In chronic kidney disease (CKD), reduced clearance of certain solutes principally excreted by the kidney results in their retention in the body fluids. The solutes are end products of endogenous metabolism as well as exogenous substances (eg, drugs). The most commonly measured indicators of renal failure are blood urea nitrogen and serum creatinine. The renal clearance of creatinine (as calculated from a 24-hour urine collection) is often used as a surrogate measure of glomerular filtration rate (GFR).
Renal failure may be classified as acute or chronic depending on the rapidity of onset and the subsequent course of azotemia. An analysis of the acute or chronic development of renal failure is important in understanding physiologic adaptations, disease mechanisms, and ultimate therapy. In individual cases, it is often difficult to establish the duration of renal failure. Historical clues such as preceding hypertension or radiologic findings such as small, shrunken kidneys tend to indicate a more chronic process. Acute renal failure may progress to irreversible chronic renal failure. For a discussion of acute renal failure, see Chapter 33.
A new classification has been made by the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (K/DOQI). This delineates CKD by varying degrees of reduced GFR, either in the presence or absence of structural or functional renal abnormalities (available on the NFK Web site: http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm). This has been useful in studies of the progression of CKD, especially in varying drug regimens to reduce the rate of worsening of GFRs.
There are now numerous online calculators that can estimate a person's GFR (eGFR) based on the creatinine value, one example of which is available through the National Kidney Foundation (http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm). Although not perfect, these calculations help us to alert patients with subtle renal function impairment in the face of creatinine values within the normal reference ranges.
The incidence of end-stage renal disease (ESRD) reached 360 cases per million population in 2006, after a period of relative stability between 2001 and 2005. Almost all of this increase can be explained by the uptake in incidence of diabetic nephropathy over the same period (Figure 35–1). Particularly affected are older patients (75+ years old) and African Americans (3.6 times higher than Caucasians, Figure 35–2). The severity and the rapidity of development of uremia are hard to predict. The use of dialysis and transplantation is expanding rapidly worldwide. As of 2007, more than 340,000 prevalent ESRD patients in the United States are currently treated with hemodialysis, with around 26,000 patients treated with peritoneal dialysis. There are approximately 158,000 patients with a functioning kidney transplant.
There are various causes of progressive renal dysfunction leading to end-stage or terminal renal failure. In the 1800s, Bright described several dying patients who presented with edema, hematuria, and proteinuria. Chemical analyses of sera drew attention to retained nitrogenous compounds and an association was made between this and the clinical findings of uremia. Although the pathologic state of uremia was well described, long-term survival was not achieved until chronic renal dialysis and renal transplantation became available after 1960–1970. Significant improvements in patient survival have been made in the past 50 years.
A variety of disorders are associated with CKD. Either a primary renal process (eg, glomerulonephritis, pyelonephritis, congenital hypoplasia) or a secondary one (owing to a systemic process such as diabetes mellitus or lupus erythematosus) may be responsible. Once there is kidney injury, it is now felt that the initially adaptive hyperfiltration to undamaged nephron units produces further stress and injury to remnant kidney tissue, ultimately leading to worsening renal function and urinary abnormalities (ie, proteinuria). The patient will show progression from one stage of CKD severity to the next. Superimposed physiologic alterations secondary to dehydration, infection, obstructive uropathy, or hypertension may put a borderline patient into uncompensated chronic uremia.
With milder CKD, there may be no clinical symptoms. Symptoms such as pruritus, generalized malaise, lassitude, forgetfulness, loss of libido, nausea, and easy fatigability are frequent and nonfocal complaints in moderate to severe CKD. Growth failure is a primary complaint in preadolescent patients. Symptoms of a multisystem disorder (eg, systemic lupus erythematosus) may be present coincidentally. Most patients with CKD have elevated blood pressure secondary to volume overload or from hyperreninemia. However, the blood pressure may be normal or low if patients have marked renal salt-losing tendencies (eg, medullary cystic disease). The pulse and respiratory rates are rapid as manifestations of anemia and metabolic acidosis. Clinical findings of uremic fetor, pericarditis, neurologic findings of asterixis, altered mentation, and peripheral neuropathy are present only with severe, stage V CKD. Palpable kidneys suggest polycystic disease. Ophthalmoscopic examination may show hypertensive or diabetic retinopathy. Alterations involving the cornea/lens have been associated with metabolic disease (eg, Fabry disease, cystinosis, and Alport hereditary nephritis).
In 20% of cases, there is a family history of CKD. A report of antecedent nephritis episodes or a history of previous proteinuria may be elicited. It is important to review drug usage and possible toxic exposures (eg, lead).
The urine volume varies depending on the type of renal disease. Quantitatively normal amounts of water and salt losses in urine can be associated with polycystic and interstitial forms of disease. Usually, however, urine volumes are quite low when the GFR falls below 5% of normal. The urinary concentrating (fixed, low value specific gravity) and acidification (high urinary pH) mechanisms may be impaired. Daily salt losses become less regulated, and, if they are low, a state of positive sodium balance results in edema. Proteinuria can be variable. Urinalysis examinations may reveal mononuclear white blood cells (leukocyturia) and occasionally broad waxy casts, but usually the urinalysis is nonspecific and inactive.
Often seen is a picture of normocytic, normochromic anemia, the so-called anemia of chronic disease. With worsening renal function, iron deficiency may ensue. Despite normal platelet counts, patients suffer from dysfunction (thrombasthenia), characterized by abnormal bleeding times.
Several abnormalities in serum electrolytes and mineral metabolism become manifest when the GFR drops below 30 mL/min (in the case of secondary hyperparathyroidism, impairment may begin with GFR < 60 mL/min). Progressive reduction of body buffer stores and an inability to excrete titratable acids result in progressive metabolic acidosis characterized by reduced serum bicarbonate and compensatory respiratory hyperventilation. The metabolic acidosis of uremia is associated with a normal anion gap, hyperchloremia, and normokalemia. However, as renal dysfunction progresses, some patients may develop an anion gap acidosis (due to the buildup of organic anions). Hyperkalemia is not usually seen unless the GFR is below 5 mL/min. In patients with interstitial renal diseases, gouty nephropathy, or diabetic nephropathy, hyperchloremic metabolic acidosis with hyperkalemia (renal tubular acidosis, type IV) may develop. In these cases, the acidosis and hyperkalemia are out of proportion to the degree of renal failure and are related to a decrease in renin and aldosterone secretion. In moderate to severe CKD, multiple factors lead to an increase in serum phosphate and a decrease in serum calcium. The hyperphosphatemia develops as a consequence of reduced phosphate clearance by the kidney. In addition, vitamin D activity is diminished because of reduced conversion of 25-OH vitamin D to the active form, 1,25-OH vitamin D in the kidney by the enzyme 1α- hydroxylase. These alterations lead to secondary hyperparathyroidism with skeletal changes of both osteomalacia and osteitis fibrosa cystica. Uric acid levels are frequently elevated but rarely lead to calculi or gout during chronic uremia.
Patients with reduced renal function should not be routinely subjected to radiographic studies involving iodinated contrast (nephrotoxic). Renal sonograms are helpful in determining renal size (usually small) and cortical thickness (usually thin) and in localizing tissue for percutaneous renal biopsy. Bone x-rays may show retarded growth, osteomalacia (renal rickets), or osteitis fibrosa (brown tumors). Soft-tissue or vascular calcification may be noted on plain films. Patients with polycystic kidney disease will have variably large kidneys with evident cysts (on sonograms or abdominal CT scans).
Renal biopsies may not reveal much except nonspecific interstitial fibrosis and glomerulosclerosis. There may be pronounced vascular changes consisting of thickening of the media, fragmentation of elastic fibers, and intimal proliferation, which may be secondary to uremic hypertension or due to primary arteriolar nephrosclerosis. Percutaneous biopsies of end-stage shrunken kidneys may be complicated by bleeding (due to the uremic platelet dysfunction; see Section “Blood testing”). The bleeding tendency can be ameliorated once patient starts on dialysis, or through the use of desmopressin (mediates release of endothelial stores of Factor VIII:von Willebrand Factor multimers).
Recent studies indicate some benefit of drugs to reduce progression of CKD. The use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in slowing down renal decline has been well documented, especially in the diabetic population with significant proteinuria. With the addition of aldosterone antagonists to optimize blood pressure control, patients need to be followed closely for potential hyperkalemia. Lipid lowering agents should be employed to lower the already accelerated risk of atherosclerotic disease in the ESRD population and can potentially retard the progression of renal dysfunction.
Overall, management should be conservative until it becomes impossible for patients to continue their customary lifestyles. Restriction of dietary protein (0.8–1.0 g/kg/d), potassium, and phosphorus is recommended. As well, maintenance of close sodium balance in the diet is necessary so that patients become neither sodium expanded nor depleted. This is best done by the accurate and frequent monitoring of the patient's weight. Use of oral bicarbonate (0.5–1 mEq/kg/d) can be helpful when moderate acidemia occurs (aim for serum HCO3 level ≥ 23 mEq/L). Anemia can be treated with recombinant erythropoietin given subcutaneously (aiming for hemoglobin levels between 11.0 and 12.0 g/dL per the K/DOQI guidelines). Prevention of possible uremic osteodystrophy and secondary hyperparathyroidism requires close attention to calcium and phosphorus balance. Phosphate-retaining antacids and calcium or vitamin D supplements may be needed to maintain the balance. Cinacalcet can directly reduce parathyroid hormone secretion. If severe secondary hyperparathyroidism occurs, subtotal parathyroidectomy may be needed.
Chronic Peritoneal Dialysis
Chronic peritoneal dialysis is used electively or when circumstances (ie, no available vascular access) prohibit chronic hemodialysis. Ten percent of dialysis is done with this treatment. Improved soft catheters can be used for repetitive peritoneal lavages. In comparison to hemodialysis, small molecules (such as creatinine and urea) are cleared less effectively than larger molecules, but excellent treatment can be accomplished. Intermittent thrice-weekly treatment (IPPD), continuous cycler-assisted peritoneal dialysis (CCPD), or chronic ambulatory peritoneal dialysis (CAPD) is possible. With the latter, the patient performs 3–5 daily exchanges using 1–2 L of dialysate at each exchange. The dialysate contains a high glucose concentration and the peritoneal surface serves as the semipermeable membrane. Bacterial contamination and peritonitis are becoming less common with improvements in connection technology. Over time, many patients will transition to hemodialysis due to either peritoneal membrane failure (eg, peritoneal sclerosis, adhesions) or inadequate dialysis as native renal clearance of solutes deteriorates.
Chronic hemodialysis using semipermeable dialysis membranes is now widely performed. Access to the vascular system is provided by an arteriovenous fistula, vascular grafts (with autologous saphenous vein or synthetic material), or by a percutaneous permcatheter (placed either surgically or with interventional radiology). Most dialyzer membranes nowadays are made with biocompatible materials (less blood–membrane reactions). Body solutes and excessive body fluids can be easily cleared by using dialysate fluids of known chemical composition. Newer, high-efficiency membranes (high/flux) are serving to reduce dialysis treatment time.
Treatment is intermittent—usually 3–5 hours three times weekly. Computer modeling, using measurements of urea kinetics, has provided more precise hemodialysis prescriptions. Treatments may be given in a kidney center, a satellite unit, or the home. Home dialysis is optimal because it provides greater scheduling flexibility and is generally more comfortable and convenient for the patient, but only 20% of dialysis patients meet the requirements for this type of therapy. There is rising interest in this modality of treatment given better patient survival and quality of life.
More widespread use of dialytic techniques has permitted greater patient mobility. Treatment on vacations and business trips can be provided by prior arrangement. There are even dedicated cruise ships that provide dialysis.
Common problems with either type of chronic dialysis include infection, bone symptoms, technical accidents, persistent anemia, and psychological disorders. The excessive morbidity and mortality associated with atherosclerosis often occurs with long-term treatment. It is now recognized that occasionally uremic patients, despite dialysis, can develop wasting syndrome, cardiomyopathy, polyneuropathy, and secondary dialysis-amyloidosis so that kidney transplant must be urgently done. Routine bilateral nephrectomy should be avoided because it increases the transfusion requirements of dialysis patients. Nephrectomy in dialysis patients should be performed in cases of refractory hypertension, reflux with infection, and cystic disease with recurrent bleeding and pain. The dialysis patient can occasionally have acquired renal-cystic disease. Such patients need close monitoring for the development of in situ renal cell carcinoma.
Yearly costs range from an average of $50,000 for patients who receive dialysis at home to as much as $50,000–$75,000 for patients treated at dialysis centers (with those dialyzing through an AV graft or catheter incurring more cost), but much of this is absorbed under HR-1 (Medicare) legislation. If the patient has no other systemic problems (eg, diabetes), the mortality rate is 8–10%/year once maintenance dialysis therapy is instituted. Despite these medical, psychological, social, and financial difficulties, most patients lead productive lives while receiving dialysis treatment.
After immunosuppression techniques and genetic matching were developed, renal allotransplantation became an acceptable alternative to maintenance hemodialysis. Improved short-term transplant results are now noted owing to the development of newer immunosuppressant drugs. Currently employed posttransplant drugs include prednisone, mycophenolate mofetil (and its enteric-coated formulation), cyclosporine, tacrolimus, and sirolimus. There are a number of novel medications under investigation that inhibit different pathways in the allorecognition mechanism, including a variety of injectable bioagents. The great advantage of transplantation is reestablishment of nearly normal and constant body physiology and chemistry. Diet can be less restrictive. The disadvantages include bone marrow suppression, susceptibility to infection, oncogenesis risks, and the psychological uncertainty of the allograft's future. Most of the disadvantages of transplantation are related to the medicines given to counteract the rejection. Later problems with transplantation include recurrent disease in the transplanted kidney and an increased incidence of cancer. Genitourinary infection appears to be of minor importance if structural urologic complications (eg, leaks) do not occur. However, the shortage of organ supply continues to plague the transplant community. As of 2007, there were more than 70,000 patients on the kidney transplant waiting list, with annual death rates of 65 patients/1000 patient-years at risk (Figure 35–3).
Number of transplants and size of active waiting list. There was a very large gap between the number of patients waiting for a transplant and the number receiving a transplant. This gap widened over the decade, meaning that the waiting times from listing to transplant continued to increase. The number of living donor transplants grew until 2004, while the number of deceased donor transplants continued to rise gradually. Source: 2008 OPTN/SRTR Annual Report, Tables 1.7, 5.1a.
Nephrology centers, with close cooperation between medical and surgical staff, attempt to use these treatment alternatives of dialysis and transplantation in an integrated fashion.
For a more detailed review, see Chapter 35.