Progressive Renal Impairment

The combination of diabetes mellitus and hypertension inexorably leads to diabetic nephropathy and is the major cause of end-stage renal failure. In numerous animal studies and in several small clinical trials, ACE inhibitors have been shown to significantly retard the loss of kidney function associated with diabetic nephropathy. A large, prospective, placebo-controlled study has clearly established that captopril slows the progression of diabetic nephropathy in patients with insulin- 

---

Dagoo T, Backman L, Mjornstedt L, Olausson M, Friman S. Progressive renal impairment in liver transplant recipients on a cyclosporine-based protocol 5 year follow-up with glomerular filtration rate measurements. Transplant Proc 1997 29 3116-3118. 

FIGURE 41-3. Linear relationship between 1/serum creatinine concentration and creatinine clearance (A) and 1/serum creatinine concentration as a function of time in a hypothetical patient with progressive renal impairment (B). The arrow indicates a change in the rate of progression, which may be related to a... 

Chronic renal failure almost always is caused by intrinsic renal diseases and is characterized by slow, progressive development. Unlike the acute condition, chronic renal impairment generally is irreversible. The degree or loss of kidney functional capacity in the chronic condition is best described in terms of the intact nephron hypothesis, in which the diseased kidney is comprised of nephrons that are essentially nonfunctional because of pathologic conditions together with normal nephrons. Progressive renal impairment is the result of an increasing fraction of nonfunctional nephrons. 

Serum creatinine concentration is constant unless there is a change in the rate of production of creatinine in the body or creatinine clearance. The creatinine clearance in normal kidneys is approximately 110 to 130 mL/min. This value declines with progressive renal impairment, and it drops to zero with severe renal impairment. Creatinine clearance values of 20 to 30 mL/min signify moderate renal impairment values of less than 10 mL/min signify several renal impairment. 

Calcium-phosphorus balance is mediated through a complex interplay of hormones and their effects on bone, GI tract, kidney, and parathyroid gland. As kidney disease progresses, renal activation of vitamin D is impaired, which reduces gut absorption of calcium. Low blood calcium concentration stimulates secretion of parathyroid hormone (PTH). As renal function declines, serum calcium balance can be maintained only at the expense of increased bone resorption, ultimately resulting in renal osteodystrophy (ROD) (Fig. 76-7). 

There are several different kinds of laboratory safety data that require interpretation. These include routine screening for study subject selection, diagnostic evaluation of the subject, identification of risk factors, monitoring the progress of the disease or treatment, detection of adverse reactions, determination of appropriate dosages for certain at-risk subject groups (e.g. those with renal impairment). 

Renal function impairment In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe CHF), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and with acute renal failure or death (rarely). No dosage adjustment is necessary for patients with renal impairment unless they are volume-depleted. AIIRAs are not dialyzable. 

Renai function impairment If increasing azotemia, oliguria, or reversible increases in BUN or creatinine occur during treatment of severe progressive renal disease, discontinue therapy. 

Myositis (inflammation of voluntary muscle) with or without increased CK, and muscle weakness, occur rarely. These conditions may progress to frank rhabdomy-olysis and renal impairment. 

In type 1 diabetes, diabetic nephropathy follows a predictable course from onset of diabetes to the onset of microalbuminuria to frank nephropathy to end-stage renal disease or death. Microalbuminuria (a tiny amount of protein in the urine) develops 10-14 years after onset of diabetes. Without treatment, clinical nephropathy follows within 5 years, and severe renal impairment leading to end-stage renal failure develops approximately 5 years later. Hypertension develops in association with microalbuminuria and progresses with diabetic nephropathy, further damaging the kidneys. Once end-stage renal disease (ESRD) is reached, the toxins in the body can no longer be cleared by the kidneys and, unless treated by dialysis, can build up to fatal levels. 

Controlling blood triglyceride and cholesterol levels helps prevent heart disease and possibly strokes, and may slow the progression of diabetic kidney disease. The current data point towards a target total cholesterol of <3.5 mmol/L if the patient has microalbuminuria, and statins are very widely prescribed in diabetic patients with renal impairment. 

To what extent long-term treatment with lithium impairs GFR is a matter of continued study (360). Lithium does not appear to impair GFR consistently, especially if correction is made for age-related changes in kidney function, although in one study there was an age-related reduction in 21% of 142 patients who had taken lithium for at least 15 years (366). There have been a few case reports of progressive renal insufficiency attributed to lithium, but it has not been possible to establish a cause-and-effect relation with absolute certainty. 

The results of two trials in patients with chronic nephropathy have reinforced the benefit of ACE inhibitors in slowing the progression of chronic renal insufficiency due to renal diseases other than diabetic nephropathy (13-15) and have provided sufficient information on the safety profile of these agents in chronic renal insufficiency. This was found to be essentially the same as in patients with normal renal function. The current practice of avoiding ACE inhibitors in severe renal insufficiency, to prevent further renal impairment and hyperkalemia, is no longer justified, although careful monitoring should still be observed. 

Mefenamic acid overdosage is characterized by nervous system symptoms, such as generalized seizures, agitation, and confusion, sometimes progressing to coma, gastrointestinal problems (bloody diarrhea, abdominal pain, and vomiting), and renal impairment (SEDA-13, 83) (SEDA-14, 95) (19). 

---