to renal damage (such as diabetes mellitus, systemic infection and neoplasms), vascular disease (such as hypertension, atherosclerosis, ischemia and vasculitis), cystic and congenital diseases (such as polycystic kidney disease and Alport syndrome), Long standing obstruction (such as kidney stones and benign prostatic hyperplasia), toxic exposures (such as nephrotoxic medications, iv contrast and gadolinium used for radiologic studies) and renal tubular disorders (such as renal tubular acidosis, nephrogenic diabetes insipidus and urinary tract infections including pyelonephritis).

In the United States, there are two conditions which have been reported to account for more than 50% of all cases of CKD. Diabetes mellitus accounts for 33% of adult CKD and, hypertension accounts for 21% of CKD. More specifically, renal artery stenosis has been reported to account for 11-14% of end stage renal failure (KDIGO, 2012 and Murphree & Thelen, 2010). 

KDIGO in 2012 established GFR categories as follows:

G1 category for a GFR > 90ml/min (Normal),

G2 category for a GFR 60-89 ml/min (Mildly decreased),

G3a for a GFR of 45-59 ml/min (Mildly to moderately decreased),

G3b for a GFR of 30-44 ml/min (Moderately to severely decreased),

G4 for a GFR of 15-29 ml/min (Severely decreased),

G5 for a GFR < 15 ml/min (Kidney failure)

Note that the G5 category is termed End Stage Renal disease.

KDIGO also established a system to categorize Albuminuria

Normal young adult - albumin to creatinine ratio < 10 mg/g

A1 category for an albumin to creatinine ratio < 30 mg/g (Normal to mildly increased)

A2 category for an albumin to creatinine ratio 30-300 mg/g (Moderately increased)

A3 category for an albumin to creatinine ratio >300 mg/g (Severely increased)

Risk factors for chronic kidney disease can be divided to two categories, demographic and clinical factors. Demographic factors include: male sex, older age, African-American race and Hispanic ethnicity. Clinical factors include a family history of CKD, diabetes, hypertension, hyperlipidemia, cardiovascular disease, smoking and obesity.

According to Grams et al (2013), in the United States, the overall lifetime risk of CKD stage 3a+ was 59.1%, for stage 3b+ the risk was 33.6%, for stage 4 + the risk was 11.5% and lastly the risk for ESRD was 3.6%. They also noted that the risk of CKD increased significantly with age estimating that almost 50% of all cases of CKD in the United States occurred in patients over the age of 70. Overall, they determined that women were at greater risk for CKD compared to men. However, fewer women progressed to ESRD compared to men.

Diabetes Mellitus is the greatest contributor to CKD in the United States and worldwide. Cardiovascular disease is the number one cause of morbidity and mortality in patients with CKD (at every stage).  Manifestations of cardiovascular disease in CKD include heart failure, left ventricular hypertrophy, ischemic heart disease, and peripheral vascular disease (Zalunardo & Levin, 2009). Other comorbidities include depression, sexual dysfunction, calciphylaxis and malnutrition just to name a few.

Diabetes Mellitus is present in about 30-40% of all patients with a diagnosis of ESRD.      According to Wu et al. (2016) the prevalence of Type II diabetes mellitus was 58.7% in patients with CKD 65 years or older and only 25.7% in patients less than 65 years old. Interestingly, they noted that comorbidities such as older age, higher hemoglobin A1c, increased systolic blood pressure and a history of hypertension were all significantly associated with the presence of CKD but did not confer an increase severity of CKD.

Of the patients less than age 65 who had CKD and Type II diabetes mellitus, about 73% of the patients were identified to be in the earlier stages of renal failure implying that it provides an opportunity to identify patients earlier in the disease process and slow, or effectively prevent, their progression to ESRD. Surprisingly, they identified that the incidence of CKD in type II diabetes mellitus was essentially equal between men and women. However, women with type II diabetes had a higher prevalence of severe CKD compared to men. Of note, there is a potential survivor bias which may be affecting this prevalence suggesting further studies should be done to confirm these findings.

ESRD was two to three times more prevalent among blacks compared with other races and ethnicities as shown by Wu et al. (2016) as well as Burrows, Li, & Williams (2008) who noted that ESRD with diabetes amongst blacks was twice as high when compared to Hispanics and four times as high compared to whites. The Burrows, Li & Williams (2008) study addressed the incidence of ESRD with type II diabetes mellitus between the years 1995-2005 while the Wu et al. study focused between the years 2007-2012. These studies highlight a social issue which is the fact that Blacks and Hispanics may have worse access to health care compared to White Americans.

It has been established that control of hypertension and hyperglycemia is critical in preventing the progression of CKD to ESRD in the Type 2 DM population (Williams, 2013 and Riegersperger & Sunder-Plassmann, 2007). The recommended target for glycemic control has been established as a hemoglobin A1C < 7 (Esposito, Chiodini, Bellastella, Maioriono, & Giugliano, 2011). In patients with CKD who have proteinuria (> 1g/24 hours) or diabetes, the target goal for blood pressure is 130/80 mmHg. A recent study by Wu et al. (2016) confirmed the validity of the NKF KDOQI guidelines which proposed that ACE inhibitors and ARBs are effective in slowing down the progression of kidney disease among patients who have hypertension and Type 2 diabetes.

As mentioned above, cardiovascular disease remains the leading cause of morbidity and mortality in CKD. It has been purported that the risk of cardiovascular disease is up to 200 fold higher compared to patients without CKD. They also report that up to 45% of the patients reaching stage 5 of CKD already have advanced manifestations of cardiovascular disease (Bargman & Skorecki, 2015).

In patients with CKD, the risk of death secondary to cardiovascular disease is much higher than the risk of a patient going on renal replacement therapy such as dialysis (Zalunardo & Levin, 2009). Patients with CKD who progress to ESRD necessitating dialysis have an astounding mortality rate of approximately 20% per year.  Meaning that about 1 in 5 of these patients will die each year. Dialysis alone increases the mortality rate from cardiovascular disease by more than 100 times greater than that of patients with normal kidney function.

Velde et al. (2011) showed that a reduced glomerular filtration rate as well as proteinuria are associated with an increased risk of cardiovascular disease even in patients who were not selected based on their extent of cardiovascular and renal disease. The increased cardiovascular risk can be partly explained by the increase in traditional risk factors associated with both diseases including diabetes, hypertension and metabolic syndrome.

There are multiple manifestations of cardiovascular disease in the patients with CKD which are ischemic vascular disease, hypertension and left ventricular hypertrophy as well as heart failure (Bargman & Skorecki, 2015). Ischemic cardiovascular disease manifestations include; peripheral vascular disease, occlusive coronary and cerebrovascular events. The increased risk inferred to patients with CKD originate from both classic risk factors (hypertension, hypervolemia, dyslipidemia, over activity of the sympathetic nervous system, and increased homocysteinemia) as well as CKD related risk factors (anemia, hyperthyroidism, sleep apnea, hyperphosphatemia and generalized inflammation).

Hypertension is a very common complication of CKD and it usually occurs very early in its course. It has been associated with a more rapid decline in renal function. Anemia and the presence of an arteriovenous fistula used for hemodialysis have been associated with a state of high output heart failure.

Water and salt retention are a consequence of chronic kidney disease and these can lead to heart failure and pulmonary edema. Pulmonary edema can sometimes, in the absence volume overload, be secondary to the increased permeability of the pulmonary capillaries due to the effects of uremia.

Additionally, hemodialysis treatments may themselves increase the risk of coronary ischemia given the frequent episodes of hypotension and hypovolemia may repeatedly abuse the myocardium. Note however that the greatest percentage of cardiovascular mortality in dialysis patients is not myocardial infarction but rather congestive heart disease and all of its ramifications including sudden cardiac death.

Lastly, the use of erythropoiesis stimulating agents such as Epogen have been shown to increase systemic blood pressure.

It is recommended that patients with CKD be referred to a nephrologist earlier rather than later and this action has been associated with decreased mortality. In patients with CKD who have proteinuria (> 1g/24 hours) or diabetes, the target goal for blood pressure is 130/80 mmHg.

In patients with ESRD, consider erythropoiesis-stimulating agents to treat anemia with target hemoglobin levels < 12g/dL (KDIGO, 2012). Previously, the challenge of treating chronic anemia associated with CKD led to the frequent transfusion of blood products amongst CKD patients. Frequent blood transfusions subsequently lead to the development of alloantibodies which sensitize the patient to potential donor antigens making a renal transplant more challenging.

Lipid lowering therapy with Statins has been shown to reduce major cardiovascular events in patients with ESRD who are not yet on dialysis (Bargman & Skorecki, 2015). The use of folic acid has not been shown to reduce cardiovascular disease in patients with CKD. CKD patients should be vaccinated for Hepatitis B, Influenza and Pneumococcus. Finally, when the GFR < 30 ml/min (Stage IV CKD), the clinicians should start discussing renal replacement therapy with the patient. Options include transplant, peritoneal dialysis and hemodialysis. Renal transplantation is the gold standard of renal replacement therapy in patients with ESRD. With the advent of better rejection drugs, it is now possible to transplant patients with less perfectly matched antigen-antibody profiles. 

Bargman J.M., & Skorecki K. (2015). Chronic Kidney Disease. In Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J (Eds), Harrison's Principles of Internal Medicine, 19e. Retrieved April 30, 2016. (Visit Source)

Burrows, N. R., Li, Y., & Williams, D. E. (2008). Racial and Ethnic Differences in Trends of End-Stage Renal Disease: United States, 1995 to 2005. Advances in Chronic Kidney Disease, 15(2), 147-152. doi:10.1053/j.ackd.2008.01.002

Esposito, K., Chiodini, P., Bellastella, G., Maiorino, M. I., & Giugliano, D. (2011). Proportion of patients at HbA1c target. Diabetes, Obesity and Metabolism, 14(3), 228-233. doi:10.1111/j.1463-1326.2011.01512.x

Grams, M. E., Chow, E. K., Segev, D. L., & Coresh, J. (2013). Lifetime Incidence of CKD Stages 3-5 in the United States. American Journal of Kidney Diseases, 62(2), 245-252. doi:10.1053/j.ajkd.2013.03.009.

Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney inter., Suppl. 2013; 3: 1–150.

Levey, A. S., Coresh, J., Balk, E., Kausz, A., Levin, A., Steffes, M.W.,…Eknoyan, G. (2003). National Kidney Foundation Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Annals of Internal Medicine 139(2), 137-147. doi:10.7326/0003-4819-139-2-200307150-00013

Murphree, D. D., & Thelen, S. M. (2010). Chronic Kidney Disease in Primary Care. The Journal of the American Board of Family Medicine, 23(4), 542-550. doi:10.3122/jabfm.2010.04.090129

Riegersperger, M., & Sunder-Plassmann, G. (2007). How to Prevent Progression to End Stage Renal Disease. Journal of Renal Care, 33(3), 105-107. doi:10.1111/j.1755-6686.2007.tb00053.x

Standards of medical care in diabetes–2015 Diabetes Care 2015;38 (Suppl 1): S1–S2.

Stevens, L. A., Coresh, J., Greene, T., & Levey, A. S. (2006). Assessing Kidney Function — Measured and Estimated Glomerular Filtration Rate. New England Journal of Medicine N Engl J Med, 354(23), 2473-2483. doi:10.1056/nejmra054415

US Renal Data System 2015 Annual Data Report: Epidemiology of Kidney Disease in the United States. (2016). American Journal of Kidney Diseases, 67(3). doi:10.1053/j.ajkd.2015.12.015

Velde, M. V., Matsushita, K., Coresh, J., Astor, B. C., Woodward, M., Levey, A. S., . . . Gansevoort, R. T. (2011). Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney International, 79(12), 1341-1352. doi:10.1038/ki.2010.536

White, C. A., Akbari, A., Doucette, S., Fergusson, D., & Knoll, G. A. (2009). Estimating Glomerular Filtration Rate in Kidney Transplantation: Is the New Chronic Kidney Disease Epidemiology Collaboration Equation Any Better? Clinical Chemistry, 56(3), 474-477. doi:10.1373/clinchem.2009.135111

Williams, M. E. (2013). Diabetic Kidney Disease in Elderly Individuals. Medical Clinics of North America, 97(1), 75-89. doi:10.1016/j.mcna.2012.10.011

Wu, B., Bell, K., Stanford, A., Kern, D. M., Tunceli, O., Vupputuri, S., … Willey, V. (2016). Understanding CKD among patients with T2DM: prevalence, temporal trends, and treatment patterns—NHANES 2007–2012. BMJ Open Diabetes Research & Care, 4(1), e000154. (Visit Source)

Zalunardo N, Levin A (2009). Chapter 19. Cardiovascular Disease in Chronic Kidney Disease. In Lerma E.V., Berns J.S., Nissenson A.R. (Eds), CURRENT Diagnosis & Treatment: Nephrology & Hypertension