Many glomerular diseases, such as those associated with diabetes mellitus or systemic lupus erythematosus, exhibit renal retention of salt and water. The cause of this sodium retention is not precisely known, but it probably involves disordered regulation of the renal microcirculation and tubular function through release of vasoconstrictors, prostaglandins, cytokines, and other mediators. When edema or hypertension develops in these patients, diuretic therapy can be very effective.
Certain forms of renal disease, particularly diabetic nephropathy, are frequently associated with development of hyperkalemia at a relatively early stage of renal failure. This is often due to type IV renal tubular acidosis. In these cases, a thiazide or loop diuretic will enhance K+ excretion by increasing delivery of salt to the K+secreting collecting tubule.
Patients with renal diseases leading to the nephrotic syndrome often present complex problems in volume management. These patients may exhibit fluid retention in the form of ascites or edema but have reduced plasma volume due to reduced plasma oncotic pressures. This is very often the case in patients with “minimal change” nephropathy. In these patients, diuretic use may cause further reductions in plasma volume that can impair GFR and may lead to orthostatic hypotension. Most other causes of nephrotic syndrome are associated with primary retention of salt and water by the kidney, leading to expanded plasma volume and hypertension despite the low plasma oncotic pressure. In these cases, diuretic therapy may be beneficial in controlling the volume-dependent component of hypertension.
In choosing a diuretic for the patient with kidney disease, there are a number of important limitations. Acetazolamide must usually be avoided because it causes NaHCO3 excretion and can exacerbate acidosis. Potassium-sparing diuretics may cause hyperkalemia. Thiazide diuretics are thought to be ineffective when GFR falls below 30 mL/min, although the exact GFR at which they no longer prove to be beneficial is still a matter of debate. In addition, it has been found that thiazides can be used to significantly reduce the dose of loop diuretics needed to promote diuresis in a patient with a GFR of 5–15 mL/min. Thus, high-dose loop diuretics (up to 500 mg/d of furosemide) or a combination of metolazone (5–10 mg/d) with furosemide (40–80 mg/d) may be useful in treating volume overload in dialysis or predialysis patients. Finally, although excessive use of diuretics can impair renal function in all patients, the consequences are obviously more serious in patients with underlying renal disease.
Liver disease is often associated with edema and ascites in conjunction with elevated portal hydrostatic pressures and reduced plasma oncotic pressures. Mechanisms for retention of Na+ by the kidney in this setting include diminished renal perfusion (from systemic vascular alterations), diminished plasma volume (due to ascites formation), and diminished oncotic pressure (hypoalbuminemia). In addition, there may be primary Na+ retention due to elevated plasma aldosterone levels.
When ascites and edema become severe, diuretic therapy can be very useful. However, cirrhotic patients are often resistant to loop diuretics because of decreased secretion of the drug into the tubular fluid and because of high aldosterone levels. In contrast, cirrhotic edema is unusually responsive to spironolactone and eplerenone. The combination of loop diuretics and an aldosterone receptor antagonist may be useful in some patients. However, considerable caution is necessary in the use of aldosterone antagonists in cirrhotic patients with even mild renal insufficiency because of the potential for causing serious hyperkalemia.