CHRONIC RENAL FAILURE

Dr. Wadhwa

Objectives

 

 

-Learn about major etiologic causes of chronic renal failure

            -Understand the pathophysiology of nitrogen, potassium, sodium and water,  acid-base, carbohydrates, lipids, and divalent ions metabolism in the course of chronic renal failure.

            -Understand the endocrine functions of the kidney and their pathology during chronic renal failure.         

            -Learn the basic principles of drug metabolism in chronic renal failure.

            -Understand basic therapeutic strategies in chronic renal failure: hemodialysis, peritoneal dialysis, kidney transplantation.

 

 

Chronic renal failure (CRF) is defined as a permanent reduction in glomerular filtration rate (GFR) sufficient to produce detectable alterations in well-being and organ function.  This usually occurs at GFR below 25 ml/min.

 

Four stages of decreased renal function may be visualized:

 

            1.  Silent – GFR up to 50 ml/min.

            2.  Renal insufficiency – GFR 25 to 50 ml/min.

            3.  Renal failure – GFR 5 to 25 ml/min

            4.  End-stage renal failure – GFR less than 5 ml/min.

 

Uremia (Azotemia) is a term applied to the manifestations of organ dysfunction seen in stages 3 and 4 as outlined above.  Literally, uremia means urine in the blood.  Azotemia, the accumulation of nitrogenous waste products, chiefly urea, in the blood is the hall mark of renal failure.  It is a clinical syndrome resulting from retention of certain substances which are normally excreted into the urine and thus accumulate causing toxicity.

 

            1.  CAUSES OF CHRONIC RENAL FAILURE

 

Any disorder that permanently destroys nephrons can result in chronic renal failure.  Most Common Causes of CRF are:

 

            Diabetic nephropathy

            Hypertensive nephrosclerosis

            Glomerulonephritis

            Interstitial nephritis

            Polycystic kidney disease

 

About 100 to 150 per million persons in the U.S. develop CRF annually (0.010 to 0.015% per year); at an annual cost of $25 – 35,000 per  patient per year.

 

            2.  PATHOGENESIS

 

since the uremic syndrome resembles a systemic intoxication, the search for a putative uremic toxin has been the subject of intensive investigation.  As yet, however, no single  compound has been found to produce the clinical picture of uremia.  Therefore it is more likely that multiple factors contribute to the pathogenesis of this syndrome.

 

2A.  Retained Metabolic Products:

 

            Many chemical compounds have been suspected to be responsible for the uremic syndrome.  Some of these include:

 

Acetoin

Methylguanidine

Aliphatic amines

B2-Microglobulin

Amino acids

“Middle molecules”

Aromatic amines

Myoinositol

2,3-Butylene glycol

 

Creatinine

Other guanidines

 

Oxalic acid

Diamine oxidase

 

Gastrin

Parathyroid hormone

    (and fragments?)

Glucagon

Phenols

B2-Glucoprotein

Polyamines

Glucuronic acid

Pyridine derivatives

Growth hormone

Renin

Guanidinosuccinic acid

Retinol-binding protein

Indoles

Ribonuclease

Lipochromes

Urea

 

Uric acid

 

However, a distinct relationship between one or a combination of these substances and the entire syndrome has not been established in man.  The toxic substances are responsible for the uremic syndrome is supported by:

 

1.  Marked symptomatic improvement occurs after decraesing protein in the diet.  This suggests that metabolites of protein are retained in renal failure and exert toxic effects.

2.  Effective dialysis results in marked symptomatic improvement even though protein continues to be ingested.  This suggests that toxic metabolites are removed by dialysis.

3.  Uremic plasma seriously interferes with a variety of normal cell functions.  The same plasma after dialysis has no adverse effects.

 

The relationship between toxic substances and uremia is exemplified by urea.  When urea is present in high concentration in the body fluids, it may decompose spontaneously into ammonia and cyanate (Figure 2.1).

 

 

Cyanate is a potential toxin which combines irreversibly with normal proteins in cells and affects their functions.  Cyanate administration in animals is followed by hypothermia, lethargy, anorexia, diarrhea, and seizures.  However, there is little evidence that cyanate plays a role in uremic toxicity in man.  Nevertheless, urea which is an end-product of protein metabolism, can decompose to substances with potential toxicity.  This observation provides support for the chemical basis of the uremic syndrome.

 

Inferential evidence (mainly clearance data from dialytic therapy) suggests that molecules in the molecular weight range of 300-1500 daltons could be responsible for the uremic state.  This has been termed the “Middle Molecule Hypothesis”.

 

2B.  Overproduction of Counter-regulatory Hormones:

 

Overproduction of parathyroid hormone in response to hypocalcemia and natriuretic hormone in response to volume overload could contribute to many aspects of the uremic state.

 

3C.  Underproduction of Renal Hormones:

 

Decreased erythropoietin production causes anemia.  Decreased 1-hydroxylation of vitamin D3 contributes to bone disease.  Clearly, these and other such deficiencies could play a role in the uremic state.

 

Undoubtedly, each of these factors plays a role in the development of the uremic syndrome.  Later we shall look at the clinical manifestations of uremia.  Let us turn for a moment to a manifestation of uremia at the cellular level.

 

            3.  CELLULAR DYSFUNCTION IN UREMIA

 

Hypometabolism and an abnormally low body temperature may be seen in patients with advanced, uncomplicated uremia.  A characteristic feature of nearly every normal cell in the body is a very low concentration of sodium ions in the intracellular water compartment, e.g. in the muscle cells, about 10 mmol/L or less.  In contrast, the concentration outside the cell is about 140 mmol/L.  Under normal conditions sodium ions leak through the cellular membrane into the cell which increases sodium concentration inside the cell which activates the enzyme adenosine triphosphatase which promptly moves sodium from the cell into the extracellular space.

 

Two important events allow sodium transport:  burning of glucose and consumption of oxygen.  Removal of positively charged sodium ions from the cell accounts for production of a substantial portion of the body’s heat.  This process also leaves in its wake a negative charge, which in turn attracts and holds potassium ions inside the cell.  Potassium is important for the proper functioning of a number of enzymes.  The transport of sodium thus helps to concentrate potassium ions in the cell and to maintain normal body temperature (Fig. 3.7).

 

 

Deranged sodium transport in advanced uremia results in accumulation of sodium and chloride inside the cell, leading to accumulation of water and a fall in potassium concentration, with consequent defects in metabolic processes and a decline in heat production.  A cell in which these changes take place has been referred to as the sick cell of uremia.  Such changes have been found in RBC’s, muscle cells and WBC’s.

These changes can be reversed by adequate dialysis or successful renal transplantation.

Certain of the abnormal characteristics in the muscle cells of patients with advanced uremia can be reversed simply by removing protein from the diet and replacing it with optimal quantities of essential amino acids.

Besides the retention of salt and water in extracellular fluid, there is marked retention inside the cell.  Although patients with end-stage renal disease may show no evidence of edema, one of the early changes commonly following initiation of dialysis therapy is a sharp decline in total body weight, which matches the loss of cellular salt and water.  This loss corresponds in timing to correction of the derangement in sodium transport in nearly all cells.

 

            4.  PATHOPHYSIOLOGY

 

The most intriguing aspect of CRF is that compensatory mechanisms allow loss of 90% of GFR before manifestations of the uremic syndrome are evident.  Thus a variety of adaptations compensate for the decreased GFR and allow a new steady state of external balance to exist, but on the other hand contribute to the uremic syndrome.  In spite of these adaptations, the hallmark of CRF is the loss of flexibility in responding to challenges to external load of solutes and water.  The adapations include

 

4A.  Intact Nephron Hypothesis:

 

Nephrons functioning in diseased kidneys maintain glomerulo-tubular balance.  That is, filtration and net excretion of various substances are coordinated.  (e.g. with normal renal function, usually 50-60% of filtered urea is reabsorbed from the tubules.  In CRF it may fall to 30% to maintain balance).

 

4B.  The Magnification Phenomenon:

 

although nephrons in diseased kidneys function homogeneously, they alter their handling of given solutes as needed to maintain balance of these solutes.  That is, nephrons can magnify their excretion of a given solute.  (e.g. tubular creatinine excretion is < 10% with normal renal function.  In CRF it may increase to 30%).

 

4C.  Trade-off Hypothesis:

 

The mechanisms that are magnified to maintain individual solute control may have deleterious effects on other systems.  This trade-off is seen in the increased parathyroid hormone (PTH) secretion seen in CRF which enhances renal phosphorus excretion.  PTH has been implicated in the pathogenesis of many disturbances of uremia (sleep, sex, bone, disease, anemia, lipidemia, vascular disease).  The corollary of the trade-off hypothesis is the concept of proportional reduction of solute, that is, reduction of solute intake (e.g. phosphorus) in proportional to decrements in GFR could prevent the compensatory changes (e.g. increased PTH) which may contribute to the development of uremia.

 

            5.  SOLUTE HANDLING IN CHRONIC RENAL FAILURE

 

5A.  Creatinine and Urea Balance.

 

Although creatinine is secreted and urea is reabsorbed through tubules, balance depends on their rates of filtration.  Balance (rate of filtration) is maintained by allowing plasma concentrations to rise until renal excretion equals production.  Urea reabsorption falls with the solute diuresis per nephron and thus the blood urea nitrogen need not rise as much as expected to maintain balance.  Creatinine secretion is enhanced and thus excretion also is balanced to production at a plasma concentration less than anticipated.

In addition, urea is metabolized in increased amounts by gut bacteria as the blood urea nitrogen rises and creatinine production is reduced by metabolic suppression.

 

 

 

The figure shows the affect of a single decrease in GFR on creatinine balance.  Note that CRF is consists of multiple decreases in GFR over time.  If production of creatinine is assumed constant, then this figure illustrates the change in creatinine balance.  The top panel shows a decrease in GFR of 50%.  The excretion of creatinine falls with accumulation in total body reflected by an increase in serum creatinine (lower panel).  A new steady state was reached when excretion again equaled production of creatinine.  This occurred at the expense of an elevated serum creatinine and total body creatinine.  Another way of visualizing this new steady states is that the product of the new serum cr and new GFR must equal the product of the old serum cr and Old GFR (if creatinine production remains stable).

 

5B.  Water Balance:

 

In order to maintain water balance, the fraction of water reabsorbed by the kidney must decrease.  Thus, an increased flow per nephron ensues.  With progressive CRF, the ability to excrete a water load is compromised and the patient may develop hypo-osmolarlity.  Urine concentration ability of  the kidney becomes fixed around 300 mosm/kg of water and thus the patient is also susceptible to dehydration if water intake is lowered.  Thus, a CRF patient is prone to both excess and deficit of water.  Nocturia develops early in CRF because of decreased concentrating ability of urine during sleep.

 

5C.  Sodium Balance:

 

In order to maintain sodium balance, the fraction of sodium reabsorbed must be decreased, thereby increased excretion of sodium fraction because of decreased GFR.  A humoral natriuretic factor in CRF helps to increase sodium excretion.

 

 

 

In CRF, the kidneys are unable to reduce sodium excretion rapidly in response to a sudden decrease in intake or extrarenal losses (e.g. G.I. loss).  Thus, major increase in

 

sodium intake results in edema and major decreases in intake or increases in extrarenal losses result in volume depletion.  The hallmark of CRF is the loss of flexibility in responding to challenges to external load of solutes and water.

 

While normal subjects can excrete sodium promptly following a sodium load with minimal effect on ECF, in CRF subjects delayed excretion results in ECF expansion.  While normal subjects on salt restricted diet reduce urine Na to 20 mEq in 48 hours, CRF subjects may require 1-2 weeks for similar sodium conservation and thus are prone to sodium depletion.  This is illustrated in fig. 9.5.

 

5D.  Potassium Balance:

 

Increased tubular secretion of potassium helps maintain potassium balance until renal failure is severe.  In normal subjects, 90% of potassium is excreted in urine and 10% in stool.  In advanced CRF, fecal excretion of potassium increases to 50% of the potassium load.  Thus, plasma potassium and body potassium are maintained on normal dietary intake.  However the patient is susceptible to hyperkalemia from sudden potassium loads.

 

5E.  Calcium and Phosphorus Balance:

 

Decreased GFR leads to a sequence of events outlined in the syllabus in the section of Ca and P metabolism.  A trade-off occurs in the development of secondary hyperparathyroidism in that the elevated PTH increases phosphate excretion but contributes to bone disease and perhaps other system dysfunction as described earlier.

 

5F.  Hydrogen Ion Balance:

 

CRF is associated with a continuous positive balance (retention) of hydrogen ions due to a decrease in the tubular ammonia production to excrete hydrogen in (Fig. 13.3).

 

Retained anions such as SO4 and PO4 contribute to acidosis.  The bottom line is that bone serves as a sump for excess hydrogen ion and plasma HCO3 concentration is preserved at only a modestly reduced concentration (about 15 mmol/L).  However, flexibility is lost and severe acidosis may occur from small challenges.

 

            6.  PROGRESSION OF CHRONIC RENAL FAILURE

 

A variety of chronic renal diseases progress to end-stage renal disease, including chronic glomerulonephritis, diabetic nephropathy, and polycystic kidney disease.  Although the underlying problem often cannot be treated, extensive studies in experimental animals and preliminary studies in humans suggest that progression in chronic renal disease may be largely due to secondary factors that are unrelated to the activity of the initial disease.  These include systemic and intraglomerular hypertension, glomerular hypertrophy, the intrarenal precipitation of calcium phosphate, hyperlipidemia, and altered prostanoid metabolism (table).

            Secondary factors and progression of chronic renal failure

          

           

§         Intraglomerular hypertension and hypertrophy

§         Phosphate retention, with interstitial CaPO4 deposition

§         Increased prostaglandin synthesis

§         Hyperlipidemia, especially in the nephrotic syndrome

§         Metabolic acidosis

§         Proteinuria

§         Tubulointerstitial disease

§         Retained “uremic” toxins

§         Filtered iron in nephrotic syndrome

 

The major histologic manifestation of these secondary causes of renal injury is focal segmental glomerulosclerosis.  Thus, glomerular damage and proteinuria typically occur with progressive renal failure.

 

6A. INTRAGLOMERULAR HYPERTENSION AND GLOMERULAR HYPERTROPHY

In animal models, for example, a rise in intraglomerular pressure, due either to the compensatory response to nephron loss or to primary renal vasodilatation (as in diabetes mellitus), appears to play an important role in the progressive glomerular scarring.  The mechanisms by which intraglomerular hypertension might promote glomerular injury are incompletely understood.  At least two factors may be involved:

 

§         Direct endothelial cell damage, similar to that induced by systemic hypertension

 

§         Increased pressure-induced movement of circulating macromolecules (such as

 

 

IgM and fibrinogen and complement metabolites) through the fenestrated endothelial cells into the subendothelial space in the glomerular capillary wall.  The characteristic accumulation of these “hyaline” deposits can progressively narrow the capillary lumens, thereby decreasing glomerular perfusion and filtration.

 

An increase in glomerular size, as well as intraglomerular pressure, also may occur in these settings.  This change can contribute to glomerular injury both by increasing wall stress and by causing detachment of the glomerular epithelial cells from the glomerular capillary wall.

 

Non-hemodynamic factors also may be important in the development of secondary glomerulosclerosis.  Marked nephron loss in experimental animals can lead to glomerular cell proliferation, macrophage influx and accumulation of extracellular matrix components (leading to narrowing of the capillary lumens).

 

How these changes occur is not well understood, but cytokines such as platelet-derived growth factor and transforming growth factor-b (TGF-b) may play a contributory role.  Experimental studies, for example, suggest that TGF-b may contribute to increased extracellular matrix production and the development of glomerulosclerosis in a variety of renal diseases.

 

Thus glomerulosclerosis results from the glomerular hypertension itself or from increased glomerular capillary flow and filtration (fig. 16-7).

 

 

In addition to processes affecting the glomeruli, secondary tubulointerstitial disease also is commonly seen.  This change is often under-appreciated, but both the glomerular filtration rate and long-term prognosis are more closely related to the degree of tubulointerstitial, rather than glomerular injury.

 

6B.  OTHER SECONDARY FACTOR -- Identification of the role of these secondary factors is important clinically because they can be treated, possibly preventing or at least minimizing further renal injury.  Dietary protein restriction and the use of anti-hypertensive agents (particularly angiotensin converting enzyme inhibitors) have been most widely studied.  In addition to the potential importance of intraglomerular hypertension and glomerular hypertrophy, the following factors also may contribute to secondary renal injury:

 

Phosphate retention -- A tendency to phosphate retention is an early problem in renal disease, beginning as soon as the glomerular filtration rate starts to fall.  In addition to promoting bone disease, the excess phosphate also may contribute to progression of the renal failure.  This may occur at least in part by phosphate precipitation with calcium in the renal interstitium, leading to an increase in renal calcium content even before the plasma creatinine concentration exceeds 1.5 mg/dL (132 mmol/L).  The calcium phosphate salts may then initiate an inflammatory reaction, resulting in interstitial fibrosis and tubular atrophy.

 

These problems can be minimized by decreasing phosphate intake or by the use of oral phosphate binders.  It has been suggested, for example, that the efficacy of protein restriction may be related in part to a concurrent decline in phosphate intake.

 

Altered prostanoid metabolism -- Glomerular prostaglandin production tends to be increased in glomerular disease.  This response may represent an appropriate intra-nephronal adaptation, since the ensuing renal vasodilatation helps to maintain the GFR in the presence of an often marked reduction in glomerular capillary permeability induced by the underlying disease.  This adapation is reversed by an NSAID, leading to renal vasoconstriction and a subsequent fall in intraglomerular pressure.  These changes are manifested clinically by reductions in glomerular filtration rate (usually by about 20 percent) and protein excretion (often by more than 50 percent) in many patients with chronic glomerular disease.

 

Non-randomized studies suggest that long-term therapy in responders (those with a substantial decline in proteinuria) may be associated with a lesser rate of progression to end-stage renal disease.

 

Hyperlipidemia – Hyperlipidemia is common in patients with chronic renal disease, particularly those with the nephrotic syndrome.  In addition to accelerating the development of systemic atherosclerosis, experimental studies suggest that high lipid levels also may promote progression of the renal disease.  The major evidence in support of this hypothesis are the observations in experimental animals that cholesterol loading enhances glomerular injury and that reducing lipid levels with a drug such as lovastatin slows the rate of progressive injury.

 

The factors responsible for the lipid effects are incompletely understood.  In different animal models, a high cholesterol intake may be deleterious in association with a rise in intraglomerular pressure, while lipid-lowering agents may be beneficial without affecting glomerular hemodynamics.  These disparate observations suggest that mechanisms other than intraglomerular pressure alone may play a contributory role.  It has been shown experimentally, for example, that hyperlipidemia activates the mesangial cells (which have LDL receptors), leading to increased production of fibronectin (a component of the extracelluar matrix) and of a chemo-attractant for  monocytes.  Both of these changes could contribute to glomerular injury.  In addition, HMG CoA reductase inhibitors such as lovastatin may act independent of plasma lipid levels by directly inhibiting mesangial cell proliferation.

 

The applicability of these findings to human disease is unproven, since there are no studies evaluating the possible protective effect of lowering lipid levels.  However, both increased mesangial lipid deposition and enhanced expression of LDL-receptors on mesangial and epithelial cells have been demonstrated in patients with chronic glomerular diseases.  Mesangial phagocytosis and increased traffic of macromolecules through the more permeable glomerular capillary wall could be responsible for the lipoprotein deposition; in addition, the increase in receptors could promote lipid accumulation even in the absence of hyperlipidemia.  Whether the deposited lipid contributes to the glomerular injury is uncertain.

 

Metabolic acidosis and increased ammonium production – As the number of functioning nephrons declines, each remaining nephron excretes more acid (primarily as ammonium).  The local accumulation of ammonia can directly activate complement, leading to secondary tubulointestitial damage (at least in experimental animals).  On the other hand, buffering the acid with alkali therapy prevents the increase in ammonium production and minimizes the renal injury.

 

Although the renal protective effect of alkali therapy unproven in humans, there are other reasons (prevention of osteopenia and muscle wasting) why correction of the acidemia might be desirable.  Sodium bicarbonate is preferred to sodium cirtrate in this setting, since citrate leads to a marked increase in intestinal aluminum absorption, possibly promoting the development of aluminum toxicity; this is most likely to occur in those patients treated with aluminum-containing antacids to bind dietary phosphate.  The effect of citrate may be mediated both by keeping aluminum soluble (via the formation of aluminum citrate) and by binding of calcium in the intestinal lumen; the ensuing fall in free calcium then may lead to increased permeability of the tight junctions between the cells and a rise in passive aluminum absorption.  Bicarbonate, on the other hand, does not produce these effects and therefore does not increase aluminum transport.

 

Anemia – Progressive anemia, due largely to erythropoietin deficiency, is a common

 

complication of advanced renal disease.  Experimental studies suggest that this may be a protective adaptation, since anemia leads to reduced vascular resistance which lowers both systemic blood pressure and intraglomerular pressure.  Prevention of anemia in animals is associated with reversal of these changes and enhancement of the glomerular injury.

 

These observations may have clinical relevance, since anemia can now be corrected in predialysis patients by the administration of recombinant erythropoietin.  Preliminary observations on a relatively small number of patients suggest that, although correction of the anemia with erythropoietin does raise the systemic blood pressure in advanced renal failure, there does not seem to be any acceleration of rate of progression.

 

Proteinuria – It has been suggested that proteinuria itself may contribute to disease progression, both by overloading the mesangium with macromolecules and by promoting tubulointerstital disease.  It is possible, for example, that a marked increase in protein filtration and subsequent proximal reabsorption leads to tubular cell injury and the release of lysozymes into the interstitium.  Thus, reversing intraglomerular hypertension with protein restriction or antihypertensive therapy may be beneficial both by diminishing hemodynamic injury to the glomeruli and by reducing protein filtration (which is in part dependent upon the intraglomerular pressure).

 

Tubulointerstital disease – All forms of chronic renal failure are associated with marked tubulointerstial injury (tubular dilatation, interstitial fibrosis), even if the primary process is a glomerulopathy.  Furthermore, the degree of tubulointerstital disease is a better predictor of the glomerular filtration rate and long-term prognosis than is the severity of glomerular damage in almost all chronic progressive glomerular diseases, including IgA nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, and lupus nephritis.

 

The mechanism by which the tubulointerstitial disease occurs is not well understood.  As described above, both calcium phosphate deposition and metabolic acidosis with secondary interstitial ammonia accumulation may play a contributory role.  There is also evidence that an active immuniologic process is involved, beginning early in the course of the disease and in some cases being an extension of the inflammatory process in the glomeruli.  In some experimental models of renal disease, conticosteroid therapy can ameliorate the tubulointerstitial damage (without effect on the glomerular injury).

 

However, even effective therapy of the intersitial inflammation may not prevent progressive injury.  In this setting, healing may be associated with interstitial fibrosis mediated in part by the release of cytokines such as transforming growth factor-b.

 

Retained toxins – Dialysis of nonuremic animals with glomerulosclerosis preserves the glomerular filtration rate and slows the rate of further glomerular damage.  This observation suggests that retention of ultrafiltrable toxins during the course of progress renal disease contributes to secondary glomerular injury.  How this might occur is not clear.

Iron toxicity – Increased glomerular permeability can result in the filtration of the normally nonfiltered iron-transferrin complex.  Dissociation of this complex in the tubular lumen leads to the release of free iron which can promote tubular injury by promoting the formation of hydroxyl radicals.

 

            7.  CLINICAL MANIFESTATIONS OF CRF

 

Clinical Manifestations:

The symptoms and signs which constitute the uremic syndrome are summarized below:

 

Neurological Disorders:  Fatigue, lethargy, sleep disturbances, headache, seizures, encephalopathy, peripheral neuropathy including restless leg syndrome, paraesthesia, motor weakness, paralysis.

 

Hematologic Disorders:  Anemia, bleeding tendency – due in part to platelet dysfunction.

 

Cardiovascular Disorders:  Pericarditis, hypertension, congestive heart failure, coronary artery disease, myocardiopathy.

 

Pulmonary Disorders:  Pleuritis, uremic lung.

 

Gastrointestinal Disorders:  Anorexia, nausea, vomiting gastroenteritis, GI bleeding, peptic ulcer.

 

Metabolic-Endocrine Disorders:  Glucose intolerance, hyperllipidemia, hyperuricemia, malnutrition, sexual dysfunction and infertility.

 

Bone, Calcium, Phosphorus Disorders:  Hyperphosphatemia, hypocalcemia, tetany, metastatic calcification, secondary hyperparathyroidism, 1,25-dihydroxy vitamin D deficiency, osteomalacia, osteitis fibrosa, osteoporosis, osteosclerosis.

 

Skin Disorders:  Pruritus, pigmentation, easy bruising, uremic frost.

 

Psychological Disorders:  Depression, anxiety, denial, psychosis.

 

Fluid and Electrolyte Disorders:  Hyponatremia, hyperkalemia, hypermagnesemia, metabolic acidosis, volume expansion or depletion.

 

Some of the important manifestations are elaborated below:

 

7A.  Anemia:

 

Anemia is universal as GFR falls below 25 ml/min.; in certain disorders it may occur with mild renal insufficiency.  Several factors contribute:

 

a.  Erythropoiesis is markedly depressed, mainly due to reduced erythropoietin production; in addition, there may be reduced end-organ response to erythropoietin with reduced heme synthesis.

 

b.  Red cell survival is shortened with a mild to moderate decrease in red cell life span, possible due to a “uremic” toxin.

 

c.  Blood loss is common in uremic patients, possibly secondary to abnormal coagulation due to decreased platelet function.

 

d.  Marrow space fibrosis occurs with osteitis fibrosa of secondary hyperparathyroidism resulting in decreased erythropoiesis.

 

7B.  Hypertension:

 

Hypertension occurs in 80% to 90% of patients with renal insufficiency.  Several factors contribute:

 

a.  Expansion of extracellular fluid volume; this may arise because of reduced ability of the kidney to excrete ingested sodium.

 

b.  Increased activity of the renin-angiotensin system is common; many patients with advanced renal failure have renin levels that are not completely suppressed by the elevated blood pressure.

 

c.  Dysfunction of the autonomic nervous system occurs with insensitive baroreceptor sensitive and with increased sympathetic tone.

 

d.  Possible diminished presence of vasodilators: there may be decreased renal generation of prostaglandins or of factors in the kallikrein-kinin system.

 

7C.  Altered Calcium and Phosphorus Metabolism (Renal Osteodystrophy):

 

a.  As GFR decreases there is a slight retention of phosphorus; this phosphorus retention can lead to hypocalcemia, which stimulates PTH.  The latter causes phosphaturia, with restoration of serum phosphorus and calcium toward normal.  However, this occurs only at the expense of elevated serum PTH levels.  This cycle repeats itself in progressive renal failure with PTH levels increasing progressively.  Ultimately, the renal tubule can no longer respond to higher levels of PTH with a further decrease in phosphorus reabsorption.  When this occurs, hyperphosphatemia develops, hypocalcemia may become prominent and PTH level can increase to very high levels.  High PTH levels cause bone disease with severe osteitis fibrosa.

 

b.  Altered vitamin D metabolism occurs secondary to decreased renal mass or to phosphate retention, with decreased synthesis of 1,25 (OH)2 D3. This deficiency leads to: 1. Diminished intestinal absorption of calcium, 2.  decreased calcemic response of the skeleton to PTH, 3. impaired suppression of PTH secretion for any increase in serum calcium level, and 4. altered collagen synthesis.  With advanced renal failure, these events can lead to secondary hyperparathyroidism and osteomalacia.

 

c.  Skeletal resistance to the calcemic action of PTH develops; thus an increased PTH is required to maintain serum calcium at any level.

 

d.  Finally, accumulation of aluminum from aluminum binding antacids may contribute to the bone disease.

 

            8.  MANAGEMENT OF CHRONIC RENAL FAILURE

 

8A.  Treatment of primary renal disease:

 

The primary disease can be responsible for the continuous deterioration in renal function.  It is important to recognize and to treat the primary renal disease.  (e.g. certain disorders such as crescentic glomerulonephriti, membranous glomerulonephronpathy or analgesic nephropathy are potentially treatable or can be stabilized).

 

8B.  Treatment of reversible aggravating factors:

 

The progression of the decrease in GFR may be documented by plotting the reciprocal of the serum creatinine (1/S cr) against time.  Conceptually, this means that GFR (nephrons) is being lost at a constant rate.  A relatively linear course should be displayed.  Deviation from this course should alert one to the presence of disorders which can acutely worsen renal function as shown below.

 

 

These factors aggravate the progression of renal failure and are known as reversible aggravating factors.  The appropriate treatment of these factors can reverse or stabilize renal function to its pre exacerbation level.  Various reversible factors are:

 

1.  Salt and water depletion leading to hypovolemia

2.  Systemic or renal infection

3.  Accelerated hypertension

4.  Nephrotoxic drugs

5.  Urinary obstruction

6.  Acute heart failure

7.  Hypercalcemia

 

8C.  Treatment of secondary factors to prevent or slow the progression of renal disease:

 

Human studies that are currently under way should determine the efficacy of treating at least some of these secondary hemodynamic and metabolic abnormalities in an attempt to preserve renal function.  If these modalities are effective, the benefit is likely to be greatest if begun before a great deal of irreversible scarring has occurred.  Thus, protective therapy may have the greatest impact if initiated relatively early in the course, before the plasma creatinine concentration exceeds 1.5 to 2 mg/dL (132 to 176 mmol/L).

 

Despite the lack of conclusive evidence, many physicians have already begun using some of the above modalities in patients with progressive renal disease.  Current recommendations might include:

 

§         Treatment of hypertension at any stage of the disease, preferably beginning with an angiotensin converting enzyme inhibitor or possibly diltiazem or verapamil.  Concurrent diuretic therapy will often be necessary in patients with fluid overload.

 

The optimal level of blood pressure control is uncertain, but diastolic pressures of < 80 mmHg may be desirable.  Even normotenisve patients should be treated if they have proteinuria, which is a marker for possible hemodynamically-mediated glomerular injury.  The aim of therapy in this setting (or in patients with overt hypertension) is to diminish protein excretion, which may be a marker for reduced intraglomerular pressure and improved glomerular permselectivity.

 

§         The optimal level of protein intake has also not been determined but it may be reasonable to restrict intake to 0.8 to 1 g/kg of high biologic value protein in mild to moderate disease (plasma creatinine concentration less than 2.0 mg/dL {176 mmol/L}) and to 0.6 to 0.7 g/kg in more advanced renal insufficiency.  This should be accompanied by phosphate restriction and , if present, treatment of hyperphosphatemia with calcium carbonate or calcium acetate.

 

§         If present, both hyperlipidemia and metabolic acidosis (plasma bicarbonate concentration less than 21 meq/L with a reduced extracellular pH) should probably be treated.  In addition to possible renal protection, these modalities also may diminish systemic atherosclerosis and muscle and bone breakdown, respectively.

 

8D.  Treatment of end stage renal failure:

 

When GFR falls below 5 ml/min, the patient usually can not live without renal replacement therapy.  Renal replacement therapy includes dialysis and kidney transplantation as illustrated below:

 

Various social or medical factors influence decisions about peritoneal or hemodialysis, and transplantation in the treatment of end-stage renal failure.  It should also be noted that none of the above are panaceas and each, modality is associated with complications and failures.