Chronic Renal Insufficiency,
Lecture #143
All figures are from Rose
and Rennke’s Renal Pathophysiology.
I. Diagnosis of Chronic Renal Insufficiency (CRI)
A. Most of the symptoms of the time there are no symptoms because the kidney adapts to maintain homeostasis despite reduced glomerular filtration rate (GRF).
B. History
1. Voiding complaints
2. Blood in the urine
C. Previous laboratory data
1. Creatinine studies
2. Urinalysis that may show evidence of previous renal abnormalities
D. Imaging Studies
1. Ultrasound of kidneys
E. Physical Exam
1. Hypertension
2. Edema
F. Steps to consider for diagnosis
1. Pre-renal or Intrinsic renal or Post-renal disease
2. Acute or Chronic
a. CRI is asymptomatic until disease is near end stage
b. In acute renal failure, the patient is more likely to show symptoms because there has not been enough time to adapt to the renal changes.
c. Old records are useful in assessing chronic versus acute.
1) If the urinalysis was abnormal 10 years ago, the renal disease is chronic. If the serum creatinine concentration is changing over time, it’s chronic.
d. Look for signs of end organ damage related to chronic renal failure. These take a long time to develop. So...if the patient has peripheral neuropathy or renal osteodystrophy from chronic hyperparathyroidism, these are signs of CRI.
e. Most forms of CRI lead to atrophy and fibrosis of the kidney.
1) The kidneys tend to be smaller bilaterally on ultrasound.
2) The kidneys are more echogenic which reflects more fibrosis.
3) Diabetics are an exception to the smaller kidney rule. Diabetic kidneys are usually enlarged in the beginning of renal insufficiency so by getting smaller, they become a normal size.
3. Glomerular or Tubular or Vascular
4. Inflammatory or Non-inflammatory
5. Is the renal dysfunction due to a systemic disease (i.e. Diabetes Mellitus) or is the disease selective for the kidney (i.e. glomerulonephritis)?
II. Categories of Kidney disease
A. Pre-renal: Something is impeding adequate flow to the kidney
B. Intrinsic Renal: This lecture will focus on intrinsic renal disease
C. Post-renal: something in the drainage system is abnormal from the renal pelvis to the end of the urethra
III. Definition of CRI
A. Best index of renal function is GFR.
1. GFR can be estimated from creatinine clearance
2. GFR can also be estimated from changes in the serum creatinine concentration. If the serum creatinine concentration is increasing, GFR is decreasing.
B. CRI- less number of functioning nephrons in each kidney
C. Tends to be progressive—even if the original disease is in remission
1. The remaining nephrons set up a positive feedback cycle which results in loss of more nephrons.
2. Uremia is a group of signs and symptoms associated with end stage renal disease (ESRD).
a. It is 100% fatal unless a reversible factor is discovered that can improve GFR –OR-
b. Renal replacement therapy is initiated such as kidney transplant or dialysis
c. Affects virtually every organ system.
d. These symptoms are late findings of CRI.
D. Most common etiologies in the US
1. Diabetes Mellitus
a. 40% of end stage renal disease patients are diabetic
b. Most of these ESRD patients are type II diabetics because there are a higher percentage of type II diabetics.
c. The frequency of type II diabetes is increasing.
d. Diabetic nephropathy is a glomerular disease
2. Hypertensive nephrosclerosis
a. Vascular disease leading to ischemic atrophy of glomeruli
3. Polycystic kidney disease
a. The most common genetic renal disease
b. Autosomal dominant with 100% penetrance
c. 10% of ESRD patients
d. Disease of cystic tubules that leads to renal failure
E. Loss of glomeruli lead to tubular dysfunction, and tubular dysfunction leads to loss of glomeruli.
IV. Progression of renal disease
A. Disease dependent
1. Loss of nephrons due to the original disease continuing to do damage
2. Vascular damage due to ongoing hypertension
3. Continuous glomerular inflammation
4. Continuous tubular inflammation
B. Disease independent
1. A loss of nephrons sets off a cascade of adaptations that causes loss of more nephrons.
2. Systemic Hypertension- the glomerulus is perfused at a higher systemic pressure
3. Glomerular capillary hypertension- increased intraglomerular pressure independent of systemic pressure. The increased glomerular pressure allows for more net filtration by each nephron to compensate for the loss of nephrons. The afferent arteriole is vasodilated which will increase GFR due to a very high capillary pressure.
4. Glomerular capillary hypertrophy- Each nephron can increase its filtration rate by 25-50%.
5. These previous 3 factors allow the kidney to adapt to the loss of nephrons but will eventually damage the remaining nephrons causing a positive feedback cycle.
C. Response to nephron loss (summary of IV. B.)
1. Compensatory glomerular hypertrophy
2. Compensatory glomerular hyperfiltration
3. Example- If you donate a kidney for transplant, you will have a 50% loss in renal mass and the GFR will decrease 25-30%. This means that each remaining nephron increased its filtration rate up to about 50%. Therefore you can remain completely asymptomatic with a modest decrease in GFR.
a. Overtime, there is no increase in frequency of renal disease in kidney donors.
b. You cannot donate a kidney unless both kidneys are fully functioning. You only need one normal kidney to remain asymptomatic.
c. Consequences seen in kidney donors:
1) Slight increase in blood pressure compared to the general population
2) Slight increase in low grade proteinuria due to FGS (see below)
3) No increase in frequency of advanced renal failure
d. Consequences of a loss of nephron mass greater than 50%
1) If a patient was born with one kidney and developed renal cancer in the viable kidney, removal of the cancer within the kidney would result in a loss of renal mass greater than 50%.
2) There is an increase in frequency of CRI in these patients manifested as low grade proteinuria, hypertension and progressive renal failure. It usually takes over 10 years for these changes to occur.
D. Histological changes as the result of disease independent processes
1. Epithelial cell does not undergo hyperplasia. It will hypertrophy but cannot increase in numbers. The epithelial cells are an important part of the glomerular barrier to protein filtration. Epithelial cell changes promote proteinuria.
2. High glomerular pressure and high systemic pressures cause hyaline accumulation in the mesangial region. Expansion of this fibrinoid material in the mesangium and under the subendothelial area causes loss of endothelial surface area. Less capillary surface area means less GFR.
3. The chronic high pressure within the glomerular capillaries causes structural changes such as microaneurysms which can rupture and thrombose. This leads to more loss of surface area.
4. Chronic pressure overload and shear stress can lead to endothelial cell injury which leads to more loss of surface area.
5. The tubulointerstitial area is damaged due to ischemia from damage to the glomerulus which supplies the tubules with circulation via the efferent arterioles.
6. Calcium and phosphorus may crystallize in the interstitium as well which activates fibrosis and inflammation in the tubules.
7. Complement can be activated due to accumulation of ammonia.
E. Response to loss of 5/6 of the renal mass (figure 11.1)
1. In animal models, one kidney and 2/3 of the other kidney were removed.
2. The remaining nephrons are going to attempt to maintain homeostasis by:
a. Raising the plasma flow to each remaining glomerulus by dilating the afferent arteriole
b. Dilating the afferent arteriole raises intraglomerular pressure which allows us to make more filtrate, but activates the damage discussed above (IV. B.)
c. Single nephron GFR is almost twice the normal value but at the expense of intraglomerular hypertension
d. The number of epithelial cells does not change but the cells hypertrophy. As the capillaries enlarge, the epithelial cells can no longer surround the capillaries and the size barrier dysfunctions resulting in proteinuria.
3. Results of adaptations (figure 11.2)
a. With glomerular injury, the capillary’s permeability changes.
b. The permeability coefficient of the capillaries is Kf. Kf relates to the pore sizes that allow normal solute clearance. The lower the Kf, the worse the GFR.
c. Chronic hypertensive change and accumulation of hyaline material leads to a progressive sclerosis (non-inflammatory process).
d. Focal segmental glomerulosclerosis (FSGS) - histologic hallmark of nephron independent injury. It does not depend on where the original disease occurred. The long term result of independent injury is FSGS.
1) An example is vesiculoureteral reflux in children which initially damages only the tubules. However, the end stage of this initial tubular disease is FSGS (progressive loss of function).
4. Figure 11.3 demonstrates the pathogenesis of secondary FGS (KNOW THIS FIGURE)
V. Prevention of progressive nephron loss
A. The original disease can usually be identified and treated. It is more difficult to treat the disease independent injury.
B. Protein restriction
1. Some protein is required to maintain body homeostasis.
2. Protein intake (particularly animal protein) causes a transient increase (25-30%) in GFR.
3. If the glomerular are already working too hard, why put the extra load on them by eating protein?
4. Reduced protein intake will reduce the workload on the remaining glomeruli.
5. Protein restriction is particularly effective in chronic renal diseases that manifest as proteinuria such as diabetes mellitus. There is indication that mild to moderate protein restriction can slow the rate of renal failure in diabetics.
6. The problem with protein restriction is that severe protein restriction can lead to malnutrition. Malnutrition is the leading indicator of mortality of patients with advanced renal failure.
7. Patient compliance is also a problem with protein restriction (patients sometimes do not adhere to a low protein diet).
8. Protein restriction is not so helpful in patients with strictly tubular disease such as polycystic kidney disease.
C. Treat systemic hypertension
1. Hypertension is present in 85-90% of patients with chronic renal failure development systemic hypertension.
2. Systemic hypertension will accelerate further nephron loss by increasing intraglomerular pressure and capillary damage.
3. Chronic hypertension causes vascular disease which can cause small vessel nephrosclerosis damaging glomeruli.
4. The second leading cause of renal failure in humans is systemic hypertension causing hypertensive nephrosclerosis.
5. Control systemic hypertension with antihypertensive medications and sodium restriction.
a. Sodium restriction is more important in renal failure patients with hypertension because the hypertension is often due to fluid retention.
6. Systemic BP control is most effective in patients with glomerular disease.
7. It is less effective in tubular disease such as polycystic kidney disease.
D. Monitoring progressive nephron loss with serum creatinine concentration
1. Limitations
a. With a loss of nephrons, each remaining nephron enhances its creatinine secretion. Secretion of creatinine overestimates GFR.
b. Each remaining nephron hyperfilters keeping serum creatinine concentration at a normal level even though there might be histological damage occurring.
2. Example of serum creatinine concentration limitations (figure 11.6)
a. Lupus causes an inflammatory glomerulonephritis. Lupus patients were treated with irradiation of their lymphocytes to put their lupus nephritis into clinical remission. Their creatinine clearance has stabilized and proteinuria was resolved.
b. These patients were monitored at 1 year and 3 years with kidney biopsies and serum creatinine levels.
c. Their creatinine clearance and serum creatinine concentration were stable over time.
d. However, their glomeruli began to enlarge and hyperfilter to maintain the GFR. The intraglomerular hypertension activated FGS while the creatinine levels remained normal.
E. Effect of antihypertensive medications on progressive nephron loss (figure 11.4)
1. Treating systemic hypertension does not necessarily decrease glomerular hypertension. Both must be treated to slow the rate of nephron loss.
2. Animals in which 5/6 of the renal mass had been removed (see text ch.11) were placed into one of three groups:
a. Untreated- the animal develops hypertension, proteinuria, progressive glomerular sclerosis, renal failure, and death. Protein excretion is used as an index of kidney damage after removal of renal mass.
b. Triple therapy treatment
1) Treat systemic hypertension with a diuretic, a direct vasodilator, and a sympatholytic drug
2) Systemic blood pressure was well controlled
3) The glomerular hypertension was not treated. These animals developed proteinuria and progressive renal failure that was not quite as severe as the untreated group.
4) Disease independent glomerular damage still occurred.
c. Angiotensin converting enzyme (ACE) inhibitor treatment
1) The animals treated with an ACE inhibitor had the same systemic blood pressure as the animals treated with triple therapy.
2) There was less proteinuria, less segmental sclerosis and better preservation of GFR.
3) WHY? The ACE inhibitors decrease glomerular hypertension by decreasing angiotensin II which normally constricts the efferent arteriole. Dilating the efferent arteriole will decrease intraglomerular pressure.
4) Dilation of the efferent arteriole should decrease GFR; however, GFR is maintained. HOW? Dilation of the efferent arteriole increases the permeability characteristics of the glomerular capillary leading to a more normal Kf.
3. ACE inhibitors are the drugs of choice for chronic renal disease because they treat both the systemic and glomerular hypertension.
4. Treating systemic hypertension decreased stroke by 50% and reduced CHF by at least 50%; however, it did not change the frequency of renal failure. Therefore, treatment of systemic hypertension alone has little effect on progressive nephron loss.
a. The kidney is different because it has resistance vessels before and after the organ.
5. Angiotensin II receptor blockers work as well as ACE inhibitors to decrease progression of renal disease.
VI. Diabetic nephropathy
A. An inherent non-inflammatory metabolic disorder that leads to progressive glomerulosclerosis.
B. Up to 40% of type I diabetics will develop diabetic nephropathy over time. It is a slow process that takes approximately 10 years of diabetes to occur.
C. It is difficult to estimate the number of type II diabetics with diabetic nephropathy because it is difficult to ascertain when their diabetic state began. There are more type II diabetics so they are the largest population with diabetic nephropathy.
D. Early in diabetes, glomerular hypertrophy and glomerular hypertension occurs.
1. GFR is larger than in normal people
2. Kidney size is larger than normal.
3. Glomerular size is bigger than normal.
4. Glomerular capillary pressure is bigger even though systemic blood pressure early on is normal.
E. Clinical signs
1. First sign of diabetic nephropathy is microalbuminuria (higher amounts of albumin in the urine than normal people, but not enough albumin to test positive on the urine dipstick).
2. Over time, overt proteinuria will occur as well as reduced GFR and systemic hypertension due to the positive feedback loop of progressive nephron loss.
3. By the time proteinuria is present, most patients will have end stage renal failure within 5 years.
F. Preventative measures are important in diabetic patients because:
1. Diabetes mellitus is the number one cause of end stage renal disease.
2. Diabetes mellitus is the number one cause of nephrotic syndrome.
G. Histological
1. By the time the patient has microalbuminuria, histologic change has already occurred with:
a. Increase in mesangial matrix
b. Damaged glomerular endothelial cells and progressive sclerosis
H. Treatment with Captopril (an ACE inhibitor) in patients with microalbuminuria (figure 11.8)
1. The y-axis is protein excretion.
2. These patients are early in the disease process with a normal systemic blood pressure and microalbuminuria.
3. During 4 years of treatment, the group receiving Captopril (an ACE inhibitor) reduced their urinary protein excretion.
4. Microalbuminuria continued to increase in the placebo group. This was a placebo study because there was no systemic hypertension at that time.
5. During the 4 years, 7 of the 23 patients in the placebo group went from microalbuminuria to overt proteinuria reflecting loss in renal function.
6. None of the Captopril group went to overt proteinuria.
7. This study documented the effectiveness in reducing glomerular hypertension as well as systemic hypertension.
I. Treatment in diabetic patients with overt proteinuria (figure 11.9)
1. Patients received either Captopril or a placebo that lowered systemic blood pressure (not an ACE inhibitor).
2. The y-axis measured doubling of the serum creatinine concentration as a marker of renal function.
3. Over 60% of the placebo group doubled their serum creatinine concentration over a 3 year period.
4. 20-25% of the ACE inhibited patients doubled their serum creatinine concentration.
5. The difference is the ACE inhibited patients had better control of their glomerular hypertension.
6. These studies were done in type I diabetics, but recent studies show the same effect in type II diabetics. The new studies also show that the angiotensin II receptor antagonists are equally as effective as ACE inhibitors.
7. ACE inhibitors do not cure diabetic nephropathy, but they slow the rate of its progression significantly.
J. Anti-hypertensive drugs other than ACE inhibitors
1. Vasodilators, diuretics, and beta blockers
2. They reduce systemic blood pressure but not glomerular pressure
3. They tend to vasodilate the afferent arteriole causing increased continued glomerular hypertension with more normal systemic hypertension.
4. ACE inhibitors (and AII receptor antagonists) decrease both systemic and glomerular hypertension.
5. Some of the non- dihydropyridine calcium channel blockers (verapamil and diltiazem) are similar to the ACE inhibitors. They reduce proteinuria and better preserve renal function.
6. Dihydropyridine calcium channel blockers are similar to the vasodilators and are not as effective at slowing the rate of progression of damage.
7. Proteinuria is a measure of reduced glomerular capillary pressure that is used as a clinical marker for treatment assessment in diabetic nephropathy.
VII. Nephron Function
A. Excretion = (Filtration – Absorbed) + Secretion
B. Organic solutes are excreted by filtration. Examples of organic solutes are creatinine and urea which are metabolic waste products.
C. Sodium, chloride, water and phosphorus are reabsorbed.
D. Potassium and hydrogen ions are actively secreted.
E. Intact nephron hypothesis
1. With CRI, loss of renal homeostasis will occur because there are not enough functioning nephrons.
2. The nephrons that remain function in a normal manner.
3. Figure 12.1- Hydrogen ion secretion
a. Hydrogen ion secretion in a damaged kidney versus secretion in a normal kidney
b. For each unit of GFR, the remaining nephrons are secreting hydrogen ions quite effectively. The net decrease in hydrogen ion secretion is due to a decrease in the number of nephrons.
F. How many nephrons can be lost before homeostasis is lost? Figure 1
1. There is a large amount of reserve renal function
2. Up to 70% of the renal mass can be lost and still maintain homeostasis.
3. Renal insufficiency is the point where you have abnormal homeostasis, renal failure with symptoms and death.
4. The terminal state is at 10-15% of renal mass. Changes in serum creatinine would parallel this curve (figure 2).
G. Trade off hypothesis
1. The kidney makes adaptive changes to maintain homeostasis.
2. Trade offs:
a. Maintain calcium and phosphorus levels at the expense of chronic hyperparathyroidism which has adverse effects on skeletal bone structure, bone marrow function, nerve function, and skeletal muscle function
b. Sodium balance can be maintained at the expense of systemic hypertension. Pressure natriuresis is the process in which a higher blood pressure augments renal tubular sodium excretion.
c. Potassium balance can be maintained with an increase in aldosterone which will affect sodium balance and hypertension.
d. Hyperfiltering nephrons lead to nephron damage.
H. Pressure natriuresis (figure 3)
1. Higher blood pressure augments sodium excretion.
2. Sodium can be balanced at the cost of hypertension and all the adverse systemic effects of hypertension.
3. Hypertension can also lead to more rapid progression of glomerular disease.
4. VERY IMPORTANT- Urine flow rate does not equal kidney function. Urine flow rate is only the difference between how much got filtered and reabsorbed. It is not an index of kidney function (GFR).
5. Figure 3 shows that we autoregulate renal blood flow and GFR very well over a wide range of blood pressures.
6. We do not autoregulate urinary flow rate. At higher blood pressure, we get pressure natriuresis and higher sodium and water excretion.
I. Hypertension in CRI patients (figure 4)
1. Reinforces that hypertension in CRI patients is largely volume dependent
2. If you reduce dietary sodium intake, you will eliminate some of the water load. You will also lose weight and decrease your blood pressure.
3. Sodium restriction is a more important treatment adjunct in hypertension due to CRI.
I. Chronic Renal Insufficiency
A. Potassium (K+)
1. With normal K+ intake, the kidney is able to maintain homeostasis until renal
failure is far advanced (when GFR < 15mL/min----10-15% of normal GFR).
2. K+ is the last electrolyte for which homeostasis is lost.
3. As renal insufficiency progresses, the kidney loses the ability to excrete a K+ load.
4. Hyperkalemia results--clinically, this is very important because hyperkalemia is the
most life threatening elecytrolyte problem of renal disease.
5. Most patients will have had other symptoms before hyperkalemia becomes a
problem and will be receiving treatment for chronic renal insufficiency.
B. Bicarbonate (HCO3-)
1. Metabolism of dietary protein leads to production of fixed acids, including sulfuric
acids and phosphoric acids, which dissociate and release a hydrogen ion (H+).
2. These H+ in the blood are buffered by HCO3-, sulfate (SO42-), and phosphate (PO43-)
3. For every 100g of protein ingested, 100mEq of H+ are produced and about 100mEq
of HCO3- are used to buffer the H+.
4. To maintain acid/base homeostasis, the kidney secretes H+ in the form of
ammonium (NH4+).
5. For every H+ secreted by the kidney, a HCO3- is reabsorbed into the blood.
6. With chronic renal insufficiency, there is a decreased number of functioning
nephrons and thus a decreased ability to secrete acid into the urine and a
decreased ability to reabsorb HCO3- into the blood.
7. Each remaining nephron can increase its ability to secrete H+ up to 4-fold and can
continue to maintain acid/base homeostasis for a while until advanced renal
failure ensues.
8. Chronic renal insufficiency has a tendency to progress to metabolic acidosis with a
normal plasma anion gap (normal because of the loss of sulfates and phosphates);
BUT, with advanced, terminal renal insufficiency, metabolic acidosis with a
plasma anion gap occurs (kidney has lost the ability to excrete the sulfates and
phosphates).
9. When treating a patient with renal insufficiency, protein intake needs to be
restricted to decrease the H+ formed by the metabolism of protein. By restricting
protein, the patient also restricts potassium and phosphate intake.
C. Anemia
1. The kidney is an endocrine organ that produces the hormone erythropoiten, which
is a glycoprotein made in response to a decrease in delivery of oxygen to the
kidney; and, the erythropoiten causes an increase in the production of red blood
cells (RBCs).
2. With chronic renal insufficiency, there are fewer functioning nephrons, there is a
decrease in GFR, and there is a decrease in the ability of the kidney to make
erythropoiten and thus a decrease in the ability of the bone marrow to make
RBCs.
3. At about 30% of normal GFR, normocytic normochromic anemia begins to occur.
Pathophysiology: Urinalysis (145), 4/15/2002, 10-11am page 2 of 11
4. There is a low reticulocyte count, but there is not a change in platelet count or
neutrophil count; however, platelet function may become impaired as chronic
renal failure progresses.
5. On a blood smear, the RBCs may appear spiculed---these are called burr cells
6. Treatment is with exogenous erythropoiten, which fully corrects the anemia; but,
the erythropoietin may also aggravate hypertension due to increased blood
viscosity and less vasodilation (the vessels vasodilate with anemia to allow
increased organ perfusion).
D. Cardiac manifestations--no organ system is left untouched by chronic renal failure
1. Early chronic renal failure is associated with hypertension.
2. Hypertension frequently results in left ventricular hypertrophy (LVH)
3. >50% of patients with end stage renal disease have LVH
4. Chronic renal failure is the most common cause of secondary hypertension because
as renal failure progresses, fluid overload occurs and symptoms of congestive
heart failure begin to occur.
5. Pericarditis, typically manifested by chest pain, pericardial friction rub, and/or
pericardial tamponade are often present with advanced chronic renal failure.
6. The leading cause of death associated with chronic renal disease is cardiovascular
related
E. GI effects cause by chronic renal insufficiency
1. Appetite begins to decrease and there is usually a spontaneous reduction in protein
intake.
2. Gastroparesis and nausea are common
3. As the renal insufficiency becomes more severe, nausea and vomiting often occur
4. The net effect of these GI manifestations is development of protein calorie
malnutrition which is a major risk factor for morbidity and mortality.
F. Nervous System effects
1. Intellectual function and the ability to concentrate decrease
2. Overt encephalopathy with confusion, stupor, and asterixis can occur as renal
failure worsens
3. Distal sensory neuropathy is commonly associated with advanced renal
insufficiency.
G. Endocrine abnormalities
1. Fasting hypoglycemia is more common with advanced renal failure due to:
a. Decreased insulin degradation by the kidney, which extends the half-life of
both endogenous and exogenous insulin; so if a person with diabetes takes
insulin, their insulin dosage needs to be decreased.
b. Decreased gluconeogenesis by the kidney and therefore decreased glucose
c. Decreased glycogen stores and therefore decreased glycogenolysis results
because the patient's protein/calorie intake is decreased.
2. The hypothalamic-pituitary-ovarian complex is often affected in females
a. With early renal insufficiency when serum creatinine is ~2mg/dL and
GFR is about 50%, the menstrual cycles are irregular and the patient is
infertile.
b. If the patient with chronic renal insufficiency does become pregnant, she has a
high risk of spontaneous abortion, hypertension and preeclampsia,
worsening of renal function, and premature delivery.
c. A pregnant woman with renal disease is a high risk obstetric patient