Chronic Renal Failure and Uremia

Transcription

1 Chronic Renal Failure and Uremia Objectives 1. Be able to identify differences between acute and chronic renal failure. 2. Be able to describe the factors that lead to a progressive decline in GFR irrespective of the inciting cause. 3. Be able to recognize antihypertensives that decrease glomerular capillary pressure and understand the rationale for their use in patients with chronic glomerular disease. 4. Be able to describe the adaptations that occur at the level of the nephron to maintain sodium, potassium, and acid-base balance. 5. Be able to characterize the pathogenesis of renal osteodystrophy and the basic methods of managing altered calcium-phosphorus metabolism in chronic renal failure. 6. Be able to understand the pathogenesis and treatment of anemia in chronic renal failure. 7. Be able to recognize the clinical features of the uremic syndrome. Outline I. Chronic renal failure A. Acute versus chronic renal failure B. Etiology C. Progression of renal failure 1. Histologic features 2. Pathogenesis D. Treatment of hypertension in chronic renal failure 1. Antihypertensive medications and glomerular capillary pressure 2. Treatment recommendations E. Nephron adaptation in chronic renal failure 1. Sodium balance 2. Potassium balance 3. Urinary concentration and dilution in chronic renal failure 4. Acid-base homeostasis F. Calcium-phosphorus metabolism in chronic renal failure 1. Pathogenesis of renal osteodystrophy 2. Management of altered calcium-phosphorus metabolism G. Anemia of chronic renal failure II. The Uremic Syndrome A. Symptoms of uremia B. Clinical features of uremia C. Pathogenesis of uremia

2 I. Chronic renal failure Estimates of U.S. Pre-ESRD Population USRDS ,600,000 Pre-ESRD 215,557 Dialysis Figure 1 78,810 Transplant The incidence of End Stage Renal Disease (ESRD) in the U.S. is projected to increase five fold over the next ten years. Currently there are an estimated 1.6 million patients at risk for developing renal failure over the next 10 years (figure 1). This obviously will place an enormous burden on health care system. Currently there are limited therapies available to delay progression of renal failure. Hopefully new therapies will emerge as new research efforts focus on understanding the pathogenesis of progressive renal failure. The role of both the primary care physician and nephrologist is to identify patients at risk for progressive renal failure and implement therapies that will both delay the progression of renal failure as well as minimize the morbidity and mortality. Differentiating Chronic Renal Failure From Acute Renal Failure Acute Table 1 Oliguria Normal or large kidneys on ultrasound Unstable azotemia Chronic Physical exam impaired growth in children hyperpigmentation uremic fetor Small echogenic kidneys Urinalysis Broad casts Renal osteodystrophy A. Acute versus chronic renal failure Chronic renal failure often follows an insidious asymptomatic course until the GFR declines to less than 10 ml/min. It is not unusual, therefore, for patients with chronic renal failure to initially present with advanced azotemia One is then left with the question whether the patient is suffering from an acute versus chronic process (Table 1). Patients with acute renal failure often present with an acute systemic illness. Patients with oliguria are more likely to have acute renal failure. Laboratory studies, unfortunately, are generally not helpful is distinguishing between acute and chronic renal failure. Anemia, hyperphosphatemia and hypocalcemia are commonly seen in both settings. Serial increases in BUN and creatinine, however, suggest a diagnosis of acute renal failure. Patients with chronic renal failure tend to have small echogenic kidneys on ultrasound. Because renal osteodystrophy develops over years, the presence of this disorder as seen on radiographs of the hands is strong evidence that the renal failure has a chronic component.

3 Table 2 Etiology of Chronic Renal Failure Diabetes mellitus 31.5% Hypertension 27.4% Unknown 18.5% Glomerulonephritis 13.8% Obstructive uropathy 5.4% Polycystic kidney disease 3.4% B. Etiology In the U.S. and in most Western countries, diabetes mellitus remains the leading cause of ESRD. This is in contrast to underdeveloped nations, where glomerulonephritis remains the most common cause of ESRD. The prevalence of the various causes of ESRD in the U.S. is summarized in table 2. Many patients are probably erroneously categorized as hypertensive glomerulosclerosis when presenting with ESRD. This stems from the fact that many patients will present with small fibrotic kidneys, and thus no further diagnostic workup can be performed. Table 3 Anatomic and Histologic Features Due to Glomerular Hypertension Glomerular hypertrophy Focal segmental glomerulosclerosis with hyalinosis Interstitial fibrosis Vascular sclerosis Epithelial foot process fusion C. Progression of renal failure Over the past 20 years, considerable insight has been gained into factors that may contribute to the progression of chronic renal failure. It was initially observed that there are common histologic features seen on renal biopsy specimens in all patients with chronic renal failure regardless of the initial insult (Table 3). Table 4 Physiologic Changes Observed in Chronic Renal Failure Increased single nephron GFR Vasodilation of the afferent arteriole with impaired autoregulation Intraglomerular hypertension Loss of glomerular permselectivity Pathogenesis of Secondary Glomerulosclerosis Glomerular Sclerosis and Hyalinosis Primary Insult Nephron Mass Epithelial Cell Density and Foot Process Fusion Proteinuria Figure 2 Glomerular Volume and Glomerular Hypertension At the same time, there are common physiologic changes that have been demonstrated in animal models of chronic renal failure (table 4). Loss of nephron mass leads to glomerular hypertension even in the absence of systemic hypertension. Experimental models of chronic renal failure have demonstrated an increase in single nephron GFR (SNGFR) in the remaining nephrons. Vascular resistance is decreased in both the afferent and efferent arterioles, thus resulting in an increase in glomerular capillary plasma flow rate. The decrease in afferent arteriolar resistance is proportionately greater than that in the efferent arteriole, leading to an increase in glomerular capillary pressure. As a result, there is epithelial cell injury and glomerular sclerosis. Proteinuria ensues, which results in worsening glomerular hypertension and sclerosis. A relentless cycle of decreased nephron mass and progressive glomerular sclerosis ultimately leads to ESRD (Figure 2).

4 D. Treatment of hypertension in chronic renal failure Control of hypertension remains the mainstay of management of patients with chronic renal failure. Recent studies have demonstrated the importance of maintaining stringent blood pressure control in these patients to minimize progression of renal failure. The target blood pressure goal, for example, is approximately mmhg systolic and mmhg diastolic, compared with a target blood pressure of 140/90 mmhg in the general population. Figure 3 Effects of Various Anti-hypertensives on Glomerular Capillary Pressure Afferent Arteriole Vasodilate Pressure Dihydropyridines Nifedipine Felodipine Amlodipine Pressure Efferent Arteriole Vasodilate ACE inhibitors AII Antagonists Verapamil Diltiazem The ultimate goal is to restore normal glomerular capillary pressure. This is achieved by employing drugs that preferentially vasodilate the efferent arteriole. Examples include ACE inhibitors, angiotensin II receptor antagonists, and nondihydropyridine calcium blockers (figure 3). Treatment of hypertension for patients with chronic renal failure, then, is indicated at any stage of the disease. Drugs that lower the glomerular capillary pressure should be used as first line agents, especially when there is more than 1 gram of urinary protein excretion in 24 hours. The goal is to keep the blood pressure less than 130/80 mmhg. E. Nephron adaptation in chronic renal failure As renal failure progresses, the number of functioning nephrons is reduced. In order to maintain homeostasis, there must be adaptive changes in the handling of solutes and water since each nephron must handle a proportionately greater load. We will now consider adaptive changes that are observed with respect to sodium, potassium, hydrogen ion, and water handling in chronic renal failure. Fractional Sodium Excretion (%) Figure 4 Steady State GFR and Fractional Sodium Excretion Slatopolsky et al., J. Clin. Invest. 47: 521, GFR (% of normal) 1. Sodium balance As GFR declines, sodium excretion remains relatively constant, thus maintaining an extracellular fluid volume that remains close to normal. In order for sodium balance to be maintained, the remaining functioning nephrons must proportionately increase sodium excretion. Studies measuring fractional excretion of sodium in a population of patients with a wide range of renal insufficiency have documented this adaptation, demonstrating a gradual increase in the fractional excretion of sodium as GFR declines (Figure 4). The mechanisms responsible for increasing the fractional excretion of sodium as GFR declines are not entirely clear, but recent work has demonstrated increased levels of atrial natriuretic peptide. Micropuncture studies have shown that most of the increased sodium excretion occurs in the distal tubule. Although zero sodium balance may be maintained in the absence of a significant change in sodium intake, the ability of the nephron to increase sodium excretion when challenged with a large sodium load is impaired in chronic renal failure.

5 In the later stages of chronic renal failure, there is transient net sodium retention leading to expansion of the extracellular fluid volume. Renal perfusion is consequently increased resulting in decreased proximal sodium reabsorption and a pressure natriuresis. Although the ECF volume may expand in the later stages of renal insufficiency, edema is not a consistent finding as the increase in the interstitial space is often less the 2-3 liters required to result in edema formation. Patients with nephrotic syndrome, however, will uniformly develop edema due to the increased renal sodium avidity associated with this syndrome. 2. Potassium balance As GFR declines, there is a progressive increase in the fractional excretion of potassium to maintain the serum potassium in the normal range. It is only when the GFR falls to about 10% normal that the serum potassium rises. Early in the course of chronic renal failure, transient elevations in the serum and intracellular potassium result in increased secretion of potassium in the cortical collecting duct. Increased aldosterone may play some role in this adaptation, but can not account for all of the observed increase in potassium excretion. Increased activity of the Na-K-ATPase on the basolateral surface of principle cells in the cortical collecting duct has been demonstrated in advanced chronic renal insufficiency, thus facilitating increased potassium excretion per nephron. Maximal Urine Concentration (mosm) Figure 5 Urinary Concentrating Capacity in Chronic Renal Failure Dorhout-Mees, EJ: Br. Med. J. 1: 1159, GFR (% of normal) 3. Urinary Concentration and Dilution in Chronic Renal Failure As GFR declines, there is an impair-ment in both urinary concentration (figure 5) and dilution due to limited renal mass. A higher solute load is imposed on each nephron, and there is insufficient tubular surface area to maintain medullary interstitial hypertonicity. The osmolarity of the urine is close to that of plasma (isosthenuria). Since solute intake remains unchanged, the obligate urine volume will increase. Patients will often complain of polyuria and nocturia due to the limited ability to concentrate urine. Limited urinary diluting capacity results in decreased free water clearance and hypoosmolality when water intake exceeds excretion and losses. 4. Acid-base Homeostasis Metabolic acidosis predictably develops as renal failure progresses. Early in the course of chronic renal failure, hydrogen balance is maintained by increased synthesis of ammonia per nephron. Eventually, the total ammonia synthesis decreases as the decline in nephron mass exceeds the increase in ammonia synthesis per functioning nephron, and a metabolic acidosis ensues. Figure 6 Hyperparathyroid Related Bone Disease Renal Mass Pi Ca 2+ Acidosis Impaired Absorption + + PTH F. Calcium-phosphorus metabolism in chronic renal failure As renal mass decreases, the excretion of phosphorus decreases resulting in a rise in the serum phosphorus. This results in a transient decrease in the serum calcium. At the same time, calcium absorption is also impaired 1-alpha-hydroxylase hydroxylase 25(OH)D 3 1,25(OH) 2 D 3 Osteitis Fibrosa Cystica

6 resulting in a fall in the serum calcium. The latter results from a deficiency in 1,25-dihydroxy-vitamin D. Recall that 1-alpha-hydroxylase is localized to the kidney, and its activity will decrease as result of both a decrease in renal mass as well as a consequence of the acidosis of chronic renal failure. Both hypocalcemia and hyperphosphatemia lead to increased parathyroid hormone synthesis or secondary hyperparathyroidism. Although this leads to restoration of the serum calcium to the normal range, it does so at the expense of increased bone turnover. Because 1,25-hydroxy-vitamin D acts as an inhibitor of parathyroid synthesis, the relative deficiency of active vitamin D in chronic renal failure also leads to increased parathyroid hormone synthesis. These alterations are summarized in figure 6. Persistent untreated hyperparathyroidism leads to a distinct form of bone disease characterized by increased bone turnover and fibrosis termed osteitis fibrosa cystica. Once established, this bone disorder is essentially irreversible. Prevention, therefore, remains the best therapeutic strategy. The objective of therapy is first to minimize the hypocalcemia and hyperphosphatemia. Calcium supplements are given with meals to act as phosphate binders. Patients should see a dietician once the GFR declines to less than 30 ml/min to receive dietary counseling to achieve adequate dietary phosphorus restriction. Finally, the active vitamin D analogue calcitriol is administered to facilitate calcium absorption and to suppress parathyroid hormone synthesis. Care should be taken to avoid increasing the calcium phosphorus product (Serum Ca {mg/dl} X Serum Phos {mg/dl}) to greater than 65. Elevations of this product above this range will result in metastatic calcification and has been shown to be associated with excess mortality. G. Anemia of Chronic Renal Failure Erythropoietin is synthesized in the kidney and is essential for normal hematopoiesis. When the GFR declines to the 30 ml/min range, a normocytic, normochromic anemia develops. In 1990, recombinant human erythropoietin became available for the care of patients with ESRD and chronic renal failure. Previously, it was not unusual for patients on dialysis to have hematocrits in the 16-18% range. Today we have the capacity to maintain hematocrits in the 33-36% range. This has markedly improved the overall sense of well being and quality of life for patients on dialysis. More recently, erythropoietin use has increased in patients in the pre-esrd stage. Table 5 Symptoms of the Uremic Syndrome II. The Uremic Syndrome Early Loss of appetite Altered taste sensation Lack of energy Poor concentration Pruritus Weight loss Late Coma Intractable vomiting Paresthesias Literally, uremia translates to urine in the blood. It refers to the clinical syndrome associated a marked reduction in GFR (<10-15 ml/min). Symptoms are non-specific and range from vague fatigue to fullblown coma (Table 5).

7 Table 6 Clinical Features of Uremia Early Expanded ECF Hypertension Anemia Bone disease Poor growth Infertility Amenorrhea Hyperlipidemia Late Pericarditis Peripheral neuropathy Asterixis Acidosis Hyperkalemia GI bleeding Hyperpigmentation Early in the course of uremia patients will complain of lassitude, altered taste and subtle cognitive changes. Because dialysis is generally initiated early in the course of uremia, it is now rare to see the end stage findings of uremia which may include coma as well as marked metabolic perturbations including severe acidosis and hyperkalemia (Table 6). The pathogenesis of the syndrome remains unexplained. The toxins responsible for the clinical symptoms have yet to be identified, but it believed that the uremic toxins are relatively small molecules with molecular weights less than 300 daltons. Indirect evidence for this derives from the fact that the syndrome resolves with dialysis, and molecules in this molecular weight range are removed by the dialysis procedure. The blood urea nitrogen (BUN) level remains the most helpful surrogate marker of uremia, although there is a wide range of levels wherein the syndrome develops in individual patients. In general, a BUN level of 100 mg/dl has served as a level at which dialysis is initiated in patients with acute renal failure, but clinical judgement remains the most important factor in determining when dialysis should be initiated. Table 7 Examples of Suspected Uremic Toxins Substance Molecular Weight Urea 60 Creatinine 113 Methylguanidine 175 Guanidinosuccinic acid 175 Phenolic acids Dimethyamine 46 Interestingly, studies in which normal volunteers are infused with urea have demonstrated none of the characteristic features of the syndrome, even when BUN levels are increased to 200 mg/dl. It is now believed that the syndrome results from the accumulation of a number of small molecules (Table 7).