Chronic renal insufficiency is the stage in chronic renal disease in which damage to the kidney has already impaired renal function but systemic manifestations are minimal. Because most patients with renal insufficiency are asymptomatic, the disease is usually identified because the serum creatinine levels are slightly elevated. Patients with chronic renal insufficiency typically have a GFR within the range of 30-75 ml/min.

In chronic renal failure, the renal dysfunction has progressed to a level that results in systemic manifestations. These include a rise in the blood concentration of urea, creatinine, and phosphate (all of which are normally removed by the kidneys), and other manifestations such as anemia, bone disease, acidosis, and salt and fluid retention. Growth failure may be seen in children. Most patients with chronic renal failure progress to end-stage renal disease.

End-stage renal disease (ESRD) is generally an irreversible state during which renal replacement therapy (dialysis or kidney transplantation) is needed to sustain life. Glomerular filtration rate in ESRD is usually less than 10 ml/min.

Diabetes mellitus is the primary cause of ESRD. Diabetic renal disease (diabetic nephropathy) represents a long-term complication of diabetes that results from direct vascular abnormalities. One of the early renal manifestations of diabetes is the presence of small quantities of albumin in the urine (microalbuminuria), which is an early sign of kidney disease. Susceptible individuals eventually develop persistent proteinuria, which presents increased risks of developing progressive renal disease and of death due to CVD (see below). Hence, the vascular abnormalities accompanying diabetes can produce chronic renal disease that, in turn, increases the risk for CVD. This scenario illustrates the intimate interaction between the kidney and CVD: Kidney disease can represent either a cause or a consequence of CVD .

Kidney Disease as a Cause of CV Disease
A primary kidney defect can produce hypertension. Renal-dependent increases in blood pressure can result from renal artery stenosis, activation of the renin-angiotensin system, and overproduction of other vasoactive substances of renal origin. A primary kidney defect is not the usual underlying cause of hypertension. (The most prevalent form of hypertension is essential hypertension, the cause of which is unknown.) However, the importance of the kidney in maintaining a constant effective blood volume has led many investigators to believe that hypertension cannot be sustained if renal function is normal.

Renal disease can also have adverse effects on the composition of plasma and extracellular fluid. For example, electrolyte imbalances in renal disease can lead to cardiac arrhythmias. Renal disease can also adversely alter plasma lipid profiles. Hyperlipidemia during nephrotic syndrome results from both increased synthesis and decreased clearance of lipoproteins from the body. Typically, these patients display increased levels of VLDL, LDL and lipoprotein(a), with little change in HDL levels. These pro-atherosclerotic alterations in the plasma lipid profile represent significant risk factors for coronary artery disease.

Kidney Disease as a Consequence of CV Disease
Malignant and severe hypertension can cause renal damage that is dramatic, extensive, and rapidly progressive. Nephrosclerotic damage develops slowly and appears late in hypertension; however, the incidence of ESRD associated with hypertension is on the rise. There are several major obstacles impeding the goal of reducing the incidence of hypertension-induced renal failure: under-diagnosis of renal damage in hypertension, insufficient lowering of blood pressure in clinical practice, or inability of antihypertensive drugs to lower blood pressure sufficiently to preserve the kidney (a goal that may need specific drugs that act, for example, on the renin-angiotensin system).

Congestive heart failure can also cause renal failure. Early complications of cardiac insufficiency include renal vasoconstriction and the development of sodium and water retention, which are hallmarks of the very early stages of congestive heart failure. Heart failure is a physiologically delicate condition in which therapy is designed to block the sodium retention and simultaneously interrupt excessively activated neurohumoral mechanisms. Profound reduction of cardiac output and arterial hypotension in severe heart failure may lead to acute renal failure.

Risk Factors Linking the Kidney and CV Disease
Cardiovascular disease is the major cause of death among patients with ESRD. In the ESRD population, CVD mortality is estimated to be thirtyfold greater than among the general population. However, the increased risk of CVD is evident in patients with renal insufficiency (i.e., before the onset of ESRD). The interplay between the direct consequences of renal disease (increased serum creatinine levels and microalbuminuria) and other risk factors for CVD likely contribute to this phenomenon.

Hypertension, left ventricular hypertrophy, increased serum creatinine levels, and microalbuminuria are independent risk factors for CVD. Hypertension increases the risk of coronary artery disease, stroke, congestive heart failure, and renal failure. Left ventricular hypertrophy is a risk factor for coronary artery disease, congestive heart failure, stroke, and peripheral arterial disease. A serum creatinine level of >1.7 mg/dL (indicative of renal disease) in individuals with hypertension may be an even stronger CVD risk factor than diabetes, smoking, left ventricular hypertrophy, or systolic blood pressure. Similarly, microalbuminuria is a strong and independent predictor of CVD morbidity and mortality in individuals with and without diabetes and/or hypertension.

Microalbuminuria is a recognized early sign of kidney disease. Simple dipstick tests can detect larger amounts of albumin in the urine (albuminuria or proteinuria). The magnitude of albumin excretion is directly correlated with risk for ESRD and the rate of progression to renal failure. The greater the magnitude of albuminuria, the faster the decline in renal function. Moreover, at any given level of albuminuria, the higher the blood pressure, the more detrimental is the effect of albuminuria on progression to renal failure. Reduction of proteinuria slows the rate of loss of renal function. Therapeutic interventions that are known to reduce proteinuria include blood pressure control, ACE inhibitor therapy, dietary salt restriction and dietary protein restriction.

Microalbuminuria is also a strong independent risk factor for cardiovascular disease. In adults, persistent microalbuminuria suggests not only the existence of renal disease, but also an increase risk for myocardial infarction and stroke. Microalbuminuria itself does not cause cardiovascular disease; rather, its presence signals and identifies those individuals who require more intensive therapy and monitoring. A more thorough assessment and intensive therapy is required for other known cardiovascular risk factors (high blood pressure, abnormal lipids, etc.). Clinical situations in which albuminuria may be associated with increased adverse cardiovascular and renal events include diabetes mellitus, hypertension, obesity, and advanced age. Furthermore, African-Americans, Hispanics, Native Americans, Pacific Islanders, and individuals with a family history of cardiovascular or renal disease are at greater risk than Caucasians. The prevalence of microalbuminuria in hypertensive individuals ranges from 7-40% (depending on age, race, and ethnicity). The prevalence of microalbuminuria in diabetes mellitus ranges from 30-40%.

For further information, consult the following articles:

1. Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol 19(8): 1992-1997, 1999.
2. Brenner RM, Wrone EM. The epidemic of cardiovascular disease in end-stage renal disease. Curr Opin Nephrol Hypertens 8(3): 365-369, 1999.
3. Cirillo M, Stellato D, De-Santo NG. Systolic hypertension: the nephrologist's point of view. Miner Electrolyte Metab 25(1-2): 69-72, 1999.
4. Crook ED. The role of hypertension, obesity, and diabetes in causing renal vascular disease. Am J Med Sci 317(3): 183-188, 1999.
5. Eknoyan G. On the epidemic of cardiovascular disease in patients with chronic renal disease and progressive renal failure: a first step to improve the outcomes. Am J Kidney Dis. 32(5 Suppl 3): S1-S4, 1998.
6. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32(5 Suppl 3): S112-S119, 1998.
7. Hall WD. Abnormalities of kidney function as a cause and a consequence of cardiovascular disease. Am J Med Sci 317(3): 176-182, 1999.
8. Johnson RJ, Kivlighn SD, Kim YG, Suga S, Fogo AB. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis 33(2): 225-234, 1999.
9. Haysen GA, de Sain-van der Velden MGM. New insights into lipid metabolism in the nephrotic syndrome. Kidney Int. 55(Suppl 71): S18-S21, 1999.
10. Levey AS, Beto JA, Coronado BE, Eknoyan G, Foley RN, Kasiske BL, Klag MJ, Mailloux LU, Manske CL, Meyer KB, Parfrey PS, Pfeffer MA, Wenger NK, Wilson PW, Wright JT Jr. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney- Dis 32(5): 853-906, 1998.
11. Levey AS. Controlling the epidemic of cardiovascular disease in chronic renal disease: where do we start? Am J Kidney Dis 32(5 Suppl 3): S5-S13, 1998.
12. Ljungman S, Wikstrand J, Hartford M, Berglund G. Urinary albumin excretion--a predictor of risk of cardiovascular disease. A prospective 10-year follow-up of middle-aged nondiabetic normal and hypertensive men. Am J Hypertens 9(8): 770-778, 1996.
13. Massy ZA, Kasiske BL. Hyperlipidemia and its management in renal disease. Curr Opin Nephrol Hypertens 5(2): 141-146, 1996.
14. Mimran A, Ribstein J, Du-Cailar G. Microalbuminuria in essential hypertension. Curr Opin Nephrol Hypertens 8(3): 359-363, 1999.
15. Rostand SG, Drueke TB. Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure. Kidney Int 56(2): 383-392, 1999.
16. Wilson PW, Culleton BF. Epidemiology of cardiovascular disease in the United States. Am J Kidney Dis 32(5 Suppl 3): S56-S65, 1998.
17. Woolfson RG. Renal disease and the heart. Hosp Med 60(2): 85-89, 1999.
18. Zanchetti A, Stella A. Cardiovascular disease and the kidney: an epidemiologic overview. J Cardiovasc Pharmacol 33 Suppl 1: S1-S6, 1999.